Intestinal Failure: Editor

Jeremy M.D.
Nightingale
Editor
Intestinal
Failure
Second Edition
123
Intestinal Failure
Jeremy M.D. Nightingale
Editor
Intestinal Failure
Second Edition
Editor
St Mark’s Hospital
Harrow, Middlesex, UK
ISBN 978-3-031-22264-1 ISBN 978-3-031-22265-8 (eBook)

https://doi.org/10.1007/978-3-031-22265-8
© Springer Nature Switzerland AG 2001, 2023

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A Doctor and or Health Worker’s Oath
I promise to treat all patients equally, with humanity, respect and to the best
of my ability.
I shall listen to their story, keep their confidences and be honest at all times.
I shall strive to bring hope, however small.
I shall endeavour to improve my knowledge, and to be aware of new
treatments.
I shall admit that which I do not know and shall not be afraid to seek help
from those who do.
I shall promote freedom of thought and its expression.
I shall willingly teach my skills to others.
In memory of my father, Jon Nightingale, who died in August 1997 of motor
neurone disease.
Foreword to Second Edition
Do we really need another textbook of intestinal failure, especially one following a very suc-
cessful first edition from Dr Jeremy M.D. Nightingale, a pioneering leader in the field? With
this second edition Jeremy delivers a resounding yes!
Intestinal failure is a devastating disease. In the five decades or so since the development of
parenteral nutrition, the present era more than any other has seen incredible improvements in
outcomes for patients with intestinal failure. Very significant improvements have stemmed
simply from the widespread recognition of the value of multidisciplinary intestinal rehabilita-
tion, approaches to prevent complications related to parenteral nutrition through better catheter
care or lipid management and incremental improvements in outcomes for intestinal transplan-
tation. There have been remarkable advancements in the characterization and approval of
intestinotrophic peptides with more along the way.
It is in this context that Dr Nightingale’s updated second edition of Intestinal Failure could not
be more timely. The book represents a herculean effort spanning five years and brings together an
international authorship of experts collectively representing several decades of experience in intes-
tinal failure. The current edition adds 27 new chapters! Of particular interest and relevance are new
or updated chapters covering mesenteric ischemia, radiology in intestinal failure, encapsulating
peritoneal sclerosis, pro-adaptive hormones, drug absorption, etc. To give just a few examples, the
chapter on mesenteric ischemia written by the experienced team from Paris describes best practices
from a multidisciplinary acute intestinal stroke unit. There is a comprehensive description and
approach to managing encapsulated peritoneal sclerosis, a vexing and poorly understood condition
that appears to be increasing in incidence. For the first time, there is a very thorough chapter on
management of impaired drug absorption in patients with short bowel syndrome. I am especially
pleased to see well-written chapters describing psychological aspects of intestinal failure, quality of
life, patient perspectives, and ethical and legal aspects of nutritional support.
In his foreword to the first edition, Sir Miles Irving wrote that “Jeremey Nightingale has per-
formed an outstanding service …the book will act as a standard text for those who need to know
how to deal with patients afflicted by this difficult condition.” I will go further—with this authori-
tative textbook, Jeremy has put together the most comprehensive text one could hope for in
intestinal failure. Far from being standard text, this book will be essential reading for established
experts in intestinal failure and all who aspire to have sound basic understanding to manage this
challenging condition well. I anticipate that my own autographed copy will see much use!
May, 2023 Kishore R. Iyer

Adult and Pediatric Intestine Rehab and Transplant Program
Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai
New York, NY, USA
ECHO Institute, Albuquerque, NM, USA
vii
Foreword to First Edition: 2001
To have been party to the recognition of a new specialty, encourage its development, see it
acknowledged as a specialty in its own right and then bring it to a maturity and set it on its
future path, all within the space of 30 years, must be regarded as both an awe inspiring experi-
ence and a privilege.
Such has been the experience of the team of authors that have contributed to this unique
volume. It is remarkable that it is only 30 years since Dudrick, Wilmore, Vars and Rhoads
showed that children could grow and mature normally when sustained by parenteral nutrition
alone. From this classic study has developed the whole field of intestinal failure and its
treatment.
This book brings together those who were the pioneers, those who refined the techniques
that enabled patients to receive safe enteral and parenteral nutrition outside the hospital and
those who now have the task of taking the management of intestinal failure to the next stages.
The assembled chapters reveal a remarkable record of international interdisciplinary collabo-
ration between scientists and clinicians, doctors and nurses, health economists and those with
expertise in the relatively new discipline of the measurement of quality of life. What is most
gratifying, however, is the inclusion of an authoritative and scientifically rigorous expression
of the patient perspective. The management of intestinal failure was arguably the trailblazer in
demonstrating that successful outcomes could only be obtained if the patient was incorporated
as an integral part of the therapeutic team.
Jeremy M.D. Nightingale has performed an outstanding service to gastroenterology by
bringing together a group of authors who provide not only an authoritative, current statement
on the total management of patients with intestinal failure but also a record of the development
of this specialty which will act as a reliable reference for many years to come.
This book sets the seal on Intestinal Failure as a distinct specialty and will act as a standard
text for those who need to know how to deal with patients afflicted with this difficult but fasci-
nating condition.
Emeritus Professor at the University of Manchester, Sir Miles Irving

Newcastle Upon Tyne, Tyne and Wear, England
May, 2001
ix
Preface
This new edition of an international multi-author textbook brings the broad subject of intesti-
nal failure in adults and children to a wide readership. A simple, easy to remember definition
of intestinal failure is presented “reduced intestinal absorption causing malnutrition and/or
dehydration”. It encompasses patients with many underlying diagnoses who need nutritional
and/or fluid support by oral, enteral or parenteral routes due to an impairment/failure of intes-
tinal absorption. Many of these patients will be managed in non-specialist hospitals and often
without the need for parenteral support.
The second edition (62 chapters) includes updated versions of the original 34 chapters. In
addition there are new chapters that cover many other aspects of intestinal failure/nutritional
support including psychology, drug absorption, pancreatitis and critical care. Each chapter
starts with practical key points and a summary, then follows clinical guidance and information
based on the recent literature.
Doctors, nurses, dietitians, pharmacists, research workers and patients have written the
chapters to give different viewpoints that relate to nutritional support in hospitals and in the
community. This edition should provide an essential source of reference to all members of a
nutrition support team and to specialist workers/researchers in the field.
Please send any comments, corrections, additional information or suggestions for inclusion
in a future edition to the editor.
St Mark’s Hospital, Harrow, UK Jeremy M.D. Nightingale
xi
Acknowledgements
I wish to thank my main trainers/mentors. These include Peter Willoughby, Rodney Burnham,
Michael Kamm, Michael Farthing, John Mayberry, Tony Wicks, Barrie Rathbone and espe-
cially John Lennard-Jones (JLJ). JLJ was an inspirational “can do” person whose research
followed from the clinical problems he managed. Following a ward round at St Mark’s Hospital
in 1987, when it was situated on City Road in London, he asked me which patients/problems I
had found most interesting. Put on the spot, I replied that it was those with a short gut and
receiving parenteral support. Thus began my research/special interest in nutritional support
which along with inflammatory bowel disease has been a major part of my professional life.
Thanks go to two committees that I have been fortunate to chair; the British Intestinal
Failure Alliance (BIFA) committee and the Nightingale Trust for Nutritional support. They
have helped develop logical ways to manage patients needing nutritional support and are
referred to when appropriate in the chapters.
I would like to thank all the authors of the first edition (published in 2001) whose contribu-
tions helped formulate many of the chapters in this new updated version.
I am grateful to the associate editors Simon Lal, Mattias Soop and Ahash Mehta who will
be responsible for future editions.
I thank Nicola Burch and the nutrition support team in Coventry for helping me maintain a
broad experience of all aspects of nutritional support while working on this book.
I thank all the many brave patients who have given me the knowledge, awareness and many
skills that I have tried to incorporate into this book.
I particularly thank my wife (Sally) and our sons (James and Peter) for tolerating the many
hours this textbook has taken to complete.
xiii
Contents
Part I Introduction

Historical Overview of Intestinal Failure�� 3
John E. Lennard-Jones, Gil Hardy, and Khursheed N. Jeejeebhoy

Normal Intestinal Anatomy and Physiology�� 13
Jeremy M.D. Nightingale and Robin Spiller

Definitions, Classification and Severity of Intestinal Failure�� 35
Part II Acute (Short and Medium Term Reversible) Intestinal Failure
Postoperative Ileus �� 43

Ian Bissett and Dileep N. Lobo

Acute Surgical Intestinal Failure. Sepsis and Enterocutaneous Fistula(s) �� 53
Akash Mehta, Carolynne Vaizey, Jeremy M.D. Nightingale, and Gordon Carlson
Mesenteric Ischemia�� 69
Alexandre Nuzzo, Yves Castier, and Olivier Corcos
Crohn’s Disease�� 87
Mattias Soop and Simon Lal

Peritoneal Adhesions and Encapsulating Peritoneal Sclerosis�� 95
Titus Augustine, Alison Culkin, and Mattias Soop

Bone Marrow and Haemopoietic Stem Cell Transplantation�� 121
Jennifer Clay, Maria Gilleece, and Clare Donnellan
Non-surgical Cancer Treatments�� 131
Mary Booth, Fiona James, Andrew Viggars, Clare Shaw, and Mark Teo

Bacterial Overgrowth and Enteric Infections �� 149
Eamonn M. M. Quigley

Extensive Mucosal Disease: Coeliac Disease and Eosinophilic Enteritis�� 161
Suzanne C. Donnelly

Intestinal Failure in Critical Care�� 177
Moran Hellerman Itzhaki and Pierre Singer
Eating Disorders in Adults�� 191
Paul Robinson and David Russell

Intestinal Failure in Children: A Paediatric Surgical Perspective�� 207
Alexander L. Macdonald, Hannah Thompson, and Mark Davenport
xv
xvi Contents
Part III Chronic (Long-Term) Intestinal Failure

Physiology and Problems of a Short Bowel �� 223

Chronic Small Bowel Dysfunction�� 243
Jeremy M.D. Nightingale and Peter Paine

Pelvic Radiation Disease and the Gastrointestinal Tract �� 269
Darren Fernandes and Jervoise Andreyev
Problems After Gastric Surgery �� 289
Alastair Forbes and Alistair McIntyre

Surgery for Obesity and Its Consequences�� 301
Cynthia-Michelle Borg and Jean Deguara

Intestinal Failure in Childhood�� 313
Olivier Goulet and Cécile Lambe
Part IV Consequences of Intestinal Failure

Consequences of Undernutrition and Dehydration�� 339
Pete Turner, Simon Alison, and Jeremy M.D. Nightingale
Refeeding Problems �� 353
Aminda De Silva and Jeremy M.D. Nightingale

Intestinal Failure Associated Liver Disease �� 363
Sue V. Beath and Alan L. Buchman
Acid-Base Disturbances�� 377
Barry J. M. Jones

Gallstones in Intestinal Failure�� 391
Jeremy M.D. Nightingale and Mattias Soop
Nephrolithiasis and Nephrocalcinosis�� 403
Charles R. V. Tomson and Matthew Bultitude

Bone and Joint Disease�� 425
Loris Pironi and Anna Simona Sasdelli
Intestinal Adaptation �� 435
Julie Bines, Jason Yap, Kelly Tappenden, and Jeremy M.D. Nightingale
Part V Assessment and Treatment of Intestinal Failure

Assessment of Nutritional and Fluid Status�� 453
Kirstine Farrer and Sorrel Burden

Radiology in Intestinal Failure �� 469
Arun Gupta, Alex Fitzhugh, Chun Wah So, Aia Mehdi, Anmol Gangi,
Michele Marshall, and Rajapandian Ilangovan

Insertion, Types and Care of Enteral Feeding Tubes�� 489

Formulation and Administration of Enteral Feeds�� 513
Gil Hardy and Hazreen Abdul Majid
Contents xvii

Access for Parenteral Support�� 523
Arun Abraham, Geert Wanten, and Jeremy M.D. Nightingale

Formulation of Parenteral Nutrition Regimens�� 545
Gil Hardy and Michael Charles Allwood

Designing Parenteral and Enteral Regimens�� 559
Nicola Vernon, Beth Rye, and Jeremy M.D. Nightingale

Nursing Care of Patients Receiving Home Parenteral Support�� 573
Cathy Cawley and Mia Small

Care of Intestinal Stoma and Enterocutaneous Fistula(s) �� 619
Louise Williams and Gordon L. Carlson
Management of a High Output Stoma, Jejunotomy or Uncomplicated
Enterocutaneous Fistula�� 631

Dietary Treatment of Patients with a Short Bowel �� 651
Morag Pearson and Jeremy M.D. Nightingale
Pro-adaptive Hormones in the Rehabilitation of Adult Patients
with a Short Bowel �� 681
Palle Bekker Jeppesen

Drug Absorption in Patients with a Short Bowel�� 699
Uchu Meade, Nadia Gabriel, Roshni Patel, Maryam Clark, Pritha Singh,
Jeremy M.D. Nightingale, and Richard Ng Kwet Shing

Distal Feeding and Hydration�� 717
Laurence Lacaze, Denis Picot, and Ronan Thibault
Chronic Abdominal Pain �� 727
Peter Paine and Justin Turner

Psychological Aspects of Intestinal Failure�� 741
Yoram Inspector
Part VI Outcome of Intestinal Failure

Home Enteral Nutrition in Adults: Indications and Outcomes �� 753
André Van Gossum, Asuncion Ballarin, Marianna Arvanitakis, Xavier Hébuterne,
and Jeremy M.D. Nightingale

Home Parenteral Support for Adults �� 761
Laura Cohen, Francisca Joly, Simon Gabe, and Jeremy Woodward

Home Enteral and Parenteral Support for Children�� 773
Theodoric Wong and Gabriela Jiménez-Arguedas

Home Parenteral Support for Patients with Incurable Advance Cancer �� 783
Mani Naghibi and Federico Bozzetti

Monitoring of Parenteral Nutrition at Home�� 793
N. M. Clermont Dejean, N. Somlaw, D. Brundrett, and J. P. Allard
Quality of Life�� 799
Ashley Bond and Simon Lal
xviii Contents
The Patient’s Requirements�� 807

Carolyn Wheatley, Monika Malickova, Joanne Shepherd, and Steven Brown
Nutritional Support Services�� 817
Simon Lal, Simon Gabe, and Jeremy M.D. Nightingale

Ethical and Legal Aspects of Nutritional Support�� 827
Andrew Rochford
Part VII Problems of Treatment
Enteral Nutrition�� 839

Timothy Bowling
Prevention, Diagnosis and Management of Catheter-Related Blood
Stream Infections �� 849
Simon Lal, P. Chadwick, M. Gompelman, and G. Wanten
Central Vein Thrombosis�� 857
Cristina Cuerda and Yaser Naji
Part VIII Surgical Treatment of Chronic Intestinal Failure

Surgery for Patients with a Short Bowel and Tissue Engineering�� 869
Mattias Soop, Laween Meran, Jeremy M.D. Nightingale, and Jon S. Thompson
Intestinal Transplantation �� 883
Lisa M. Sharkey, Stephen J. Middleton, Irum Amin, and Andrew J. Butler

Abdominal Wall Repair in Intestinal Failure�� 901
Akash Mehta and Ciaran Walsh
Part IX Pancreatitis

Intestinal Dysfunction and Failure in Acute Pancreatitis�� 923
John A. Windsor and Stephen A. McClave

Medical, Nutritional and Surgical Management of Chronic Pancreatitis�� 935
John S. Leeds
Appendix: Useful Websites�� 947

Index�� 949
Abbreviations
A&E Accident and emergency

AA Amino acid
AABF Amino acid-based formula
AANH Artificially assisted nutrition and hydration
ABD Acid-base disturbance
ACR Acute cellular rejection
ACS American College of Surgeons
ACT Acceptance and commitment therapy
ADA Adalimumab
ADP Adenosine diphosphate
ADP Air displacement plethysmography
AGI Acute gastrointestinal injury
AgRP Agouti-related peptide
AIDS Acquired immunodeficiency syndrome
AIO All-in-one
AIR Autologous intestinal reconstruction
ALP Alkaline phosphatase
AMI Acute mesenteric ischaemia
ANC Acute necrotic collection
ANTT Aseptic non-touch technique
AP Acute pancreatitis
Apo AIV Apolipoprotein AIV
ART Anti-retroviral therapy
ASPEN American Society for Parenteral and Enteral Nutrition
AST Aspartate aminotransferase
ATP Adenosine triphosphate
AuSPEN Australian Society of Parenteral and Enteral Nutrition
AVF Arteriovenous fistula
AWR Abdominal wall repair
AXR Abdominal radiograph
BANS British Artificial Nutrition Survey
BAPEN British Association for Parenteral and Enteral Nutrition
BCS Biopharmaceutical classification system
BDA British Dietetic Association
BDP Beclomethasone dipropionate
BFT Barium follow through
BIA Bioelectrical impedance analysis
BIFA British Intestinal Failure Alliance
BMC Bone mineral content
BMD Bone mineral density
BMI Body mass index
BMR Basal metabolic rate
xix
xx Abbreviations
BMS Bare metal stents

BNF British National Formulary
BO Bowel obstruction
BP Blood pressure
BPD Bilio-pancreatic diversion
BPNG British Pharmaceutical Nutrition Group
BSG British Society of Gastroenterology
Ca Calcium
CA Coeliac artery
cAMP Cyclic adenosine monophosphate
CANH Clinically assisted nutrition and hydration
CBD Common bile duct
CBT Cognitive behavioural therapy
CCN2 Cellular communication network factor 2
CDED Congenital diseases of enterocyte development
CDT Catheter-directed thrombolysis
CE Conforormité européenne. European conformity mark indicating a product
meets the essential requirements of the relevant EU directives and standards for
that product
CFTR Cystic fibrosis transmembrane conductance regulator
CHG Chlorhexidine gluconate
CHI Creatinine height index
CHO Carbohydrate
CIF Chronic intestinal failure
CIPO Chronic intestinal pseudo-obstruction
Cl Chloride
CLABSI Central line-associated bloodstream infection
CMV Cytomegalovirus
CNI Calcineurin inhibitor
CNS Central nervous system
COVID Coronavirus disease
CPPD Calcium pyrophosphate dihydrate
Cr Chromium
CR Chyme reinfusion
CRBSI Catheter-related blood stream infection
CRF Chronic renal failure
CRP C-reactive protein
CSD Congenital sodium diarrhoea
CT Computerised tomography
CTCAE Common terminology criteria for adverse events
CTE Computerised tomography enterography
CTE Congenital tufting enteropathy
CTZ Chemoreceptor trigger zone
Cu Copper
CVC Central venous catheter
CVID Common variable immunodeficiency
CVT Central vein thrombosis
DAMP Danger-associated molecular patterns
DBD Donation after brain death
DC Dendritic cell
DCH Delayed cutaneous hypersensitivity
DEXA Dual-energy x-ray absorptiometry
DFH Distal feeding and/or hydration
Abbreviations xxi
DIT Diet-induced thermogenesis

DJ Duodeno-jejunal
DJBL Duodenal-jejunal bypass liner
DNA Deoxyribonucleic acid
DNI Drug-nutrient interactions
DPEG Direct percutaneous endoscopic jejunostomy
DPP Dipeptidyl peptidase
DR Digital radiography
DTP Differential time to positivity
EA Enteropathic arthritis
EAA Essential amino acids
EAF Entero-atmospheric fistula
EATL Enteropathy-associated T-cell lymphoma
EBV Epstein-Barr virus
ECCO European Crohn´s and Colitis Organisation
ECF Enterocutaneous fistula
ECG Electrocardiogram
ECL Enterochromaffin-like cells
ECMO Extracorporeal membrane oxygenation
EDS Ehlers-Danlos syndrome
EDTA Ethylenediaminetetraacetic acid
EEN Early enteral nutrition
EF Enteral feed
EFA Essential fatty acid
EGF Epidermal growth factor
EGFR Epidermal growth factor receptor
EHF Extensively hydrolysed formulae
EI Energy intake
EMA Endomysial antibody
EMA European Medicines Agency
EMDR Eye movement desensitisation and reprocessing
EPS Encapsulating peritonitis
ERAS Enhanced recovery after surgery
ERCP Endoscopic retrograde pancreatography
ESG Endoscopic sleeve gastroplasty
ESICM European Society of Intensive Care Medicine
ESPEN European Society of Enteral and Parenteral Nutrition (European Society of
Clinical Nutrition and Metabolism)
ESPGHAN European Society for Paediatric Gastroenterology, Hepatology and Nutrition
ESWL Extracorporeal shockwave lithotripsy
ETEC Enterotoxigenic
ETF Enteral tube feeding
EUS Endoscopic ultrasound
FABP Fatty acid binding protein
FDA Food and Drug Administration (USA)
FGF Fibroblast growth factor
FISH Fluorescence in-situ hybridisation
FMT Faecal microbiota transplantation
FODMAP Fermentable oligosaccharides, disaccharides, monosaccharides and polyols
Fr French gauge (same as CH =Charrière) circumference of a tube in millimetres
(Fr =diameter x π)
FU Fluorouracil
fURS Flexible ureteroscopy
xxii Abbreviations
FXR Farnesoid X receptor

GALT Gut-associated lymphoid tissue
GCSF Granulocyte colony-stimulating factor
GFR Glomerular filtration rate
GH Growth hormone (hGH: human growth hormone)
GHR Growth hormone receptor
GHRH Growth hormone releasing hormone
GI Gastrointestinal
GIP Gastric inhibitory peptide or polypeptide, or glucose-dependent insulinotropic
polypeptide
GIT Gastrointestinal tract
GLIM Global leadership initiative on malnutrition
GLP-1 and 2 Glucagon-like peptide-1 and -2
GLP-2R Glucagon-like peptide-2 receptor
GORD Gastro-oesophageal reflux
GPS Glasgow prognostic score
GRS Glucose rehydration solution
GSV Great saphenous vein
GVHD Graft versus host disease (acute or chronic)
HAART Highly active antiretroviral therapy
HACCP Hazard analysis critical control point
HB-EGF Heparin-binding growth factor
HCO3 Bicarbonate
HD Haemodialysis
HES Hospital episode statistics
HETF Home enteral tube feeding
HGF Hepatocyte growth factor
HIV Human immunodeficiency virus
HLA Human leucocyte antigen
HOS High output stoma
HPAC High amplitude propagated contractions
HPN Home parenteral nutrition
HPS Home parenteral support (includes fluid and nutrition)
HSC Haematopoietic stem cell
HSCT Haemopoietic stem cell transplantation
HVM Hollow visceral myopathy
I Iodine
IAP Intra-abdominal pressure
IASP International Association for the Study of Pain
IBD Inflammatory bowel disease
ICAM Intercellular adhesion molecule
ICER Incremental cost effectiveness ratio
ICPI Immune checkpoint inhibitor
ICU Intensive care unit
ICV Ileocaecal valve
IDA Iron deficiency anaemia
IDSA Infectious Disease Society of America
IF Intestinal failure
IFALD Intestinal failure-associated liver disease
IFRD1 Interferon-related developmental regulator
IFU Intestinal failure unit
IFX Infliximab
IGF Insulin-like growth factor
Abbreviations xxiii
IHD Intermittent haemodialysis

IJV Internal jugular vein
Il Interleukin
ILE Intravenous lopid emulsion
IMA Inferior mesenteric artery
iNOS Inducible NO synthase
INS Intestinal insufficiency
IPA Isopropyl alcohol
IRU Intestinal rehabilitation unit
ITX Intestinal transplantation
IVC Inferior vena cava
IVF Intravenous fluids
IVS Intravenous saline
JCB Jejuno-colic bypass
JIB End-to-end jejuno-ileal bypass
K Potassium
KGF Keratinocyte growth factor
LAMS Lumen apposing metal stents
LCFA Long-chain fatty acids
LCT Long-chain triglycerides (14–24 carbon atoms)
LFA Lymphocyte function antigen
LFT Liver function test.
LILT Longitudinal intestinal lengthening and tailoring
LITRE Looking into the requirements for equipment
LOS Length of stay
LSB Liver small bowel transplant
MAHA Microangiopathic haemolytic anaemia
MAMC Mid-arm muscle circumference
MAMP Microbial-associated molecular patterns
MARSI Medical adhesive-related skin injury
MARSIPAN Management of Really Sick Patients with Anorexia Nervosa
MBD Metabolic bone disease
MCT Medium-chain triglycerides (6–12 carbon atoms)
MDT Multidisciplinary team
MEED Medical emergencies in eating disorders
MEF Minimal enteral feeding
MELD Model for end-stage liver disease
Mg Magnesium
mGIF Modified gastrointestinal failure
MHC Major histocompatibility complex
MHRA Medicines and Healthcare products Regulatory Agency
MIN Minimally invasive necrosectomy
MMC Migrating motor complex or interdigestive migrating complex
Mn Manganese
MNA Mini nutritional assessment
MNGIE Mitochondrial neurogastrointestinal encephalomyopathy
Mo Molybdenum
MODS Multiple organ dysfunction syndrome
MPC Myeloid progenitor cells
MR Magnetic resonance
MRCP Magnetic resonance cholangio-pancreatography
MRE Magnetic resonance enterography
MRI Magnetic resonance imaging
xxiv Abbreviations
MRP Multidrug resistance-associated protein

MTBT Mixed triglyceride breath test
MUAC Mid-upper arm circumference
MUFA Monounsaturated fatty acid
MUST Malnutrition universal screening tool
MVID Microvillus inclusion disease
MVT Multi-visceral transplant
N Nitrogen
Na Sodium
NAFLD Non-alcoholic fatty liver disease
NASH Non-alcoholic steatohepatitis
NASIT National Adult Small Intestinal Transplantation forum
ND Nasoduodenal
NEC Necrotizing enterocolitis
NFC Needle-free connector
NF-KB Nuclear factor kappa light chain enhancer of activated B cells
NG Nasogastric
NGT Nasogastric tube
NHS National Health Service (in United Kingdom)
NICE The National Institute for Health and Care Excellence (formerly the National
Institute for Clinical Excellence)
NIOSH National Institute for Occupational Safety and Health
NIS National inpatient sample
NJ Nasojejunal
NJT Nasojejunal tube
NK Natural killer cell
NLR NOD-like receptors
NOD Nucleotide-binding oligomerization domain
NOMI Non-occlusive mesenteric ischaemia
npRQ Non-protein respiratory quotient
NPSA National Patient Safety Agency
NPY Neuropeptide Y
NSAID Non-steroidal anti-inflammatory drugs
NSQIP National Surgical Quality Improvement Program
NST Nutrition support team
OAGB One anastomosis gastric bypass
OGD Oesophago-gastro-duodenoscopy
OGS Oral glucose saline solution
ORS Oral rehydration solution
OSFED Other specific feeding and eating disorder
OSHA Occupational Safety and Health Administration
OXM Oxyntomodulin
P Phosphate
PABA Para-aminobenzoate test
PAI Peritoneal adhesion index
PAL Physical activity level
PAU Peri-anastomotic ulcerations
PBSC Peripheral blood stem cells
PCDT Percutaneous catheter-directed thrombolysis
PCNL Percutaneous nephrolithotomy
PD Peritoneal dialysis
PEEL Peritonectomy and enterolysis
PEG Percutaneous endoscopic gastrostomy
Abbreviations xxv
PEGJ Percutaneous endoscopic gastro-jejunostomy

PEJ Percutaneous endoscopic jejunostomy
PERT Pancreatic enzyme replacement therapy
PET-CT Positron emission tomography and computed tomography
PFG Percutaneous fluoroscopic gastrostomy
PFGJ Percutaneous fluoroscopic gastro-jejunostomy
pH Potential hydrogen
PICC peripherally inserted central catheter
PINNT Patients on Intravenous and Nasogastric Nutrition Therapy
PIPOS Paediatric intestinal pseudo-obstruction syndromes
PIT Psychodynamic interpersonal therapy
PLAG Percutaneous laparoscopically assisted gastrostomy
PMT Percutaneous mechanical thrombectomy
PMU Psychological medicine unit
PN Parenteral nutrition
PNALD Parenteral nutrition-associated liver disease
PNIQ Parenteral nutrition impact questionnaire
PPI Proton pump inhibitor
PPOI Prolonged postoperative ileus
PRES Posterior reversible encephalopathy syndrome
PRG Percutaneous radiological gastrostomy
PRGJ Percutaneous radiologically inserted gastro-jejunostomy
PRR Pattern recognition receptors
PS Parenteral support (includes fluid and nutrition)
PTA Percutaneous transluminal angioplasty
PTFE Polytetrafluoroethylene
PTLD Post-transplant lymphoproliferative disorder
PUFA Polyunsaturated fatty acid
PVC Polyvinyl chloride
PVT Porto-mesenteric and splenic vein thrombosis
PWO Persistent withdrawal occlusion
PYY Peptide YY
QoL Quality of life
RA Rheumatoid arthritis
RBC Red blood cell
RCD Refractory coeliac disease
RCT Randomised clinical trial
REE Resting energy expenditure
RFS Refeeding syndrome
RIG Radiologically inserted gastrostomy
RIGJ Radiologically inserted gastro-jejunostomy
RIRS Retrograde intrarenal surgery
RIV Reference intake value
RNA Ribonucleic acid
RNI Reference nutrient intake
ROMS Retrograde open superior mesenteric artery stenting
RRT Renal replacement therapy
RT Radiotherapy
rURS Rigid ureteroscopy
RYGB Roux en y gastric bypass
SACT Systemic anti-cancer treatment
SARC Simple questionnaire of sarcopenia
SBS Short bowel syndrome
xxvi Abbreviations
SC Subclavian vein
SCFA Short chain fatty acids
SCT Secretin cerulean test
Se Selenium
SEP Sclerosing encapsulating peritonitis
SGA Subjective global assessment
SGLT Sodium-glucose co-transporter
SIBO Small intestinal bacterial overgrowth
SILT Spiral intestinal lengthening and tailoring
SIRS Systemic inflammation response syndrome
SLE Systemic lupus erythematosus
SMA Superior mesenteric artery
SMV Superior mesenteric vein
SNAP Sepsis-nutrition-anatomy-plan
SPT Secretin pancreozymin test
SRSB Segmental reversal of the small bowel
SSTR Somatostatin receptor
STEP Serial transverse enteroplasty
SUSS Sit up-squat-stand test
SVC Superior vena cava
T2D/T2DM Type 2 diabetes mellitus
TAR Transversus abdominis release
TA-TMA Transplant-associated thrombotic microangiopathy
TBI Total body irradiation
TEE Total energy expenditure
TGF Transforming growth factor (alpha and beta)
TLR Toll-like receptor
TNF Tumour necrosis factor
TRM Transplant-related mortality
TST Triceps skinfold thickness
tTG Tissue transglutaminase
UDCA Ursodeoxycholic acid
UFED Unspecified feeding or eating disorder
UHT Ultra-high temperatures
UK United Kingdom
UKELD United Kingdom model for end-stage liver disease
US Ultrasound
USA United States of America
USTE Ustekinumab
UV Ultraviolet
VBG Vertical banded gastrostomy
VCAM Vascular cell adhesion molecule
VEDO Vedolizumab
VEGF Vascular endothelial growth factor
VIP Vasoactive intestinal peptide
VOD Veno-occlusive disease of the liver
VTE Venous thromboembolism
WBC White blood cell
WHO World Health Organisation
WON Walled-off-necrosis
WTP Willingness to pay
Zn Zinc
Part I
Introduction
Historical Overview of Intestinal Failure
John E. Lennard-Jones, Gil Hardy,

and Khursheed N. Jeejeebhoy
Key Points aseptic care the incidence of catheter related blood stream
1. The first resection of more than 200 cm small bowel was infection has reduced.
described in 1880 and in 1980 the term intestinal failure
was first coined.
2. The first attempt at parenteral nutrition (PN) was with
milk infusions in 1873 and 100 years later the first patient Introduction
was reported receiving PN at home (in 1973).
3. An everted mucosal ileostomy and the development of The term ‘intestinal failure’ was used by Irving and col-
satisfactory appliances that adhered to the skin in 1952 leagues in the title of a paper published in 1980 [1]. In the
helped the management of many patients after a bowel following year, a book chapter by Fleming and Remington
resection. gave the first definition as a ‘reduction in functioning gut
4. The reasons for intestinal failure have widened from mas- mass below the minimal amount necessary for adequate
sive resections due to volvulus/strangulated hernia, digestion and absorption of nutrients’ [2]. Irving and his col-
Crohn’s disease and mesenteric infarction to include sur- leagues popularized the term when they described their work
gical complications and dysmotility. in a specially designated ‘Intestinal Failure Unit’ for the
5. The composition of PN nutrition and the bags has been treatment of complex intestinal disorders [3]. A key feature
changing since the 1960s with improvements in amino of this unit was the ability to provide safe, effective, long-
acid and micronutrient formulations, the development of term parenteral nutrition. The phrase ‘intestinal failure’
lipid emulsions and recently the multi-chamber bags. began in surgical practice as a unifying concept for appar-
6. Venous access for PN started with arteriovenous fistulas, ently different conditions all of which have the common fea-
then with safe aseptic placement catheters with their tips ture that the normal absorptive function of the small intestine
at the vena caval/atrial junction were used. With careful is impaired, usually to such an extent that parenteral feeding
is needed [3]. It is now recognized that some patients can
also be treated by giving extra or special nutrients via the
J. E. Lennard-Jones has died before the publication of this book. intestine. The definition of intestinal failure in the first edi-
tion of this book is of ‘a reduction of intestinal absorption
that, without treatment or compensatory mechanisms, results
J. E. Lennard-Jones (Deceased)
Department of Gastroenterology, St. Mark’s Hospital, Harrow, UK in malnutrition and/or dehydration’. This includes the need
for enteral or parenteral supplements (nutrition and fluid) to
G. Hardy (*)
Clinical Nutrition, Ipanema Research Trust, Devonport, maintain a normal nutritional/hydration state. Malabsorption
Auckland, New Zealand of a single nutrient, such as Vitamin B12, or the need for a
K. N. Jeejeebhoy (*) special diet to exclude a damaging component such as glu-
Department of Medicine, Toronto General Hospital, ten, is not included within this definition.
Toronto, ON, Canada Loss of intestinal absorptive function can be complete or
Department of Gastroenterology, University of Toronto, partial. Intestinal failure may be described as acute when it is
Toronto, ON, Canada reversible in the short term or chronic if long-term treatment
Department of Medicine, University of Toronto, over weeks, months, or longer is required especially if con-
Toronto, ON, Canada tinued treatment is needed at home. The conditions leading
© Springer Nature Switzerland AG 2023 3

J. M.D. Nightingale (ed.), Intestinal Failure, https://doi.org/10.1007/978-3-031-22265-8_1
4 J. E. Lennard-Jones et al.
to intestinal failure are such surgical conditions as intra- the ileum was resected fat malabsorption increased with
abdominal sepsis and ileus, a high volume entero-cutaneous increasing amounts of fed fat [5–7]. Based on intubations
fistula, intestinal obstruction or temporary severe malabsorp- studies of Borgstrom et al. [4] ileal resection should have no
tion after extensive small bowel resection or it can be due to effect on fat absorption. This paradox was solved in the
chemotherapy. 1960s by the observation that bile salts necessary for fat
absorption are recycled through the ileum and during a meal,
calculations by Borgstrom et al. suggest that the bile salt
Parallel Developments pool is recycled twice. Hence loss of the ileum depletes the
bile salt pool in the jejunum and reduces fat absorption.
Developments in different disciplines since the middle years Intestinal resection studies also showed another unique func-
of last century have led to our current understanding and tion of the ileum namely vitamin B12 absorption [5].
treatment of intestinal failure. First, the application to both The need of patients with distal ileal resection for paren-
normal subjects and those with intestinal resection of new teral supplements of vitamin B12 is now well recognised.
laboratory techniques, has advanced understanding of small
intestinal function. Second, the scope of surgical treatment
has extended to include more complex operations on the Fluid and Electrolyte Fluxes
intestine so that intestinal failure occurs more frequently, and
is often more severe, than hitherto. During the same time In addition to macronutrient absorption the small bowel was
period medical causes of intestinal failure have been recog- shown to be the site of massive fluid and electrolyte fluxes.
nized. Third, clinical necessity has stimulated the application The intubation studies by Borgstrom et al. [4] indicated that
of innovative techniques to treat the condition in the short- or the ingested meal is diluted three to five times as it passes the
long-term. These parallel developments in time will be duodenum. Seminal studies showed that the jejunum had
described sequentially in the following review. large pores and absorption was mainly by solvent drag leav-
ing the luminal electrolyte concentration similar to plasma.
While there was coupled sodium and glucose active trans-
Advances in Knowledge port throughout the small bowel [8–10], osmotic gradient
was not maintained in the jejunum. Hence a hyperosmotic
ites of Nutrient Absorption and Effect
S meal of milk and doughnuts caused a greater dilution in the
of Resection proximal bowel than a steak meal of lower osmolality. In
contrast there was an osmotic gradient between plasma and
Many of the laboratory measurements, now regarded as rou- lumen in the ileum where there were smaller pores and espe-
tine, were developed at the beginning of the second half of cially in the colon [11–13].
the twentieth century. For example, a widely used method for
measurement of fat in faeces was first reported in 1949 and
microbiological techniques for the measurement of folic acid Effect of Malabsorption on the Colon
or vitamin B12 in blood were devised in 1956 and 1961
respectively. Radio-isotope methods for measuring vitamin Malabsorption of bile salts results in these salts entering the
B12 absorption were developed in the late 1950s. colon where they promote water secretion and thus diarrhea.
In 1957 the first direct measurements of nutrients in Bile acid malabsorption caused by ileal resection causes fat
human intestine was made by Borgstrom et al. [4] who fed a malabsorption. After resection of the ileum the entry of bile
liquid meal with an unabsorbed marker and using intubation salts and fatty acids into the colon stimulated colonic peri-
sampled the intestinal contents at various distances to deter- staltic motor activity and inhibited water and electrolyte
mine the absorption of nutrients as the bolus fed progressed absorption by long-chain fatty acids entering the colon was
down the small bowel. They found that over 90% of all mac- shown in the 1970s and 1980s to be a potential factor in
ronutrients namely carbohydrate, protein and fat were causing diarrhoea in patients with a short small intestine
absorbed within 100 cm of jejunum [4]. Although in intact anastomosed to colon [14, 15]. The mechanism of increased
human subjects fat absorption was complete in the jejunum, oxalate absorption by the colon in patients with a short gut,
Intestinal resection studies showed that after jejunal resec- leading to hyperoxaluria and oxalate renal stones, was
tion feeding increasing amounts of fat did not increase loss unraveled in the 1970s as due to a combination of colonic
in stool indicating that the remaining ileum could maintain calcium binding by long-chain fatty acids and the effect of a
normal fat absorption despite the absence of the jejunum higher than normal concentration of bile salts on the colonic
which is the normal site of fat absorption. In contrast when mucosa [16].
Historical Overview of Intestinal Failure 5
daptation of the Residual Small Intestine

A Table 1 Reasons for ‘extensive’ and ‘massive’ intestinal resections in
adults in 1912 and 1935
After a Partial Resection
Flint 1912: ‘Extensive’ intestinal resection [23]
Experiments in animals, dating from the early years of the Strangulated hernia 19
Tumour 10
century, but particularly from the late 1960s onwards, have
Gangrene 4
shown that when a length of small intestine is resected, with Adhesions/bands 4
anastomosis of the proximal jejunal and distal ileal seg- Tuberculosis 3
ments, marked hypertrophy with increased absorptive func- Uterine perforation 3
tion of the distal ileum occurs [17]. It seems that the distal Other 6
ileum which plays little part in normal nutrient absorption Unknown 6
has a capacity for increasing its absorptive role when nutri- Total 55
Haymond 1935: ‘Massive’ intestinal resection [24]
ents reach it due to proximal resection of intestine. Functional
Volvulus 76
investigation in man has shown increased absorption of Strangulated hernia 45
water, sodium, glucose and calcium in the jejunum [18–20], Mesenteric thrombosis 34
but villous hyperplasia has not been demonstrated in man Tuberculosis 16
when distal intestine is resected with formation of a terminal Mesenteric tumours 14
jejunostomy [21]. These findings were explained in the Uterine perforation 11
1990s by the findings that isolated glucagon- like peptide 2 Adhesions/bands 7
Other 54
(GLP2) produced by L cells of the ileum and colon increased
Total 257
intestinal epithelium proliferation [22].
whole small bowel for a condition such as desmoid tumour

Development of Surgical Practice of the mesentery. There are now also many people in whom
the residual intestine is limited to a relatively short length of
Extensive Resection residual jejunum ending in a stoma.
The first resection in humans of more than 200 cm of small

intestine has been attributed to Koberle in 1880, and 55 of Construction of a Stoma
such operations were reported up to 1912 [23]. Most such
operations until the middle years of the century were per- The surgery of ulcerative colitis was greatly facilitated by the
formed as an emergency for removal of non-viable intestine development and introduction of an everted mucosal ileos-
infarcted due to strangulation or volvulus. Thus, in a 1935 tomy in 1952 and the development of satisfactory appliances
review of 257 cases the commonest reasons for resection adherent to the skin during the same period [26]. From time
were volvulus in 76 and strangulated hernia in 45 (Table 1) to time colectomy for ulcerative colitis is complicated by a
[24]. Mesenteric artery or vein occlusion constituted only vascular accident which leads to loss not only of the colon
13% of the cases at that time, whereas by 1969 the propor- but also a large part of the small bowel with creation of a
tion had risen to 48% [25]. This change may reflect a terminal jejunostomy.
decreased incidence of hernial strangulation, increasing age This operation may be needed electively for the treatment
of the population and the fact that surgeons became willing of Crohn’s disease when there is extensive involvement of
to resect a long length of infarcted intestine in the knowledge both small and large bowel. Thus in a series reported in 1992
that treatment was now available to compensate for the of 86 patients each with less than 200 cm of small bowel
resulting malabsorption. remaining, 38 had a jejunostomy as the result of surgical
Extensive small bowel resection for vascular insufficiency treatment for Crohn’s disease or ulcerative colitis [27].
of the central portion of the small bowel usually spares the
proximal and distal ends. Such operations lead to removal of
mid-small bowel with jejuno-ileal anastomosis and retention Entero-Cutaneous Fistula
of the colon. The distal ileum has considerable potential for
adaptation and the colon, with its capacity for avid absorp- A high volume entero-cutaneous fistula is similar in its efflu-
tion of sodium and water, prevents severe fluid and sodium ent to a high jejunostomy, but is often complicated by sepsis.
depletion. These cases, with a reasonable good prognosis, While maintaining nutrition parenterally, surgeons can now
still occur but the knowledge that parenteral therapy is avail- delay definitive operation for a high-volume entero-
able (see below) now allows surgeons to resect even the cutaneous fistula until sepsis is dealt with, the anatomical
situation is defined and the patient’s general condition is ecognition of Medical Causes of Intestinal
R
optimal. Treatment in this way has greatly reduced the mor- Failure
tality of this condition.
A number of congenital disorders associated with intestinal
failure were described during the 1970s and 1980s. For
Characterization of the Resection example, a rare congenital defect of intestinal villus forma-
tion in babies [34] and a number of different familial types of
The term ‘extensive’ small bowel resection was reserved in pseudo-obstruction have been identified [35]. The latter may
the earlier literature to describe removal of at least 200 cm. present as a myopathy in which the intestine becomes wide,
This length was chosen because it was believed to represent atonic and subject to bacterial overgrowth or as a disorder of
about one-third of the small intestinal length and experimen- the myenteric nerve plexus which leads to obstructive epi-
tal work suggested that up to this proportion can be removed sodes without mechanical cause. Chronic pseudo-obstruction
without detriment to weight and strength. These observa- has also been recognized later in life secondary to a systemic
tions failed to take account of the variable length of the disorder such as scleroderma or as a sporadic condition of
human small intestine. In 1935, Haymond [24] drew attention unknown cause.
to this variability and observed correctly that ‘a resection of
a large amount in one individual would constitute a different
percentage of the total length in another’. Before closing the Development of Treatment
abdomen after a resection, surgeons should thus measure the
length of residual intestine along the anti-mesenteric border, Enteral Nutrition (Table 2)
and define the proportions of proximal and distal intestine.
Follow-up observations have shown the prognostic impor- The earliest enteral feeds were given rectally by enema. The
tance of these records. Patients with less than 200 cm of ancient Egyptians gave wine, whey, milk and/or barley broth
small bowel remaining fall into three groups: those with an nutrient enemas [36]. John Hunter gave one of the earliest
anastomosis between residual jejunum and ileum proximal orogastric feeds documented in 1790 to a patient who had had
to an intact colon; those with anastomosis of small bowel to a stroke. He used a pig bladder as a reservoir for an egg,
colon; and those with a terminal small intestinal stoma [27]. water, sugar, milk or wine feed and this was squeezed into the
The prognosis as regards the need for long-term parenteral stomach through a feeding tube, made by a watchmaker, con-
nutrition (PN) therapy depends in each group on the length sisting of a whale bone and eel skin [36]. Feeding tubes were
of residual small bowel [28] but those with a colon can toler- at first large and made of rubber, gradually these have been
ate shorter lengths of small bowel than those with a jejunos- refined to radio-opaque fine-bore tubes initially made of poly-
tomy. The role of residual ileum and colon to allow the bowel vinyl chloride but now largely replaced by silicone or poly-
to adapt and permit patients to return to oral nutrition after urethane [37]. While the first gastrostomies and jejunostomies
resection and initial dependence on home parenteral nutri- were fashioned at laparotomy, they are now mostly placed
tion (HPN) was demonstrated in the 1990s. The findings using endoscopic and radiological techniques [38–42].
showed that the presence of ileum and colon allowed very In 1943 milk protein was used to make casein hydroly-
short bowels to become independent of PN followed by the sates as the protein component of a feed, subsequently some
presence of colon alone joined to jejunum and those least feeds have been based on soya bean or egg white.
likely to become independent of PN were those with a jeju- Carbohydrate was first given as glucose or sucrose, but in
nostomy [29].
Table 2 Key developments in enteral nutrition
BC Nutrient enemas used by Ancient Egyptians [36]
Surgical Treatment of Intestinal Failure 1790 Oro-gastric feeding tube [36]
1867 Soft rubber tubing for gastric lavage [37]
Although procedures [30, 31] have been performed with 1876 Surgical gastrostomy [38]
1885 Surgical feeding jejunostomy [39]
some success to lengthen a short residual intestine or delay
1910 Oro-duodenal feeding [40]
passage of its contents to allow absorption to occur, the main 1943 Casein hydrolysates [36]
hope of surgical advance centres on intestinal transplantation 1952 Surgically placed needle jejunostomy [41]
[32]. Rejection of the graft remains a problem but the suc- 1963 Chemically defined (elemental) diet for space travel [36]
cessful result when an identical twin was the donor pointeds 1980 Endoscopic gastrostomy [41]
to the success of the surgical technique; the problems to be 1981 Radiological gastrostomy [42]
overcome remain mainly immunological [33]. 1990s Immunomodulation (glutamine, arginine and MCTs)
order to keep the osmolality low, glucose-polymer mixtures defined the optimal amino acid composition, including the
derived from the hydrolysis of corn starch were used [36, ratio of essential to nonessential amino acids and the need to
43]. Lipid as long-chain triglyceride was derived from soya, provide the amino acids in an l-form. It was recognized that
corn or safflower oils, and lipid as medium-chain triglycer- a mixture of crystalline amino acids would have the advan-
ide from coconut oil. tage of providing flexible solutions of known composition
and such a solution was first used clinically in 1940 for intra-
venous nutrition in children [47]. However, the initial techni-
Parenteral Nutrition (Table 3) cal difficulty, and thus high commercial cost, of such
solutions delayed their introduction for routine use until the
Fluid and electrolyte balance has been maintained in patients 1960s and early 1970s, since when they have superseded the
with intestinal failure since the earliest days of intravenous use of protein hydrolysates.
fluid administration. One of the earliest reports of giving An ILE offered the possibility of a rich caloric source which
intravenous nutrition was when three patients who had would not be osmotically active. However, there were many
cholera and were considered about to die, were given intra- initial difficulties. Low molecular weight triglycerides were
venous fresh (still warm) cow’s milk, two of these patients found to be acutely toxic. Cotton seed oil and soya bean oil
survived [44]. Isotonic, or slightly hypertonic, solutions of emulsions had low acute toxicity and between 1948 and 1972
glucose were given by peripheral infusion but not enough to Meng and colleagues in Nashville USA studied the former in
provide an adequate energy source because higher concen- animal and human models [49], but unfortunately a minor
trations caused thrombosis of the vein. The problems to be impurity gave rise to toxic effects. Consequently the product
solved before intravenous feeding could become a reality, was withdrawn and ILE were not approved for use by the
were to devise solutions which provide a non-irritant form of United States Food and Drug Administration (FDA) until 1972.
amino-nitrogen for synthesis of protein and an adequate Meanwhile development of the soya bean oil ILE, emulsi-
energy source. fied with egg yolk phosphatides, continued in Sweden. The
Intact protein, other than human plasma or albumin, tends product, which mimicked the structure of chylomicrons,
to be allergenic. These whole proteins were used in the first proved non-toxic in animals and was used successfully in
half of the twentieth century for temporary nutritional sup- humans for the first time during the early 1960s [50]. During
port but expansion of the circulating plasma volume and a 1963 conference in London, organized and chaired by
slow turnover of the protein were limiting factors. Early Meng, the Swedish group, led by Wretlind and Schuberth
workers suggested that amino acid solutions might be effec- described their research on the experimental and clinical
tive but it was not until 1937 that an amino acid solution development of this preparation, which was approved for use
produced by hydrolysis of casein was first shown to be a in UK and many other European countries in 1962 and is still
practicable method of treatment [45]. By 1943, a review in use today. This was a major advance and, there was an
recorded treatment of at least 500 patients with this product immediate surge of interest in the use of ILE as a high energy
and included a reference to combined treatment with an source of essential fatty acids.
intravenous lipid emulsion (ILE) [46]. A casein enzymatic In 1965 Lawson [51] was able to provide PN using pro-
hydrolysate, in which amino acids and small peptides were tein hydrolysate, glucose and lipid, separately through a cen-
separated from residual large peptides by dialysis, was tral venous catheter and Sherwood Jones and Peaston
widely used in Europe during the 1950s and 1960s, and a reported that in the ICU at Whiston hospital, Liverpool,
fibrin hydrolysate was used in America. Intensive work “intravenous feeding is routinely instituted if either oral or
tube feeding is contraindicated or complicated by side-
effects” [52]. Fructose, sorbitol, xylitol and ethanol were all
Table 3 Key developments in parenteral nutrition
popular as alternative energy sources in Australia, Germany
1873 Milk infusions to treat cholera [44] and the UK in the 1970’s/‘80’s [53–55] but all have meta-
1937 Protein hydrolysates (amino acids) infusions [45]
bolic disadvantages compared to glucose. Which is meta-
1952 Subclavian vein catheterization using infraclavicular approach
[48] bolically the most suitable energy substrate. However, at
1961 Lipid emulsion [50] only 4 kcal/g the quantity needed was limited by the need to
1965 Complete Parenteral Nutrition using central catheter [50] keep the volume of infusate physiological and avoid throm-
1968 Hypertonic glucose infused into a large vein [56] bosis of peripheral veins. Dudrick and colleagues overcame
1970 Long-term parenteral nutrition (‘the artificial gut’) using the high osmolality problem in 1968 by infusing hypertonic
arterio-venous shunt [57]
1973 All-in-One system for ambulatory PN [60]
glucose into a large central vein where the blood flow is ade-
1973 Home PN using a tunneled catheter [67] quate to dilute the solution and thus avoid local phlebitis and
1973 Teflon-cuffed tunnelled silicone rubber catheter [68] thrombosis [56]. This technique was widely adopted in
2000 Multi Chamber Bags for PN [71] America where ILE were unavailable, and administration of
PN through a central vein has been standard practice, par- [70]. The need for expensive hospital-based Aseptic Units
ticularly for long-term parenteral feeding. Some patients (ASU) for compounding PN has now diminished, with
with chronic intestinal failure require prolonged, even life- industry manufacturing a range of ‘ready-to-use’ multi
long, parenteral feeding. There was excitement when the chamber bags (MCB) with the nutrients sterilized in separate
concept of an ‘artificial gut’ based on the experience of pro- chambers, that can be stored at room temperature, resulting
longed renal dialysis was introduced by Scribner and colin long shelf lives prior to mixing. MCB, introduced in
leagues in 1970 [57]. The original technique based on Europe during the 1990’s, significantly improve pharmacy
intermittent infusion via an arterio-venous fistula was suc- workload, can be more cost effective and may reduce risk of
cessfully adopted in Australia, New Zealand and The bloodstream infections [71, 72].
Netherlands where there are still some long-term PN patients Most important of all, protocols and educational pro-
managing this technique at home [58, 59]. In 1973, the grams, that cover PN prescription, compounding and admin-
Broviac silicone rubber catheter with a Dacron cuff to seal istration, have been developed to minimize infection and
and fix it within a skin tunnel, proved satisfactory and nine venous thrombosis so that the risk of these complications is
patients were treated at home in USA [60, 61]. This remains now low when care is provided by an experienced team [73].
a long-term catheter of choice.
Solassol and Joyeux in the 1970’s, pioneered the first
‘All-in One’ (AIO) admixtures, in a single re-usable silicone Resection and Anastomosis
rubber container, that could be prepared aseptically in their
hospital pharmacy [62]. The novel French PN system was Metabolic studies of patients after resection date back at
administered to cancer and bowel disease patients, in least to 1938. An example of an investigation aimed at
Montpellier, via a small portable pump. This innovative sys- improving management is a report in 1949 of giving a patient
tem reduced the number of manipulations and daily infusion with short gut a liquid feed made up of protein hydrolysate,
time to 8 hrs, allowing the patient to become ambulatory and milk, cream and glucose compared with a normal diet [74].
eventually to manage their PN at home (HPN). However, The patient retained only 15 cm of jejunum anastomosed to
because of stability and microbiological concerns at that transverse colon. She had lost weight from 64 kg to 42 kg,
time, AIO admixtures were not immediately popular outside complained of weakness and dizziness (blood pressure
of France and mixing any other solutions with ILE was dis- 80/60), abdominal pain and bloating, and passed 3–6 stools
couraged by Wretlind [63]. In Canada, Jeejeebhoy and col- daily. This is a vivid description of the chronic poor health of
leagues described an alternative system for HPN using a a patient at that time with a major resection of small intes-
tunneled silicone for short bowel patients and published tine. The synthetic diet did not help her but it is interesting to
details of 13 patients treated at home for up to 23 months note that she was taking only 1345 kcal daily in her normal
[64]. At the same time Jarnum reported on Danish experi- diet which contained 48 g of fat.
ences with long term HPN patients in Copenhagen since It gradually became apparent that patients with a short
1967 [65, 66]. In UK, the use of the tunnelling technique was small intestine in continuity with colon benefit from a low
first mentioned in 1978 and 25 patients treated at different fat, high carbohydrate diet. Such patients need to eat more
centres were described in 1980 at a conference held for the energy-giving foods than normal to compensate for malab-
purpose [67, 68]. HPN is now a standard technique in many sorption. A child reported in 1961 who had lost the whole of
countries for patients with long-standing intestinal failure his jejunum and retained only 39 cm of ileum showed imme-
who cannot be treated successfully using an enteral diate improvement on a low fat, high protein, high carbohy-
regimen. drate diet. Weight loss was reversed, a growth spurt
During the 1970s and 1980s much R&D was conducted commenced and diarrhoea diminished [75]. Similarly, an
on nutrient solutions to ensure optimal ratio of energy to pro- adolescent who retained only 13 cm of jejunum and 5 cm of
tein, relative proportions of different amino acids, and con- terminal ileum did well when dietary carbohydrate and pro-
tent of vitamins and trace elements. The safety of the tein were increased and part of the fat intake was replaced by
technique of fluid administration both in hospital and at medium-chain triglycerides [76].
home was improved. For example, the original need for mul- The work of Booth et al. [6] and Andersson et al. [77] dur-
tiple bottle changes and additions was simplified in the ing the 1960s and 1970s showed that a low fat diet decreases
1970’s by adopting the French approach but aseptically mix- diarrhoea, loss of divalent cations (calcium and magnesium)
ing the ingredients in a single disposable 3 litre bag [68, 69]. and urinary oxalate. It is only in recent years that a further
Sophisticated pumps have been developed to control the rate benefit of increased dietary carbohydrate has been demon-
of flow and warn of air bubbles or line blockage. Air bubbles strated; unabsorbed carbohydrate entering the colon is fer-
in the solution have been minimized, and stability enhanced mented by colonic bacteria yielding short-chain fatty acids
by manufacturing the bag from oxygen impermeable plastics which are absorbed as a source of energy [78, 79].
Terminal Jejunostomy controlled trials by Jeppeson et al. showed that it was capa-
ble of improving intestinal function in patients on HPN so as
A patient who underwent an extensive small bowel resection to reduce the need for Parenteral Nutrition [96].
in 1958 which left 120 cm of small bowel ending in a jeju-
nostomy was troubled mainly by profuse drainage from the
stoma [80]. When investigated in 1973, the jejunostomy Conclusion
effluent at times exceeded the volume of nutrients taken by
mouth. Such profuse losses, with incipient sodium and mag- The concept of intestinal failure, the reasons for it, physio-
nesium deficiency, are a common problem in patients with a logical understanding of impaired intestinal absorption and
short gut and a jejunostomy. the development of treatments have largely occurred during
Developments in treatment to minimize sodium losses the last 50 years. It is perhaps because this concept is rela-
from the jejunostomy have been threefold. First, it was tively new that the term is not yet part of core medical teach-
shown that when such a patient drinks water, or a dilute ing, as is the case with cardiac, respiratory, hepatic or renal
sodium solution, there is a net sodium loss from the jejunos- failure. The following chapters do much to establish intesti-
tomy [81, 82]. When a normal person drinks water, sodium nal malabsorption, severe enough to require replacement
enters the upper intestine from the blood but this sodium is therapy, as another universally recognized type of system
re-absorbed by the ileum or colon; in these patients it is lost failure.
from the body via the stoma. Second, the same research
showed that the coupling of sodium and glucose absorption
can be utilized to promote sodium absorption [81, 82]. Thus
such patients should restrict their water intake and substitute
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Normal Intestinal Anatomy
and Physiology
Jeremy M.D. Nightingale and Robin Spiller
Key Points 8. Humans are hind gut fermenters. Healthy adults have
1. The components of the gut all function as one with all more than 1000 species of bacteria most belonging to the
parts communicating (by nerves or hormones) with each phyla with Bacteroidetes and Firmicutes. The bacteria are
other (intestinal orchestra). increasingly recognised not only for producing short
2. Endogenous gut secretions while consuming a normal chain fatty acids, vitamins and amino acids but for their
diet (about 2 kg) amount to about 4 L/24 h. role in diseases.
3. Small intestinal length is very variable at 160–1510 cm 9. Luminal content is constantly being sampled by M cells
while colon length is 100–330 cm. and dendritic cells as part of immunological
4. Jejunal mucosa has leaky intracellular junctions so its surveillance.
contents are near to iso-osmolar with plasma.
5. Macronutrients are broken down to small molecules (e.g
peptides and oligosaccharides) by pancreatic enzymes Introduction
and only to small hyperosmolar ones as they are absorbed
by the intestinal mucosa. The gastrointestinal tract extends from the mouth to the anus
6. Lipids are absorbed along the whole small intestine. and includes many vital organs that secrete, mix and gradu-
7. Colonic peptide hormones slow gastric emptying and gut ally break down food into molecules that can be absorbed.
transit (e.g. peptide YY) and increase upper gut mucosal (Fig. 1).
growth (e.g. GLP2).
J. M.D. Nightingale (*)

St Mark’s Hospital, Harrow, Middlesex, UK
e-mail: [email protected]
R. Spiller
Division of Gastroenterology School of Medical and Surgical
Sciences, University Hospital, Nottingham, UK

14 J. M.D. Nightingale and R. Spiller
Fig. 1 Normal
gastrointestinal anatomy
Stomach
Liver
Pancreas
Gallbladder
Jejunum
Duodenum
lleum
Colon
Appendix
Rectum
Oesophagus from 1.8 to 2.0; addition of food buffers this, raising the
luminal gastric pH to 4–5. It should be noted that mixing is
The oesophagus is a muscular tube about 25 cm long; its not perfect and a rim of secreted acid with pH 1 exists can
function is to propel the food bolus from the pharynx to the form an “acid pocket” just below the lower eosophageal
gastric cardia. It is lined with a tough squamous epithelium. sphincter, which may be important in reflux oesophagitis.
The upper two-thirds has striated voluntary skeletal muscle Acid kills most micro-organisms, denatures protein, making
and the lower one-third involuntary smooth muscle [1]. it more susceptible to hydrolysis, and converts inactive pep-
About 2 kg of food and drink pass down it each day, diluted sinogen to pepsin, which is the active form of the enzyme.
and lubricated by about 500 ml of saliva from lingual, sublin- Intrinsic factor, a mucoprotein with a molecular weight of
gual, sub-mandibular and parotid salivary glands. Food vis- 55,000, binds B12 and this complex is absorbed in the distal
cosity is reduced by the acts of chewing, dilution and 60 cm of ileum [2]. Fundal chief cells secrete pepsinogen
swallowing which stimulate a tenfold increase in salivary and rennin. Pepsin is important in the breakdown of colla-
flow. gen, as it cleaves protein at the site of aromatic amino acids.
Rennin (chymosin), which coagulates milk, may be pro-
duced by infants only.
Stomach Partly digested food from the fundus enters the antrum.
The antrum has less of a secretory role and is responsible for
The adult stomach is an acidic storage area that can hold up mixing food and grinding it into small particles. Repetitive
to 1.5 [1]. It starts digestion and delivers partly processed antral contractions occurring at 3 per minute propel chyme
food at a controlled rate into the duodenum. It consists of towards the pylorus, whose closure causes frequent retro-
two functionally different parts: the fundus and the antrum. grade flow. This to-and-fro flow produces shearing that
The fundus is mainly a storage area in which gastric juice reduces most food particles to less than 2 mm in diameter, a
is secreted and mixed with food to begin digestion. In addi- size at which they can pass through the pylorus into the duo-
tion to the many mucus-secreting cells found throughout the denum. These shearing forces are weak (65 N) compared to
stomach, the fundal parietal cells secrete 0.1 M hydrochloric those in the mouth (masticatory force 150 N) and so if food
acid and intrinsic factor. During fasting the gastric pH ranges is not adequately, chewed chunks of material like meat will
Normal Intestinal Anatomy and Physiology 15
empty as indigestible residue and will only empty with the Table 1 Approximate daily volume and composition of intestinal
MMC at the end of gastric emptying and thus may enter the secretions produced in response to food
small bowel as large chunks which will be less efficiently Volume Cl
(litres) pH Na K (mmol/L) HCO3 Mg Ca
digested.
Saliva 0.5 7 45 20 44 60 0.7 1.3
Thus the pylorus acts as a sieve [3]. Endocrine G cells in
Gastric juice 2.0 2 10 10 130 0 0.5 2.0
the antrum release gastrin, which stimulates the fundal pari- Pancreatic 0.6 8 140 10 30 110 0.2 0.3
etal cells to secrete acid. The mixture of food, drink and juice
secretion leaving the stomach is called chyme. Although the Hepatic bile 0.9 7 145 5 100 28 0.6 2.5
surface area of the stomach is small and the epithelium rela- Small bowel 1.8a 7 138 6 141 <5 <0.1 2.5
secretion
tively impermeable, some molecules (e.g. alcohol and aspi-
Serum 7.4 140 4 100 24 1.0 2.4
rin) can be absorbed from the stomach. a
This fluid is released and absorbed on the mucosa and rarely needs to
be taken into account in calculating fluid losses. Estimates of its electro-
lyte composition are unreliable [8]
Duodenum
The duodenum is the widest part of the small bowel. It is shown, using non-absorbed markers in healthy subjects, that
20–25 cm long and extends from the pylorus to the duodeno- about 4.0 L of endogenous secretions pass the duodeno-
jejunal flexure. In its structure it is essentially the same as jejunal flexure daily. This quantity is made up of about 0.5 L
the jejunum in that a villus structure starts absorption, but it saliva, 1–2 L gastric juice [6] and 1.5 L of pancreatico-biliary
contains submucosal bicarbonate-secreting glands of secretions (0.6 L is pancreatic juice [7]). Thus, each day
Brunner. The alkaline secretion from these glands helps to about 6 L of chyme pass the duodeno-jejunal flexure. The
neutralize the gastric acid and provide a pH closer to the process of digestion usually adds further secretions in the
optimum for pancreatic enzymes to work. In the second part upper jejunum, increasing the flow still further until the mid
of the duodenum, alkaline pancreatico-biliary secretions are jejunum when absorption comes to predominate and flow
added to the chyme. The pancreatic enzymes are responsi- decreases progressively until only 1–2 L enter the colon
ble for breaking macronutrients (protein, carbohydrate, lipid (Table 1).
and nucleic acids) into smaller molecules (peptides, oligo/
disaccharides, fatty acids/glycerol and nucleotides). Bile
contains bile salts that aid lipid digestion and absorption; it Jejunum and Ileum
also contains some end products of metabolism such as hae-
moglobin, cholesterol and some drugs. Bile is concentrated The proximal two-fifths of the small bowel is called the
by the 7–10 cm long gallbladder which can hold 30–50 ml jejunum, and the distal three-fifths the ileum. The jejunum
of fluid [1]. When lipid-containing chyme is within the duo- diameter is 4 cm, and that of the ileum 3.5 cm. The small
denum, the gallbladder contracts and the sphincter of Oddi intestinal absorptive area is vastly increased by the villi,
relaxes so that concentrated gallbladder bile is secreted into there being 20–40 per mm of small bowel [1]; villi are lon-
the duodenum. ger and more numerous in the jejunum than in the ileum
(Fig. 2). The endothelial cells that line the villus are made in
the crypts and migrate to the villus tip from where they are
Volume of Gastrointestinal Secretions shed; these cells have a life span of only 2–5 days. The jeju-
num has many circular folds and is thicker, more vascular
The work of Borgström et al. [4] and Fordtran and Locklear and muscular than the ileum but it has few lymphatics. The
[5] provides an estimate for the daily volume of intestinal ileum has few circular folds and it contains many lymphoid
secretions when a normal diet is consumed. They have follicles [1].
a b
Fig. 2 Histological full-thickness sections of (a) stomach, (b) jejunum, (c) ileum and (d) colon. Kindly provided by P Domizio
Length of the Small Intestine distension leading to overall shortening. The bowel may
also be apparently shortened when measurements are made
The normal human small intestinal length from the duodeno- after passing a small flexible polyvinyl plastic tube through
jejunal flexure to the ileocaecal valve as measured at the nose to the caecum [20] as this causes the bowel to con-
autopsy, by a small bowel enema or at surgery varies from certina around the tube [24]. The differences in length
160–1510 cm (Table 2) [9–22] and is shorter in women and between fully stretched small bowel and non-stretched
in most studies correlates with height. The full intestinal small bowel and between fully stretched small bowel and
length is achieved by 10 years of age [9]. Congenital cases laparoscopic bowel was 137 ± 19 cm and 32.4 ± 11.4 cm,
of patients having problems due to a short length of intestine respectively [19].
have been reported [23]. Radiological measurements of An appreciation of the wide range of normal small intes-
small bowel length give shorter results than those obtained tinal length is important and emphasizes the need, after a
at autopsy or surgery, partly because radiographs are only in bowel resection, to refer to the remaining length of small
two dimensions. A small bowel enema [21, 22] causes bowel intestine rather than to the amount resected.
Table 2 Measured lengths of small intestine from the duodeno-jejunal igestion and Absorption in the Small
D
flexure in subjects without bowel disease except Ref. 12
Intestine
Small intestinal
length
Water, Sodium and Chloride
Range
Author Date Sex Number Mean (cm)
Autopsy Although some water and sodium may be absorbed before
Bryant [9]a 1924 Both 160 620 300–850 chyme reaches the jejunum in most normal subjects, a meal
M 27 650 460–810 continues to be diluted by secretions at a distance of 100 cm
F 17 590 410–760 distal to the duodeno-jejunal flexure [4, 5]. This distance is
Underhill [10]a 1955 Both 100 620 340–790 clinically important: if a patient has a stoma situated in the
M 65 640 490–790
upper 100 cm of jejunum, the volume that emerges from the
F 35 590 340–720
Hounnou [11] 2002 Both 200 609 280–1000 stoma is likely to be greater than the volume taken by mouth.
M 100 644 365–1000 Such a patient will be in negative fluid and sodium balance
F 100 574 280–840 after any food or drink [25]. Most meals have a low sodium
Hosseinpour [12] 2008 Both 30 633 +/− 90 content (10–40 mmol/L), generating a steep concentration
Surgery gradient between the lumen and plasma. Sodium-rich sali-
Backman and Hallberg 1974 Both 42 660 400–850 vary and pancreatico-biliary secretions raise the luminal
[13]
level, as do intestinal secretions, so that the sodium concen-
M 12 700 500–850
F 20 620 400–780 tration at the duodeno-jejunal flexure reaches about
Guzman [14] 1977 121 525 SD 91 90 mmol/L and increases further towards 140 mmol/L in the
M 83 530 SD 85 terminal ileum [5].
F 38 507 SD 102 Jejunal mucosa is more permeable to water, sodium and
Slater and Aufsesb [15] 1991 Both 38 500 300–780 chloride than ileal mucosa. It allows back diffusion through
M 14 540 330–780 leaky intracellular junctions so the jejunal contents become
F 24 480 300–640
iso-osmolar. Thus water movements in response to an
Nordgren [16] 1997 Both 77 564 360–1090
M 37 534 360–740 osmotic gradient in the jejunum are nine times as great [26]
F 40 591 380–1090 and sodium fluxes twice as great [27] as in the ileum. Sodium
Hosseinpour [12] 2008 Both 100 460 285–620 absorption in the jejunum can occur only against a small
M 54 452 +/− 79 concentration gradient, depends upon water movement, and
F 46 468 +/− 80 is coupled to the absorption of glucose and some amino acids
Teitelbaum [17] 2013 Both 240 506 285–845 [28]. When the small bowel is intubated and perfused with
M 113 533 +/−105 solutions containing different amounts of sodium, absorption
F 127 482 +/− 99
of sodium from the perfusate occurs if its sodium concentra-
Tacchino [18] 2015 Both 443 690 350–1049
M 101 729
tion is 90 mmol/L or more, while secretion of sodium into
+/−85
F 342 678 +/−92
the lumen occurs if the concentration is less. Several studies
Raines [19] 2015 Both 91 999 630–1510 have shown that maximal jejunal absorption of sodium from
(51 M) a perfused solution occurs at a concentration of around
Radiological 120 mmol/L [29–31]. In contrast, the ileum can absorb
Intubation sodium against a concentration gradient, and movement of
Hirsch et al. [20] 1956 Both 10 260 210–320 sodium is not coupled with glucose or other nutrients. The
M 6 260 220–320
ileum is important in conserving sodium and water when the
F 4 260 210–320
Small bowel enema body becomes depleted since, unlike the jejunum, the ileal
Fanucci et al. [22] 1984 M 5 310 260–370 mucosa can increase its sodium absorption in response to
F 5 260 230–280 aldosterone [32]. Some chloride is actively absorbed in the
Fanucci et al. [21] 1988 Both 158 291 160–430 ileum in exchange for bicarbonate.
a
Autopsy measurements from pylorus, all others from the duodeno-
jejunal flexure (duodenum = 25 cm)
b
21 of these patients had small bowel and 4 others colonic Crohn’s dis-
ease but their small intestinal lengths were not different from 13 patients
without Crohn’s disease
Macronutrients brush border immediately before absorption (Table 3).

Intubation studies in healthy subjects have shown that most
The salivary, gastric and pancreatico-biliary secretions polysaccharides, proteins and fats are digested and absorbed
reduce large molecules (e.g. polypeptides, polysaccharides, within the upper 200 cm of the small intestine [4]. The site of
nucleotides) into medium-sized ones (e.g. oligopeptides, oli- absorption of a meal depends upon its nature. Fibre may trap
gosaccharides and nucleosides) within the gut lumen. They water and impede access to the mucosa and/or bind digestive
are not designed to create small molecules (e.g. amino acids, enzymes reducing their efficacy. In general meat and salad
glucose or nucleic acids) as these would be hyperosmolar are absorbed high in the jejunum, while milk and doughnuts
and thus cause water secretion and an osmotic diarrhoea. The are absorbed more distally, after a large amount of water has
final breakdown to small molecules occurs at the mucosal been secreted.
Table 3 Content and function of most upper gastrointestinal secretions

Secretion Content Functions/released/activated by
Saliva α-Amylase Converts starch to oligosaccharides, maltose, maltotriose and α limit dextrins. Needs pH 7,
inactive in gastric acid
Lipase From lingual glands, cleaves MCTG to MCFA/glycerol, active at pH 2.5–6. Irreversibly
inactivated at pH < 2.4 [33]
Gastric juice HCl Denatures protein, kills micro-organisms, activates pepsinogen released by gastrin, food,
cholinergic agents and hypoglycaemia
Pepsin(ogen) Hydrolyses bonds by aromatic amino acids (tyrosine and phenylalanine) and leucine (collagen)
at pH 2–3. Activated by acid
Lipase Cleaves MCTG to MCFA/glycerol, acid stable
Intrinsic factor Binds B12 and the complex is absorbed in the terminal ileum
Gelatinase Liquefies gelatine
Pancreatic Bicarbonate To neutralize acid and provide optimum pH for pancreatic enzymes, released by secretin
juice
α-Amylase Starch to oligosaccharides, maltose, maltotriose and α limit dextrins
Lipase 1 and 3 glycerol/fatty acid bonds hydrolysed, inhibited by acid
Endopeptidases Trypsin(ogen) Cleaves bonds next to arginine and lysine. It is activated by enterokinase an enzyme produced by
duodenal mucosa and by itself. It activates all other pancreatic proteolytic enzymes
Chymotrypsin(ogen) Cleaves bonds by tyrosine, tryptophan, phenylalanine, methionine and leucine. Activated by
trypsin
(pro)Elastase Cleaves bonds by alanine, glycine and serine, activated by trypsin
Exopeptidases (pro) Cleaves bonds by valine, leucine, isoleucine and alanine (contains zinc), activated by trypsin
Carboxypolypeptidase A
(pro) Cleaves bonds by arginine and lysine
Carboxypolypeptidase B
DNA/RNAases Nucleotides to nucleosides
Esterase Cleaves cholesterol esters
(pro)Phospholipase A Cleaves lecithin to lysolecithin
Bile Bile salts (primary/ Bind fat to form globules; then, after lipase has acted, form small micelles which transport the
secondary) lipid to the brush border
Mucosaa Bicarbonate Neutralizes acid generated in process of digestion
Enterokinase Activates trypsin
Disaccharidases Disaccharides to monosaccharides
Maltase Maltose to glucose
Isomaltase Isomaltose to glucose
Sucrase Sucrose to glucose and fructose
Lactase Lactose to glucose and galactose
Trehalase Trehalose to glucose
α-Dextrinase α Limit dextrins to glucose
Exopeptidases
Aminopeptidase Peptides to amino acids hydrolysis starting at amino end
Dipeptidases Dipeptides to amino acids
Nucleosidases Cleave nucleoside to nucleic acid and hexose/pentose
(): the name of the enzyme in its inactive secreted form
a
Mucosal brush border (secretion of glycoprotein enzymes)
Carbohydrate and Protein insoluble lithocholic acid respectively. Most lithocholic acid
is sulphated and amidated and lost in the stool. Normal
Saliva and gastric and pancreaticobiliary secretions break human bile therefore consists of 50% cholic acid, 39% che-
down carbohydrate and protein to oligosaccharides and oli- nodeoxycholic acid, 15% deoxycholic acid and 5% lithocho-
gopeptides. The final stage of carbohydrate and protein lic acid. The individual bile salt pool amounts to 3–5 g that
digestion therefore occurs on the mucosal brush border circulates through the entero-hepatic circulation 5–14 times
where oligosaccharides are broken down to monosaccha- daily. This circulation is important for the action of some
rides and oligopeptides are broken down to amino acids drugs, such as loperamide, that enter it; if the entero-hepatic
immediately before absorption. In the jejunum, glucose and circulation is disrupted (e.g. by an ileal resection) higher
galactose absorption is partly coupled with that of sodium; than normal doses of loperamide are needed for the same
fructose absorption occurs largely via the facilitative trans- effect. Cholesterol also undergoes secretion in the bile and
porter GLUT5. reabsorption in the small intestine, the balance of which has
Protein is digested by enzymes that cleave protein either an important effect on serum levels. Reabsorption can be
at specific points in the middle of proteins, endopeptidases reduced by poorly absorbed plant phytosterols such as sitos-
(pepsin, trypsin, chymotrypsin and elastase), or work sys- terol, which competitively inhibit cholesterol uptake into
tematically from the ends, exopeptidases. Carboxypeptidases micelles [34]. Fibre supplementation reduces reabsorption of
from pancreatic juice start at the carboxyl end while amino- bile salts by increasing ileal contents’ viscosity. Ispaghula
peptidases on the brush border start at the amino end. and pectin are particularly effective, while bran is ineffec-
tive. This is important because bile salt excretion stimulates
bile acid synthesis from cholesterol and hence lowers serum
Lipid cholesterol [35].
Long-chain fatty acids (C14–20) are absorbed and formed
Triglycerides and fatty acids separate into a lipid phase and into chylomicrons which pass via the thoracic duct to the
do not contribute to the osmotic forces that dominate fluid systemic circulation. Medium-chain fatty acids (C6–12) are
flux across the small intestinal mucosa. Salivary and gastric absorbed in the small and large bowel and pass directly into
lipase are active in the gastric juice and start digestion by the portal venous system; they are readily oxidized in the
splitting monoglycerides from triacylglycerol. liver via a carnitine independent pathway.
Monoglycerides combine with bile salts to generate micelles.
Shearing forces around the pylorus are believed to contribute
to emulsification, the process that generates fatty droplets in Nucleotides
the duodenum. This requires agents such as bile salts and
lecithin to lower surface tension, thereby acting like soap and Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)
keeping the droplets in solution. The increased surface area are broken down to nucleosides by pancreatic DNA/RNA
of lipid is acted upon by co-lipase and lipase which cleave endonucleases and exonucleases, which cleave from either
fatty acids from triglyceride mainly at the 1 and 3 positions. the middle or the end of the molecules respectively.
This enzymatic reaction continues as the products (free fatty Phosphodiesterase hydrolyses nucleotides from the 3′ end.
acids and 2 monoglycerides) are immediately bound by bile The resulting nucleosides are split into nucleic acids and
salts to form micelles, allowing them to diffuse to the muco- pentoses by nucleosidases at the brush border immediately
sal brush border for active absorption. There, fatty acid bind- before absorption.
ing proteins allow removal of fatty acids from the micelles,
which then diffuse back into the lumen to solubilize more
lipid. The micelles protect the brush border from the damag- Micronutrients
ing effects of free fatty acids.
The liver makes two bile acids, cholic and chenodeoxy- Vitamins
cholic acid. These are conjugated with glycine or taurine in
the ratio 3:1. The taurine conjugates are more soluble and are Water-soluble vitamins are actively absorbed from the upper
present in a greater amount in people who eat meat than in intestine, with the exception of vitamin B12 which is selec-
vegetarians. Each day, one-third to one-quarter of the pri- tively absorbed from the distal 60 cm of ileum [2]. The fat-
mary bile acids undergo anaerobic bacterial dehydroxylation soluble vitamins A, D, E and K, essential fatty acids and
within the terminal ileum and colon. This dehydroxylation cholesterol do not have specific active uptake mechanisms
takes place at position 7 and results in the formation of the but dissolve in the lipophilic centre of the micelles; this
secondary bile acids, deoxycholic acid and a little relatively allows these hydrophobic molecules to diffuse through the
aqueous chyme to reach the lipid outer membrane of the fully controlled by the liver-derived regulator, hepcidin.
brush border into which these lipophilic substances readily Only a small amount is allowed to enter the circulation,
diffuse. while the rest is bound to apoferritin to form ferritin within a
mucosal cell. This poorly absorbable complex enters the gut
lumen when the mucosal cell is shed and is thus lost from the
Minerals body.
Magnesium
Zinc
Magnesium is an important cation that is a cofactor for many
intracellular enzymatic reactions while its extracellular con- Like iron and calcium, zinc is mainly absorbed in the upper
centration modulates neuromuscular excitability; 50% is in small intestine; blood levels peak 2–3 h after ingestion.
bone. Each day, about 10–20 mmol of magnesium are con- Endogenous, particularly pancreatic, secretions contain sub-
sumed, of which about one-third is absorbed, principally by stantial amounts of zinc. Intestinal luminal levels of zinc fall
a gradient-driven saturable process occurring mainly in the distally as it is actively absorbed, a process facilitated by the
distal small intestine and colon [36]. The proportion absorbed absorption of dipeptides. Once absorbed, it is bound to albu-
varies according to the amount of magnesium in the diet. min and circulating macroglobulin. Excretion is via sweat
When the total dietary magnesium is increased to 24 mmol and in urine and faeces. Zinc absorption is, like that of cal-
in a healthy person only 24% is absorbed, while if the dietary cium, impaired by dietary phytate and oxalate [43].
intake is reduced to 1 mmol 76% is absorbed [37]. The jeju- Geophagia (ingestion of clay) is associated with severe zinc
nal absorption of magnesium, like that of calcium, is deficiency characterized by hypopituitarism and dwarfism
increased by 1,25-dihydroxycholecalciferol [38]. Magnesium [44]. Zinc deficiency is frequent in patients with Crohn’s dis-
in the circulation is 30% bound to albumin. The serum levels, ease as there are excessive faecal losses together with a poor
however, are an unreliable index of magnesium status, and intake [45].
severe deficiency can occur when the serum levels are nor-
mal [39]. Under conditions of magnesium deprivation the
kidney can reduce magnesium excretion to less than Copper
0.5 mmol/day [40]. Aldosterone increases [41] and parathor-
mone reduces renal magnesium excretion [42]. Very little This potentially toxic metal is rapidly absorbed and loosely
magnesium is found in the intestinal secretions (Table 1). bound to albumin. It is rapidly taken up by the liver and
avidly secreted into the circulation bound to caeruloplasmin.
Deficiency is extremely rare; it can cause a microcytic anae-
Calcium mia and twisted abdominal hair. The main clinical problem
in copper metabolism is failure to excrete it adequately.
Of the calcium ingested, 30–80% is normally absorbed, Urine excretion is normally low and the main route of excre-
mainly by active transport in the upper small intestine. The tion is via bile where copper forms a complex with a frag-
transport is facilitated by 1,25-dihydroxycholecalciferol, lac- ment of caeruloplasmin which prevents its reabsorption.
tose and protein. Phosphates, phytates and oxalate form Defective excretion is seen in Wilson’s disease, an autosomal
insoluble complexes with calcium and thus inhibit calcium recessive trait characterized by caeruloplasmin deficiency
absorption. and hence an accumulation of copper in the liver with result-
ing fibrosis.
Iron
Ileocaecal Valve
Normally, only 3–6% of the iron ingested is absorbed; this is
sufficient to replace losses of 0.6 mg/day in men and 1.2 mg/ The ileocaecal valve consists of two semilunar flaps pro-
day in women. Gastric acid dissolves insoluble iron salts and jecting into the lumen of the large bowel at the junction of
facilitates the reduction of ferric iron (Fe3+) present in most the caecum and colon. Two main functions are classically
food to ferrous iron (Fe2+) which can be actively absorbed in attributed to the ileocaecal valve: (1) to control the passage
the upper small bowel. This reduction depends on ascorbic of ileal contents into the caecum, so allowing adequate time
acid, which is actively secreted in gastric juice, and other for digestion and absorption; and (2), more importantly, to
reducing agents in the diet. The amount of iron entering the prevent the regurgitation of caecal contents into the small
circulation via the iron export protein ferroportin 1 is care- bowel [46]. These functions are questionable: in patients
who had had a right hemicolectomy for localized colon These cells, whose microvilli extend into the gut lumen,
cancer, transit of a scrambled egg meal from the small to respond to a range of stimuli including bacteria toxins, pH,
large bowel was qualitatively and quantitatively the same osmolality and lipid, as well as direct contact. Stretch of the
as in healthy subjects [47]. The mean anaerobic bacterial gut wall may also activate tension receptors in the muscle
count in the distal ileum is 104/ml compared with 108/ml in layers. The gut is additionally innervated from the spinal
the caecum; the mean coliform content is 103/ml in the (sympathetic) nerves. There is a complex interchange of
ileum and 106/ml in the caecum [48]. No major episodes of information between the submucosal and myenteric plexus
colo-ileal reflux occur when the ileocaecal valve has been and the brain. The pattern of gastrointestinal motility depends
removed [47], thus the bacterial population in the ileum is upon whether an individual is in a fasted or fed state. The
unlikely to be changed. Ileal peristalsis is probably the electrical activity recorded from the gut does not always cor-
main factor that keeps the number of bacteria in the small respond to the pressure activity.
bowel so much lower than in the colon. The ileum can dif-
ferentiate between liquid and solid but the ileocaecal junc-
tion cannot [49]. Stomach and Small Intestine
Fasting
Colon During fasting, three phases of pressure activity can be iden-
tified: during phase I there is no activity; irregular activity
The average length of the colon at autopsy is about 1.6 m occurs during phase II; phase III is characterized by strong
(range 0.8–3.3) [8, 9, 11], being longer in men than in rhythmic contractions starting in the stomach and spreading
women. The unstretched colon at colonoscopy is much distally. Phase III, also called the interdigestive migrating
shorter at about 0.9 m and its undisturbed volume averages complex or migrating motor complex (MMC), occurs every
551 ml [50]. The colon has many haustra and its longitudinal 90 min (range 50–140) and lasts for 5–10 min in any one
muscle is reduced to three longitudinal bands (taeniae coli) area; it takes about 90 min to reach the terminal ileum.
[1]. It has the functions of absorbing water (up to 6 l/day) Although the MMC shows great regularity in a trained labo-
[51], sodium, minerals (e.g. magnesium and calcium), some ratory dog, in man its frequency and form varies both
vitamins and fermenting unabsorbed non-starch carbohy- between and within an individual [53]. Some MMCs start in
drate to short-chain fatty acids (acetate, propionate and the stomach while the majority commence in the mid-
butyrate). The appendix and terminal ileum may secrete anti- jejunum, many petering out before reaching the terminal
microbial substances to regulate the colonic bacterial flora. ileum. The MMC is strongly propulsive and is thought to be
The functions of the right and left sides of the colon are dif- responsible for clearing the last part of a meal from the stom-
ferent. The right side is mainly involved with water and ach and small intestine, thus having a ‘housekeeper’ function
sodium absorption and with fermentation (to produce short [54]. Loss of the MMC is associated with small bowel bacte-
chain fatty acids and amino acids); the left colon is largely a rial overgrowth [55].
storage and propulsive organ. The colon avidly absorbs Just before the MMC, there is an increase in the concen-
sodium and chloride against a high concentration gradient tration of gastric acid and pepsinogen secreted, followed by
and so normal stool contains very little sodium and an increase in the concentration of secreted pancreatic
chloride. enzymes and bicarbonate [56]. These secretions may be the
Evidence that the colon can absorb nutrients and minerals reason why, even in the fasting state, there is some output
comes from reports dating as far back as ancient Egypt of from a high jejunostomy.
various mixed enema solutions containing such ingredients
as milk, egg, beef broth, wine or brandy being used to give ed
F
nutrition support [51], and from the fact that magnesium poi- In the fed stomach, a wave of depolarization (gastric slow
soning can occur from magnesium sulphate enemas [52]. wave or basic electrical rhythm) is associated with a peristal-
tic wave that starts in the mid-stomach and spreads to the
pylorus every 20 s (3/min). Liquid from a mixed liquid and
Gastrointestinal Motility solid meal starts to empty as soon as it reaches the stomach,
and 50% of 200 ml orange juice consumed with a pancake
The gut is innervated by the vagus nerve (parasympathetic) has left the stomach at 98 min. If the liquid is taken alone, the
which contains 90% sensory (afferent) and 10% efferent rate of gastric emptying is much faster. The solid emptying
neurones. Information travels from the gut lumen to the brain usually occurs in a linear fashion after a variable lag phase
via mucosal free nerve endings and entero-endocrine cells. (usually 20–30 min) during which the meal remains in the
fundus undergoing digestion and dilution by gastric secre- Gastrointestinal Tract

tions. Thus the time taken for 50% of a solid pancake to leave
the stomach is 150 min [57]. The rate of gastric emptying is normally controlled by both
The frequency of the slow wave, which is now thought to neural and hormonal mechanisms so that chyme is delivered
originate in the interstitial cell of Cahal, varies from 12/min into the intestine at a rate optimal for digestion and absorp-
in the jejunum to 8/min in the ileum. Small bowel contraction. There are at least four gastrointestinal sites which,
tions can be segmental or peristaltic (rate 2–25 cm/s), peri- depending on their luminal contents, may affect gastric emp-
stalsis predominating in the duodenum while segmenting tying: the stomach itself, the proximal small bowel, the distal
contractions predominate further distally. Peristalsis can small bowel, and the colon and rectum. Large volume [60],
cause very rapid transit if there is no inhibitory feedback high nutrient density (e.g. lipid-based) [61], hyper- or hypo-
from nutrients; thus water can reach the caecum in 15 min. osmolar solutions [62] or acid [63] meals all slow gastric
Even with nutrients, the first part of a liquid meal can travel emptying. A painful stimulus applied outside the gut will
very rapidly, reaching the caecum in just 14 min for liquid also delay gastric emptying [64], as do various inflammatory
and 24 min for solid [57]. This first sample then excites cytokines released during infections. The upper small intes-
inhibitory feedback responses which slow gastric emptying tine regulates the rate of gastric emptying: studies in dogs
to allow time for digestion and absorption. After the bulk of have shown that the longer the length of duodenum and jeju-
a meal has been emptied from the stomach, ‘fasting’ activity num exposed to glucose [65], acid [66] or lipid (sodium ole-
resumes. ate) [67], the greater the delay in gastric emptying. An
infusion into the human ileum of lipid [68–70], protein
hydrolysate [71] or carbohydrate [72, 73] delays proximal
Colon small bowel transit, and lipid [69, 74, 75] and carbohydrate
[76] also delay gastric emptying. The effect of nutrients in
Most of the time there is segmental contracting non- the ileum in delaying gastric emptying and small bowel tran-
propulsive activity within the colon which allows mixing of sit is referred to as the ‘ileal brake’.
the colonic contents and time for absorption. Several times a Evidence for two mechanisms, one delaying gastric emp-
day, high-pressure propulsive peristaltic waves propel some tying and the other delaying small bowel transit, comes from
of the colonic contents to the rectum (‘mass movement’). experiments which show that intravenous naloxone prevents
Isotope studies have shown that the first part of a meal intralipid infused into the ileum from slowing small bowel
remains in the colon for a median of 31 h (range 24–48). In transit but does not prevent it from slowing gastric emptying
normal subjects most of a meal will have left the bowel [77, 78].
within 3 days of being eaten. Colonic transit is slower in Events within the colon affect the rate of gastric empty-
women [58]. On a Western diet, stool weight is about 200 g/ ing. Balloon distension in the colon or rectum of animals
day. [79–82] and man [83] causes a rapid inhibition of gastric and
intestinal contractions and tone, so delaying gastric empty-
ing and intestinal transit. This is probably the result of a neu-
Controlling Mechanisms ral mechanism as the effect in animals can be abolished by
splanchnic nerve excision [80, 81]. However, there is also a
Appetite hormonal component as balloon inflation of the rectum
causes delayed inhibition of motility in denervated jejunal
Body weight is a result of the balance between food intake loops [82]. When unabsorbed nutrients reach the colon in
and energy expenditure/losses. There are many factors that patients with jejunum anastomosed to colon, there is rapid
control appetite (regulated in the hypothalamus) and thus slowing of gastric emptying [57]; this is probably caused by
food intake (hunger and satiety). They include the hormone raised peptide YY levels [84] and is referred to as the ‘colonic
ghrelin which is the only known orexigenic gut hormone that brake’.
promotes appetite while many anorexigenic gut hormones,
including cholecystokinin (CCK), pancreatic polypeptide
(PP), peptide YY (PYY), glucagon-like peptide (GLP)-1, Gastrointestinal Hormones
and oxyntomodulin reduce appetite. Leptin is another hor-
mone that is secreted exclusively by white adipose tissue adi- A hormone is a blood-borne chemical messenger that has an
pocytes and reduces food intake and body weight [59]. Some identifiable structure, is released in one part of the body and,
bacterial metabolites (e.g. SCFAs which inhibit gastric emp- after passing in the blood stream, has a physiological action
tying) reduce appetite. in another part, even when all neural connections between
the two parts have been severed. It should also be possible to culation in the fasting state. Little gastrin, G17, which is
inject the hormone and induce its physiological effects. mainly found in the gastric antrum, has a t1/2 of 5 min and is
The various gastrointestinal hormones are described here a more powerful stimulus in causing gastric acid secretion.
in some detail not only because they are important in control- Gastrin release is caused by amino acids and peptides in the
ling the activity of the gut but because they are used and may stomach and by vagal nerve stimulation as occurs with hypo-
be increasingly used in the future to treat some patients with glycaemia or hypercalcaemia. Both forms of gastrin are
intestinal failure. Most of the hormones fall into one of two inactivated in the small bowel and kidney, which may in part
families according to their molecular structure: the gastrin explain the hypergastrinaemia seen after an extensive small
family (gastrin and cholecystokinin) or the secretin family bowel resection or in patients with renal failure. Gastrin
(gastric inhibitory peptide, glucagons, secretin and vasoac- stimulates gastric acid and pepsin secretion in the stomach
tive intestinal peptide). The hormones (Table 4), which all partly by causing histamine release from enterochromaffin-
are produced in response to luminal stimuli, have four main like (ECL) cells. Gastrin increases antral smooth muscle
areas of action: (1) to control gastric emptying or secretion activity and may have a trophic effect. Excess gastrin gives
(gastrin and somatostatin); (2) to regulate the rate of diges- rise to the Zollinger–Ellison syndrome which is character-
tion (cholecystokinin, secretin, gastric inhibitory peptide and ized by duodenal and jejunal ulcers [86] and diarrhoea; the
motilin); (3) to slow the rate of gastrointestinal transit (GLP- diarrhoea is the result of malabsorption caused by the excess
1, neurotensin and peptide YY); or (4) to promote intestinal gastric acid inhibiting pancreatic enzyme function and
growth (GLP-2, enteroglucagon and neurotensin). Only micelle formation.
five—gastrin, secretin, CCK, GIP and motilin—are true hor-
mones, the others being better regarded as neuromodulators
with a principally local or paracrine action. The link with the Somatostatin
nervous system is important and many hormones are released
after vagal stimulation (e.g. gastrin, somatostatin, pancreatic Somatostatin has been referred to as ‘endocrine cyanide’ as
polypeptide and VIP). it reduces the circulating levels of all known gastrointestinal
peptide hormones, most anterior pituitary hormones, and
many others (e.g. calcitonin and renin). By endocrine, para-
Ghrelin crine and neurotransmitter actions, it inhibits most gastroin-
testinal functions. It reduces gastric, pancreatic and biliary
Ghrelin is a 28–amino acid peptide hormone, produced secretions [87] and reduces pentagastrin-stimulated salivary
mainly in the stomach and is the only known orexigenic gut flow [88]. It slows small bowel transit, may delay gastric
hormone (increases appetite/hunger and reduces satiety). It emptying, reduces gastrointestinal blood flow and reduces
binds to the growth hormone secretagogue receptor (GHSR) the absorption of carbohydrate, lipid and amino acids.
1a which is highly expressed in the hypothalamus and brain Tumours that produce excess somatostatin (somatostatino-
stem. It has been shown to stimulate appetite in both lean and mas) may give rise to a triad of diabetes, gallstones and mal-
obese humans, and intravenous infusions given to healthy absorption [89].
volunteers, at a concentration similar to that observed after a
24 h fast, increase appetite and food intake by almost 30%.
There is animal evidence that blocking its signaling results in Cholecystokinin
a reduced body weight [85]. Ghrelin levels rise pre-prandially
and decrease to baseline levels within the first hour after a Cholecystokinin (CCK), which was shown to be the same as
meal. pancreozymin in 1966, is rapidly metabolized by the liver. It
acts as a primary regulator of upper gastrointestinal function
as it balances lipid and protein digestion with the rate at
Gastrin which they are delivered to the small intestine. It reduces the
amount of chyme reaching the upper small intestine by caus-
Gastrin exists as two forms produced by the G cells situated ing satiety [90–92] and reducing gastric emptying, while at
in the gastric antrum, duodenum and jejunum. Big gastrin, the same time promoting digestion by causing gallbladder
G34, is found mainly in the duodenum; it has plasma half- contraction and pancreatic secretion [93]. There are two
life (t1/2) of 42 min and is the most abundant form in the cir- types of CCK receptors: CCK-A in the gallbladder, pancreas
Table 4 Gastrointestinal hormones

Amino t1/2
Hormone acids min Main site Released by Main functions
Ghrelin 28 35 Parietal cells of the Fasting (inhibited by food Increase appetite
gastric fundus esp. protein/CHO)
Gastrin 17/34 5/42 Antral G cells Protein Gastric acid secretion
High serum calcium
Pepsinogen secretion
Somatostatin 14/28 3 Antral/pancreatic D Food (especially lipid) or acid Reduces salivary, gastric and
cells in duodenum pancreatico-biliary secretions
Slows gastric emptying
Slows small bowel transit
Reduces portal blood flow
‘Endocrine cyanide’
Cholecystokinin (CCK) 8/33 2/5 Duodenum/jejunum I Lipid and protein Pancreatic secretion (B)
cells Gallbladder contraction (A)
Inhibits gastric emptying
Pancreatic growth
Satiety and memory
Secretin 27 3 Duodenum/jejunum S Acid Pancreatic bicarbonate secretion
cells Starvation Pancreatic growth
Pepsinogen secretion
Gastric inhibitory peptide 42 20 Duodenum/jejunum K Lipid and carbohydrate Inhibits gastric secretion
(GIP) cells Inhibits gastric motility
‘Incretin’a
Motilin 22 4.5 Duodenum/jejunum High-fat meal Alkali Increases gastric and small intestinal
M cells motility
Causes MMC
Pancreatic polypeptide 36 7 Pancreas Hypoglycaemia Gallbladder relaxation
Reduces pancreatico-biliary secretions
(not HCO3)
Vasoactive intestinal 28 <1 Upper small intestine, Intraduodenal acid Relaxes smooth muscle
peptide (VIP) colon Increases blood flow, pancreatic
HCO3 secretion, intestinal secretions
Inhibits gastric secretion
Neurotensin 13 1.5 Ileum N cells Fatty meal in upper gut Inhibits gastric secretion, pancreatic
bicarbonate secretion
Relaxes gallbladder
Villus/crypt growth
Glycogenolysis
Peptide YY (PYY) 36 9 Ileum/colon L cells Lipid or bile salts in ileum/ Slows gastric emptying, small bowel
colon transit
‘Ileal and colonic brakes’
Reduces gastric secretion, small bowel
water/electrolyte absorption
Pancreatic glucagon 29 10 Pancreas A cells Amino acids in duodenum Inhibits pancreatic secretion
Hypoglycaemia Relaxes smooth muscle
Increases blood glucose
Glucagon-like peptide-1 31 4.5 Ileum/pancreas Rapid gastric emptying Inhibits gastric secretion
(GLP-1) Lipid and carbohydrate Inhibits gastric emptying
‘Incretin’a
Glucagon-like peptide-2 33 2.5 Ileum/colon L cells Nutrients in ileum/colon Small and large bowel villus/crypt
(GLP-2) growth
Reduces gastric antral motility
Glicentin 69 NK Ileum/colon L cells Nutrients Villus growth
(“Enteroglucagon”) Slows gut transit
(continued)
Table 4 (continued)
Amino t1/2
Hormone acids min Main site Released by Main functions
Oxyntomodulin 37 12 Ileum/colon L cells Nutrients Reduces gastric and pancreatic secretion
Reduces gastric emptying
Reduce appetite
Incretina
NK not known
a
An ‘incretin’ augments the rise in plasma insulin level after oral glucose
and intestine, while CCK-B predominates in the stomach Motilin

and brain. Only the first eight amino acids are needed for
potency at these receptors. Motilin release from the duodenum and proximal jejunum is
stimulated by a high-fat meal and suppressed by a carbohy-
drate or protein meal [102]. Mixed meals thus have little
Secretin overall effect on circulating motilin levels [102]. In man,
unlike dogs, acid in the duodenum (not alkali) causes its
Secretin was the first of all hormones to be discovered in release [103]. Motilin may inhibit gastric emptying at a high
1902 by Baylis and Starling who observed bicarbonate and but physiological plasma level and promote it at a low level
pancreatic secretions to occur from a denervated pancreas [104]. Motilin probably plays only a minor role in the control
after acid was instilled into the duodenum, and after injec- of normal gastric emptying; for acid infused into the duode-
tions of small bowel extracts [94]. It is released by duodenal num or fat ingestion both delay gastric emptying yet cause
and jejunal mucosa in response to acid (pH <4.5) [95], star- motilin release [102, 103]. Motilin, however, is the only gas-
vation and alcohol. It is metabolized in the vascular system trointestinal hormone that has been shown to increase the
and kidneys. rate of gastric emptying.
Motilin may be responsible for inducing the MMC, as
there is a cyclical rise in plasma levels before the complex
Gastric Inhibitory Polypeptide occurs and an infusion of motilin causes them to occur with
increased frequency [105]. Motilin analogues such as macro-
Gastric inhibitory polypeptide (GIP) was originally thought lide antibiotics (e.g. erythromycin) cause premature phase
to be an ‘enterogastrone’ (a substance from the bowel that III-like intense contractions of the gastric antrum and small
inhibits gastric activity) as it is released by fat, especially bowel. These contractions accelerate gastric emptying and
long-chain fatty acids derived from triglyceride hydrolysis may be used to treat gastroparesis; however, the intense
[96], glucose in the duodenum and to a lesser extent by cramps from the small bowel contractions and diarrhoea may
amino acids. While it inhibits gastric acid secretion (also cause the course of antibiotics to be aborted.
pepsin and gastrin secretion) [97] and gastric motility, these
effects may not be of physiological importance in man [98].
Its main action is probably as an ‘incretin’ for, if GIP is Vasoactive Intestinal Peptide
infused together with glucose, a greater rise in plasma insu-
lin occurs than if glucose alone is infused [99]. It is inacti- Vasoactive intestinal peptide (VIP) acts mainly as a neu-
vated and cleared by the kidney. rotransmitter but has some hormonal actions. It is metabo-
lized locally. It is a powerful smooth muscle relaxant, and
thus systemically causes hypotension, flushing and tachy-
Pancreatic Polypeptide cardia. Its main role may be to increase the blood flow to the
gut following a meal. At high levels it inhibits gastric acid
Pancreatic polypeptide has actions directly opposite to those of secretion while stimulating pancreatic bicarbonate and
CCK. It is released rapidly after a meal but its levels remain intestinal fluid secretion. Tumours producing VIP (vipomas)
raised long after the other hormone levels have returned to nor- were first reported in 1958 and are an extremely rare cause
mal and its role may be to promote the storage of bile and pan- of profuse watery diarrhoea with stool volumes of 2–11
creatic enzymes before the next meal [100]. It is metabolized by l/24 h associated with hypokalaemia and achlorhydria [106].
the liver and excreted by the kidneys. Fasting levels of pancre- Symptoms may respond to injections of a long-acting syn-
atic polypeptide increase with age [101] and this could contrib- thetic somatostatin analogue, which will inhibit VIP
ute to the increased incidence of gallstones with age. secretion.
Neurotensin Glucagon-Like Peptides
Neurotensin is so named because it caused vasodilatation The existence of a bowel source of a glucagon was first real-
and hypotension in the rat; it also increased vascular perme- ized in 1961 when the non-specific antisera for glucagon
ability [107]. It is rapidly broken down into two fragments, detected immunoreactive material in the gut as well as the
each having a long half-life and being biologically active pancreas [123, 124]. The plasma levels of this ‘enterogluca-
[108]. Neurotensin is found in N cells which are located gon’ were determined by measuring total glucagon-like
mainly in the ileal mucosa; few are found in the jejunum and immunoreactivity using antisera to the middle and N-terminal
almost none in the colon [109]. The mechanism of neuroten- portion of the glucagon sequence. Pancreatic glucagon was
sin release is complex: lipid in any form taken orally or measured with specific C-terminal directed antisera. The
administered into the proximal jejunum causes a high and enteroglucagon levels were derived by subtracting the pan-
rapid rise in neurotensin levels, more so than if administered creatic glucagon level from the total glucagon-like immuno-
distally into the ileum [110]. It is probable that fat in the reactivity [125]; This value is higher than the pancreatic
upper small intestine primes the ileal N cells by a neural or glucagon level.
hormonal mechanism so that they can release neurotensin Enteroglucagon, as first described, consists of several dif-
when exposed to this fat [110]. Neurotensin promotes small ferent molecules all derived within the L-cells in the jeju-
bowel growth [111]. num, ileum, and colon, often with PYY (especially in the
distal gut) [114, 115] these include GLP-1, GLP-2, glicentin,
and oxyntomodulin. Glicentin is probably the main molecule
Peptide YY detected as “enteroglucagon”. The greatest concentration of
enteroglucagon activity is found in the ileum and colon (duo-
Peptide YY has structural similarities to pancreatic polypep- denum 15 pmol/g, jejunum 58 pmol/g, ileum 275 pmol/g,
tide. It consists of 36 amino acids with a tyrosine at each end colon 179 pmol/g and rectum 96 pmol/g) [125]; there is none
and hence was called peptide YY [112]. It is distributed in the gastric fundus and antrum. High levels may occur if
throughout the small and large intestine from duodenum to there is a loss of small bowel absorptive surface area, such as
rectum (there is none in the stomach) and increases in amount in patients who have undergone small intestinal resection or
from the ileum to the rectum (concentrations: jejunum jejuno-ileal bypass surgery for obesity [126].
5 pmol/g, terminal ileum 84 pmol/g, ascending colon Much information about the role of enteroglucagon in
82 pmol/g, sigmoid 196 pmol/g and rectum 480 pmol/g man come from the study of a single patient with a tumour
[113]). It coexists in the L cells with GLP-2/enteroglucagon that secreted enteroglucagon; it caused villus hypertrophy
[114, 115] and has a 70% sequence homology with the neu- and increased intestinal transit time [127, 128].
rotransmitter neuropeptide Y. High levels of peptide YY are The structure of human proglucagon (160 amino acids),
observed in situations in which unabsorbed nutrients reach the common precursor from which all glucagon-like mole-
the colon, such as tropical sprue or chronic pancreatitis cules are post-synthetically modified, was determined in
[116], dumping syndrome [117] and after an ileal resection 1983 [129]. The processing of the molecule is different in the
which leaves the colon in situ [84, 118]. Low levels occur in pancreas and intestine. In the pancreas it is cleaved to pro-
jejunostomy and ileostomy patients as their colons have been duce glicentin-related pancreatic polypeptide (GRPP), pan-
removed [84, 118]. creatic glucagon and a large fragment called the major
Peptide YY may be the major hormone responsible for proglucagon-derived fragment (MPGF). MPGF contains
the ileal and colonic brakes [70, 84, 119] which slow gas- GLP-1 and GLP-2. In the intestine proglucagon is cleaved to
tric emptying and small bowel transit when unabsorbed produce glicentin (69 amino acids), oxyntomodulin, both of
nutrients reach the ileum or colon. Although peptide YY is which have glucagon activity and the glucagon-like peptides
stored in the same cells as GLP-2/enteroglucagon, it is (GLP-1 and GLP-2) [130, 131]. It appears that the different
unlikely to exert a major trophic effect on the gastrointesti- molecules are produced preferentially in different sites of the
nal tract [120]. intestine (e.g. GLP-1and oxyntomodulin in the small bowel
An infusion of peptide YY at a level that reproduces and GLP-2 and glicentin in the more distal ileum/colon).
post-prandial concentrations causes a sustained natriuresis,
probably by reducing plasma renin and aldosterone [121]. Pancreatic Glucagon
Peptide YY abolished the flushing associated with a vipoma Pancreatic glucagon consists of 14 amino acids which are in
[122]. the same position as in secretin, thus it can inhibit the pan-
creatic secretory response to secretin. It increases blood glu- tric and pancreatic acid secretion, reduces gastric emptying,
cose by stimulating hepatic glycogenolysis. It is metabolized and is an incretin, suppressing appetite and causing weight
in the liver. Pancreatic glucagon is used therapeutically to loss. OXM binds to both the glucagon-like peptide-1 (GLP-
relax the stomach for a barium study, and is used as a posi- 1) receptor and the glucagon receptor. OXM and GLP-1 are
tive inotrope to treat β-blocker overdoses. Glucagonomas 5–30 min after food ingestion and in proportion to meal
produce a mixture of products and are characterized by energy content. It has a plasma half-life of approximately
necrolytic migratory erythema, weight loss and diabetes. 12 min.
lucagon-Like Peptide-1 (GLP-1)

G Glicentin
GLP-1 immunoactivity is co-localized with glucagon in the Glicentin was named “gli-” for “glucagon-like imunoreactiv-
pancreas α-cells and enteroglucagon in the L cells in the ity” and “-cent-” because it was thought to be composed of
ileum [131]. GLP-1 is secreted at the same time as pancreatic 100 amino acid residues. Later it was found to consist of
glucagon and enteroglucagon [132]. GLP-1 plasma levels only 69 amino acids. Residues 33 to 61 corresponded exactly
rise most when gastric emptying is fast [133]. GLP-1 levels to the sequence of pancreatic glucagon. While this may be
peaked 15 min after a solid meal and 15 min before insulin mainly what was detected as “enteroglucagon”, it may not
[133]. GLP-1 has been shown to stimulate insulin release have a major role in slowing gastrointestinal transit and
[134, 135] and it is a more powerful ‘incretin’ than GIP increasing mucosal growth.
[134]. Agonists are used to treat diabetes. It slows gastric
emptying and reduces gastric secretions and there may be an
effect in promoting mucosal growth so it is used in patients Kinetic Architecture of the Gut
with a short bowel (see Chapter “Pro-adaptive hormones in
the rehabilitation of adult patients with a short bowel”). The proliferative zone is restricted to the basal two-thirds
of the crypt in the small bowel and most of the colon, and
lucagon-Like Peptide-2 (GLP-2)
G to the neck region in the stomach (Fig. 3). A small number
GLP-2 has been synthesized and its receptor characterized of cells at the base of this proliferative zone give rise to all
[136]. Its structure is highly conserved throughout all mam- the other epithelial cells [138] and can be regarded as the
malian species (only 1 amino acid different in the rat). It is an ‘stem’ cells [139]. These stem cells are of great signifi-
enterocyte-specific growth hormone that in mice causes cance as they may be the prime sites for growth control
small and large bowel villus/crypt growth and increases (and the main target for carcinogenesis) since they do not
small and large bowel length and weight. In mice, it also migrate, whereas their daughter cells are transitory and dis-
reduces body weight loss and restores mucosal integrity after posable. Stem cells may divide slowly and be extremely
colitis has been induced with dextran. In pigs, it reduces gas- radio-sensitive; they may also be pre-programmed to self-
tric antral motility [137]. destruct if their DNA template is badly damaged [140]. The
As GLP-2 stimulates mucosal growth, analogues (e.g. daughter cells produced in the stem cell zone migrate up
teduglutide) have been made and given therapeutically to the crypt and undergo three or four ‘transit’ divisions before
patients with a short bowel to promote adaptation (see they leave the cell division cycle and differentiate to take
Chapter “Intestinal Adaptation”). on their functional role for their last few days before being
lost. Cell death can either be a passive process, as in cell
Oxyntomodulin (OXM) necrosis, or it can be the energy-requiring, active, gene-
OXM is named after its inhibitory action on the oxyntic directed, endonuclease-activating process known as apop-
glands of the stomach, it is a naturally occurring 37-amino tosis [141]. Cell loss from the villus tip was once thought to
acid peptide hormone found in the the L-cells in the small be a passive sloughing of cells, but now is considered an
and large bowel, together with GLP-1 and it decreases gas- active apoptotic process.
Fig. 3 Kinetic architecture of the main regions of the gastrointestinal tract. Kindly provided by RA Goodlad and RJ Playford
Crypt Proliferation and oral tolerance of dietary antigens. The importance of this
function is underlined by the fact that diarrhoeal diseases in
Cell division can be divided into four phases, which make up infancy remain the commonest cause of premature death
the cell cycle. Chromosomes can readily be seen separating world-wide. Further evidence of the importance of adequate
at mitosis, which is called the M phase. The daughter cells mucosal immunity is seen in AIDS patients who frequently
then enter the first portion of interphase, the post-mitotic, suffer debilitating wasting and diarrhoea from viral, bacterial
pre-synthetic gap called G1. Cells can either remain in G1 or and protozoal infections. Non-immune defences are also
go on to the next phase of the cell cycle, the S phase, in important; these include salivary lysozyme which attacks
which DNA synthesis occurs. There is then a short, second bacterial cell walls, lactoferrin which chelates iron, thereby
gap phase, known as G2, in which the cell prepares for mito- preventing the growth of organisms that need it, destruction
sis and assembles the spindle proteins. The output of cells of ingested organisms by gastric acid and digestive prote-
from the crypt depends on three main factors: (i) the duration ases, together with exclusion of pathogens by the mucus bar-
of the cell cycle; (ii) the proportion of the crypt involved in rier and effective clearing of gut contents by propulsive
proliferation, known as the growth fraction; and (iii) the size motility patterns. Bile salts and antibacterial peptides
of the crypt. Proliferative activity is not constant: there are secreted from Paneth cells in the base of the crypts, known as
marked circadian rhythms in proliferative activity in the gut. ‘defensins’ are also important, as are antibiotics secreted by
Some of these may be inherent but others appear to be cou- the normal colonic flora.
pled to the food intake pattern several hours previously and
may be more pronounced in the colon [142].
In addition to control of cell production in the crypts, the Organization of the Mucosal Immune System
gut can also increase its cellularity by a process of crypt divi-
sion or fission, in which a crypt can be seen to develop a The mucosal immune system is provided by the gut-
septum at its end; the septum then enlarges until two new associated lymphoid tissue (GALT), which contains
crypts are created. This process is known as the crypt cycle 1010 cells/m and accounts for 80% of the total body immuno-
[143]. Increased crypt fission is seen in the adult after intes- cytes. This tissue can be divided into organized and diffuse
tinal damage [144] and after intestinal resection [145]. compartments. The organized GALT comprises isolated
lymphoid follicles and Peyer’s patches, which are collections
of follicles containing precursors of T- and B-cells, common-
Immunological Functions est in the terminal ileum and proximal colon. These respond
to antigenic stimulation, increasing rapidly on exposure to
The huge surface area necessary for absorption renders the bacteria following birth, peaking in adolescence, and declin-
gut vulnerable to invasion and necessitates a complex series ing gradually thereafter. The diffuse GALT includes immu-
of defences to exclude pathogens while allowing absorption nologically committed T- and B-cells (plasma cells producing
predominantly IgA immunoglobulin) found diffusely Their role is unclear but they are markedly raised in coeliac
throughout the lamina propria and acting as the effector limb disease, a condition in which the T-cell receptors are pre-
of the immune response. dominantly of the γδ type rather than the more usual αβ type.
The significance of this finding is as yet unclear but it appears
to be a marker of disease susceptibility, being found in
Antigen Sampling asymptomatic relatives [149].
Ingested bacteria, viruses and other dietary antigens are

absorbed by specialized M cells that overlie the aggregates Dendritic Cells
of ileal lymphoid tissue (Peyer’s patches). These cells, which
account for about 10% of epithelial cells overlying the folli- Dendritic cells (DCs) are antigen-presenting cells derived
cles, are flattened and specially adapted to rapidly pinocy- from bone marrow precursors and form a widely distributed
tose bacteria and other dietary antigens and pass them to cellular system throughout the body and are especially
macrophages and lymphoid cells that lie within intraepithe- important throughout the intestine. Similarly to the M cells,
lial ‘pockets’ in the M cell. Some bacteria, such as Shigella, they sample gut luminal content, capturing (phagocytosing),
have taken advantage of this process and use the M cell to processing, and presenting antigens to naive T lymphocytes
breach the gut barrier and subsequently spread from entero- to activate them so triggering adaptive immunity.
cyte to enterocyte [146]. Macrophages are the main but not
the sole [147] antigen-presenting cells; they take up antigens
and, after processing them, present them to T-cells bound to Gut Microbiome
class II major histocompatibility complex (MHC) antigens
on the macrophage surface. The T-cells have receptors, struc- The composition of gut microbiota (bacteria, viruses, proto-
turally similar to immunoglobulins, which recognize specific zoa and fungi) is commonly quantified using DNA sequenc-
antigens. They are composed of two subunits, most coming based methods, which may also allow analysis of
monly of α and β type or less commonly of γ and δ type. metabolic potential (using metagenetic analysis). Healthy
These bind to the antigen–MHC complex and are thereby adult humans each typically harbor more than 1000 species
activated, a process facilitated by CD8 or CD4 adhesion of bacteria belonging to relatively few known bacterial phyla
molecules which bind to a constant region of either the class with Bacteroidetes and Firmicutes being the dominant phyla,
I or II MHC molecules respectively. Class II MHC mole- followed by Actinobacteria, and Proteobacteria. An indi-
cules are expressed on antigen-presenting cells (mainly mac- vidual’s microbiome changes rapidly after birth, acquiring
rophages but also some epithelial cells), but class I MHC microbiota from mother and immediate close contacts and
may be expressed by almost any cell in the body. These bind thereafter steadily acquiring adult characteristics during ado-
‘foreign’ or ‘neo’ antigens derived from the cytosol of lescence, becoming quite stable over time in adulthood with
infected or altered cells such as viral antigens or tumour later changes with ageing, at all times showing considerable
products. This process of antigen presentation takes place inter-individual variation. Diet and other environmental fac-
mainly in the dome of the lymphoid follicle, after which tors also affect the composition of the microbiome. The gut
antigen-specific T- and B-cell precursors migrate along the microbe–host interactions have effects on metabolism,
lymphatics to the mesenteric lymph nodes where they mature immune, and neuroendocrine responses. The gut microbiota
and clonally expand. Further migration via the thoracic duct plays a role in nutrient and mineral absorption, synthesis of
allows distribution to the entire gut lymphoid tissue. This enzymes, vitamins (e.g. vitamin K) and amino acids, and the
homing back to the gut depends on the expression of adhe- production of short-chain fatty acids (SCFAs). The fermen-
sion molecules, such as lymphocyte function antigen (LFA- tation by-products acetate, propionate, and butyrate are
1) on the lymphocyte and up-regulation of adhesion important for gut health and provide energy for epithelial
molecules known as ‘addressins’ such as VCAM-1 (vascular cells, enhancing epithelial barrier integrity, and provide
cell adhesion molecules) and ICAM-1 or 2 (intercellular immunomodulation and protection against pathogens. Urea
adhesion molecules), on the endothelial cells in the lym- can be secreted into the colon and there is converted into
phoid follicle [148]. There B-cells differentiate into plasma essential and non-essential amino acids according to the
cells producing immunoglobulin, mostly IgA, while acti- individuals need [150]. Changes in microbiome may relate
vated T-cells act as cytotoxic lymphocytes as well as T-helper to many diseases including IBD, rheumatoid arthritis, anky-
cells facilitating immune response to further antigenic losing spondylitis, type 1 diabetes and obesity.
exposure. Probiotics are live bacteria and yeasts that, when adminis-
Intraepithelial T-cells are predominantly CD8+ (cytotoxic trated in a viable form and in adequate amounts, are benefi-
phenotype) with only 10% being CD4+ (helper T-cells). cial to human health. Prebiotics (microbiota accessible
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Definitions, Classification and Severity
of Intestinal Failure
Key Points Introduction

1. Intestinal failure (IF) may be defined as reduced intestinal
absorption causing malnutrition and/or dehydration. Patients needing clinically assisted nutrition and hydration
2. IF may be classified according to predicted duration as (CANH) (previously termed artificial nutritional support) are
short (type I-acute), medium (type II-prolonged acute) or likely to have one (or more) of three problems: Inadequate
long term (type III-chronic). oral intake, digestive failure, or absorptive (intestinal) failure
3. Further classification is based upon the disease processes, that results in them being referred to a nutritional support
residual anatomy and pathophysiology. This gives five team (NST) (Fig. 1).
groups: extensive small bowel mucosal disease, intestinal
dysmotility, mechanical obstruction, fistula(s) and short Intake (oral) failure is most commonly due to a failure to
bowel/bypass. swallow or anorexia with associated malnutrition. A swal-
4. The severity of IF can be graded according to the type of lowing disorder is most commonly due to neurological
nutritional/fluid support given. problems (e.g. stroke, motor neurone disease, multiple
5. The severity of IF is a continuum and intestinal rehabili- sclerosis, cerebral palsy, trauma, persistent vegetative
tation aims to maximize gut function while using the least state, dementia or Parkinson’s disease) or due to cancer of
invasive route for nutrition/and or fluid support. the head and neck. These patients often have a functional
Fig. 1 Reasons for Nutritional support

nutritional support
Intake (Oral) failure Digestive failure Absorptive (Intestinal) failure

Neurological/muscular Gastric or pancreatico-biliary
problems or cancer problems


36 J. M.D. Nightingale
gastrointestinal tract (distal to the oesophagus) so are with severe IF, whereas the ESPEN definition of II/D com-
appropriate for feeding into the gut (enteral nutrition). prises both the moderate and mild IF, as defined and classi-
Some have an eating disorder (e.g. anorexia nervosa) and fied in the first edition of this book.
some are unable to consume sufficient nutrition/fluid In 2019/20, the England NHS specification used the term
from eating and drinking for other reasons. severe IF for those patients needing PS [6].
Digestive failure may result from the stomach being removed In 2021, the ESPEN definition of IF has been included in
or bypassed or due to a failure of pancreatico-biliary the 11th revision of the International Classification of
secretions (e.g. pancreatitis, cystic fibrosis or pancreatic Diseases (ICD-11: DA96.05 Intestinal failure), which is the
resection/bypass). These patients may benefit from pan- global standard for diagnostic health information [7].
creatic enzyme replacement in addition to oral/enteral For many diseases reference is made to a system failure,
feeding. though sometimes the phrase “failure” is thought to be nega-
Absorptive (intestinal) failure has multiple underlying aeti- tive. Hence other terms including impairment, insufficiency,
ologies. Its definition, classification and severity are dis- inadequacy, injury, deficiency and disease, have all been
cussed below. used and currently the phrase intestinal rehabilitation is used
when possible (e.g. in naming an IF unit). This book keeps
the term IF but considers that it may change in the future.
Definition of Intestinal failure

Classification of IF
In 1981, Fleming CR and Remington M proposed the first
definition of intestinal failure as a “reduction in functioning Expected Duration
gut mass below the minimum amount necessary for adequate
digestion and absorption of nutrients” [1]. Most diseases are first classified based upon expected dura-
In the first edition of this book (2001), intestinal failure tion of illness as acute (short term illness that resolves) or
was defined as” reduced intestinal absorption so that macro- chronic (long term illness that may be progressive). While
nutrient and / or water and electrolyte supplements are this is still true for IF, there are 3 accepted groups: short (type
needed to maintain health and/or growth. Undernutrition 1-acute), medium (type 2-prolongedacute) and long term
and/or dehydration result if no treatment is given or if com- (type 3-chronic). Together short and medium term make up
pensatory mechanisms do not occur. IF was also classified as the acute group of previous classifications [2, 5].
mild, moderate or severe, according to the method by which
nutritional supplementation was given; orally, enterally (by Short term (Type I or acute IF) is usually a self-limiting
tube) or parenterally [2, 3]. condition (e.g. post-operative ileus, enteritis – infective or
In 2005, Jeejeebhoy KN considered IF as when gastroin- from chemotherapy). It lasts for less than 28 days.
testinal function is inadequate to maintain the nutrition and Medium term (type II ot prolonged acute) is a prolonged and
hydration of the individual without supplements being given often more severe condition that is potentially reversible.
orally or intravenously [4]. In his lectures he likens the gut to The patients may be metabolically unstable, requiring com-
an “intestinal orchestra” such that if any one part fails (e.g. plex multi-disciplinary care often in a high dependency unit
stomach liquidizing, pancreas digesting or small intestine for weeks or months. These patients usually have abdomi-
absorbing) then the overall function (absorbing nutrition nal sepsis (often due to perforation/fistulisation), ischaemia
and/or fluid) fails. or intestinal obstruction. This state usually lasts less than
In 2015, the European Society of Enteral and Parenteral 6 months or until reconstructive surgery is performed. This
Nutrition (European Society of Clinical Nutrition and group also includes those who have a resection (e.g. for
Metabolism) (ESPEN) devised recommendations on defini- ischaemia or Crohn’s disease), a temporary short bowel
tion and classification of IF. IF was defined as “the reduction (usually a jejunostomy) so need nutritional support before
of gut function below the minimum necessary for the absorp- electively having bowel continuity restored [3].
tion of macronutrients and/or water and electrolytes, such Long-term (type III or chronic IF) can be due to gastroin-
that intravenous supplementation (IVS) is required to main- testinal resection(s) short bowel (or gastrectomy), gut
tain health and/or growth [5]. ESPEN defined “intestinal bypass (as in the surgery for obesity) or small bowel dys-
insufficiency” (or “deficiency” in those languages where function or a chronic enteritis. The patients are metaboli-
“insufficiency” and “failure” have the same meaning) (II/D), cally stable, requiring nutritional and/or fluid support for
as the reduction of gut absorptive function that doesn’t more than 6 months and often for many years. It is most
require IVS supplementation to maintain health and/or commonly irreversible unless a small bowel transplant is
growth [5]. Therefore, the ESPEN definition of IF coincides performed.
Definitions, Classification and Severity of Intestinal Failure 37
Fig. 2 Classification of IF INTESTINAL FAILURE
Short term Medium term Long term

Type 1-Acute Type 2-Prologed acute Type 3-Chronic
Enteritis Ileus Obstruction Fistula Defunctioned Short bowel Bypass Dysmotility Enteritis
Jejunostomy Jejunum-colon Jejunum-ileum
Table 1 Common underlying diseases causing IF

isease Process, Residual Anatomy
D
Short term
and Physiology
Mucosal Gastroenteritis (includes HIV), chemo or
disease radiotherapy
The second part of the classification is based upon the dis- Dysmotility Post-operative ileus (increased bowel handling,
ease process (also referred to as the patho-physiological pro- saline excess, medication and sepsis), pancreatitis
cess), residual anatomy and physiology. This results in five and metabolic (e.g. low K)
Medium term
major groups: extensive small bowel mucosal disease, intes-
Obstruction Adhesions, neoplasia (includes desmoid) and hernias
tinal dysmotility, mechanical obstruction, fistula(s), and
Fistula Post-operative complications, Crohn’s disease,
short bowel/gut bypass (Fig. 2). A postoperative ileus is the irradiation damage
most common reason for short term IF while a leaking gut/ Defunctioned
fistula is the most common reason for medium term IF. A Long term
short bowel is the most common reason for long-term IF and Short bowel Crohn’s disease, ischaemia (arterial/venous), surgical
complications,trauma, volvulus, neoplasia (e.g.
divides mainly into those with a jejunostomy and those with
desmoid), atresia, gastroschisis or necrotizing
a colon in continuity. enterocolitis
Notes on Fig. 2. Bypass Bariatric surgery, tumor and adhesions
Extensive small bowel mucosal disease is referred to as Dysmotility Myopathy (e.g. chronic intestinal pseudo-obstruction
enteritis and can be a short or a long-term situation. (CIPO)), neuropathy or idiopathic
Mucosal Crohn’s disease, coeliac disease, chronic ischaemia,
Dysmotility is represented in the short term by an ileus
disease irradiation damage, congenital (e.g. microvillus
and in the long term by an enteric myopathy or neuropathy. atrophy) or autoimmune enteropathy
Any medium term condition can become long-term. For
example if defunctioned bowel if not brought into circuit
then the patient will be classified as having a short bowel Severity of IF
(long-term IF).
In other diseases the severity is graded upon a simple mea-
sure (e.g. ejection fraction in cardiac failure, blood gases in
Underlying Disease respiratory failure or glomerular filtration rate/creatinine in
renal failure). There are measures of gut function that include
The third part of classification is naming the specific diseases xylose absorption, fasting plasma citrulline, non-fasting
which can be included in one or more of the disease process/ plasma apolipoprotein A-IV, or percentage energy absorp-
anatomical/physiolocical groups (Table 1) [2, 5]. tion after a test meal (or with a normal diet). The results are
variable and balance studies are laborious and not performed severe IF (or II/D categorized as IF), because PS is pre-
in most units. scribed instead of an otherwise effective oral/enteral support
As no one test has been accepted to grade the severity of [7]. The same may occur when a patient doesn’t comply with
IF, the type/amount of nutritional support is used as a proxy the prescribed drug and/or the dietary advice aimed to
indicator of gut function (Fig. 3). improve the intestinal absorption or to reduce the intestinal
In the previous edition of this book, the severity of IF was losses of fluid, so that PS is required. Indeed, the conversion
graded according to the type of nutritional support given of a patient from PS to oral/enteral nutrition/fluid may vary
severe IF: parenteral nutrition (PN) and/or parenteral saline between units and also may depend upon the expertise of a
are required because health cannot be sustained by exposing unit in maximizing residual gut function. For example, giv-
the small bowel mucosa to more, continuous or altered nutri- ing a mucosal growth factor, establishing complete distal
ents and/or electrolytes; moderate IF: an enteral tube is used feeding by enteroclysis or restricting oral hypotonic fluids in
for the administration of macronutrients and/or a glucose/ patients with a jejunostomy or jejunally feeding a patient
saline solution; mild IF: dietary adjustments, oral nutrients with dysmotility may alleviate the need for PS. Also, the
and/or a glucose/saline solution (or sodium chloride supple- opposite may occur, when units with low expertise in giving
ments) are needed. Patient with mild IF are the most com- PS treat patients with severe IF (or IF) by a scarcely effective
mon group and are often unrecognized. oral/enteral nutrition, so that they are classified as moderate/
An ESPEN one-year prospective study in adults, catego- mild IF (or II/D). Furthermore, some patients may frequently
rized the IF into 5 groups of severity according to the type change their diagnosis and classification depending upon
and the volume of the required PS, (PN volumes of <1, 1–2, whether they are given PS or if it is stopped. Finally, a patient
2–3 and >3 L/day or fluid and electrolyte alone), to be used may change with time, due to compensatory mechanisms,
in clinical practice and research. Clinically an aim for reha- treatment (including growth factors or distal feeding) and
bilitating a patients having PS is to reduce the time over patient compliance, from having severe IF to mild/moderate
which an infusion given, then permit days off the PS before IF (or IF to II/D). For example, a patient who has had a mas-
it is stopped [8, 9] (Fig. 3). sive small intestinal resection, and in whom intestinal adap-
The use of the type of the nutritional support required as tation has occurred, with careful dietary advice and
a proxy of gut function is helpful to define cost, economic appropriate drug therapy may be able to stop PN over
impact, and severity of the disease. However, a grey zone of 6 months to 3 years.
overlapping occurs between the categories, severe, moderate Research is required for a simple and objective indicator
and mild IF (or IF and II/D according to ESPEN). Only to measure the degree of intestinal dysfunction as a contin-
60–80% of patients admitted initially to a UK IF unit for PN uum [10].
ultimately go home receiving PS [9]. This may be due to fac-
tors more related to the management expertise of the profes- Acknowledgements I am grateful to Loris Pironi, Khursheed
sions caring for the patients and to the patient compliance Jeejeebhoy, Ezra Steiger and Mattias Soop for commenting on this
introduction.
with treatment than to the severity of the condition. In some
cases, patients with mild/moderate IF may be categorized as
Fig. 3 Diagram to show the Intestinal Nutrition Water / electrolyte

progression of intestinal Impairment
impairment according to the
route of nutritional support. Mild Oral supplements Oral glucose saline solution
Intestinal rehabilitation Dietary adjustments Sodium chloride capsules
improves the intestinal
function
Moderate Enteral Enteral Intestinal

Rehabilitation
Severe) Parenteral* Parenteral*
*: 5 groups of severity for PS (PN volumes of <1, 1-2, 2-3 and >3 L/day or fluid and
electrolyte alone)
Definitions, Classification and Severity of Intestinal Failure 39
References Daniels J, Serlie MJ, Cooper SC, Poullenot F, Rasmussen HH,

Compher CW, Crivelli A, Hughes SJ, Santarpia L, Guglielmi FW,
Rotovnik Kozjek N, Ellegard L, Schneider SM, Matras P, Forbes A,
1. Fleming CR, Remington M. Intestinal failure. In: Hill GL, editor.
Wyer N, Zmarzly A, Taus M, O'Callaghan M, Osland E, Thibault
Nutrition and the surgical patient. New York: Churchill Livingstone;
R, Cuerda C, Jones L, Chapman B, Sahin P, Virgili NM, Lee ADW,
1981. p. 219–35.
Orlandoni P, Matysiak K, Di Caro S, Doitchinova-Simeonova M,
2. Nightingale J. Definition and classification of intestinal failure.
Masconale L, Spaggiari C, Garde C, Serralde-Zúñiga AE, Olveira
In: Nightingale J, editor. Intestinal failure. London: Greenwich
G, Krznaric Z, Petrina Jáuregui E, Zugasti Murillo A, Suárez-
Medical Media Limited; 2001. p. xix–xx.3.
Llanos JP, Nardi E, Van Gossum A, Lal S. Intravenous supplemen-
3. Nightingale JMD, Woodward J, Small bowel/Nutrition Committee
tation type and volume are associated with 1-year outcome and
of BSG. Guidelines for the management of patients with a short
major complications in patients with chronic intestinal failure. Gut.
bowel. Gut. 2006;55(suppl IV):iv1–iv12.
2020;69(10):1787–95.
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9. Pironi L, Konrad D, Brandt C, Joly F, Wanten G, Agostini F,
In: Matarese LE, Steiger E, Seidner DL, editors. Intestinal failure
Chambrier C, Aimasso U, Zeraschi S, Kelly D, Szczepanek K, Jukes
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p. 25–37.
F, Wu J, Cooper SC, Rasmussen HH, Compher C, Seguy D, Crivelli
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A, Pagano MC, Hughes SJ, Guglielmi FW, Kozjek NR, Schneider
Forbes A, Gabe S, Gillanders L, Holst M, Jeppesen PB, Joly F, Kelly
SM, Gillanders L, Ellegard L, Thibault R, Matras P, Zmarzly A,
D, Klek S, Irtun Ø, Olde Damink SW, Panisic M, Rasmussen HH,
Matysiak K, Van Gossum A, Forbes A, Wyer N, Taus M, Virgili
Staun M, Szczepanek K, Van Gossum A, Wanten G, Schneider SM,
NM, O’Callaghan M, Chapman B, Osland E, Cuerda C, Sahin P,
Shaffer J, Home Artificial Nutrition & Chronic Intestinal Failure,
Jones L, Lee ADW, Bertasi V, Orlandoni P, Izbéki F, Spaggiari C,
Acute Intestinal Failure Special Interest Groups of ESPEN. ESPEN
Díez MB, Doitchinova-Simeonova M, Garde C, Serralde-Zúñiga
endorsed recommendations. Definition and classification of intesti-
AE, Olveira G, Krznaric Z, Czako L, Kekstas G, Sanz-Paris A,
nal failure in adults. Clin Nutr. 2015;34(2):171–80.
Jáuregui EP, Murillo AZ, Schafer E, Arends J, Suárez-Llanos JP,
6. Intestinal failure service specification (A08/S/a). www.england.
Shaffer J, Lal S. Clinical classification of adult patients with chronic
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Service-Specification.pdf.
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7. ICD-11 for mortality and morbidity statistics: DA96.05 Intestinal
10. Nightingale JMD, Small M, Jeejeebhoy K. Intestinal failure defini-
failure. https://icd.who.int/dev11/l-m/en#/http%3a%2f%2fid.who.
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int%2ficd%2fentity%2f778202494.
Clin Nutr. 2016;35(2):536.
8. Pironi L, Steiger E, Joly F, Wanten GJA, Chambrier C, Aimasso
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Part II
Acute (Short and Medium Term Reversible) Intestinal
Failure
Postoperative Ileus
Ian Bissett and Dileep N. Lobo
Key Points lack of passage of flatus or stool and abdominal distension

1. Avoid perioperative fluid overload. from the bowel dilatation. This dilatation of the bowel can be
2. Employ a standard enhanced recovery after surgery identified on abdominal X-ray or CT scan as bowel disten-
(ERAS) protocol. sion with air-fluid levels in the absence of a clear transition
3. Minimise the use of opioids. point to collapsed bowel on CT (Fig. 1). It is generally
4. Utilise minimal access techniques. accepted that there is a period of ‘normal’ or physiological
5. Prevent blood loss. gut dysfunction following major abdominal surgery that
6. Don’t re-operate for postoperative ileus. should resolve spontaneously after a day or two. Prolongation
of this period or the reoccurrence of it after return of normal
function postoperatively have been recognised as Prolonged
Introduction or Recurrent Postoperative Ileus.
Various definitions of PPOI have been proposed in the
In this chapter we will consider the definition and incidence past including the necessity to insert a nasogastric tube after
of this condition, explore the burden of prolonged postopera- surgery, nausea and vomiting, inability to tolerate oral diet
tive ileus (PPOI) on both the patient and the health system, and failure to pass stool or flatus.
describe of the pathophysiology of PPOI and the main risk A novel study from the Netherlands included patients
factors for its occurrence, list interventions that may prevent undergoing elective surgery for colonic cancer and compared
or reduce the occurrence of PPOI and present the evidence scintigraphic studies of gastric emptying on day 1 and
for the treatment of established PPOI. The chapter concludes colonic scintigraphy on days 2 and 3 with specific symptoms
with a proposed management strategy. associated with return of gut function [1]. They showed that
the best measure of return on GI function was the combined
measure of tolerance of solid food and defaecation. This also
Definition and Incidence of Ileus correlated inversely with length of hospital stay. They did
not, however, provide a definition of PPOI but rather consid-
Postoperative ileus is an abnormality of the motility of the ered that all patients had postoperative ileus until both defae-
gastrointestinal tract that prevents the normal ingestion and cation and tolerance of oral food had been achieved.
absorption of food and elimination of waste products. In an attempt to clarify the definition of PPOI, Vather
Symptoms depend on the site of dysfunction. Involvement of et al. carried out a systematic review and global survey
the stomach and proximal small bowel is characterised by amongst those who had recently published in this area [2].
nausea and vomiting while more distal dysfunction results in This study differentiated between normal physiological
bowel dysfunction that follows surgery and when this
becomes pathological as PPOI. Based on this survey they
I. Bissett (*) defined PPOI as the presence of any 2 of the five cardinal
Department of Surgery, University of Auckland,
symptoms on or after day 4 post operatively. These are nau-
Auckland, New Zealand
e-mail: [email protected] sea or vomiting, inability to tolerate an oral diet, failure to
pass flatus or stool, abdominal distension, and radiological
D. N. Lobo
Department of Surgery Gastrointestinal Surgery, Queen’s Medical signs of PPOI. Each of these were carefully defined. This
Centre, Nottingham, UK definition provides not only the essential elements to be
e-mail: [email protected] included but also a timeline for the commencement of

44 I. Bissett and D. N. Lobo
Fig. 1 A 57 year old man a b

seven days following
proctectomy and ileoanal
pouch. (a) A plain abdominal
film demonstrating distension
of the small bowel and
stomach. (b) A coronal
abdominal CT demonstrating
distention of the entire small
bowel with a nasogastric tube
visible in the stomach
PPOI. Subsequent studies have utilised this definition in their This often requires insertion of a nasogastric tube and if it
randomised clinical trials [3–5]. does not resolve quickly intravenous feeding is required.
The incidence of PPOI varies greatly between studies For patients it is frightening, unpleasant and extremely dis-
from 3% to greater than 30% [3, 6]. This variation is likely heartening. PPOI is associated with an increase in hospital
to be explained by the difference in populations included in stay, prolonged intravenous fluid administration and sev-
the studies, whether the data were collected prospectively eral major complications. The most serious and sometimes
and most importantly the definitions used. A recent system- fatal complication is aspiration pneumonia but broncho-
atic review that included 54 studies reported a pooled rate of pneumonia, thromboembolic events, electrolyte imbalance
10% for PPOI. Unfortunately the definition of PPOI dif- and psychological distress are also frequently associated.
fered across the studies with the commonest definition being Recent studies have identified it as the commonest postop-
the reinsertion of a nasogastric tube. They showed that the erative complication after colorectal surgery [9]. This com-
rates varied depending on the definition used [7]. A snapshot plication along with anastomotic leak caused the greatest
study over six weeks in 10 hospitals in United Kingdom increase in hospital stay and total treatment cost following
reported that 22.5% of the patients having a left or right- colectomy [9].
sided colonic resection required nasogastric tube insertion This increased cost associated with PPOI has been esti-
[8]. A very large study out of United States using American mated by Goldstein et al. to be greater than $1.5 Billion
College of Surgeons National Surgical Quality Improvement annually in USA alone [11]. A study utilising the Premier
Program (ACS NSQIP) data for patients undergoing colec- Perspective Database in USA assessed nearly 20,000 patients
tomy identified prolonged postoperative ileus as the most with colectomy. Postoperative ileus was associated with a
common complication, occurring in 10% of the patients [9]. 29% increase in length of stay and a 15% increase in cost
Recent prospective studies using the definition proposed by after adjusting for the influence of all other factors [12].
Vather et al. have identified that more than one patient in
four is likely to develop PPOI following a colorectal resec-
tion [3, 10]. Pathophysiology
The aetiology of PPOI is multifactorial. Its initiation is asso-

urden of Ileus (Effect on Morbidity and Cost
B ciated with activation of inflammatory cells, autonomic dys-
of Stay) function, opioid stimulation of gut opioid receptors,
electrolyte abnormalities, direct injury to the intestine and
Prolonged postoperative ileus has major negative impacts derangement of gastrointestinal hormones. These interac-
on the patient. The patient may initially appear to be pro- tions, triggered by both a somatic and a visceral insult and
gressing well but then develops nausea and abdominal dis- resulting in the final gut dysmotility of PPOI, are summarised
tension. Vomiting follows and the bowels cease functioning. in Fig. 2.
Postoperative Ileus 45
Fig. 2 Pathophysiological basis for the development of a postoperative tide, TNF-α, tumour necrosis factor alpha, iNOS, inducible nitric oxide
ileus. DAMPs, damage-associated molecular patterns; PAMPs, synthetase, ROS, reactive oxygen species [13, 19] with permission [13].
pathogen-associated molecular patterns; VIP, vasoactive intestinal pep-
Table 1 Risk factors and possible mechanisms for postoperative ileus

Risk Factors [6, 14, 16, 18–25]. Adapted from Bragg, et al. [19], with permission
Risk factor Possible mechanisms
Multiple risk factors for PPOI have been identified in ret- Increasing age [6, 24] Reduced overall capacity to recover
rospective analysis of data including; increasing age, male from surgical insult [24]
gender, pre-existing chronic airway disease, increasing Male gender [16] Greater inflammatory response to
perioperative opioid consumption, increasing intra-opera- surgery [21]
Increased pain threshold in males, [18]
tive blood loss and the formation of an ileostomy [6, 14–
resulting in higher catecholamine
16]. These are summarised in Table 1. In a prospective release [22]
study in colorectal surgery patients using a precise defini- Low preoperative albumin Increased oedema and intestinal stretch
tion of PPOI the factors that were independently identi- concentration [16]
fied out of 92 different variables were; male gender, Acute and chronic opioid μ-opioid receptor stimulation reduces
use [6, 14] peristalsis [20, 24]
decreasing preoperative albumin, open or converted tech-
Previous abdominal Increased need for adhesiolysis,
nique (vs laparoscopic), increasing wound size, operative surgery [6] increased bowel handling
difficulty, operative bowel handling, red cell transfusion, Pre-existing airways/ Reduced physiological reserve
intravenous crystalloid administration over postoperative peripheral vascular disease
day 0–3, and delayed first mobilization. These factors [16]
were then combined to create an I-Score that differenti- Long duration of surgery Increased bowel handling [23] and
[14, 16] opioid use
ated between those with a low, intermediate and high risk Emergency surgery [18, Increased inflammatory and
of developing PPOI [17]. 21] catecholamine response; secondary
causes of POI
Blood loss and need for Increased crystalloid administration
transfusion [6, 14, 16] resulting in oedema [25]
Procedures requiring Oedema in abdominal wall muscle and
stomas [21] cut bowel
Prevention of PPOI ing has not been confirmed in other randomised studies [31–
33]. A possible mechanism relating the association of fluid
An understanding of the pathophysiology of and risk factors overload with PPOI is summarised in Fig. 3 [25].
for PPOI as described above provides a foundation for the A recent systematic review of preventive measures for
possible interventions that may reduce the risk of developing PPOI has summarised the different interventions [34]. These
this condition. Many of the advances in the perioperative include early feeding, chewing gum, epidural anaesthetic,
management of patients undergoing major elective abdomi- laparoscopy, peripheral μ-opioid receptor antagonists, proki-
nal surgery potentially impact on the trigger factors for netic agents, non-steroidal anti-inflammatories, and coffee.
PPOI. The advent of Enhanced Recovery after Surgery
(ERAS) protocols has seen a much greater emphasis on opti-
mising the patient’s physiology in the perioperative setting. Early Enteral Feeding
Recent evidence suggests that the ERAS protocol may actu-
ally have an anti-inflammatory effect at both the gut wall and Early feeding has become a central plank of the ERAS path-
mucosal level [26]. Systematic reviews of ERAS have conway, RCT evidence of its efficacy in reducing PPOI is incon-
sistently demonstrated reduced complications and earlier sistent. In the eleven RCTs that were reviewed by Chapman
discharge from hospital [27, 28]. Increased volume of crys- et al. six showed a significant reduction in time to flatus,
talloids in the perioperative setting was an independent risk stool or oral tolerance, two of which also showed a reduction
factor for development of PPOI in Vather’s study and those in length of hospital stay [34]. Early enteral feeding is widely
of VandeHei et al. and Lobo et al., [17, 29, 30] but this find- accepted as beneficial and safe in postoperative management
Fig. 3 Mechanisms for adverse effects of salt and water overload on gastrointestinal function, summarising data from human and animal studies.
(From Chowdhury and Lobo [25], with permission)
of elective abdominal surgery with a likely benefit in hasten- randomised clinical trials, four of which demonstrated an
ing the return of normal intestinal function. improvement in gastrointestinal function using a combined
upper and lower GI function measure [42–45]. At present it
Chewing Gum is only available in USA in restricted centres but it has the
Chewing gum in the immediate postoperative period has the potential to mitigate the opioid-related gut dysmotility that
potential to stimulate salivation, swallowing and gastrointes- so often impairs postoperative recovery.
tinal hormones. A systematic review of eleven randomised
studies has assessed this intervention in promoting intestinal
recovery after surgery. There was no significant reduction in Prokinetic Agents
time to normal oral intake or time to flatus or stool in the
high-quality studies but five other studies that were prone to Multiple prokinetic agents, although theoretically promis-
bias did have significant reductions in time to pass flatus and/ ing, in practice have mostly been disappointing. However,
or stool. A Cochrane review that included 81 randomised the serotonin 4 receptor agonists, cisapride and mosapride
studies and 9702 participants did demonstrate a reduction in have demonstrated enhanced gastrointestinal recovery [46,
time to flatus and stool but no other benefit in terms of toler- 47]. Cisapride has been withdrawn because of its significant
ating food or shortening length of stay [35]. The reviewers cardiac side-effects, but other Serotonin 4 receptor antago-
state that most of the included studies had a high risk of bias. nists, such as prucalopride are under investigation.
Chewing gum has little risk of causing harm and may be ben-
eficial in reducing the time to return of normal intestinal
function. Non-steroidal Anti-Inflammatory Drugs
A systematic review that identified 10 RCTs comparing non-

Epidural Anaesthetic steroidal anti-inflammatory drugs (NSAIDs) with placebo in
the perioperative setting found that those receiving NSAID
There is robust evidence provided in a Cochrane review passed both flatus and stool earlier, and tolerated a diet
including more than 20 studies and over 100 patients that sooner than those receiving placebo [48]. The possible role
epidural anaesthesia leads to a decrease of time to passage of of NSAIDs in anastomotic leak needs to be considered when
stool and flatus in patients undergoing open surgery, but that deciding on the use of these agents. The studies addressing
there is no decrease in nausea and vomiting in the first post- this are conflicting, but to date the selective COX-2 inhibi-
operative day [36]. The evidence for a benefit in laparoscopic tors have not been implicated in increasing the risk of this
surgery is however much less clear. A large retrospective complication [49].
case matched study of US data found that in laparoscopic
colorectal surgery epidural is associated with longer hospital
stays, higher expense and a greater risk of urinary tract infec- Coffee
tions [37]. The benefits of epidural anaesthesia are probably
limited to those undergoing open surgery. Coffee has been proposed as an agent to reduce postopera-
tive gut dysmotility. A randomised clinical trial comparing
decaffeinated coffee, caffeinated coffee and water in the
Laparoscopy postoperative period demonstrated accelerated passage of
stool and tolerance of solid diet in the decaffeinated group
The laparoscopic approach to surgery has repeatedly been compared with both of the other groups. This suggests that
demonstrated to result in a more rapid return of gastrointes- some component of coffee rather than caffeine may stimu-
tinal function and reduction of PPOI [17, 38]. Randomised late earlier return of normal GI function [50].
studies that have specifically addressed this issue, using gas-
trointestinal transit studies as the outcome, have shown lapa-
roscopy was associated with improved gastrointestinal Treatment of Prolonged Postoperative Ileus
motility [39–41].
Although the interventions above have been associated with
prevention of PPOI, the treatment of an established PPOI is
Alvimopan more problematic. At the outset a precipitating intra-
abdominal complication such as anastomotic leak, intra-
Alvimopan is a peripheral μ-opioid receptor antagonist with- abdominal abscess or mechanical obstruction should be
out central effects. It has been compared with placebo in 5 sought (usually with a contrast enhanced CT scan) and
paracetamol, NSAID medication and tramadol while keep-

ing the amount of opioid analgesia to a minimum. Alvimopan
may also be used if it is available and opioids cannot be
avoided.
Most patients with PPOI will require a nasogastric tube
and this should be inserted if there is recurrent vomiting even
if this is low volume as it may represent an overflow of a very
distended stomach. Distressing abdominal distension may
also be markedly relieved by insertion of a nasogastric tube.
Aspiration with subsequent pneumonitis is perhaps the com-
monest cause of death in those with PPOI and adequate emp-
tying of the stomach is likely to reduce the chance of this
serious complication.
A combined analysis of two placebo controlled, ran-
domised clinical trials of the use of Gastrografin in an estab-
lished postoperative ileus has demonstrated an earlier onset
of oral intake in those receiving Gastrografin [52]. However,
the study of only 108 patients was not able to demonstrate
either a shorter hospital stay or duration of the composite
PPOI definition used in the studies. A potential risk associ-
ated with Gastrografin is the severe, often fatal, pneumonitis
associated with its aspiration and therefore it should only be
Fig. 4 A coronal CT of a 77 Year old male following right hemicolec- used when the stomach is known to be empty.
tomy demonstrating distended small bowel with the distension bowel
distension also involving the anastomosis. Patients’ nutritional requirements need to be considered
as oral intake is not feasible in the context of PPOI. Parenteral
feeding should be initiated by 7 days postoperatively and
treated appropriately if identified (Fig. 4). The foundation of earlier for those presenting with malnutrition to ensure that
treatment of PPOI, however, is conservative and involves the patient does not suffer serious nutritional decline during
optimising the patient’s physiology. The main features of management of PPOI [53]. Prolonged under-nutrition in the
this are: correction of fluid and electrolyte balance, reduction postoperative setting is associated with increased complica-
of opioid administration, decompression of a distended gas- tions and mortality [54]. Provision of 25 kcal/kg and1.5 g/kg
trointestinal tract and ensuring ongoing nutritional require- protein (based on ideal body weight) in the administered PN
ments are met. is likely to lead to an improvement in nitrogen balance [53].
The specific electrolytes associated with PPOI that have The patient should be transitioned back to enteral nutrition as
been reported are hypokalaemia, hyponatraemia, and hypo- soon as tolerated.
calcaemia [51]. Regular monitoring of these electrolytes
with appropriate correction of abnormalities is required.
Often patients will also have a burden of extra fluid leading Summary
to oedema of multiple tissues including the intestinal wall.
Overzealous replacement of fluids must be avoided and this Prolonged postoperative ileus is the commonest postopera-
can be achieved by providing maintenance as isotonic tive complication following colorectal surgery and is associ-
dextrose-saline at a rate of 1–1.25 ml/kg/h and replacing gas- ated with a large burden of expense. Perioperative measures
tric losses with an equivalent volume of balanced isotonic to reduce its incidence include careful avoidance of fluid
crystalloid solution including supplemental potassium. overload, minimally invasive surgical approaches, adherence
Patients in the postoperative setting with PPOI may have with ERAS principles, avoidance of postoperative opioids,
both postoperative wound pain and discomfort associated early feeding and mobilisation postoperatively, non-steroidal
with intestinal distension. The management of this requires a anti-inflammatories and possibly gum chewing and coffee.
careful balance to ensure that the analgesia is adequate to Interventions once PPOI is established are primarily conser-
control the pain without producing opioid-induced intestinal vative aimed at optimising nutrition and physiology. See
dysmotility. This can often be achieved using regular Table 2 prevention and Table 3 treatment below.
Table 2 Prevention
Intervention Strength of evidence Summary of evidence Patient group
Early feeding ++ Early feeding is safe and may reduce time to postoperative gut All
SR recovery
Early mobilisation + Delayed mobilisation is a risk factor for prolonged postoperative All
OS ileus. No consensus regarding optimal mobilisation interventions
Avoidance of opioids + Increased use of postoperative opioid analgesia impairs recovery of All
Large OS gut motility and prolongs length of stay. Minimise opioid analgesia
postoperatively
Minimally invasive surgery ++ Laparoscopic surgery leads to clinically significant reductions in All
SR time to gut recovery and reduces postoperative ileus compared to
open surgery
Avoidance of fluid overload + Perioperative fluid overload may impair gut motility All
RCTs, large OS postoperatively. Restrict IV fluid where possible, using a chloride-
restricted crystalloid
NSAIDs + Use of perioperative NSAIDs reduces time to passage of flatus, All
SR stool and tolerance of diet in patients undergoing open bowel
resection. Role in laparoscopic resection is unclear
Alvimopan ++ Alvimopan improves time to gut recovery and reduces ileus after Open surgery
SR open surgery. It may reduce ileus after laparoscopic surgery. The
cost effectiveness of Alvimopan in an enhanced recovery setting is
unclear
Thoracic Epidural ++ Thoracic epidural reduces time to passage of flatus and stool after Open surgery
SR abdominal surgery. Unproven benefit in laparoscopic surgery
Prokinetics ++ Currently used prokinetics (erythromycin, metoclopramide) are NR
SR unlikely to improve postoperative gut recovery and to reduce
postoperative ileus
Chewing gum +/− Chewing gum is safe postoperatively and leads to small NR
SR improvements in time to gut recovery. Clinical relevance is unclear
Coffee +/− Coffee may improve postoperative gut recovery but the evidence is NR
Small RCTs of low quality
Novel agents (Prucalopride) +/− Serotonin-4 receptor agonists, such as Prucalopride, may reduce Await further
RCTs postoperative ileus and improve time to pass flatus and stool after studies
colorectal surgery
SR Systematic Review, RCT Randomised Clinical Trial, OS Observational Studies, NR Not recommended
Table 3 Treatment
Correct electrolytes + Electrolyte disturbances (sodium, potassium, calcium and All
OS magnesium) impair gut motility and may prolong postoperative
ileus
Balance IV fluids with losses + Maintenance fluid with a balanced crystalloid solution, instead of All
OS 0.9% saline, based on patient hydration status. Replacement of
gastric losses with an equivalent volume of potassium-rich
crystalloid
NG placement if required + Selective use of nasogastric tube for patients with postoperative Selective use as
OS nausea and vomiting for symptomatic relief. Not all patients with required
prolonged postoperative ileus require NGT insertion
Optimize analgesia ++ Opioid analgesia should be used sparingly during postoperative All
OS ileus. Use of paracetamol, non-steroidal anti-inflammatories and
tramadol may be effective
Provide PN if prolonged + Commence parenteral nutrition if patient is unable to tolerate Selective use as
OS adequate oral intake for 7 days postoperatively. Can commence required
earlier if evidence of preoperative malnutrition
Alvimopan +/− Alvimopan reduces the incidence of postoperative ileus after Await further studies
colorectal surgery. Not yet proven to reduce the duration of an
established ileus
Hyperosmolar radiocontrast media + Gastrografin given at the onset of prolonged postoperative ileus Await further studies
(Gastrografin) RCTs may improve time to tolerance of diet and passage of flatus/stool.
Further studies are required
SR Systematic review, RCT Randomised Clinical Trial, OS Observational Studies, NG Nasogastric
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antagonist: results of a multicenter, randomized, double-blind,
Acute Surgical Intestinal Failure. Sepsis
and Enterocutaneous Fistula(s)
Akash Mehta, Carolynne Vaizey, Jeremy M.D. Nightingale,

and Gordon Carlson
Key Points cumstances, fluid and electrolyte absorption, as opposed to

1. Sepsis is the main cause of death in patients with acute nutrient absorption, may be the principal clinical problem.
intestinal failure so must be continually suspected, Most cases of acute intestinal failure are short lived,
detected and treated. require artificial nutritional support for fewer than 14 days
2. Up to 50% of post-operative fistula(s) heal and are managed in non-specialized units. Although the
spontaneously. incidence of acute intestinal failure in these circumstances
3. Oral/enteral feeding can be used in preference to paren- is unknown, it is extremely common, and the vast majority
teral feeding if small bowel effluent is draining adequately of such cases present to and are managed in non-special-
rather than collecting and there is more than 100 cm func- ized units. When an epidemiological assessment is
tional small intestine available. restricted to those cases in which referral to a specialist
4. Definitive surgery for enterocutaneous fistula(s) should intestinal failure unit is made for the management of severe
be delayed until the patient’s condition has been fully acute intestinal failure, the annual incidence of intestinal
optimised. In many cases, notably with fistulation in an failure requiring specialist treatment is slightly in excess of
open abdomen, this involves a delay of 6 months or more 5.5 new patients per million population [2]. This figure may
after fistulation occurred. be an underestimate of the true incidence of acute intestinal
failure associated with intestinal fistula, complex metabolic
derangement or postoperative abdominal sepsis, as many of
Introduction these cases are managed with difficulty in non-specialist
centres.
Acute intestinal failure has been recognized as a specific
clinical entity for many years [1], and occurs when there is a
potentially reversible cause (Table 1). In surgical patients Table 1 Causes of acute intestinal failure. Adapted from Pettigrew and
acute intestinal failure is usually associated with enterocuta- Hill 1984 [16]
neous fistulas, intestinal obstruction and ileus. In these cir- When the gastrointestinal tract is ‘blocked’
Mechanical obstruction
Paralytic ileus
Intestinal pseudo-obstruction
When the intestinal tract is too short
A. Mehta (*) Massive resection
Department of Colorectal Surgery, Intestinal Rehabilitation Unit, Internal or external fistulas
St Mark’s Hospital, London, UK When the intestinal tract is inflamed
e-mail: [email protected] Inflammatory bowel disease
C. Vaizey · J. M.D. Nightingale Severe infective enteritis
Department of Gastroenterology, Intestinal Rehabilitation Unit, Radiotherapy
St Mark’s Hospital, London, UK Chemotherapy
e-mail: [email protected]; [email protected] When the gastrointestinal tract fails to function adequately for other
reasons
G. Carlson
Department of Colorectal Surgery, Salford Royal Hospital, Intra-abdominal sepsis
Northern Care Alliance NHS Foundation Trust, Salford, UK Multiple organ failure
e-mail: [email protected] Acute pancreatitis

54 A. Mehta et al.
Table 2 Criteria for referring patients with acute intestinal failure to a operation. In these cases, ongoing intestinal decompression
specialist unit alongside active nutritional intervention is necessary; this
Persistent intestinal failure beyond 6 weeks complicated by venous may be achieved by insertion of a venting gastrostomy/jeju-
access problems
nostomy or, rarely, a long-term nasogastric tube. Venting
Multiple fistulas within a totally dehisced abdominal wound
Total or near total (<30 cm remaining) enterectomy
gastrostomy/jejunostomy placement is typically achieved
Recurrent venous access problems due to sepsis or thrombosis either endoscopically (PEG or PEJ) or, for gastrostomies, by
Persistent severe abdominal sepsis interventional radiology (RIG); however, specifically in
Persistent nutritional or metabolic problems associated with a high patients with ongoing small bowel obstruction, percutaneous
output stoma or fistula access to the stomach or small bowel may be hindered by the
Any patient with an intestinal fistula beyond the expertise of the presence of dilated loops of small bowel interposed between
referring hospital
the anterior abdominal wall and stomach or jejunum. In these
instances, a long-term indwelling nasogastric tube may be
In the UK, future estimates of the true incidence of severe the only means of achieving and maintaining adequate
acute intestinal failure are likely to become more accurate decompression, but this should obviously not be considered
following the development of specialized integrated intesti- a permanent solution.
nal failure centres for the management of patients (Table 2). The above demonstrates that surgical intestinal failure,
whether type 1 or type 2 (the focus of the remainder of this
chapter), is a serious condition, associated with high rates of
Small Bowel Obstruction mortality, and early nutritional assessment and intervention
is warranted in all such patients.
Small bowel obstruction is usually short-lived and, in most
patients, will only cause type 1 intestinal failure. It is one of
the most common causes of emergency surgery presenta- Aetiology and Pathogenesis
tions and admissions and is mostly managed in non-
specialized units [3], with only a small proportion of patients Acute intestinal failure occurs as a consequence of condi-
transitioning into type 2 intestinal failure and requiring more tions which primarily or secondarily affect the gastrointesti-
specialist input. nal tract (Table 1). Within a specialized intestinal failure unit,
Acute bowel obstruction occurs due to interruption to the the most common underlying condition responsible for
antegrade flow of intestinal contents; the most common intestinal failure is Crohn’s disease (Fig. 1), and the principal
cause of small bowel obstruction in industrialised countries
is postoperative adhesions (70%), followed by malignancy,
inflammatory bowel disease, and hernias. Malignancy and
volvulus are the commonest causes of large bowel obstruc-
tion [3]. 28%
The management of acute small bowel obstruction is well
established and encompasses early contrast-enhanced cross- 42%
sectional imaging, with early consultant-led multidisci-
plinary decision-making regarding surgery (and a possible
role for enteric water-soluble contrast agents).
Although intestinal failure caused by (adhesional) small
bowel obstruction is usually type 1 and therefore short-lived, 6%
2 recent reports on the assessment and management of
(small) bowel obstruction in the United Kingdom and Ireland 7%
have highlighted the relatively low levels of early nutritional
assessment and intervention in this patient category, with 8% 9%
poor nutritional status at admission being an independent
predictor of reduced survival after presentation with small Crohn’s Peptic ulcer
bowel obstruction [3, 4]. In particular, patients not undergo-
Pancreatitis Mesenteric vascular disease
ing immediate surgery to address small bowel obstruction
were less likely to receive parenteral nutritional support [4]. Malignancy Other
In a minority of patients, small bowel obstruction either
recurs early after surgery, persists despite intervention, or Fig. 1 Aetiology of acute intestinal failure in a specialized unit.
cannot be operated on immediately and requires an elective (Adapted from Scott et al. [2])
Acute Surgical Intestinal Failure. Sepsis and Enterocutaneous Fistula(s) 55
Table 3 Aetiology & pathogenesis of enterocutaneous fistula

Surgery
30% Anastomotic leak
Abdominal closure
Serosal tear
44% Obstruction / Stricture (adhesions)
Peri-operative management
Abdominal sepsis
Smoking
Poor glucose control
Low albumin
10% Excessive fluid resuscitation
Disease
Crohn’s
16% Malignancy
Diverticula(s)
Fistula Short Bowel Sepsis Other Irradiation damage
Fig. 2 Clinical problems leading to acute intestinal failure. (Adapted

from Scott et al. [2]) Table 4 Factors indicating an enterocutaneous fistula is unlikely to
close spontaneously
Distal bowel obstruction
reason for acute intestinal failure is the development of an Diseased bowel at the fistula site (e.g. Crohn’s, irradiation or
intestinal fistula (Fig. 2). This population of patients is very malignancy)
different to that seen in most hospitals, because the majority Discontinuity of the bowel ends
of cases (62%) referred to specialized units will require sur- Active disease, foreign body or continuing sepsis/abscess at the site
of the fistula
gical treatment [2].
Mucocutaneous continuity (i.e. bowel mucosa is visible on the
surface of the abdomen)
Short fistula track
Intestinal Fistulas Multiple (complicated) fistulas
A fistula is defined as an abnormal communication between patient is undernourished, septic (as indicated by a low
two epithelialized surfaces. A fistula communicating with a serum albumin or transferrin) or has another systemic prob-
hollow viscus is called an internal fistula and one commu- lem (e.g. cardiac, respiratory, renal or hepatic failure).
nicating with the skin an external fistula. In some cases, The pathogenesis of acute intestinal failure is often multi-
notably when a fistula has developed within an open abdo- factorial and complex. For example, many patients with an
men, there is said to be an “enteroatmospheric fistula”. A intestinal fistula also have an intra-abdominal abscess. In
fistula can be single or complicated. An intestinal fistula is some cases, an intestinal fistula may have developed as a
said to have a high output if more than 500 ml is produced consequence of impaired anastomotic healing because the
in 24 h [5]. anastomosis was constructed within a pre-existing abscess
In non-Crohn’s patients enterocutaneous fistulas most cavity (typically in Crohn’s disease) or in a patient with
commonly develop as a postoperative complication from established sepsis.
either partial breakdown of an intestinal anastomosis or inad-
vertent bowel injury (Table 3). Death from enterocutaneous
fistulas is most commonly due to sepsis (>80% of deaths); Management
other causes of death include electrolyte imbalance (e.g. due
to high fistula outputs), undernutrition, massive bleeding or The initial priorities in the management of the patient with
progression of the underlying disease. Spontaneous closure acute intestinal failure are the correction of electrolytes and
of a fistula may occur within 6 weeks of its first appearance hydration, the detection and management of sepsis, wound
in up to 50% of patients. This tends to occur only in postop- management and pain control (Table 5).
erative fistulation. Table 4 lists some of the factors that make It is important to note that the management of sepsis is of
spontaneous closure unlikely. In the vast majority of such overwhelming importance because inadequately treated sep-
cases a fistula will fail to heal because there is mucocutane- sis is the most common cause of death in patients with com-
ous continuity, distal obstruction or disease at the fistula site. plicated acute intestinal failure. In the management of
Although there is little published evidence, the chance of intestinal fistulas, control of sepsis has been shown to be the
spontaneous closure of a fistula may also be reduced if a major determinant of successful outcome [6].
56 A. Mehta et al.
Table 5 Principles of managing acute intestinal failure Table 6 Principles causes of death in enterocutaneous fistula patients
Immediate Early Sepsis
(minutes-hours) (1–2 days) Late (2–12 weeks) Electrolyte imbalance
Resuscitation Nutrition Anatomy—mapping Bleeding
including water/ – fistula—site/drainage Undernutrition
electrolyte (Na+, – proximal + distal gut Underlying disease
Mg2+) balance − length/quality
– presence and nature of
abdominal wall defect
Treat sepsis Reduce stoma/ Procedure—this should
fistula output preferably be carefully
iagnosis and Management of Abdominal
D
planned and may need to be Sepsis
deferred for at least
6 months There is evidence that intestinal function is impaired in sep-
Wound management Psychosocial Treatment of underlying
sis, as a consequence of mucosal oedema [7], defective
disease
Pain control Mobility enterocyte maturation [8] and down-regulation of nutrient
transporters [9]. When combined with the increased meta-
bolic demand and impaired fuel utilization associated with
sepsis [10], the presence of impaired intestinal function may
iagnosis and Management of Acute
D lead rapidly to a state of cachexia not unlike that observed in
Intestinal Failure advanced malignant disease [11]. In addition, nutritional
support, however aggressive, is unlikely to be successful in
Acute intestinal failure is a complex condition requiring a the restoration of lean body mass in the presence of sepsis
truly multidisciplinary management strategy. Various useful [12]. A major priority in managing the patient with acute
algorithms have been suggested for the different components intestinal failure is therefore to detect and eradicate sepsis.
of such strategies, of which SNAP (Sepsis management, Other factors may also be of importance in the development
Nutritional optimisation, Anatomical mapping, Planning of or maintenance of acute intestinal failure, particularly in the
surgery) is the most popular. It was devised to resemble the setting of critical illness: changes in intestinal motility
ABC of trauma resuscitation, listing the most serious issues undoubtedly occur and although their aetiology is unclear,
in order of importance. Regardless of the mnemonic may cause difficulty with enteral feeding. In general, reduced
employed, the management strategy for patients with acute intestinal motility is observed [13], possibly as a conse-
intestinal and concomitant abdominal wall failure should quence of impaired absorption of fluid, altered nervous and
always address the management of sepsis, wound care, nutri- regulatory peptide control of motility patterns [14], decreased
tional support and optimisation (including the management intestinal blood flow [15], and bacterial colonization of the
of high fistula/stoma outputs), intestinal mapping, prehabili- small intestine (which may itself develop as a consequence
tation and surgical planning. of impaired motility [16]). In addition, handling of the gut at
Intravenous correction of electrolytes and hydration is an surgical operation may result in ileus because of the develop-
immediate and potentially life-saving priority for these ment of an inflammatory response within the intestinal mus-
patients. Ongoing control of hypotonic fluid intake is usually cle [17]. Finally, other factors that may contribute to impaired
required for high output fistulas and stomas. motility are pulmonary and liver disease and centrally acting
As stated above, the management of sepsis is of over- sedative and narcotic drugs [18]. The net effect of these
whelming importance because inadequately treated sepsis is changes, which may disturb gastric and colonic motility to a
the most common cause of death in patients with compli- greater extent than small intestinal motility, is to cause
cated acute intestinal failure (Table 6). In the management of abdominal distension, nausea and vomiting.
intestinal fistulas, control of sepsis has been shown to be the The diagnosis of sepsis should be entertained in any
major determinant of successful outcome [6]. patient with a history of gastrointestinal surgery who is fail-
Table 7 Markers of hidden sepsis

1. Pyrexia (often absent in malnutrition)
2. Tachycardia
3. Raised inflammatory markers
• WBC, Platelets
• CRP
• Ferritin/B12
4. Persistent hypoalbuminaemia
5. Abnormal liver function tests (jaundice)
6. Hyponatraemia
7. Low phosphate
8. Failure of muscle mass to increase with nutritional support
ing to make satisfactory progress (Table 7). Failure to

respond to adequate nutritional support is a classical sign of
Fig. 3 CT scan showing intra-abdominal abscess (arrowed)
sepsis. The classical picture of a high white cell count and
high CRP may not be present but more subtle signs of raised
platelets and low ferritin and B12 should be heeded. Although
swinging pyrexia, leucocytosis and abdominal signs are clas-
sical features of sepsis, they are not invariably present, espe-
cially in malnourished patients. Hypoalbuminaemia,
hyponatraemia, hypophosphataemia or unexplained jaundice
may be more subtle signs of abdominal sepsis and should
lead to a careful search for a septic focus. In some cases this
may prove to be within the chest or urinary tract or may
relate to central venous lines but the abdomen should be sus-
pected whenever abdominal surgery has been performed.
Whilst ultrasound may be of value in the detection of sub-
phrenic or pelvic collections this may be difficult to perform
in the presence of large abdominal wounds, stomas and
drains [19]. A plain chest radiography may show elevation of Fig. 4 CT scan showing percutaneous drainage (arrowed) of intra-
the diaphragm and basal collapse with a ‘sympathetic’ pleu- abdominal abscess shown in Fig. 3
ral effusion indicative of a subphrenic abscess.
Computed tomography (CT) is, in general, the most effec- but it will not lead to the resolution of sepsis unless com-
tive imaging modality (Fig. 3) and, if combined with oral bined with treatment of the abscess cavity itself. Fortunately,
contrast, will distinguish intra-abdominal or pelvic abscesses it is increasingly possible to use percutaneous drainage of
from immotile, fluid-filled loops of bowel [20, 21]. The diag- abscesses under radiological guidance because of improved
nostic accuracy of CT scanning in abdominal sepsis is of the imaging and drainage techniques. As abscess cavities
order of 97%. enlarge, they tend to assume a globular shape and push
Especially when intestinal failure first becomes apparent, neighbouring structures aside [21]. Large drains (8–10 F)
patients may be profoundly septic. The compulsion to “jump can be inserted into abscess cavities under local anaesthetic
in” in an attempt to surgically address the underlying issue (Fig. 4). Drains can also be upsized under local anaesthesia.
(especially in case of iatrogenic intestinal failure) may lead If more than one drain is inserted simultaneously, the cavity
to further enteric injury and loss of intestinal mass. Every can be irrigated regularly with saline to ensure adequate and
attempt should be made to manage sepsis with a combination prolonged drainage. Often, the drains are kept in place and a
of antimicrobial treatment and targeted percutaneous (radiocontrast study performed through one of them to ensure that
logical) drainage procedures, with due consideration given the abscess cavity has collapsed prior to drain removal.
to targeted and careful surgical drainage procedures for clini- Increased size of percutaneous drains and the ability to
cally significant collections not amenable to radiological insert multiple drains and irrigate means that the need for
drainage [5]. surgical exploration has markedly reduced.
Once a focus of abdominal or pelvic sepsis has been diag- However, in some cases, percutaneous drainage of
nosed, prompt drainage is mandatory. Antibiotic therapy abscesses is likely to be ineffective. This is particularly likely
may be of value in the management of patients with sepsis where there is discontinuity between the bowel ends, or a CT
58 A. Mehta et al.
scan has shown multiple interloop abscesses, and where the

pus is of particularly thick consistency (for example in
infected pancreatic necrosis). In such cases surgical explora-
tion may be required, especially if sepsis persists or deterio-
rates. Intestinal manipulation should be kept to a minimum
and the surgical exploration should be aimed at drainage and,
in some cases, exteriorization of the proximal bowel.
Where intra-abdominal contamination is severe and sep-
sis continues, with further collections of infected fluid, or
where the underlying focus of sepsis cannot be removed (for
example in necrotizing pancreatitis), further attempts to deal
with sepsis are necessary. A variety of approaches have been
advocated, including radical peritoneal debridement [22],
and continuous postoperative peritoneal lavage [23], neither
of which has been shown to be effective. Other options Fig. 5 Newly-created laparostomy wound
include repeated laparotomies, either on demand or as
planned procedures. Controlled trials of repeated planned
laparotomy for severe abdominal sepsis have not shown that
it improves survival and the therapeutic value of each succes-
sive operation diminishes with an associated risk of intesti-
nal injury, leading to secondary intestinal fistula formation
[24–26].
An alternative approach in such cases is to leave the abdo-
men open and fashion a laparostomy. As discussed in more
detail in the “Abdominal Wall Repair in Intestinal Failure”
chapter, although laparostomies have a role in damage con-
trol settings (primarily trauma and mesenteric ischemia),
they are to be avoided in other settings [27–29]. Moreover, if
the abdomen is left open at the index operation, there must
be a definitive plan to achieve delayed primary fascial clo- Fig. 6 Laparostomy wound after 6 weeks, showing viscera covered
sure [29]. The open abdomen is fistulogenic; moreover, lapa- with dense granulation tissue
rostomies create a significant problem for the future with the
formation of a giant incisional hernia, which is difficult to In the (hopefully rare) instances that an abdomen is left
repair with good outcomes and low morbidity. open, the laparostomy (Fig. 5) is allowed to heal by second-
Although there are many strategies to avoid having to ary intention and, initially, fistulating loops of bowel become
leave the abdomen open and/or to achieve delayed fascial fixed within a dense mass of granulation tissue (Fig. 6).
closure, the technique of choice is that of mesh mediated fas- Intestinal continuity can generally be safely established by a
cial traction (MMFT) combined with negative pressure further laparotomy undertaken 6 months later when the peri-
wound therapy (NPWT) [27–29], as described in more detail toneal cavity has become re-established [30]; the best indica-
in the “Abdominal Wall Repair in Intestinal Failure” tion of this is prolapse of the fistulating bowel segments
chapter. (Fig. 7) [5].
stoma care products including fistula isolation may be

employed to avoid repeated leakages. In some cases, it may
be necessary to undertake a limited surgical exploration,
simply to exteriorize a loop stoma proximal to the fistula. A
period with a well-fashioned high output proximal loop
stoma is usually preferable to an unmanageable fistula.
Intestinal failure is often accompanied by abdominal wall
failure which, especially in the presence of enteric fistulas,
poses significant challenges to patients, family and nursing
staff. Mortality is especially high in patients who fistulate
within an open abdomen (enteroatmospheric fistulas), par-
ticularly because of the difficulties in controlling abdominal
sepsis. The development and application of a custom-made
wound management system (traditionally by tissue viability
and stoma care nurses) is an often laborious and time-
intensive process, but crucial to avoid further wound break-
down and ongoing low-grade sepsis in the abdominal wall.
Nutritional Support and Optimisation
Early nutritional intervention in these often catabolic patients

is essential in order to prevent and mitigate further decon-
ditioning and encourage wound healing as well as increase
the likelihood of spontaneous closure of enteric fistulae and
increase the success rate of further major surgical procedures
whilst limiting the associated morbidity. Although a substan-
tial proportion of patients will require parenteral nutritional
support, efforts should be made to explore the possibilities of
enteral feeding, supplemented by enteroclysis/fistuloclysis
(“distal limb feeding”) [5, 31].
Fig. 7 Prolapse of a fistula within a completely healed laparostomy
wound High stoma and fistula outputs should be assessed in the
context of the patient’s intestinal anatomy and any intra-
abdominal sepsis. Once the latter has been sufficiently
Wound Care addressed, management of the high output state should focus
on addressing not just the volumes, but also the nature of oral
In the presence of an intestinal fistula, maintenance of skin intake and include the use of antimotility and antisecretory
integrity is of major importance and should be considered at medication (Table 8) (see Chapter “Management of a high
an early stage. The output of intestinal fistulas, particularly output stoma, jejunotomy or uncomplicated enterocutaneous
from the proximal gastrointestinal tract may be massive and fistula”).
if inadequately controlled, may cause widespread skin In general, the aim of nutritional support in the patient with
destruction. It is important therefore to involve a stoma nurse acute intestinal failure is to provide at least basal requirements
specialist in the care of such patients. Fortunately, a wide of energy and nitrogen until normal diet can be tolerated.
variety of stoma and fistula appliances are presently avail- Nutritional intervention should be considered whenever [32]:
able (see Chapter “Care of intestinal stoma and enterocuta-
neous fistula(s)”). Large Eakin bags can be cut to suit the • Starvation for longer than 5 days is expected or has
shape of the abdominal wall and, when combined with suc- occurred, whether as a result of impaired intake or gastro-
tion catheters and Stomahesive® paste, will control the vast intestinal disease.
majority of fistulas. In certain cases it may be almost impos- • The underlying disease has led to an increase in nutri-
sible to adequately control the output of a fistula. This is, for tional requirements beyond that which can be provided by
example, likely to be the case where a high output fistula has a ‘normal diet’.
developed in the base of a deep or an irregularly shaped • Nutritional depletion already existed prior to the onset of
wound or in a large area of granulation tissue. Improved acute gastrointestinal failure.
60 A. Mehta et al.
Table 8 Therapy to reduce a stoma/fistula output given to the possibility of distal limb feeding by enterocly-
Drink little hypotonic fluid (up to 1 L/24 h) sis/fistuloclysis [5, 31].
Drink a glucose-saline solution (sodium 90–120 mmol/L, up to The decision regarding optimal route of nutritional sup-
1 L/24 h) port also depends on the length of small bowel still in circuit.
Drug therapy – antimotility – loperamide up to 40 mg qds Although this can be more accurately assessed on contrast-
– codeine phosphate up to 60 mg
qds
enhanced cross-sectional imaging, the aspect (colour and
– antisecretory – omeprazole 40 mg bd (titrate soconsistency) of fistula effluent often provides clues as to the
stomal pH >5) length of upstream small bowel and the preferred route of
– occasionally octreotide 50 μgm bd
nutrition.
Magnesium – oral magnesium aspartate or In patients with an estimated small bowel length of
correction oxide, or topical magnesium
<50 cm upstream of a fistula, parenteral nutrition will be nec-
chloride
– hexahydrate spray essary to ensure adequate nutritional support; in patients
– 1 alpha cholecalciferol with >100 cm, enteral support may be sufficient, although
Nutrition – low fibre/residue diet this may need to be supplemented by intravenous fluid/elec-
trolyte supplementation.
Therefore, the traditional treatment of enterocutaneous
The vast majority of patients with acute intestinal failure fistulas of almost exclusive TPN + NBM may no longer be
will require nutritional support. In many cases with a short- appropriate in a substantial proportion of patients; in the
lived period of intestinal failure (e.g. ileus), this will only be early stages of fistulation, TPN may be appropriate but may
necessary until intestinal function has returned to normal. be replaced by enteral nutrition once a fistula track has
However, in patients with severe acute intestinal failure asso- become firmly established.
ciated, for example, with a proximal intestinal fistula, nutri-
tional support is likely to be required until the fistula has
closed spontaneously or until optimal conditions for surgery Enteral Nutrition
to close the fistula have been achieved. In the case of the
patient with a combination of a fistula and an open abdomen, As a general principle, the enteral route should be used for
this may take more than 6 months and under these circum- nutritional support whenever possible. Enteral feeding is
stances it may be appropriate, in an otherwise fit individual safer, more physiological, may preserve intestinal mucosal
with satisfactory home circumstances, to discharge the integrity and is certainly far less expensive than parenteral
patient with a suitable regimen of artificial feeding, pending nutrition. There is no evidence to suggest that enteral nutri-
definitive surgery. The decision regarding the optimal route tion is inferior to parenteral nutrition in the maintenance of
of nutritional support (enteral versus parenteral) depends on nutritional status or in allowing the spontaneous closure of
the developmental “stage” of a given enterocutaneous fistula enterocutaneous fistulas, provided enteral feed can be deliv-
and the length of proximal small bowel (Fig. 8). ered to healthy intestine [33]. In acute intestinal failure, how-
In general, the presence of a complex fistula with an associ- ever, enteral feeding may be impractical or inappropriate.
ated cavity is usually a contraindication to enteral feeding, and Although postoperative ‘ileus’ generally affects predomi-
successful enteral feeding requires an adequate length of healthy nantly the stomach and colon, rather than the small intestine,
bowel above the fistula track without an associated abscess. the resulting abdominal distension may cause intolerance of
There is some anecdotal evidence to suggest that, in enteral feeding, with nausea and vomiting. One study of
patients who are well nourished, the time to maturation of a aggressive early postoperative enteral feeding after upper
fistula track is relatively short, whereas in patients who are gastrointestinal surgery has suggested that the resulting
already undernourished, the process of maturation can be abdominal distension may lead to respiratory impairment
much slower. [34]. Nevertheless, successful enteral feeding has been
There is some evidence that administration of proximal achieved early in the postoperative period [35]. A combina-
enteral feedings even in the presence of a high output distal tion of nasoenteric tube, prokinetic drugs and thoracic epi-
enterocutaneous fistula is of no harm and may help enhance dural analgesia (allowing the avoidance of opiates) may
fistula closure [33]. make enteral nutrition easier to tolerate [36, 37], and studies
Especially in patients with a degree of intestinal have also indicated that enteral feeding may even be safe and
obstruction/stricturing distal to the fistula, a low fibre effective in acute pancreatitis [38]. Enteral nutrition may
enteral support option would be appropriate. In patients prove satisfactory in patients with a low output distal ileal or
without distal obstruction, serious consideration should be colonic fistula but is inappropriate when there is obstruction
Note there is often a stricture of the bowel just distal to the fistula site. Image kindly provided by Dr Simon
Gabe (St Mark’s Hospital) redrawn from Dr Jeremy Nightingale lecture slide.
Fig. 8 Development of enterocutaneous fistulas and consequences for nutrition. (Note there is often a stricture of the bowel just distal to the fistula
site. Image kindly provided by Dr. Simon Gabe (St Mark’s Hospital) redrawn from Dr. Jeremy Nightingale lecture slide)
or a fistula of the upper gastrointestinal tract, unless access nutrition, an inability to tolerate enteral nutrition or altered
can be gained to the gut below the diseased segment. nutritional requirements such as those associated with severe
As stated, consideration should be given to “using” the sepsis or injury.
distal, out of circuit bowel for nutritional support as well as If the anticipated period of nutritional support is fewer
to prevent mucosal atrophy [5, 31]. Distal feeding, either than 14 days, parenteral nutrition can be provided safely via
with enteral feed alone or by chyme reinfusion, requires a peripheral vein. However, the ability to provide TPN for
specialist nursing and dietetic input, as well as quite an prolonged periods via the peripheral route is limited by the
effort on the part of the patient; however, preliminary data development, in many cases, of thrombophlebitis [40]. This
shows that the defunctioned gut, once distally fed, changes can be minimized by the use of lipid-containing regimens
its metabolome and microbiome to that of healthy, in-circuit (which have a lower osmolality than glucose-based regi-
intestine. Limited data also suggests that, in selected patients mens and are therefore less irritant to venous endothelium)
with enough small bowel in situ distal to a proximal fistula, [41], by adding heparin and hydrocortisone to the feed and
distal feeding might reduce the dependence on parenteral by the application of nitrate patches to promote venodilata-
nutrition [39]. tion at the feeding site [42]. While standard intravenous can-
nulae can be used, purpose-designed peripheral feeding
lines, which are of extremely small calibre and made of inert
Parenteral Nutrition polyurethane are available and have been used with success
[41, 43]. Despite these manoeuvres it may not be possible to
For the majority of patients with acute intestinal failure, par- administer more than 3 L of TPN without phlebitis because
enteral nutrition will be the preferred modality of nutritional of the flow rates required in small veins. Central venous
support. This may either be because of the presence of dis- TPN is therefore recommended in patients with large fluid
ease of the intestine, which precludes satisfactory enteral requirements or acutely ill adult patients, who may have
62 A. Mehta et al.
energy requirements greater than 2000 kcal/day. Central grams, tubograms and fistulograms. In Crohn’s disease, full
venous TPN is also necessary where it is evident that a pro- restaging of the disease (both of the small bowel and the col-
longed period of parenteral feeding is likely to be required. orectum) should be considered. Intravenous urography,
For expected relatively short periods of TPN (months rather endoscopic retrograde cholangiopancreatography,
than years), peripherally inserted central venous catheters CT-mesenteric angiography and other mapping modalities
(PICCs) may be used, whilst for patients requiring pro- may also be required, depending upon the anatomy of the
longed (years rather than months) TPN, true central vascu- fistula.
lar access (e.g. Hickmann or Broviac catheters) will be more Taken together, the information gathered from these vari-
appropriate [44]. ous sources forms a comprehensive map of the patient’s
The ability to manage complex cases of acute intestinal anatomy which can be used to guide further management
failure associated with abdominal sepsis or fistulas is, to a and optimisation, as well as to enable adequate planning of
very considerable extent, dependent upon the ability to pro- the definitive surgical procedure(s). Most clinicians have
vide complication-free parenteral nutrition. Irrespective of found it helpful to amalgamate all the information from dif-
the route chosen for venous access, a strict aseptic technique ferent sources and schematically represent these in one sin-
is essential. The lines used for nutritional support should be gle anatomical diagram, which has been useful for other
set aside for this purpose alone and maintained by dedicated healthcare professionals involved in the care of the patient, in
nursing teams according to a strict aseptic protocol. It has determining the challenges to enteral nutrition and to inform
clearly been established that under these conditions, catheter- patients about their own anatomy and what further surgery
related sepsis rates are negligible [2]. would involve. It has also proved useful in planning surgical
procedures. Figure 9 below provides an example of this
schematic representation of the anatomy of a patient who,
Intestinal Mapping after undergoing an abdominoperineal excision of rectum,
underwent a repeat laparotomy due to stoma necrosis and
The anatomy of the digestive tract and abdominal wall is full thickness dehiscence; his abdominal wall defect was
almost always significantly disrupted in patients with acute bridged with an absorbable mesh and unfortunately, he
intestinal failure. These changes will often affect decisions developed multiple enterocutaneous fistulae (ECFs). A CT
regarding nutritional support, the likelihood of spontaneous of the abdomen and pelvis with intravenous and positive oral
fistula closure and, ultimately, the proposed strategy for contrast was performed, followed by a series of fistulograms
definitive surgical procedures. Crucial information regarding to assess the segments of small bowel between the various
the current anatomy of the digestive tract may often be ECFs as well as the distal small bowel, and a water-soluble
gained by meticulous perusal of operative records; this will contrast enema study via his end colostomy to assess the
also often yield valuable information on what, if any, attempts colon.
were made at abdominal wall closure, whether prosthetic A similar approach can be used to document postoper-
mesh was used, and, if so, in which plane and position. ative anatomy, where surgery has deliberately led to tem-
Further mapping of the intestinal anatomy is based on imag- porary intestinal failure and temporary enteroclysis is
ing; in most centres, the mainstay of this mapping is a CT of being considered, as well as to guide further targeted
the abdomen and pelvis with intravenous and positive oral imaging, etc. An example of this is provided in Fig. 10
contrast (supplemented with arterial phase scans for patients below, showing the anatomy of a patient who had previ-
with a history of mesenteric ischemia). In addition, contrast- ously undergoing a partial jejunal resection en bloc with
enhanced studies of those sections of the digestive tract the splenic flexure, an ileocolic resection with a double
which are out of circuit and not amenable to oral contrast barreled ileocolostomy and more recently underwent
enhancement, are often warranted, especially to assess the resection of a fistulating ileal Crohn’s phlegmon; during
patency and length of distal bowel when distal limb feeding this procedure he underwent restoration of continuity of
is being considered and to rule out any distal obstruction his ileocolostomy as well as his left-sided colon, defunc-
which might need to be addressed prior to or during defini- tioned by exteriorising his ileal resection limbs as a dou-
tive surgical management; these modalities include loopo- ble barreled stoma.
Fig. 9 Diagram to show

mapping of a patient with
multiple enterocutaneous
fistulas
Fig. 10 Diagram to show

mapping of a patient with
double barrel (loop) ileostomy
64 A. Mehta et al.
Prehabilitation essential for this relatively small but highly complex group
of IF patients.
Prehabilitation encompasses all of the aforementioned con- Attempts should be made to alleviate any obstructions/
siderations regarding nutrition and wound care, but goes strictures distal to a fistula. For example, a patient with an
beyond these principles in formulating a pathway (quite enterocutaneous fistula proximal to a strictured ileostomy
often personalised) to enable the team and the patient to will benefit from either stoma dilatation or a stoma revision
work towards their common goal of offering the patient a (via a local approach), even if just as a temporizing measure
definitive procedure with the highest possible chance of suc- to mitigate fistula output.
cess with the lowest possible risk of complications. Although Many fistulas (possibly up to 60%) will close spontane-
individualised, basic components of such a prehabilitation ously within 4–6 weeks of supportive treatment. One major
“programme” should include the following: intestinal failure unit has reported 46.4% spontaneous clo-
sure rate with conservative management alone after a median
• Exercise and cardiovascular fitness. follow-up of nearly 2 years, with borderline significant dif-
• Smoking cessation. ference in fistula closure rates between low versus high out-
• Nutritional assessment and optimisation including micro- put fistulas (58.8% vs. 18.2%, respectively) [45]. In addition,
nutrient status and consideration of distal limb feeding epithelialization of the track negatively affects fistula heal-
(also as a trial of integrity of downstream bowel over and ing; long fistula tracks epithelialize slowly and therefore
above radiology). have a greater chance of healing. The range for closure is
• Controlled weight loss (ideally to a BMI of less than 30). estimated 3–90 days and, although closure can still occur
• Acceptable diabetic control (measured by HbA1C levels beyond 90 days, the chances of this are quite small.
with a cut-off point frequently agreed at 7.3% or
56.3 mmol/mol).
• Anaemia and iron status correction. Medical Therapy for Enterocutaneous
• Psychological well-being and preparation, expectation Fistula(s)
management, shared decision making on priorities and
what the patient considers a good outcome. The role of medical agents in promoting fistula closure is
• Assessment of superficial abdominal lipocutaneous tis- controversial. Somatostatin was discovered in 1972 and is a
sues if significant weight loss from when catabolic and naturally occurring peptide hormone. It has an inhibitory
what to do with pannus. effect on gastrointestinal secretion. It is used in the manage-
• Analgesics and opiate weaning preop to provide head- ment of upper gastrointestinal hemorrhage, secretory diar-
room for perioperative analgesia. rhea, dumping syndrome, and peptide-secreting neuro
endocrine tumors because of its antisecretory action. As the
plasma half-life is 1 to 2 min, it must be administered by
Definitive Treatment continuous intravenous infusion. Somatostatin reduces the
secretion of a range of gastrointestinal hormones, including
Once sepsis has been excluded or eradicated and nutritional gastrin and cholecystokinin, which in turn reduce gastric and
and metabolic support initiated, the management of acute pancreatic secretions. In addition, somatostatin reduces
intestinal failure is directed at the underlying cause. Clearly, splanchnic blood flow, reduces the rate of gastric emptying,
definitive treatment will depend upon the exact cause of and inhibits gallbladder contraction. As a result of the short
intestinal failure. In many cases, the cause will be self- half-life, a number of synthetic analogues have been devel-
limiting (for example in paralytic ileus, severe infective diar- oped, and of these, octreotide is used most commonly in the
rhoea or uncomplicated acute pancreatitis) and recovery can treatment of gastrointestinal fistula. Its significantly longer
be expected. half-life allows it to be given by intermittent subcutaneous
Aggressive medical therapy may be required to deal with injection (usually 3 times daily). Despite the similarities, the
the underlying cause in some cases (e.g. high-dose steroid receptor binding properties of somatostatin and octreotide
therapy for Crohn’s disease, or anticoagulation for patients are not identical and their actions may not be equivalent.
who have sustained a mesenteric vascular occlusion because Somatostatin receptors comprise a family of 5 heptahelical
of thrombophilia). Patients who have undergone resections membrane proteins encoded by 5 related genes that map to
due to mesenteric ischemia on a background of thrombo- separate chromosomes. The clinically used somatostatin
occlusive vascular disease may need to be considered for analogues, octreotide and lanreotide, act mainly by binding
arterial revascularization prior to restoration of intestinal to somatostatin receptors 2 and 5 and this may contribute to
continuity. Specialist (endo)vascular input into the MDT is a comparatively less effective outcome (Fig. 11).
Fig. 11 Somatostatin Receptor subtype

receptors subtypes and
affinity of somatostatin and
octreotide for each SSTR 1 SSTR 2 SSTR 3 SSTR 4 SSTR 5
Somatostatin-14 ++ ++ ++ ++ ++
Octreotide – ++ + – ++
+ +, high affinity; +, moderate affinity; –, does not bind
The evidence regarding the role of somatostatin and its Table 9 The risk of mortality and ECF recurrence associated with
analogues in non-pancreatic intestinal fistulas is conflict- reconstructive surgery relative to the last laparotomy
ing and inconclusive at best. Although several small, Early 3–12 weeks 6–12 months >12 months
uncontrolled trials suggest that octreotide (a somatostatin- Mortality 30–100% 7–20% 3–9% 0–3%
analogue) may reduce fistula output and decrease the time ECF recurrence 40–60% 17–31% 10–14% 3%
to fistula closure, the expected effect on fistula closure rate
with somatostatin and its analogues is small, and the effect las are unlikely to close spontaneously if the factors outlined
on more distal fistula outputs is not well established [46, in Table 4 are present.
47]. Although a meta-analysis did show favourable out- Patients who are referred to a specialized unit for manage-
comes with use of somatostatin and analogues in the treatment have usually selected themselves by virtue of the
ment of enterocutaneous fistulas, the studies included in underlying pathology or failure of spontaneous fistula clo-
the meta- analysis were small, with wide variability in sure. The exact nature of surgery required will depend upon
study design and patient characteristics. On balance, it the anatomy and aetiology of the fistula but the general prin-
seems unlikely that octreotide will help fistula closure ciples are as follows: attempts to deal definitively with the
where local factors are in favour of continued fistula fistula should not be made until the patient is well, free from
patency, however, and, in addition, the use of octreotide is sepsis and adequately nourished. Surgical intervention
not supported by the findings of more carefully designed should be planned and is usually delayed. In the case of IF
randomized trials which have failed to show evidence of associated with ECF, early operative intervention to close the
benefit [48–50]. The European Society of Coloproctology fistula is contraindicated by the associated high mortality
consensus statement on the surgical management of intes- due to re-fistulisation, sepsis, malnutrition and difficulties
tinal failure in adults does not support the routine use of with fluid balance [51].
somatostatin and its analogues in patients with enterocuta- Delaying surgery for 6–12 months after the last operation
neous fistulas [5]. has been shown to reduce both the mortality and fistula
Other non-surgical strategies aimed at closure of entero- recurrence rates at subsequent definitive surgery (Table 9)
cutaneous fistulas have been developed and reported, with [45, 52–54].
varying degrees of success. Percutaneous catheter manage- It is desirable to leave at least 6 months between the previ-
ment of abscess-fistula complexes and fistula tracks has ous laparotomy and definitive surgical treatment to allow for
been reported to lead to fistula closure in 57–100% of softening of adhesions within the abdomen. This may neces-
patients, although it is unclear what the criteria for this sitate discharging the patient on home parenteral nutrition.
treatment were and how many of these fistulas would have Re-operative surgery of this nature is extremely technically
closed spontaneously without any intervention. Fistula demanding and adequate amounts of time should be set
track embolization has been reported utilizing a wide range aside. Sharp, rather than blunt dissection is required to avoid
of substances, including fibrin glue, synthetic glues, and tearing the bowel at the site of adhesions and segments of
biological plugs. None of these has been studied in a con- bowel with fistulas should be resected rather than bypassed.
trolled fashion and many have been reported in the success- Intestinal anastomosis should only be attempted if the patient
ful closure of low- output fistulas, where spontaneous is free from sepsis, well-nourished and local conditions are
closure may have been reasonably expected without any entirely favourable. It is particularly important to avoid leav-
intervention. ing an anastomosis within an old abscess cavity as this will
Definitive surgical treatment for acute intestinal failure inevitably lead to re-fistulation. In patients with a jejunos-
attributable to intestinal fistulas will be required if spontane- tomy and an intact colon, consideration should be given to
ous fistula closure does not occur. Internal fistulas will not, in intestinal re-anastomosis, even if it will not prevent the need
general, close spontaneously. External gastrointestinal fistu- for long-term parenteral nutrition. Once intestinal continuity
66 A. Mehta et al.
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Mesenteric Ischemia
Alexandre Nuzzo, Yves Castier, and Olivier Corcos
Key Points for parenteral support, increases survival and quality of

1. Mesenteric ischaemia can be acute or chronic, non- life.
occlusive (low-flow states, vasospasm) or occlusive 6. A specialized intestinal stroke center may improve the
(venous or arterial thrombosis or embolism), segmental acute management of these patients allowing revascular-
or extensive. ization, preventing irreversible necrosis, and when a lapa-
2. In those less than 60 years old the aetiology is likely to be rotomy is necessary reducing the amount of bowel that is
a haematological abnormality and in those older than 60 resected.
atherosclerosis or a cardiovascular abnormality.
3. An acute mesenteric ischemia is suspected from the his-
tory of sudden unremitting abdominal pain. Normal Introduction
plasma lactate levels are observed in the early stage of
mesenteric ischemia and cannot rule out the diagnosis. Acute mesenteric ischemia (or intestinal ischemia) repre-
Contrast-enhanced computed tomography (CT) is the sents the most severe and the most challenging of digestive
most definitive way of making the diagnosis and differen- vascular disease. The progression to mesenteric infarction
tiating an arterial from venous infarction. (or intestinal necrosis) is an irreversible complication poten-
4. If an early diagnosis is made an attempt should be made tially leading to a resection of a large amount of small intes-
to revascularize the gut, even before a resection for a defi- tinal and resulting in short bowel syndrome or death [1].
nite infarction. However if advanced ischaemia there may Thus, any intestinal ischemia should be recognized and
be a severe reperfusion injury. Surgeon should aim to treated at a reversible, early or chronic stage [2]. In the
restore blood flow before doing a resection, except in the absence of validated and available biomarkers, the diagnosis
case of instable patients in whom emergent resection is requires a high degree of clinical suspicion and an urgent
indicated first specific therapy with two linked objectives: saving the gut, to
5. After the resection, secondary elective reanastomosis of save the life of the patient [3]. Developed on the model of
remaining small bowel to ileum/colon reduces the need “stroke units”, a new intensive care unit dedicated to the
acute care of AMI offering expert multimodal and multidis-
ciplinary 24/7 management has been implemented in Paris,
A. Nuzzo · O. Corcos (*) France. The first results of this intestinal stroke center have
Intestinal Stroke Center, Department of Gastroenterology, IBD,
shown high rates of survival without intestinal resection in
Intestinal Failure—Beaujon Hospital, Paris-Cité University
Hospitals, Clichy, France most patients. In this chapter, the latest scientific and clinical
knowledge on AMI as well as a treatment strategy will be
Paris-Cité University Hospitals, Paris, France
presented.
INSERM U1148 Laboratory for Vascular Translationnal Science,
Bichat Hospital, Paris, France
Y. Castier
efinition of Mesenteric Ischemia
D
Paris-Cité University Hospitals, Paris, France and Anatomy
INSERM U1148 Laboratory for Vascular Translationnal Science,
Bichat Hospital, Paris, France Mesenteric ischemia is defined by (1) an intestinal injury,
secondary to (2) a vascular insufficiency in the territory of
Department of Vascular Surgery, Bichat Hospital, Paris-Cité
University Hospitals, Paris, France the splanchnic vessels, in (3) the absence of an alternative

70 A. Nuzzo et al.
diagnosis. The perfusion disorder can be acute or chronic, more likely to be complicated by extensive intestinal and
non-occlusive (low-flow states, vasospasm) or occlusive right-side colon necrosis. Conversely, non-occlusive isch-
(venous or arterial thrombosis or embolism), segmental or emia is more likely to present as multifocal ischemia, involv-
extensive [1, 4]. ing watershed areas of the GI tract with large superficial
The digestive tract vascularization is ensured by the three mucosal injuries rather than wall deep.
main arteries originating from the anterior face of the abdom- The GI tract arteries are terminal (straight vessels), perfo-
inal aorta (Fig. 1 and Table 1): rating the digestive wall on the mesenteric edge, dividing
into intramural arterioles penetrating through each villus up
• the celiac artery (CA) which supplies the stomach, the to its summit and connecting on a wide submucosal capillary
duodenum, the first centimeters of the jejunumn, the bile network without constituting an arterial-venous shunt. These
ducts, the pancreas and the spleen; capillaries form intramural venules which run parallel to the
• the superior mesenteric artery (SMA) which supplies the arterioles, at the base of the villus. This micro-vascular net-
small bowel, the ileocecal valve and the right colon; work facilitates the diffusion of oxygen at the base of the
• the inferior mesenteric artery (IMA) which supplies the villus and makes of the top of the villus the most sensitive
colon from the right angle to the upper rectum. The mid- area to ischemia. The villous venules merge into straight
dle and lower rectums are supplied by the middle and veins and empty into the mesenteric veins and the portal sys-
lower rectal arteries, branches of the internal iliac tem. The right and left parts of the colon are vascularized by
arteries. the superior and inferior mesenteric arteries, respectively.
Left-side colon ischemia, which represents the most com-
The topography of digestive ischemic lesions generally mon type of digestive vascular injury, is generally mild, self-
depends on the territories of vessel involved. Consequently, limited and the consequence of a transient decrease in
the distal occlusion of a branch of the SMA (embolism or microvascular blood flow from a non-occlusive (vasospasm)
vasculitis of small vessels, for instance) may lead to a seg- and/or drug-induced origin [5]. Instead, ischemia affecting
mental and focal ischemia, while a proximal thrombus is the right colon is associated with a vascular lesion of the
a b
Fig. 1 Gastrointestinal tract arterial vascularization. (Source: Anatomy whereas the left side of the colon is supplied by the inferior mesenteric
of the human body. 20th edition. Henry 1918). The superior mesenteric artery (b)
artery supplies the entire small bowel and the right side of the colon (a),
Mesenteric Ischemia 71
Table 1 Intestinal injury location depending on the mechanism and olism and the membrane pumps involved with ionic and
the type of vascular insufficiency
acid-base regulation. This leads to a profound alteration of
Intestinal injury location cellular homeostasis and, ultimately, to cell death by apopto-
Non-occlusive, sis [7–9].
Proximal or distal
occlusive occlusive, Initially, there is a dissociation between high porto-
ischemia (ex: ischemia (ex: mesenteric blood lactate levels and normal peripheral blood
Splanchnic atherosclerotic embolus, lactate levels due to the active liver metabolism [4]. Systemic
vessel Organ supplied thrombosis) vasculitides) lactic acidosis is, therefore, a late phenomenon, which often
Celiac Stomach, Gastric & Gastro-intestinal
indicates intestinal necrosis and the onset of organ failures
artery Duodenum, duodenal or segmental and
proximal jejunum, duodeno-jejunal multiterritory [10]. Associated endothelial lesions can lead to platelet, pro-
Gallbladder and ulcers, ischemia and anti-thrombotic agents (protein C, S, and antithrombin)
bile ducts, cholecystitis, consumption that cause a hemorrhagic syndrome.
Pancreas, Liver, pancreatitis,
Furthermore, the intestinal neuro-hormonal regulation of
Spleen spleen infarcts
Superior Jejunum, ileum Extensive small vasomotricity is associated with the activation of the renin-
mesenteric Right and traverse bowel and/or angiotensin-aldosterone system, to try to maintain a mucosal
artery and colon right-side colon oxygen extraction rate. This induces a reflex splanchnic arte-
vein ischemia rial vasospasm, irrespective of the initial vascular mecha-
Inferior Left-side colon, Left-side colon
mesenteric upper rectum ischemia with
nism, that may prolong and worsen ischemia despite the
artery and frequent rectum revascularization treatment. This vasoconstriction accompa-
vein sparing nies, for example, situations of hypovolemia, during which
digestive ischemia develops before clinical hemodynamic
instability [11, 12].
SMA in 25% of patients and then should be considered as a The disruption of the epithelial barrier resulting from
segmental form of AMI [6]. mucosal alterations (Fig. 3) leads to interactions between
microorganisms, bacterial antigens, endotoxins of the intes-
tinal lumen and the mucosal and submucosal immune sys-
Pathophysiology tem. The stimulation of innate immunity will result in local
then systemic inflammatory pathways activation such as
Acute mesenteric ischemia (AMI) should be considered as TLR, NF-KB or TNF [13, 14]. Through the bloodstream,
one stage of a multistep process (Fig. 2) leading, from a bacteria, endotoxins, cells degradation products and acti-
digestive vascular insufficiency, to intestinal necrosis, organ vated immune cells translocate and promote systemic
failure and death. Ischemia begins early and superficially inflammation response syndrome (SIRS). Cytokines, che-
and then spreads in deep and surface of the intestinal wall. mokines, cellular and bacterial debris can also reach the pul-
Vascular insufficiency is initially the trigger for an inade- monary circulation from the lymphatic circulation and thus
quacy between inputs and requirements for energy substrates cause acute respiratory distress syndromes [15, 16]. The
by overcoming the adaptive processes of a digestive territory. translocation of bacteria and/or bacterial products into the
This loss of homeostasis results from a sudden decrease or mesenteric lymph nodes and/or bloodstream is reported in
interruption of the splanchnic-mesenteric blood flow. The intestinal ischemia in up to 25–100% of experimental ani-
decrease in splanchnic blood flow in the proximal circulation mal models. It further increases the SIRS making the isch-
induces a deep extension of the ischemia which then becomes emic small bowel an infection site [17]. The absence of a
transmural and gangrenous. rapid recovery of a sufficient digestive perfusion leads to
Conversely, when perfusion abnormalities relate to intra- irreversible transmural necrosis with peritonitis. Without
parietal arterioles, lesions of ischemia remain superficial. intestinal resection, the SIRS leads to multiple organ failure
Intestinal vascular insufficiency leads to hypoxia, first with and death [16].
mucosal and submucosal consequences. The hypoperfusion In the model of the “gut origin of sepsis”, the gut was
of the intestinal mucosa is responsible for an early hypoxic considered to be the ‘motor’ of multi-organ failure [11, 15,
cellular desquamation of the intestinal villi. 16, 18]. Aside from its barrier function, the gut contains
Polymorphonuclear neutrophils are early major actors that growth factors, adenosine, and hormones, which are poten-
adhere and migrate to the ischemic site to ensure the removal tial mediators for the modulation of intestinal inflammation
of tissue debris during necrosis. Mucosal and submucosal and repair, due to their roles in cellular proliferation, differ-
cells switch to anaerobic glycolysis with local production of entiation, migration, apoptosis, and autophagy [19–23].
lactate which initially is fully metabolized by the liver. The Physiologically, the gut could initiate and propagate sepsis
increase in intracellular acidosis blocks the anaerobic metab- due to the ability of bacteria, endotoxins, and other antigens
72 A. Nuzzo et al.
Fig. 2 Multistep pathophysiology of acute mesenteric ischemia. Intestinal ischemia should be considered as the reversible stage of a pathophysi-
ological multistep process leading to necrosis and death
to translocate, along with the production of pro-inflammatory

cytokines and toxins [11]. In The ‘Three Hits Model’ Deitch
et al. added the phenomenon of reperfusion injury [24]. In
the ‘Gut-Lymph’ theory, bacteria, cellular components,
immune cells, cytokines and chemokines generated by the
injured gut travel via the lymphatics to reach the pulmonary
circulation, activating alveolar macrophages, and contribut-
ing to acute lung injury, acute respiratory distress syndrome
and multi-organ failure related to AMI [15, 16, 25]. The sys-
temic consequences of bowel ischemia and necrosis are
lethal in most patients in the absence of curative treatment
including revascularization [26, 27]. However, reoxygen-
ation of the digestive mucosa can also paradoxically worsen
epithelial and vascular lesions, due to an oxidative burst
Fig. 3 Pathological analysis of acute ileal ischemia. Acute ileal isch- mechanism causing the influx and death of neutrophils with
emia characterized grossly by congestive small bowel loops and super- the formation of neutrophil extracellular traps and the secre-
ficial mucosal ischemia starting at the tip of the villi tion of their granular content [28].
Another mechanism of epithelial self-digestion would [31]. These figures are consistent with epidemiological stud-
contribute to aggravate this alteration of the gut barrier ies on chronic mesenteric ischemia with an estimated inci-
function via proteolysis of tight enterocytic junctions by dence of 9.2/100,000 inhabitants per years from a Dutch
bilio-pancreatic secretory enzymes [22]. This quite recent prospective database between 2014 and 2019 [32]. The inci-
concept describes the effect of pancreatic enzymes on the dence of arterial AMI increases exponentialy with age, with
intestinal barrier altered by ischemia. Self-digestion con- an incidence of 25/100,000 person-years after 70 years old,
tributes to the worsening of intestinal ischemic lesions and and a peak incidence of 217/100,000 person-years after
the development of the related systemic inflammatory 85 years-old [29, 30, 32].
response. Degradation products of pancreatic enzymes,
residues of bacterial products pass through the lymphatic,
hematogenous or peritoneal barrier and are likely to induce Causes
a loco-regional but also systemic reaction [20, 21]. In ani-
mal models, inhibition of these enzymes results in a Main causes of mesenteric ischemia can be classified accord-
decrease in intra-parietal micro-bleeding, in the systemic ing to the two main mechanisms of vascular insufficiency,
inflammatory response, and even in mortality in some stud- often associated: (1) occlusive mesenteric ischemia (85%),
ies [22]. The action of these enzymes would involve degra- due to atherosclerotic lesions, embolism or thrombosis,
dation of inter-enterocytic tight junction’s proteins such as involving splanchnic artery (70%) and/or vein (15%), and
E-cadherin. Moreover, these enzymes would also induce a (2) non-occlusive mesenteric ischemia (15%) caused by
cleavage of the pro-metalloproteinases into active metallo- mesenteric vasospasm secondary to a systemic low flow or a
proteinases [23]. vasoconstrictive drug. Each of these forms can occur on
Mesenteric vein thrombosis can be anterograde (primary pathological vessels (atheroma, dissection, dysplasia, vascu-
occlusion of the straight veins, generally secondary to an litis) or on healthy vessels. In the latter case, the origin of the
enteritis or an intra-abdominal inflammatory process) or ret- occlusion is often due to a systemic cause of thromboembo-
rograde (primary occlusion of the portal vein, generally sec- lism (cardiogenic embolism, thrombophilia, myeloprolifera-
ondary to portal hypertension). In this context, the occurrence tive syndrome) and/or a regional risk factor (inflammatory or
of intestinal ischemia may be more likely in case of the infectious intra-abdominal process or neoplasm, portal
occlusion of second order radicles of the superior mesenteric hypertension).
vein and in the context of arterial insufficiency/associated The main cause of arterial mesenteric ischemia is athero-
arteriosclerosis [19]. Downstream the portal/mesenteric vein sclerosis. Although the prevalence of significant splanchnic
thrombosis, the hepatic consequences are weakly marked arterial atheromatous stenosis in the general population is
due to rapid compensatory mechanisms such as hepatic arte- high (17 to 50%), most are asymptomatic [33]. In this set-
rial vasodilation and the development of a cavernoma, visiting, the incidence and predictive factors for the onset of
ble as early as a few days after thrombosis. mesenteric ischemia are unknown. Other causes of mesen-
teric arterial occlusion include embolism, vasculitides, infec-
tious arteritis, fibromuscular dysplasia, median arcuate
Epidemiology ligament syndrome, dissection and hypercoagulability [1, 4].
Their respective prevalence and incidence have not been pre-
Incidence cisely evaluated.
Causes of venous mesenteric ischemia include portal
Given that the clinical diagnosis of mesenteric ischemia is hypertension, intra-abdominal inflammatory processes (pan-
still a challenge, the incidence of digestive vascular diseases creatitis, inflammatory bowel disease, sepsis, trauma),
is still difficult to assess and then potentially largely underes- malignancies, hematologic disorders, and thrombophilia.
timated. However, it is likely increasing due to an increase in Risk factors for non-occlusive mesenteric ischemia
the population at cardiovascular risk and improvements of its include vasoconstrictors (noradrenaline, cocaine (not
recognition by CT scanning [27]. uncommon in young adults)) and hypovolemia (sepsis,
Based on autopsy studies in Sweden, Acosta et al. esti- hypotension, dialytic depletion) [18, 34]. (Table 2) The
mated an incidence of 13/100,000 person-years between knowledge on the risk factors of AMI might be incomplete
1970 and 1982, when autopsy rate was 87% [29, 30]. In a US given that half of patients, no prior cardiovascular or pro-
comprehensive database and population analysis in thrombotic history is found [35]. As a result, AMI should be
Maryland, Crawford et al. reported a statewide admission considered regardless of the patient’s age and cardiovascu-
rate of 10/100,000 inhabitants per years during 2009–2013 lar history.
74 A. Nuzzo et al.
Table 2 Main causes of mesenteric ischemia ible at its early stage [2]. However, the late recognition of the
Causes et facteurs favorisants à diagnosis and intestinal necrosis, at the stages of peritonitis
Mesenteric ischemia rechercher and multi-visceral failure, explain the mortality still reported
Occlusive Vascular disease – Atherosclerosis today by other centers and the prevalence of short bowel syn-
– thrombosis
– Embolism (cardiogenic and drome in survivors [37].
arteriogenic)
– Aneurysm, dissection
– Fibromuscular dysplasia Diagnosis of Mesenteric Ischemia
– Vasculitides, neuro-endocrin
tumors, radiation enteritis
– Vascular injury (endovascular or Clinical Suspicion
open vascular surgery, trauma,
compression by a mesenteric In the absence of a biomarker allowing a rapid non-invasive
malignancy)
Hypercoagulability – Intra-abdominal inflammatory
diagnosis, the clinician’s only weapon remains his diagnostic
process, cancer or surgery suspicion and confirmation by the contrast-enhanced abdom-
– Inherited thrombophilia inal CT scan. At this stage, the time of onset of acute abdom-
(prothrombin gene mutation inal pain should be considered as the starting point for a
G20210A, favtor V Leiden,
antithrombin, protein S and C
countdown leading, without prompt and adequate treatment,
deficiencies, increased factor VIII) to intestinal necrosis and death. Contrary to popular belief,
– Hematological disorders most patients with AMI present to the emergency department
(polycythhaemia, myelofibrosis, at a potentially reversible, but still insufficiently recognized
thrombocythemia, JAK2 V617F
mutation, antiphospholipid
early stage. Indeed, 50% of patients present initially with no
antibodies, paroxysmal noctrunal known cardiovascular history, without surgical abdomen,
haemoglobinuria) without organ failure and without elevation of plasma lactate
– Malignancies [35, 38, 39].
– Oral contraceptive, pregnancy,
obesity
The acute abdominal pain is constant, apart from the par-
– Portal hypertension, congestive ticular case of the intensive care patient receiving a sedation
heart failure [1, 4]. Pain can be inaugural or succeed to symptoms of
– Other: CMV, nephrotic syndrome, chronic mesenteric ischemia in 30% of patients, the diagno-
SARS-COV-2 infection
sis of which is most often overlooked [29, 35]. Pain is typi-
Non-occlusive – Low flow states (hypovolemia,
shock, dialysis) cally sudden (“vascular”) or rapidly progressive, intense and
– Extra-corporal life support, requiring opioids, continuous and relentless, peri-umbilical
clamping in vascular surgery or diffuse, and contrasts with an abdominal palpation ini-
– Toxic/iatrogenic (cocaine,
tially falsely reassuring. It can be associated with vomiting
amphetamine, catecholamines)
– Sickle cell disease, leukostasis (48%), diarrhea (31%), digestive hemorrhage (18%) and an
– Heavy exercise (marathon inflammatory biological syndrome which, inconstant and/or
runners) too late have no diagnostic value [10, 39].
– Electrocution and burns
Biomarkers
Prognosis
While biologic abnormalities—such as leucocytosis or lactic
In a systematic review of 45 studies including 3692 patients, acidosis – have been documented in patients with AMI, their
acute mesenteric ischemia (AMI) was consistently fatal performance to establish the early diagnosis is poor [40, 41].
without adequate treatment [26]. Despite treatment, mortal- Worse, in a cohort study, a delayed diagnosis was more likely
ity varied from 40% (venous ischemia) to more than 80% when initial plasma lactate levels were <2 mmol/L suggest-
(arterial ischemia), the main prognostic factors being the ing that physicians might be misguided by unremarkable
precocity of the diagnosis and treatment, the occurrence of plasma lactate levels. The high complexity of the layered
transmural necrosis, the mechanism of ischemia (venous vs intestinal wall structure increases the diversity of the pro-
arterial) and the age of the patient [36]. In the 2010s, our teins and metabolites released in AMI. Their hepatic metabo-
most recent results have shown that multimodal and multi- lism through the hepatic portal system results in substantial
disciplinary SURVI management made it possible to obtain overlap with liver proteins and metabolites. These factors,
a survival of 91%, without intestinal resection in 58% of along with the heterogeneity of the disease, explain why
cases, [4, 10] making AMI a potentially disease fully revers- identifying clinically reliable biological early markers of
AMI has been unsuccessful so far [1, 4, 41]. Three blood will guide the treatment of revascularization, [51] and the
biomarkers have gained attention over the past decades: indication for digestive surgery [10].
citrulline, a marker of enterocyte function; I-FABP, a marker
of enterocyte damage; and d-lactate, a marker of intestinal ascular Imaging Findings
V
barrier dysfunction and microbial translocation [41–44]. As Intra-luminal defects or occlusions of the mesenteric vessels
a result, these tests are increasingly used in basic and clinical are highly specific for the diagnosis (94–100%), but reported
research as indirect markers of an ischemic intestinal injury sensitivity is rather low (12–15%) [52]. Yet, in our experi-
in a broad range of emergency clinical settings. However, ence, vascular anomalies are encountered in more than 75%
their alleged diagnostic performances have only been of patients. In occlusive forms of AMI, CT allows visualiza-
assessed in small heterogeneous cohorts. Besides, conflict- tion of the site of the vascular obstruction and helps distin-
ing results have been reported, and most of the studies con- guish emboli from thrombosis. It also depicts other vascular
sist of preoperative data in late-stage necrotic AMI patients anomalies such as calcified or non-calcified plaques, or rare
[45]. Early diagnosis remains a critical clinical and research dissections. In non-occlusive mesenteric ischemia, CT may
challenge as it would allow early management and conse- show narrowed veins, flattened inferior vena cava [53], dif-
quently improve the dire prognosis of AMI. To meet this fuse irregularities or stenoses of the SMA and SMA branches,
challenge, relevant new biomarkers may be identified using and poor visualization of intestinal arcades and intramural
non-targeted multi-omics discovery approaches in large vessels [54], as described by Siegelman et al. with angiogra-
cohorts of early-stage AMI patients admitted in dedicated phy [55].
units.
owel Imaging Findings
B
Numerous findings associated with intestinal ischemic
Diagnostic Imaging injury, including bowel wall thickening or thinning, sponta-
neous wall hyper-attenuation on unenhanced CT acquisi-
The cornerstone of the diagnosis is contrast-enhanced com- tion, decreased or absent bowel wall enhancement, bowel
puted tomography (CT). Its excellent reported sensitivity dilatation, pneumatosis intestinalis and portal venous gas,
and specificity [46] suggest that it may be used as the first- peritoneal fat stranding and ascites. These features are
line imaging technique. However, lower sensitivities were often associated, and bear different prognostic value [49]
reported when the CT scan was performed during both arte- (Fig. 4).
rial and venous phases (83%) or venous phase only (72%)
[35], or when in the real-life setting, the clinical suspicion Prognostic Value of CT
was not always mentioned to the radiologist, [47] resulting in CT helps distinguish early from late forms of AMI by depict-
either an inappropriate IV contrast protocol and/or an analy- ing imaging features of necrosis or complications. (Fig. 4)
sis that did not focus on the mesenteric vessels [48]. Finally, From this perspective, radiologists should not only recognize
the unenhanced CT scan should be avoided because it does bowel ischemia on CT, but also differentiate it from bowel
not detect signs of AMI, causing a significant delay in diag- necrosis that requires surgical resection. Free intraperitoneal
nosis [35]. A recent study focused on the impact of contrast- gas is the only pathognomonic finding of bowel perforation,
enhanced multidetector CT on the survival in patients with and therefore of wall necrosis in patients with AMI [56]. Yet,
acute superior mesenteric artery occlusion; in-hospitality it is a delayed feature, and patients need to be diagnosed and
mortality rate was 42% for patients who underwent contrast- treated before this occurs. Another important finding is pneu-
enhanced multidetector CT, versus 71% for patients not matosis intestinalis. Importantly, pneumatosis intestinalis
examined with CT [48]. As a result, CT should be performed may occur in ischemic bowel segments that have not yet
as quickly as possible after the onset of symptoms in all undergone transmural infarction. Duron et al. found that
patients, and include contrast-enhanced images to visualize 47% of patients with AMI showing pneumatosis still had
both mesenteric vessels and digestive structures, including in viable bowel, with only partial mural ischemia without trans-
the presence of renal insufficiency, the risk of overlooking an mural infarction on surgical or pathological analysis [57].
AMI greatly exceeding that of the injection of the contrast Patients with associated porto-mesenteric venous gas are
agent [1, 4, 49, 50]. more likely to have transmural infarction than those with
CT plays a double role in patients with AMI. First, diag- pneumatosis intestinalis alone. In AMI of arterial origin,
nosis is reached based on the combination of two sets of fea- bowel dilatation and decreased wall enhancement have been
tures that parallel the pathophysiology of the disease: 1/ shown to be more frequent in cases of bowel necrosis [10]. A
vascular insufficiency, and 2/ ischemic intestinal injury. recent prospective study from our group identified both fea-
Second, CT should help identify negative prognostic factors, tures in univariate analysis, with necrosis in 68% of cases
suggestive of extensive necrosis, or complications which when bowel wall enhancement was decreased, and in 64%
76 A. Nuzzo et al.
a b
c d
e f
Fig. 4 The contrast-enhanced abdominal CT-scan: the cornerstone of thrombolysis (d). (e and f) CT-signs of transmural intestinal necrosis.
the diagnosis. (a and b): Axial view, (a) showing a spontaneous hyper- (e) Axial view, venous phase, porto-mesenteric extensive thrombosis
density of the intestinal wall at the non-contrast time, not to mistake (arrows) with small bowel dilatation and decreased wall enhancement
with wall enhancement (b) unchanged after contrast injection. (c and d) of the proximal jejunum (white arrowheads) when compared to normal
Sagittal view, arterial phase, 90% stenosis by thrombi of the superior ileum (black arrowheads). (f) Sagittal view, venous phase, small bowel
mesenteric artery (black arrows) before (c) and after intra-arterial dilatation and feces sign (arrows)
when bowel loops were dilated. Only bowel dilatation was the context of vascular occlusion or low flow. Given the life-
significant in multivariate analysis [10]. threatening risk of translocation in AMI, most experts rec-
ommend early and widespread use of antibiotics consistent
with our experience [1, 36, 60, 61].
Treatment of Acute Mesenteric Ischemia The effectiveness of the treatment is judged on the disap-
pearance of the pain. Any persistent digestive clinical symp-
Management in Dedicated Stroke Units tom (pain, food intolerance, hemorrhage, persistence of a
failure) should suspect for residual ischemia. Exclusive par-
In the 2010s, our unit showed that a multimodal and multi- enteral nutrition is offered until the ischemia is relieved,
disciplinary management of AMI, focused on preserving especially when there is pre-existing undernutrition or a
intestinal viability in a specialized intestinal stroke center, short bowel syndrome. Although a Chinese study suggests
could decrease the rate of intestinal resection, as well as that enteral nutrition should be systematically considered,
improve short- and long-term survival [58]. These results many biases inherent in the retrospective and univariate
demonstrated that intestinal ischemic injury during AMI is nature of the analysis limit its interpretation [62]. In practice,
potentially reversible, and that intestinal necrosis could be oral and / or enteral feeding should be resumed gradually
considered an unwanted outcome and a late complication [2, only after joint disappearance of pain and biological inflam-
10]. Following these results, in 2016, a 8-bed dedicated matory syndrome.
intestinal stroke unit was created at Beaujon Hospital, Paris In the particular case of non-occlusive ischemia, the ther-
University, France, that provides 24/7 standardized apeutic priority is to restore and maintain sufficient splanch-
multimodal and multidisciplinary care to AMI patients
nic hemodynamics by treating the cause of hypoperfusion
referred from all hospitals in the Paris area. (hypovolemia, sepsis, heart failure, hemorrhage), by prefer-
Preventing the progression from reversible to irreversible ring fluids to the use of catecholamines (Figs. 5 and 6).
intestinal ischemic injury should be a primary goal in the Despite the absence of vascular occlusion, the similar isch-
management of AMI. Indeed, in our experience mortality emic injury of the digestive mucosa justifies the maintenance
goes from 2% in early AMI to 35% when intestinal ischemia of the common medical protocol. In the absence of rapid
is treated at the stage of irreversible necrosis [59]. The treat- improvement, an arteriography with intra-arterial infusion of
ment strategy developed in our intestinal stroke unit simulta- vasodilators (papaverine) is recommended. Surgical treat-
neously follows three main objectives: (Fig. 5). ment is therefore offered as a last step in case of the patient
worsening or immediately in the event of peritonitis /
1. Prevent worsening, SIRS and organ failure by a specific perforation.
medical protocol for intestinal ischemia (Table 3);
2. Preserve the non-necrotic intestine by systematic
revascularization; Revascularization
3. Resect intestinal necrosis according to a non-invasive risk
score (Fig. 5), before its complications (perforation, As with any vascular emergency, early revascularization is
peritonitis). the only therapy that can prevent/limit irreversible necrosis
and its life-threatening complications [58]. Depending on the
This multidisciplinary emergency strategy is coordinated by accessibility of vascular lesions and local expertise, arterial
a gastroenterologist and requires a structure with available revascularization is ideally carried out percutaneously first
24-h revascularization and intestinal resection, in an inten- and before any digestive surgery in order to preserve a maxi-
sive care environment and in collaboration with an intestinal mum of viable small intestine [4, 51].
failure unit. A specific medical protocol targeting each step
of the pathophysiological process of intestinal ischemia is Endovascular Strategies
administered upon diagnostic confirmation, regardless of the If a vascular impairment is reachable, percutaneous revascu-
mechanism and form of the AMI. Systematic administration larization (intra-arterial thrombolysis, angioplasty-stenting,
of oral antibiotics yielded a protective effect against trans- thrombectomy) should be considered. Recent literature
mural intestinal necrosis (HR = 0.16, 95% CI: 0.03–0.62, reports a success rate of endovascular revascularization of
p = 0.01) [59]. Oral antibiotics may prevent intestinal necro- 87% [63]. The choice of techniques depends on the etiology,
sis by (1) decreasing the luminal bacterial load which inter- and the localization of the vascular occlusion.
acts with the intestinal innate immune system through the To date, no randomized controlled studies have compared
disrupted epithelial barrier, (2) limiting local and systemic an up-front endovascular approach with open surgery for the
inflammation which results from bacterial interaction/trans- treatment of AMI. Because AMI is a relatively rare and
location, and (3) improving their luminal bioavailability in urgent condition, such trials are unlikely to be performed.
78 A. Nuzzo et al.
Medical protocol
including oral antibiotics
Arterial
Revascularization
Intestinal necrosis factors
Organ failure ≥ 1
Serum lactate levels > 2 mmol/L
CT bowel dilation > 2.5 cm
3 factors or
0 factors 1-2 factors surgical complication
(perforation)
Consider
laparotomy1
and/or
No
Close monitoring of Laparotomy
laparotomy
factors2
Fig. 5 Treatment algorithm used in the intestinal stroke unit. (1) especially when the factor value is close to the upper normal cut-off and
Consider laparotomy, especially when the factors value is high and when an improvement is expected with successful revascularization
when a revascularization is not feasible. (2) Consider close monitoring,
Most published studies are therefore retrospective monocen- Endovascular treatment was applied as first-line in 88% of
tric series, with all methodological biases associated with the patients [64]. Mortality was acceptable (32%) yet the
such study design. A group from the University Hospital of endovascular strategy failed in 50% of the patients, and a
Kuopio, Finland, recently reported a consecutive series of surgical bypass was finally achieved. The 30-day mortality
patients with AMI treated over a five-year period. rate was lower than that reported by Endean et al. after surgi-
Table 3 Systematic medical protocol provided in the intestinal stroke by surgical revascularization and 165 (24%) by endovascular
unit [58.
procedure. The proportion of patients who had endovascular
Common medical Blood volume resuscitation (Mean repair increased from 12% in 2005 to 30% in 2009. Mortality
protocol arterial pressure >65 mm Hg, Urine
output >0.5 mL kg−1 h−1)
was 39% after surgery and 25% after endovascular proce-
Curative unfractionated heparin therapy dure. Among survivors, the proportion of patients requiring
(Anti-Xa target: 0.4–0.8) total parenteral nutrition was also significantly higher after
Oral digestive decontamination surgery than after endovascular strategy (24% versus 14%)
PO gentamicin 80 mg/d [69]. Thus, although Level I evidence is lacking, this data
PO metronidazole 1.5 g/day seems convincing.
IV proton pump inhibitors
This approach of surgery versus endovascular revascular-
IV pantoprazole, 80 mg/day
Oxygen therapy ization, seems to us to be limited and erroneous. If endovas-
Food resting cular interventions are sometimes performed alone, optimal
PN if prolonged >5 day patient management must combine the two approaches in a
Conditional medical IV aspirin 100 mg/day if arterial complementary perspective, the benefits of each being able
protocol thrombosis or revascularization to support those of the other. Indeed, the majority of patients
IV piperacillin-tazobactam 12 g/day if
treated with the endovascular route have laparotomy and
SIRS or organ failure
Upper gastrointestinal aspiration if ileus intestinal resection in a second phase. However, the mean
Blood transfusion if hemoglobin level length of the resected small intestine is significantly shorter
IV intravenous, PO orally, SIRS systemic inflammatory response than with surgery alone [51].
syndrome
Open Vascular Surgery
Vascular surgery is often required to restore the mesenteric
cal strategy alone (62%) [65]. Recently, a review conducted revascularization in order to improve the prognostic of the
by Zhao et al. reported that radiological revascularization AMI (increase survival and prevent intestinal failure). The
should be considered as a first-line therapy in patients with a most common situations when revascularization is done sur-
low suspicion of intestinal necrosis [66]. gically are:
The analysis of population registers makes it possible to
obtain data of greater value. Swedvasc, the Swedish vascu- –– surgical abdominal exploration is needed and urgent
lar register, founded in 1987 comprises more than 90% of –– surgical exploration has already been done by the visceral
all vascular surgical procedures in a country of 9.5 million surgeon
inhabitants. Two publications from Swedvasc reported the –– endovascular procedures failed to restore the mesenteric
results of revascularization of the superior mesenteric revascularization
artery for AMI for the periods 1987–1998 and 1999–2006 –– vascular surgeon and/or radiologist consider that the case
[67, 68]. Overall, total surgical activity quadrupled from not appropriate for endovascular revascularization
1999 to 2006, while the number of endovascular revascu- –– contraindication to endovascular technique (local throm-
larizations increased sixfold. If overall mortality decreased, bolysis for example)
this decline was observed only in patients treated with –– visceral surgeon is not familiar with endovascular proce-
endovascular strategy. Long-term survival was also better dures but is able to perform basic vascular surgery (embo-
after endovascular strategy. The difference between the two lectomy for example)
periods could be explained by a difference in patient sever-
ity, but the length of the resected intestine was similar in In our experience, the three most common surgical vascu-
both groups and the endovascular strategy was identified as lar procedures to restore the blood flow in the superior
an independent factor of survival in multivariate analysis mesenteric artery (SMA) are: (1) the SMA embolectomy,
(odds ratio 3.7). However, as in the Kuopio Hospital expe- (2) the retrograde SMA bypass, (3) the retrograde open
rience, one of the main reasons for successful endovascular SMA stenting. The vascular surgeon may need to harvest
strategy was the possibility of surgical revascularization if a segment of saphenous or femoral vein. Hence, we rec-
the former fails. ommend having one of the thighs prepared in the surgical
Similar observations emerge from the analysis of the field in anticipation of possible access. A radiologic sys-
National Inpatient Sample (NIS) based in the United States tem to perform arteriography during the procedure is
[69]. The NIS is a database of 20% of the hospitalization mandatory (C-arm fluoroscopy or hybrid operating room).
episodes of nearly 1000 hospitals. Of the 679 patients with All the vascular surgical procedures need systemic
AMI treated between 2005 and 2009, 514 (76%) were treated heparinization.
80 A. Nuzzo et al.
Systematic
medical
protocol
Intra-arterial
Optimize vasodilation
volemia (papaverin)
Non-occlusive
mesenteric
ischemia
Digestive
Limit surgery if
catechol perforation or
amines as a last
resort
Fig. 6 Treatment principles of non-occlusive mesenteric ischemia
SMA Embolectomy taken to avoid damage or rupture to fragile collaterals of the

Anterior exposure to the SMA for straightforward embolec- SMA. When necessary, small Fogarty embolectomy cathe-
tomy is achieved by elevating the omentum and transverse ters are used. After all macroscopic clot is cleared, we can
colon, the small intestine is wrapped and retracted to the consider administration of a single dose of thrombolytic
right. A segment of the proximal SMA between the middle agent into the distal mesenteric vessels. An arteriogram can
and the right colic branches is isolated. Circumferantial dis- be performed at the end of the procedure to assess the quality
section is required to isolate and to control any of the jejunal of the revascularization.
branches in this segment. The artery is open transversely if
the SMA has a sufficient diameter and is not too atheroma- etrograde SMA Bypass
R
tous. For diminutive or diseased vessels, we firmly recom- Antegrade bypass using the distal thoracic aorta or suprare-
mend performing a longitudinal arteriotomy using a patch nal aorta as the inflow source is not recommended in case
closure (prosthetic or a saphenous patch). Great care must be of AMI. A retrograde bypass based on the infrarenal aorta,
a previous aortic graft, or the iliac artery is strongly pre- associated to intestinal necrosis, [60, 61] as even serum lac-
ferred with the advantage of avoiding cross-clamping the tate might be normal in necrotic patients or elevated in
aorta. Most retrograde reconstruction deals with only the patients with reversible ischemia, due to dehydration and
SMA, but reconstruction of the common hepatic artery can decreased oral intake [60]. In this setting, we performed a
also be achieved by tunneling the graft retroperitoneally or prospective cohort study of 67 patients with acute mesenteric
via the transverse mesocolon. As the graft assumes a ischemia, of which 34% presented with intestinal necrosis
C-shaped configuration, it is important to avoid graft elon- [10]. From this group organ failure, elevated serum lactate≥
gation, angulation or kinking. Synthetic bypass grafts 2, and bowel loop dilation (defined as a diameter > 2.5 cm)
(Dacron or externally supported polytetrafluoroethylene) on CT scan were independent factors predictive of intestinal
are preferred because of the better size match, ease of han- necrosis. On the basis of these findings, the incidence of
dling, availability and kink resistance. The choice of con- intestinal necrosis rose from 3% in patients with no predic-
duit is heavily influenced by the degree of abdominal tive factor to 38%, 89%, and 100% in patients with 1, 2, and
contamination and the perceived risk of subsequent infec- 3 factors, respectively. Therefore, in routine clinical practice,
tion. Therefore, if good-quality vein is available (saphe- we consider that all patients presenting with 2 or more fac-
nous vein or femoral thigh vein), it is preferred in the tors should undergo immediate explorative surgery to assess
presence of significant peritoneal soilage. In the presence for intestinal viability [10] (Fig. 5).
of a diseased SMA, an endarterectomy may be necessary If a surgical exploration is decided upon, this procedure
before doing the distal anastomosis. Reports suggest that should be, whenever possible, carefully planned according to
retrograde grafts perform as well as antegrade grafts [70]. the feasibility of a revascularization procedure. In highly
unstable patients and/or in patients with overt peritonitis, we
etrograde Open SMA Stenting (ROMS)
R advocate a primary blood flow restoration procedure prior to
The ROMS technique uses a hybrid approach via midline a surgical resection, as this might reduce the extent of intes-
laparotomy to expose de SMA combined with endovascular tinal resection and reduce the risk of secondary necrosis of
retrograde stenting. Because several of these patients already the remnant bowel [51]. In all other patients, we routinely
have an indication for laparotomy to address advanced bowel perform a radiological or surgical revascularization proce-
gangrene or ischemia, direct surgical exposure of the SMA dure prior to the explorative laparotomy, for the same
allows expeditious access for direct puncture. The proximity reasons.
of the sheath to the lesion affords excellent support to cross a
difficult occlusion with less risk of distal embolization by Surgical Approach
occlusion of side branches. Furthermore, primary stenting is Very few studies reported the use of laparoscopic approach
an excellent method of revascularization that avoids the need for the management of acute mesenteric ischemia [74–78].
to reconstruct the vessel by surgical bypass, minimizing sur- Despite this small series, the European Society for Trauma
gical dissection and potentially eliminating the need to har- and Emergency Surgery guidelines does not recommend the
vest a vein or to use a prosthetic graft for conduit. use of minimally invasive approach for acute mesenteric
We recommend the use of covered balloon expandable ischemia, due to the paucity of reported evidence [60]. In our
stent, 7 mm diameter stent are most often used [71, 72]. In experience, laparoscopic approach is not the gold standard
our experience, a majority of the SMA needs an endarterec- approach for the management of acute mesenteric ischemia
tomy and we recommend to perform a longitudinal arteriot- as: (1) the complete visualization and viability assessment of
omy using a patch closure (prosthetic or a saphenous patch). the small bowel and colon might be difficult, (2) patients’
ROMS during emergent laparotomy for AMI is a very prom- tolerance of the pneumoperitoneum might be compromised,
ising technique and an attractive alternative to emergent sur- especially in unstable patients, (3) surgical revascularization
gical bypass. procedures require an open approach. We usually perform an
open approach in our patients, reserving a laparoscopic
approach in cases of difficult diagnosis and especially in
Intestinal Resection non-occlusive patients [76].
on-invasive Predictors of Transmural Necrosis

N Bowel Viability Assessment
The cornerstone of acute mesenteric ischemia surgical man- Most of the time, necrotic bowel will be clearly identifiable
agement in the acute phase is the diagnosis of intestinal during the laparotomy, and will be based on the bowel color,
necrosis, that will not be reversible despite revasculariza- motility and bleeding of cut ends [60, 79, 80]. (Fig. 7) As
tions procedures [3, 51, 73]. However, the identification of described before, this viability should be assessed after
patients with intestinal necrosis has been shown as difficult. revascularization procedure, whenever possible. However,
Indeed, no clinical sign or laboratory study is specifically viability assessment might sometimes be difficult, especially
82 A. Nuzzo et al.
second look laparotomy – indeed, Park et al. reported the

outcomes of patients operated on for acute mesenteric isch-
emia and reported that an additional bowel resection was
performed during the second look in the minority of patients
(11/23), thus exposing the majority of patients to the risk of
an unnecessary laparotomy; [86] (2) The presence of a stoma
allows the direct evaluation of the remnant bowel viability,
as the mucosa can be easily evaluated and, if necessary, biop-
sied; and (3) this strategy does not expose the patient of the
complications of intestinal anastomosis, as anastomotic
leakage is frequent is those patients that will receive inten-
sive resuscitation and vasopressor injections [60]. We never
perform any anastomosis in the acute phase of acute mesen-
teric ischemia management. In this setting, during bowel
resection, care should be taken to facilitate the intestinal con-
Fig. 7 Acute arterial mesenteric infarction. Resection specimen show- tinuity restoration. Double end stomas should be preferred
ing transmural intestinal necrosis from arterial intestinal ischemia over single stomas in separate incisions, as this will allow to
perform intestinal continuity restoration through an elective
in cases of hypotension, vascular impairment, and the con- approach, rather than a midline laparotomy.
current use of vasopressors. In such patients, the use of dop-
pler ultrasound of the vascular arcade, [81] fluorescein xtensive Bowel Resection
E
angiography, [82] and indocyanine green angiography [83] In severe patients, with extensive intestinal necrosis requir-
have been reported but have failed to gain widespread use. In ing large bowel resection, the surgeon might face a philo-
our practice, we usually perform a frozen section examina- sophical decision whether to expose the patient to a short
tion in order to avoid unnecessary extensive resection. bowel syndrome, requiring total parenteral nutrition, or not
Vacsular surgeons from our center use to feel for the arte- to do anything. This decision may be based on the associated
rial SMA pulse, but it is not indicative of the quality of the comorbidities, and the long-term probability of patient dis-
reperfusion and the quality of revascularization of the col- charge from medical assistance. In the past the difficult deci-
laterals of the SMA and distal arteries. CT angiography is sion to close the abdomen and not resect was often made
preferred for this purpose. Differentiating arterial from after intra-operative discussions with the intensivists, the
venous infarction is also done using the the CT-scan images. gastroenterologist, and the nutritionist in charge of the
At surgery venous AMI usually leads to more congestive patient. However with the success of long-term parenteral
“blue” colored bowel, a more proximal injury (jejunum), but support and the fact that many patients, even if the remaining
lower/slower progression to infarction than arterial AMI. small bowel length is very short (less than 50 cm), will stop
the parenteral support when the colon is in continuity [38,
amage Control Surgery
D 87] and/or if a growth factor (e.g. teduglutide [88]) is given,
The strategy of Damage Control Surgery includes an abbre- this decision is now rarely made and we propose an aggres-
viated laparotomy with resection of necrotic bowel and the sive strategy regarding small resection.
absence of anastomosis or stoma [79, 84, 85], in an attempt
to reduce the operative time and to prioritize the resuscitation
in intensive care unit. For many surgeons, it has become the Follow-Up and Rehabilitation
standard of care for acute mesenteric ischemia management.
However, this strategy imposes the realization of a second- Post-ischemic Stenoses and Disorders
look surgery, which is usually performed 48 h after the pri-
mary procedure. When it does not progress to transmural necrosis, any mes-
In our routine practice, we do not advocate such strategy enteric ischemia can cause functional intestinal “sequelae”,
for all patients. As stated in the European Society for Trauma especially dysmotility disorders. In most cases, these lesions
and Emergency Surgery guidelines published in 2016, may appear when the intestinal injury has exceeded the heal-
Damage Control Surgery might only be performed in patients ing capacity mechanisms and has progressed to stenosing
with severe septic shock, [60] which in fact represent a parietal fibrosis and/or chronic mucosal ulcers. Occurring
minority of patients. We favor a strategy that includes the within a variable delay after refeeding, post-ischemic disor-
establishment of stomas of all resected bowel segments, as ders present as pseudo-occlusive syndrome, chronic diarrhea
this may have several advantages: (1) To avoid unnecessary and/or septic episodes of digestive origin (microbial translo-
a b
Fig. 8 Histopathological picture of post-ischemic enteritis. (a) Resection specimen showing a chronic post-ischemic enteritis with fis-
Resection specimen showing a non-penetrating chronic post-ischemic tula: the mucosa is ulcerated with a deep fistula infiltrating a fibrosed
enteritis: the mucosa is destroyed, ulcerated with submucosal fibrosis, muscularis propria
increased angiogenesis, and normal underlying muscularis propria. (b)
cations). The treatment is generally surgical. In some cases, –– Vascular: detection of persistent ischemia related to a
the motility disorder is transient and could be linked to the residual vascular stenosis, and secondary cardiovascular
intestinal smooth muscle response to ischemia-reperfusion. prevention with long-term anti-thrombotic treatment;
Indeed, recent physio-morphological studies of gastrointesti- [94]
nal peristalsis by magnetic enteromyography, have shown –– Digestive with the restoration of continuity with possible
that peristalsis was early and significantly decreased in the interposition of a reverse loop [95].
case of chronic mesenteric ischemia and normalized after
revascularization [89]. This could explain some functional
GI disorders, such as gastroparesis, which refeeding after Reanastomosis of Defunctioned Bowel
revascularization could unveil [90].(Fig. 8).
Patients, who are maintained with parenteral support, and
have had an extensive bowel resection with defunctioned
Nutritional, Vascular and Intestinal ileum and/or colon remaining in situ should, if possible, have
Rehabilitation bowel continuity restored. Preference is for doing this after
the acute AMI stage (the acute ischemia/reperfusion injury
In the event of multiple vascular involvement, primary revas- may compromise anastomosis healing and lead to septic
cularization of the superior mesenteric artery should always complications and further infarction and resction). This res-
be offered. If this is impossible, and due to the collateral net- toration of continuity is usually done at least six weeks after
work between the digestive arteries, revascularization of the the initial surgery, when the patient is healthy with a normal
celiac trunk and / or the inferior mesenteric artery can lead to BMI, and when the aetiology of the infarction has been iden-
resolution of the IIC [91]. In the extreme, in the patient not tified (thrombophilia screen, echocardiogram, 24 h tape and
eligible for revascularization, clinical improvement occurred CT angiography) and treated (e.g. under 60 years old and a
in 4 of 6 patients after infusion of iloprost (ilomedine®), a haematological/clotting abnormality given anticoagulation).
prostacyclin analog having a peripheral vasodilator, antiag- Before surgery the defunctioned bowel is outlined radiologi-
gregating and immunomodulatory effect and used in the cally to check mainly that there is no obstruction, and endo-
Raynaud syndrome, critical ischemia of the lower limbs and scopically to check that there is no sign of chronic mesenteric
high blood pressure [92]. ischemia. For the latter point, CT angiography may be
Proximal and/or extensive resection of intestinal necrosis repeated to check that the remnant gut blood supply is suffi-
can be complicated by a transient or definite short bowel syn- cient. Trophic distal feeding may be given into the defunc-
drome. The care of these patients must be provided in col- tioned ileum/colon after careful assessment of its viability
laboration with an expert intestinal failure unit [38, 93]. and vascular patency (see Chapter “Distal feeding and hydra-
Rehabilitation after mesenteric infarction is threefold: tion”). Following the re-anastomosis/stoma closure there
will be a reduction in parenteral requirements (volume,
–– Nutritional: screening and correction of hydro-electrolytic, energy and more nights off PS), stool frequency will decrease
caloric and / or vitamin / trace element deficits, and paren- (althought the stool is likely to be malodourous), there is less
teral support; chance of cholestasis and survival is increased. In one series
84 A. Nuzzo et al.
32% of patients (n = 28) with a residual small bowel length 8. Deitch EA. Multiple organ failure. Pathophysiology and potential
future therapy. Ann Surg. 1992;216(2):117–34.
of less than 51 cm had stopped parenteral nutrition com-
9. Zimmerman BJ, Granger DN. Mechanisms of reperfusion injury.
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established [38]. There is no need for a routine defunctioning 10. Nuzzo A, Maggiori L, Ronot M, Becq A, Plessier A, Gault N,
colostomy (to reduce stool frequency) even when the resid- et al. Predictive factors of intestinal necrosis in acute mesenteric
ischemia: prospective study from an intestinal stroke center. Am J
ual small bowel length is very short (e.g. less than 20 cm).
11. Boley SJ, Brandt LJ, Sammartano RJ. History of mesenteric isch-
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6) after septic shock, hemorrhagic shock, and severe trauma. Crit
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Care Med. 1997;25(11):1813–9.
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the recruitment into dedicated medical and research teams is
15. Deitch EA, Xu D, Kaise VL. Role of the gut in the development of
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EA. Gut-lymph hypothesis of systemic inflammatory response
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Crohn’s Disease
Mattias Soop and Simon Lal
Key Points apy. A pro-active approach to post-operative therapy is

1. The limited data on the risk of a patient with Crohn’s dis- required, where appropriate, with early radiological and
ease developing intestinal failure (IF) indicate a risk of at endoscopic surveillance and adjustment of medical ther-
least 8.5% in 20 years following index abdominal surgery. apy for recrudescent disease.
2. Crohn’s disease remains one of the most prevalent under- 9. Following surgery, attention must be given to subsequent
lying diagnoses among patients referred to an IF unit. Crohn’s disease management that aimed at preventing
3. Half of the patients with Crohn’s disease who develop IF recurrent disease.
do so due to abdominal septic complications following
surgery.
4. The incidence of abdominal surgery in Crohn’s disease is Introduction
decreasing in population-based studies.
5. Recognition of the risk factors in abdominal surgery for Intestinal surgery for Crohn’s disease may be for obstruc-
Crohn’s disease and judicious usage of double-barrelled tion, bleeding, perforation, abscess/fistula or rarely carci-
stomas are vital in reducing abdominal septic noma. Intestinal failure (IF) is a feared complication of
complications. Crohn’s disease. It is traditionally assumed that the main
6. Preoperative optimisation includes: delaying surgery mechanism is repeated surgical resections leading a short
until certain medications are reduced or weaned, malnu- bowel [1]. This assumption has led to a focus on bowel-
trition and anaemia are corrected by enteral or parenteral sparing strategies such as resection limited to macroscopic
nutrition (may be exclusive), smoking cessation and erad- disease [2] and strictureplasty [3]. While such strategies
ication of phlegmons and abscesses may allow safer pri- appear sensible, data on the epidemiology and mechanisms
mary anastomosis and improve outcomes. of IF in Crohn’s disease are limited. By reviewing these data,
7. The ‘Sepsis-Nutrition-Anatomy-Plan (SNAP)’ algorith- we will identify practices that have the greatest potential to
mic approach fosters a cohesive and systematic approach minimise the risk of IF in Crohn’s, and review special con-
for the multi-disciplinary team required to care for siderations in the management of IF in the context of Crohn’s
patients with type II intestinal failure. This includes disease.
detailed anatomical evaluation to define fistula(s), stric-
turing and areas of disease activity.
8. Characterisation of the patient’s pre-operative Crohn’s pidemiology of Intestinal Failure in Crohn’s
E
disease phenotype and response to previous medications Disease
will facilitate a tailored approach to post-operative ther-
In reports from intestinal failure units, Crohn’s disease is fre-
quently the most prevalent underlying diagnosis. Between
M. Soop (*)
Department of Inflammatory Bowel Disease and Intestinal Failure 1987 and 2011, 545 patients received home parenteral nutri-
Surgery, Karolinska University Hospital & Karolinska Institutet, tion (HPN) at the National Intestinal Failure Unit in Salford.
Stockholm, Sweden Of those, 168 or 31% had Crohn’s disease [4]. The corre-
sponding proportion from the Lennard-Jones Intestinal Failure
S. Lal Unit at St Mark’s Hospital in Harrow is 32% [5]. Notably, the
National Intestinal Failure Reference Centre, Salford Care
proportion of patients with IF who have Crohn’s disease has
Organisation & University of Manchester, Manchester, UK
e-mail: [email protected] reduced in the last few years in Salford; while Crohn’s was the

88 M. Soop and S. Lal
leading cause of IF in the 1980s, in recent years, the principal requiring re-laparotomy and that, cumulative loss of small
cause of IF in patients referred to the unit has been surgical bowel is the mechanism in a smaller proportion of patients.
complications in non-Crohn’s conditions [4]. The same trend Minimising the risk for abdominal septic complications is
has also been seen in a large cohort of managed at the therefore the most important priority in reducing the risk for
Rigshospitalet in Copenhagen over the last four decades [6]. IF in people with Crohn’s disease.
For people with Crohn’s disease and clinicians managing Several studies report attempts to single out demographic
this condition, the converse statistic, the risk of developing characteristics and phenotype at presentation of patients with
IF in Crohn’s disease, is more important. Unfortunately, the Crohn’s disease who develop IF. Given that complications of
prevalence and incidence of IF in Crohn’s disease are largely abdominal surgery are the main mechanism, it is not surpris-
unknown quantities. The only published large study ing that associations between such characteristics and IF
addressing this question is a Japanese multi-centre study of have been found to be weak; [10] not least because septic
the incidence of chronic, or type III, IF after index surgery complications following any operation are likely to be more
for Crohn’s [7]. In this unique study, some 1700 patients strongly associated with surgical factors, perioperative phys-
were prospectively followed over an extended time period iology and medications, rather than patient demographics
following index abdominal surgery. The cumulative inci- and phenotype. Nevertheless, such studies have reported
dence of type III IF (defined here as home parenteral nutri- associations between IF and an early diagnosis of Crohn’s
tion for a period of more than 12 months) was 0.8%, 3.6% disease, family history of inflammatory bowel disease, and
and 8.5% over 5, 10 and 20 years, respectively [7]. As some penetrating disease at diagnosis [10, 11]. It must be remem-
patients with Crohn’s disease will develop IF as a result of bered that the small number of cases in such studies limit the
extensive mucosal disease, without prior surgery, the overall validity of multivariable regression performed.
risk of IF in Crohn’s remains unclear. Nonetheless, the study
by Watanabe et al. indicates the potential magnitude of the
risk, at least following surgery [7]. Alternatives to Surgery in Crohn’s Disease
Given that surgery, and specifically complications of surgery,

echanisms of Intestinal Failure in Crohn’s
M cause most cases of IF in Crohn’s disease, evidence-based
Disease and multi-disciplinary efforts to reduce both the number of
operations required, and the associated risk of septic compli-
It is widely thought and taught that successive bowel resec- cations, will be the most effective strategies to reduce IF in
tions resulting in a short bowel is the main mechanism of IF this population.
in Crohn’s disease. This has led to development of bowel- The overall incidence of abdominal surgery in Crohn’s dis-
sparing techniques such as resection limited to macroscopic ease is currently falling. Recent population-based studies have
disease [2], strictureplasty [3] and endoscopic balloon dilata- shown that the rate of abdominal surgery in people with
tion, in efforts to minimise loss of small bowel. Crohn’s disease has decreased steadily during the past decades
Few data exist on this issue. A recent study of the cause of in Canada, the Netherlands, Sweden and other regions [12–
IF in 121 consecutive patients with Crohn’s disease referred 14]. This observation, as well as the relative reduction in
to a national unit in England found that successive bowel Crohn’s disease as a principal cause of IF in the UK and
resections were the cause only in 31% of patients referred Denmark as outlined earlier, [4, 6] may be attributed to shifts
[8]. This study found that 51% of referred patients with in medical management of the disease, improved training and
Crohn’s disease had developed IF as a direct consequence of specialisation of inflammatory bowel disease (IBD) clinicians,
abdominal septic complications to intestinal surgery. Patients centralisation of IBD care, increasing multidisciplinary man-
in this group all had re-laparotomies to address septic com- agement and, perhaps, increased patient empowerment in the
plications, resulting in enterocutaneous fistulation, loss of management of the disease through advocacy through patient
small bowel, or both. In many cases, the index operation was organisations leading to increased awareness of therapeutic
an elective ileocaecal resection complicated by anastomotic options available. Indeed, cohesive working between the
dehiscence or overlooked enterotomy. In this study, a further patient, physicians, dietitians, IBD nurses, pharmacists, psy-
12% of referred patients developed IF directly due to exten- chologists and surgeons is now recognized as the cornerstone
sive mucosal disease without surgery, and the remaining 6% to ensuring optimal care is tailored to the individual [15].
had a proximal small bowel stoma [8]. This large study con- Many interventions have been shown to directly reduce
firms findings in an earlier study from the same centre [9]. the rates of surgery or the risk of postoperative recrudescent
Therefore, existing data, although scant, suggest that Crohn’s disease. Smoking is the strongest modifiable risk
most patients with Crohn’s disease who develop IF do so fol- factor for recrudescent disease following surgery for Crohn’s
lowing abdominal surgery complicated by abdominal sepsis disease, increasing this risk by 150% [16]. Smoking cessa-
Crohn’s Disease 89
tion should therefore be a central component in the manage- enced practitioner and in an institution with 24-h surgical
ment of Crohn’s disease. This intervention needs to be service due to the risk of early or delayed perforation [23].
intensive and prolonged, necessitating investment of ade-
quate resource, in order to be successful [17].
Biologic monoclonal antibody therapy has become the educing Postoperative Morbidity
R
backbone of medical therapy for Crohn’s disease, and in Abdominal Surgery for Crohn’s Disease
population-based data suggest that the emergence of this
class of medication has been associated with a reduced rate Despite strategies aimed at reducing the need for surgery dis-
of abdominal surgery, [18]. One in five patients with lumi- cussed above, bowel resection will remain a pillar of man-
nal Crohn’s disease present with a so-called Crohn’s mass, agement in Crohn’s disease. Indeed, a recent multi-centre
due to an abscess or a phlegmon [19]. Traditionally, the randomised trial demonstrated that laparoscopic ileocaecal
finding of a Crohn’s mass has been considered an indication resection of primary unifocal disease may result in better
for laparotomy and bowel resection, as medical therapy outcomes than initial medical therapy, suggesting that sur-
alone has been thought insufficient to heal penetrating dis- gery should be part of ‘top-down’ management [26, 27].
ease. Data from the current biologic era suggests this may A key strategy to prevent IF in Crohn’s disease is to
no longer be an absolute rule. In a small case series of 13 reduce the risk of abdominal septic complications when sur-
patients who presented with a phlegmon or an abscess at gery is required. Specifically, this entails reducing the risk of
Beth Israel Hospital in Boston, 11 avoided surgery using a sepsis from anastomotic dehiscence and overlooked
combination of antibiotics, percutaneous drainage and inf- enterotomies.
liximab, while two required delayed surgery [20]. In a larger The data on risk factors for anastomotic complications in
study, 55 of 95 patients who presented with an intra-abdom- Crohn’s disease are abundant and relatively consistent [28–
inal abscess at Mayo Clinic in Rochester were managed 30]. The low number of events (dehiscence) is a caveat for
non-operatively with a combination of percutaneous drain- multivariable regressions often presented in such studies.
age, antibiotics and immunomodulator and/or anti-TNF Nevertheless, risk factors that are frequently identified
therapy. While all patients in this group responded to non- include: intra-abdominal abscess at the time of surgery, ste-
operarative treatment, 12 of the 55 patients required abdom- roid usage (≥10 mg prednisolone daily or equivalent) within
inal surgery during the subsequent 45 months [21]. A 2 weeks of surgery and preoperative weight loss (>10%).
meta-analysis of the role of percutaneous drainage in intra- Recrudescent disease, hypoalbuminaemia and smoking are
abdominal abscesses in Crohn’s disease suggests that this other risk factors identified in some studies [17, 28].
approach may help avoid laparotomy in up to 30% of A contested issue in inflammatory bowel disease surgery
patients [22]. is whether concurrent biologic therapy increases periopera-
As the above studies indicate, case selection is important tive morbidity, and anastomotic complications in particular.
and many patients with intra-abdominal collections will still The largest prospective published study on this issue in
require surgical resection. Also in this group, a staged Crohn’s disease is a French multi-centre study in 592
approach with initial percutaneous drainage is likely to reduce patients. Following adjustments for differences in disease
morbidity and stoma rates and may make laparoscopic resec- severity, an increase of overall morbidity and intraabdominal
tion more realistic. Percutaneous drainage, rather than sur- septic complications in patients treated by preoperative anti-
gery, is therefore the initial approach recommended by the TNF therapy was demonstrated [31]. It is important to note
European Crohn’s and Colitis Organisation (ECCO) [23]. that data associating systemic steroid therapy and postopera-
Furthermore, when septic complications following surgery tive morbidity are stronger and more consistent than the data
do occur, percutaneous drainage has an additional important on biologic agents, hence most clinicians regard steroid ther-
role in treating peri-anastomotic abscesses, thereby avoiding apy as the more hazardous of the two classes [32–34].
immediate relaparotomy in selected cases [24]. Recognition of risk factors present enables a more
In recent years, endoscopic balloon dilatation has also informed decision-making at surgery, in particular regarding
taken a key place in the management of short strictures, in whether to form a primary anastomosis at resection. For
particular anastomotic strictures. In the largest case series to patients with significant risk factors, a double-barrelled
date, 776 dilatations were performed in 178 patients with (split) stoma should instead be formed, which can then sub-
strictures <5 cm in length. The technical success rate was sequently be reversed via a peristomal incision when risk
89% and the perforation rate 1.4%. After 5 years, 64% of factors have been fully addressed [34].
patients had avoided surgery [25]. The ECCO guidelines Importantly, nearly all of the risk factors discussed above
place endoscopic balloon dilatation as the preferred tech- are modifiable. Preoperative optimisation pathways for sur-
nique to manage symptomatic short anastomotic strictures, gery for Crohn’s disease have recently been proposed, com-
but such procedures should only be performed by an experi- bining interventions that correct or minimise the impact of
Fig. 1 Example of a preoperative optimisation pathway that can be used in surgery for Crohn’s disease. As data are still emerging on several
components, chosen targets are pragmatic. ADA, adalimumab. IFX, infliximab. VEDO, vedolizumab. USTE, ustekinumab
identified risk factors [35–37]. Such pathways complement exclusive enteral diet is increasingly used to minimise the
enhanced-recovery pathways for patients undergoing sur- risk of disease flare-up and to correct malnutrition, [42, 43]
gery for Crohn’s disease [38]. They aim to reduced overall and often parenteral nutrition is indicated. An example of a
risk, reduce the risk of anastomotic complication and mini- preoperative optimisation pathway for IBD surgery is sum-
mise stoma rates. marised in Fig. 1.
Furthermore, by down-staging Crohn’s disease and eradi- It is important to monitor patients during such preopera-
cating Crohn’s masses, a laparoscopic approach may be pos- tive optimisation, and to recognise that some patients are too
sible in more cases. Laparoscopy has specific benefits in unwell to allow full optimisation. In those cases, early sur-
Crohn’s disease. In addition to the well-described short-term gery is safer, with exteriorisation of the bowel as stomas, and
benefits on postoperative recovery, [39] laparoscopy results laparotomy rather than laparoscopy is often required.
in less wound morbidity and reoperation rates than
laparotomy [40]. Cumulatively, this advantage becomes
increasingly important in the patient with Crohn’s disease educing the Risk of Recrudescent Disease
R
who may require several abdominal operations during their After Surgery for Crohn’s Disease
life. Laparoscopy is therefore the recommended modality for
surgery for Crohn’s disease in the ECCO guidelines, [23] A well functioning IBD unit with clear communication
and is possible also in penetrating disease treated prior to between surgical and medical teams is required to time ini-
surgery [41]. tiation of medications aimed at reducing the risk of recrudes-
The duration of preoperative optimisation pathways cent disease and resume monitoring of disease activity.
described varies from 4–8 weeks, during which malnutrition, The literature on post-resectional medical therapy is too
smoking, sepsis and steroid and/or biologic therapy are large to summarise here. A large network meta-analysis has
addressed. For steroid therapy, one proposed target is to comprehensively reviewed this literature in 2015 [44]. This
reduce the dose to <10 mg prednisolone daily (or equivalent) landmark status update demonstrated that anti-TNF mono-
for a period of 4 weeks [29]. For biologic agents, safety data therapy is by far the most efficient therapy (relative risk of
are still emerging. In practice, an estimate of safe wash-out clinical recrudescence 0.04 compared to placebo) followed
periods for each drug has to be made. During this period, by antibiotics (RR 0.26), immunomodulator therapy (RR
Traditional Future teral nutrition if it is allowed to prevail [50]. Early interven-

tional radiology is a key resource in management of type II
IF, as it achieves source control in most cases [51].
Occasionally, early relapatotomy is required for source con-
Diagnosis Diagnosis
trol [52].
Bowel resection Clinicians who do not regularly manage type II IF may be
Bowel resection tempted to embark on definitive surgery early after presenta-
tion, in an attempt to restore gastrointestinal continuity and
Bowel resection Endoscopic balloon discharge the patient in nutritional autonomy. However, early
dilatation reconstructive surgery is detrimental for two important rea-
Bowel resection sons. Firstly, a majority of postoperative enterocutaneous
Bowel resection fistulas heal spontaneously within the first 8 weeks. Bowel
rest and parenteral nutrition may be helpful and are reason-
Endoscopic balloon
Bowel resection able interventions during this period [48]. Secondly and
dilatation
more importantly, results of definitive surgery for persistent
fistulas are directly related to the interval allowed for local,
Fig. 2 A challenge in contemporary management of Crohn’s disease:
physiological and psychological recovery to occur. Fistula
To reduce the lifetime incidence of abdominal surgery, and to make
each operation safer, as compared to traditional surgery. Current data recurrence rates are as high as 25% when definitive surgery
from several regions of the world suggest that these changes are already is performed within the first couple of months, [53] but
occurring below 5% after 12–18 months. During this interval, most
patients are at home with parenteral nutrition while they
0.36) and mesalasine (RR 0.60). Therapy should be tailored recover nutritionally, and also psychologically, from previ-
to the individual patient, taking into account factors such as ous surgery and complications.
disease phenotype and previous surgeries. Regardless of In Crohn’s disease, surveillance of disease remains impor-
post-resectional medical therapy, early surveillance with tant during this phase. Disease recrudescence is rarely seen
ileocolonoscopy after 6 months after ileocaecal resection, in practice during this phase, perhaps because the gastroin-
with step-up of medical therapy when recrudescent mucosal testinal tract is rarely in continuity and the amount of small
disease is found, has been shown to reduce the risk of endo- bowel may be reduced. Rarely, aggressive medical therapy is
scopic recrudescence on colonoscopy performed at indicated once, of course, any sepsis has been eradicated.
18 months [45].
With optimal disease surveillance, medical therapy, judi-
cious surgery with preoperative optimisation and usage of Management of Type III Intestinal Failure
endoscopic balloon dilatation when possible, a picture in Crohn’s Disease
emerges with safer operations being performed more widely
spaced out during the lifetime of people with Crohn’s dis- Safe HPN allows long-term survival in type III IF. In the lon-
ease, (Fig. 2) as indeed demonstrated by recent population- gest and largest series published, data collected over 30 years
based studies. Future data will show whether this will result suggest that long-term survival depends primarily on under-
in a reduced incidence of intestinal failure in Crohn’s. lying diagnosis [4]. Overall 10-year survival was 59% in this
series for all disease types, with patients with Crohn’s dis-
ease having the best survival of the diagnostic groups [4].
Management of Type II Intestinal Failure As in type II IF, it is an empirical observation that flare-
in Crohn’s Disease ups of Crohn’s disease activity are rare. This may be due to
reduction of the intestinal length, lack of gastrointestinal
The management of IF in Crohn’s disease is no different than continuity, particularly lack of colonic continuity reducing
the general management of IF and, indeed, much of the any risk of anastomotic recurrence. When it does occur, it
SNAP (Sepsis, Nutrition, Anatomy, Procedure) protocol (see can present insidiously as increasing fistula or stoma output,
Chapter “Acute surgical intestinal failure. Sepsis and entero- failure to thrive, weight loss, jaundice or unexplained sys-
cutaneous fistula(s)”) was developed specifically for Crohn’s temic inflammation.
disease [46]. When flares do occur, standard medical management
Briefly, sepsis control is the first priority, because sepsis is principles apply, modified by often impaired absorption of
the cause of death in the majority of the 10% of patients with orally administered medications. It is important to consider
type II IF who do not survive [47–49]. In addition, sepsis the individual’s previous phenotype in this setting and, in
prevents anabolism and recovery despite aggressive paren- those with a previous aggressive small bowel phenotype
should be considered for prophylactic Crohn’s disease ther- Case selection is key for favourable outcomes and safety
apy, with on-going monitoring for recurrence. While concern for these three novel therapies. In England, proposed surgi-
may exist for catheter-related infections in patients receiving cal candidates are discussed at the bimonthly National Adult
immunosuppressive medications, recent data from the Small Intestinal Transplantation forum, which advises on
authors’ unit demonstrate that the risk of such infections is whether to proceed.
not increased in patients with Crohn’s disease receiving ther-
apy and that a meticulous approach to catheter care and train-
ing is the cornerstone to preventing catheter infections,
enabling very low infection rates to be achieved over many
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Peritoneal Adhesions
and Encapsulating Peritoneal Sclerosis
Titus Augustine, Alison Culkin, and Mattias Soop
Key Points 7. Patients with adhesions/EPS are encouraged to chew

1. Adhesions are common after abdominal surgery and up their food well before swallowing. A low insoluble fibre/
to 5% will need a repeat admission for them. The chance low residue diet can reduce the chance of obstructive
of developing them increases with the number of abdomi- symptoms occurring.
nal operations.
2. Adhesions/intraperitoneal fibrosis may be caused by
ischaemia, infection, abrasions, spillage of gastrointesti- Adhesions
nal contents, desiccation, excessive heat/light/electrocau-
tery/sutures, fibres/glove powder and some medications. What Are They?
Reducing these factors reduces the chance of developing
adhesions. Adhesions in the peritoneal cavity are non-anatomical attach-
3. Adhesions may cause recurrent episodes (partial or comments between visceral and/or parietal peritoneal surfaces.
plete) of bowel obstruction. These episodes may be They can be congenital or acquired. Congenital adhesions
reduced by a low fibre diet. They may also be associated can range from complete peritoneal encapsulation, a rare
with infertility. cause of bowel obstruction in children and adults, to con-
4. Adhesions and adhesion-related readmission to hospital genital bands that can cause internal herniation and volvulus.
are more common after open than laparoscopic surgery Studies reveal that 5–27% of those who have never had
5. Topical agents reduce the formation of adhesions but abdominal surgery have abdominal adhesions [1, 2]. This
have not been shown to reduce readmissions or reopera- prevalence increases with age, suggesting that adhesions
tions for adhesions. often form secondary to abdominopelvic events such as
6. Encapsulating peritoneal sclerosis (EPS) is the most diverticulitis [2].
severe form of adhesions and may cause a frozen abdo- Adhesions are most prevalent in people who have had
men on which surgery is very difficult. previous surgery. Prospective data from the pre-laparoscopic
era demonstrated that the prevalence of adhesions in people
T. Augustine (*) undergoing laparotomy increased from 11.5% in people who
Manchester Royal Infirmary, Manchester University NHS had not undergone previous surgery to 93% in those who had
Foundation Trust, A United Kingdom National Referral Centre for
[2]. Most of the adhesions noted had formed between the
Encapsulating Peritoneal Sclerosis Surgery, Manchester, UK
greater omentum and the abdominal wall scar.
Division of Diabetes, Endocrinology and Gastroenterology, Faculty
Histological studies of postoperative adhesions reveal
of Biology, Medicine and Health, University of Manchester,
Manchester Academic Health Science Centre, Manchester, UK that they are typically collagenous bands initiated either by
e-mail: [email protected] peritoneal injury or bleeding or a combination [1]. In the
A. Culkin past, foreign bodies were the dominant cause of postopera-
Nutrition & Dietetic Department, St Mark’s Hospital, tive adhesions, but this has likely diminished as talcum pow-
London, England der, starch and textile materials have become replaced by
safer materials [1].
M. Soop Additional causes of acquired adhesions between sur-
IBD and Intestinal Failure Surgery, Karolinska University
faces in the peritoneal cavity include neoplasia, endometrio-
Hospital, Solna, Sweden
sis, radiotherapy and a range of infections such as chlamydia
Karolinska Institutet at Danderyd Hospital, Stockholm, Sweden
and tuberculosis.

96 T. Augustine et al.
Adhesions in the Context of General Surgery gery. In a much larger number of readmissions, 38% of the
21,347, adhesions were judged to be “possibly” causative
Peritoneal adhesions play a role in the pathogenesis of an based on a set of criteria. The SCAR-1 study established that
array of symptoms and conditions of affected organ systems. readmission to hospital after open abdominal surgery is com-
Gastrointestinal and gynaecological complaints are the most mon and frequently directly or possibly caused by adhesions.
common. Here, we will focus on complaints seen in general The subsequent SCAR-2 study assessed changes during the
surgery that may or may not be associated with adhesions. time period 1996–1999, observing no change in the risk of
readmission after open abdominal surgery [9].
Abdominal Pain The SCAR-3 study further analysed a cohort operated in
Chronic or recurring abdominopelvic pain is common after the financial year 1996 with regard to types of index surgery
abdominal surgery and adhesions are often thought of as an [10]. The risk of readmission for documented adhesions dur-
important cause of such symptoms. However, the evidence ing the subsequent 5 years was 3.8% for the whole cohort,
linking adhesions themselves and pain is poor. There is sup- and 5.2% excluding appendectomy. The risk was particularly
portive experimental evidence, such as the findings of sen- increased following panproctocolectomy (15.4%), total col-
sory nerve fibers in adhesions [3, 4]. ectomy (8.8%) and ileostomy procedures (10.6%) and
It is not straightforward to scientifically study the role of decreased following small bowel surgery (1.8%) and appen-
adhesions as a cause of symptoms, as intraperitoneal adhe- dicectomy (0.9%) [10]. The risk in patients who previously
sions are so prevalent in the population [2]. We instead have had had open abdominal surgery was twice that of those who
to rely on studies of adhesiolysis to examine this role. In a had not. Although multivariable analyses were not per-
landmark study from the Netherlands, 100 patients with formed, univariable analyses suggested that increasing age
long-term abdominal pain after laparotomy underwent diag- appeared to protect against readmission for adhesions, and
nostic laparoscopy and, if adhesions were found, randomised Crohn’s disease did not change the risk [10].
to laparoscopic adhesiolysis or no further dissection [5]. The concept that some patients form adhesions more
Three to 12 months after laparoscopy, pain scores decreased readily than others is supported by long-term follow-up in
in both study groups, with no differences between groups. the LAPAD study from the Netherlands [11]. In this study of
This suggests a placebo effect, and no additional effect of 604 patients who had elective abdominal surgery in a single
adhesiolysis on pain. centre from 2008 to 2010, 32% were found to have severe
Seventy-three patients were then followed up at 12 years adhesions, mostly from previous laparotomies, while 68%
[6], and at this timepoint significantly worse outcomes were had mild or no adhesions. During a relatively short median
found in the group that had undergone adhesiolysis, includ- follow-up of 46 months, 38 of the 604 (6.3%) re-presented
ing more frequent pain and use of analgesics and, perhaps with adhesive bowel obstruction. On multivariable regres-
most significantly, an increased number of reoperations to sion, the finding of severe adhesions at index surgery was a
address adhesions. strong predictor of subsequent adhesive small bowel obstruc-
Thus, while it remains possible that adhesions cause tion [11].
abdominal pain, adhesiolysis has no benefit in the short term, In summary, some 60% of cases of small bowel obstruc-
and an adverse impact in the long term, on this symptom. It tion are caused by adhesions, and in the long term of
should be avoided as a therapy for pain alone. 4–10 years, at least 5% of patients undergoing abdominal
surgery will be readmitted with proven adhesive bowel
Intestinal Obstruction obstruction. Of note, these data are from cohorts of patients
It is clear that peritoneal adhesions, whether congenital, who nearly all underwent open surgery. The impact of mini-
postoperative or otherwise acquired, are a dominant cause of mally invasive surgery on adhesion-related morbidity is
small bowel obstruction: meta-analysis suggests that 56% of examined below.
cases are caused by adhesions [7].
The magnitude of the problem of postoperative adhesions orbidity During Future Operations
M
has been extensively studied in the so-called SCAR studies, Another consequence of adhesions is lengthy adhesiolysis
registry studies that followed large cohorts who had abdomi- during future intraperitoneal operations. This is not only
nal surgery in Scotland. In the SCAR-1 study, 29,790 patients time-consuming, but is associated with increased morbidity.
who underwent laparotomy in 1986 were retrospectively The initial LAPAD study focused on adhesiolysis as a risk
studied for 10 years [8]. One in three patients were readmit- factor for adverse outcomes [12]. In this prospective study,
ted to hospital during this time period. Most were readmitted 755 elective open or laparoscopic abdominal operations
more than once, resulting in a total number of readmissions were observed. Adhesiolysis was required in 475 operations,
of 21,347. Of those readmissions, 5.7% were documented as and in 50 of those (10.5%) an accidental enterotomy was
being caused by adhesions, in most cases by findings at sur- made. Adhesiolysis added a median of 20 (range 1–177)
Peritoneal Adhesions and Encapsulating Peritoneal Sclerosis 97
minutes to the operation. The risk was of enterotomy was adhesiolysis will improve intestinal function. Helpful tools
particularly increased in operations requiring more than an in this assessment include longitudinal imaging to identify
hour of adhesiolysis. In the 280 operations during which any fixed transition points, histopathology with specific
adhesiolysis was not required, no enterotomies were made. immunohistochemistry on full-thickness small bowel sam-
The difference in enterotomy risk helps explain several asso- ples to identify known dysmotility disorders such as visceral
ciations between adhesiolysis and adverse outcomes seen in myopathy [17], and in selected cases a trial of a loop enter-
this study, such as postoperative sepsis, increased length of ostomy proximal to a suspected obstructive site to assess
hospital stay and increased costs [12]. whether function in the proximal small bowel normalises.
ost to Healthcare Services

C
Calculating the economic costs of adhesions is complicated Diagnosis
as it encompasses the costs of clinic and emergency visits,
diagnostic tests, hospital admissions, surgery performed to Diagnosing Adhesions
treat adhesions, adhesiolysis during other peritoneal surgery, In the absence of concurrent small bowel obstruction, adhe-
loss of income from admissions, and other costs. sions in the peritoneal cavity are not visualised by static
The LAPAD study estimated that the mean hospital cost radiological imaging such as computed tomography or mag-
for each patient undergoing elective surgery increased from netic resonance imaging. However, dynamic ultrasonogra-
USD 14,063 in those without adhesions to USD 18,579 in phy is emerging as a promising diagnostic modality, in
those with adhesions in the Netherlands in 2010 [12]. particular in the obstetric field. In the so-called visceral slide
A Finnish population-based study estimated that, at 1999 test, the viscera are visualised by ultrasound in different
currency levels, annual direct hospital for small bowel adhe- regions of the abdomen, and the extent of movement in
sion in the country was GBP 2,077,796, similar to the costs response to normal or forced respiration is assessed.
of treating rectal cancer throughout the country [13]. Restricted or absent movement, or slide, is thought to reflect
peritoneal adhesions. A recent meta-analysis of 25 observa-
tional studies focused on the periumbilical area, commonly
Adhesions in the Context of Intestinal Failure used for laparoscopic access to the peritoneal cavity [18]. A
positive predictive value of 60.4% and, more importantly, a
Although extensive peritoneal adhesions have long been rec- negative predictive value of 99.2% was demonstrated [18].
ognised as a cause of intestinal failure [14], data on this asso- The gold standard used in these studies was the findings on
ciation are scarce. In the largest published series of long-term laparotomy or laparoscopy. While this finding has implica-
(3 months or longer) parenteral nutrition, mechanical tions for minimally invasive surgical techniques, better data
obstruction was the mechanism of intestinal failure in 20/545 are needed on visceral slide sonography in the rest of the
(3.7%) of patients treated at the Irving National Intestinal abdomen.
Failure Unit in Manchester, UK during the period 1978–2011 Abdominal dynamic magnetic resonance imaging, or
[15]. In a snapshot study from the same unit in 2017, the cine-MRI, is a similar technique that has been evaluated with
proportion was 15/273 (5.5%) cases [16]. However, these promising results [19]. In a head-to-head comparison,
studies included patients with cancer as the underlying diag- dynamic ultrasound and MRI both performed well, and cine-
nosis, and the number of patients with benign adhesions is MRI was superior in detecting adhesions between viscera
likely to be less. such as small bowel [20].
Given the prevalence of peritoneal adhesions in the popu- Dynamic imaging is yet to enter routine clinical practice,
lation, the risk of developing intestinal failure through this but the techniques are available and could prove valuable in
mechanism can reasonably be assumed to be small. investigating unclear symptoms or preparing for complex
Empirically, cases where benign adhesions are the dominant abdominal re-operative surgery. The gold standard in diag-
cause of intestinal failure are unusual. Where this occurs, nosing adhesions remains direct visualisation at surgery.
adhesions are often the result of multiple operations, previ- During surgery it is also possible to systemically assess and
ous peritonitis and/or implanted mesh. grade adhesions (Fig. 1). Several scores have been proposed.
A much more common clinical challenge is the patient The Zühlke score described in 1990 is based on the histopa-
with small bowel dysmotility who has previously undergone thology of adhesions, grading them from weak to thick [22].
surgery, often subtotal colectomy for suspected slow-transit The increasingly used peritoneal adhesion index (PAI)
constipation. Such patients frequently have radiological find- instead describes the severity of adhesions in the regions of
ings consistent with both intestinal dysmotility and adhesive the abdomen, and provides a summative score (Fig. 2) [23].
obstruction. Assessing the contribution of adhesions in such In brief, adhesions observed at surgery are scored 0 (no
cases is crucial in order to predict the likelihood that surgical adhesions)–3 (very strong vascularised adhesions). The
a b
c d
Fig. 1 Severity of adhesions. (a) no adhesions (grade 0); (b) flimsy et al., Adhesions after laparoscopic and open ileal pouch–anal anasto-
thickness, avascular (grade 1); (c) moderate thickness, limited vascular- mosis surgery for ulcerative colitis, Br J Surg, 2012, 99(2);270–5, by
ity (grade 2); and (d) dense thickness, vascularized (grade 3). (Hull permission of Oxford University Press [21])
abdomen is divided in nine even regions, and adhesions in an obstruction resolves it is followed for 1–3 days by diar-
each region are scored on this scale. A tenth score is deter- rhoea or if a stoma a high output.
mined for inter-loop adhesions. The ten scores are added up Useful radiology includes plain abdominal X-ray and
and the sum is the total PAI score. cross-sectional imaging, and findings include dilated small
bowel up to the point of obstruction (diameter above 3 cm),
iagnosing Adhesive Intestinal Obstruction
D air–fluid levels and an absence of gas in the colon. Cross-
When adhesions are complicated by concurrent intestinal sectional imaging often confers additional information, such
obstruction, the clinical presentation and radiological find- as the cause of obstruction and can show signs of
ings are more sensitive and specific. The patient often pres- ischaemia.
ents with a sudden onset of colicky central abdominal pain A difficulty arises when a patient presents with intermit-
which is worse in the ileum than jejunum and may follow tent symptoms suggesting small bowel obstruction. Ensuring
eating a fibrous/grisly bit of food (often not well chewed). that urgent diagnostic imaging is obtained before symptoms
This may be followed by vomiting, a yellow/green vomit resolve is the only way to diagnose obstruction in such
suggest proximal small bowel obstruction and a dark brown cases.
fluid a more distal one. The bowel/stoma may stop working. A similar problem is posed when diagnosing low-grade
The abdomen may be distended with loud bowel sounds. If small bowel obstruction. Such relative obstruction may not
Fig. 2 Peritoneal Adhesion Index (adapted from Coccolini et al. [23]). Each area of the abdomen is ascribed an adhesion related score. The sum
of the scores will result in the PAI
result in pre-stenotic dilatation, resulting in a sensitivity of rate through a nasojejunal tube, is more sensitive to detect
CT in this condition of only 50% [24]. Enteroclysis, in which low-grade obstruction; indeed, some studies suggest the
contrast is delivered directly into the small bowel at a high technique is near 100% sensitive [25].
Prevention Table 1 Adhesion prevention strategies

Awareness of risk factors
The literature reviewed above shows that surgical adhesioly- Increasing age
sis is followed by formation of new adhesions. There is cur- Number of previous laparotomies
Complexity of the procedure
rently no other treatment of adhesions. Therefore, prevention
Location of the procedure (increased in pelvic procedures)
in routine surgical practice is a crucial priority to reduce the Crohn’s disease
considerable morbidity and costs associated with adhesions. Resections for colonic cancer
Proctocolectomy, total colectomy, ileostomy
Surgical Technique Conservatively treated localised peritonitis (appendicitis,
Several surgical techniques have been proposed to decrease diverticulitis)
adhesion formation following intraperitoneal surgery Surgical technique
Careful tissue handling
(Table 1). They include minimally invasive approaches; clo-
Sharp dissection using sharp instruments
sure of the parietal peritoneum; avoidance of foreign bodies Avoid crushing tissue
such as glove powder, sutures and meshes; prevention of Avoid unnecessary dissection
infection; and peritoneal lavage. A 2012 meta-analysis found Attention to detail with ligatures
no effects of such techniques on rates of subsequent clini- Optimum tissue beyond ligature to reduce ischemic tissue
cally significant adhesions or adhesions on subsequent sur- Avoid excessive redundant ends of non-absorbable tissue
gery [26]. Avoid bowel exposure and desiccation
Avoid drying of tissue, in exposed area with adherence of clot
In regards to minimally invasive surgery, however, the
Use laparoscopic technique if possible
amount of high-quality data has matured further since this Robotic techniques
meta-analysis. There is now high-grade evidence that sup- Avoid peritoneal suturing during wound closure
ports the hypothesis that laparoscopic surgery significantly Use of physical antiadhesion barriers
decreases subsequent adhesion-related morbidity. The SCAR Seprafilm® Adhesion Barrier (Cambridge, MA; Genzyme
study group retrospectively studied 72,270 patients who Corporation)
Gore Preclude Surgical Membrane Adhesion Barrier Flagstaff, AZ;
underwent laparoscopic or open abdominal or pelvic surgery
Gore and Associates Inc.
in the period 2009–2011 [26]. After 5 years, 1.7% in the Gynecare Interceed Absorbable Adhesion Barrier (Somerville, NJ;
laparoscopic cohort vs. 4.3% in the open surgery cohort had Johnson and Johnson)
been readmitted to hospital with proven adhesion-related Adept Solution: Adhesion Reduction Solution (Deerfield, IL; Baxter
morbidity, mainly adhesive small bowel obstruction. Healthcare Corporation)
Intercoat (AC AG Group, Kaltenkirchen, Germany)
Adjusting for confounders, the authors found that laparos-
Fibrin Sheet (TachoComb, Tokyo, Japan)
copy reduced the risk of adhesion-related readmission within
Antibiosis techniques to reduce bacterial translocation
5 years of surgery by 32% [27]. Mechanical bowel preparation
Data from the series of large randomised trials that first Antibiotics
evaluated safety and efficacy of laparoscopic colon and rec- Pharmacologic agents (anecdotal and experimental)
tal cancer resection have mostly been unable to demonstrate Antiinflammatory agents (Steroids, NSAIDS)
effects on long-term adhesion-related morbidity [28–30]. Tamoxifen (Synthetic nonsteroidal antiestrogen agent, with
antifibrotic properties)
One recent randomised trial did demonstrate reduces rates of
Anticoagulants including heparin, ancrod.
adhesions in the minimally invasive surgery group [31]. A Calcium channel blockers
recent meta-analysis of randomised trials pooled 4656 Vitamin E
patients and did not find an association between laparoscopy Halofuginone
and rates of adhesion-related morbidity [32]. The lack of
effect in randomised trials is not surprising given the low
event rate. Very large study groups would be required to attention to detail is important in preventing adhesion forma-
definitively demonstrate an effect of laparoscopy on adhe- tion, although this factor is difficult to quantify and study.
sions in a randomised design. Both tissue injury and bleeding play a role in initiating adhe-
In summary, available randomised trials are small in rela- sion formation, and are best minimised. Tissue injury is min-
tion to the event rate of measurable outcomes, and arguably imised by focused sharp dissection, avoiding blunt dissection,
the best evidence available is large clinical registry data. The optimum settings in energy devices, careful retraction of tis-
recent, large SCAR study update provides strong support for sues and using inert irrigation fluid at body temperature.
the reasonable notion that less tissue damage results in less
formation of adhesions. opical Biochemical Agents
T
It is also reasonable to suggest that, regardless of surgical Given the significant prevalence of adhesions following
approach, atraumatic surgical technique and meticulous intraperitoneal surgery and their associated morbidity
and costs, their prevention by chemical and pharmaco- anagement in the Context of Intestinal
M
logical agents has been a large and active research field. Failure
Strategies evaluated include systemic agents such as anti-
inflammatory drugs and anticoagulants, and chemicals While type 3 intestinal failure is rarely attributed solely to
applied topically in the surgical wound. To summarise intraperitoneal adhesions, they are an important factor in the
this field, to date none has been widely applied in clinical management of type 2 intestinal failure, specifically in deter-
practice. mining the timing of reconstructive surgery. For many rea-
A Cochrane meta-analysis of randomised and pseudo- sons discussed extensively in chapter “Acute Surgical
randomised trials of topical agents, most recently updated in Intestinal Failure. Sepsis and Enterocutaneous Fistula(s)”,
2009, concluded that a hyaluronic acid/carboxymethyl mem- reconstructive surgery for IF is typically delayed until
brane reduced the incidence and severity of adhesions as 6–12 months after the most recent surgery. One of the key
assessed at a second, planned operation months later (Odds considerations is the maturation and, ideally, resolution of
ratio 0.15), but did not affect the need for unplanned reopera- adhesions. There is no longitudinal data on these processes,
tion for adhesive small bowel obstruction (Odds ratio 0.84) but it is a common clinical observation that reoperative sur-
[33]. It cautioned that some data suggested an increased risk gery within the first 2–3 months is very technically challeng-
of anastomotic dehiscence when the agent was applied near ing with dense and often still inflamed adhesions; that
an anastomosis. The hyaluronic acid/carboxymethyl mem- reoperative surgery after a period of years is much more fre-
brane was the only agent for which sufficiently high-quality quently straightforward and the adhesions encountered soft
data were available for meta-analysis [33]. and filmy. The difficulty is determining the ideal time point
A 2014 meta-analysis included non-randomised stud- between these extremes when relaparotomy is reasonably
ies in addition to randomised trials, and made similar con- safe.
clusions regarding effects of topical agents on adhesion Useful clinical tests are simple inspection and palpation
formation, reoperative rates, and importantly on anasto- of the abdomen. A soft, flexible abdominal wall is promising.
motic complications [34]. Furthermore, other adverse If there is a stoma or an enterocutaneous fistula, it is highly
effects were also evaluated, and found to be no different useful to observe its movement when the patient coughs or
between treatment and control groups. These included strains; free movement and a slight prolapse of the bowel is
wound healing complications and abscess formation. The a good sign that the abdominal viscera are not rigidly held in
latter conclusion has been challenged, however, as a pre- a frozen abdomen. If clinical examination suggests that the
liminary report of a large observational study was not abdomen is dense and inflammation not yet resolved, it is
included [35]. This study of 1885 patients who underwent best to delay reconstructive surgery and re-evaluate after
proctectomy and ileal pouch-anal anastomosis reported an 6 months.
increased incidence of pelvic sepsis in patients treated In type 3 IF, adhesions are often present and the challenge
with hyaluronic acid/carboxymethyl membrane (10.2%) is to assess their relevance. As mentioned above, this is par-
when compared to those who were not treated (6.8%, P ticularly the case in conditions associated with impaired
0.016) [36]. small bowel motility, such as dysmotility syndromes.
In the absence of clinical efficacy, it is difficult to support
routine usage of hyaluronic acid/carboxymethyl membranes
or any other agents to prevent adhesions. Some centres rou- Encapsulating Peritoneal Sclerosis
tinely use the membranes around the two limbs of a tempo-
rary diverting loop ileostomy as it traverses the abdominal Encapsulating peritoneal sclerosis (EPS) is the most severe
wall, in order to reduce adhesions when it is taken down form of adhesions/intraperitoneal fibrosis and is a descrip-
some 6–12 weeks later. Such usage appears safe and advan- tive abdominal manifestation of a spectrum of aetiologic
tageous. It is also reasonable to consider the agent when conditions [37]. A diagnosis of EPS in the current era is con-
reoperating patients with a known capacity to form trouble- sidered synonymous with the clinic-pathologic syndrome
some adhesions. which is an important morbidity of long-term peritoneal
dialysis. All forms of peritoneal sclerosis with or without
Systemic Agents encapsulation can lead to intestinal dysfunction and even-
Non-steroidal anti-inflammatory drugs are the most widely tual intestinal failure. The pathophysiologic mechanism in
studied but their clinical efficacy is questionable. the different diseases varies depending on the specific aeti-
Corticosteroids have poor efficacy and are associated with ology. Clinical manifestations occur when there is the for-
immunosuppression and delayed wound healing. mation of a membrane or peritoneal sclerosis which causes
Fibrinolytics have a risk of impaired wound healing and/or adhesions, between bowel loops, and also between the
bleeding. bowel and the parietal peritoneum, causing restriction of gut
motility. With progression of disease, the gut can become the pelvis and the visceral peritoneum covering the abdomi-
cocooned and completely encased, causing progressive nal viscera and the bowel. The surface area of the peritoneum
intestinal failure. The biologic processes underlying the is over 1.8 m2 in area, with an interface of peritoneal fluid, of
individual aetiology, disease progression and presentation approximately 100 mL, which allows lubrication and free
are varied and multifactorial and clinical presentations can movement of the bowel. The fluid is an ultrafiltrate of plasma,
be subtle and mimic other pathology, leading to delayed providing a frictionless environment for the abdominal
diagnosis or late presentations. The overarching clinical pic- organs.
ture however is one of GI dysfunction associated with intra- The peritoneal surface is formed of a single layer of cells
peritoneal inflammation associated with progressive lining the peritoneal cavity, first described by James Douglas
nutritional deficiency, eventually leading, if untreated to an in 1730, and then later called the mesothelium by Binot in
acute presentation requiring surgical intervention. On a 1980. These mesothelial cells are 25 μm in diameter, are
background of significant associated comorbidity, there derived from the mesoderm and possess both mesenchymal
may be a high risk of mortality or intestinal failure. and epithelial characteristics (Figs. 3 and 4).
The diagnosis of EPS is often made late and in a large Physiologically, the peritoneum plays an important role
number of cases only at surgery. Early diagnosis requires a in maintaining the intra-abdominal homeostatic equilib-
knowledge and suspicion of the condition in the clinical con- rium. The functions of the peritoneal membrane include,
text, and is confirmed by combining the clinical history, pre- transport of fluid and particulate matter, regulation of leu-
sentation and imaging, surgical findings and histology. EPS cocyte migration, control of coagulation and fibrinolysis,
is not a histological diagnosis. Surgery remains the mainstay antigen presentation, synthesis of inflammatory cytokines,
of treatment, and best results are obtained in centres which growth factors and extracellular matrix for repair. These
have experience with managing this relatively rare condition. multiple functions enable the several important clinical
However, the overall management is complex, requiring a therapeutic interventions via the peritoneal cavity, includ-
number of disciplines, with nutritional support and surgery ing peritoneal dialysis, chemotherapy and immunotherapy
playing a key role in management. [39]. Kastelein et al. have provided an excellent up to date
review of the embryology, anatomy, physiology, patho-
physiology and pathophysiology of the peritoneum and
he Peritoneum Structure, Physiology
T peritoneal vasculature [40]. More recently studies suggest
and Function that exosomes contribute to peritoneal function, by the
intracellular transfer of DNA, mRNA, proteins, and lipids.
The peritoneal cavity is a potential space, separating the pari- They are thought to play a part in regulating peritoneal
etal peritoneum, covering the inner walls of the abdomen and membrane function [41].
Fig. 3 A schematic
representation of the
peritoneum with mesothelial Peritoneal
Cavity Lymphatic
organization and functions.
stomata 1c
The mesothelium is composed
of flat mesothelial cells (1a),
and cuboidal mesothelial cells
(1b). Water transport (two
headed white arrow) occurs Mesothelium
through aquaporins, while
zonula adherens (two headed
dot arrow) and tight junctions
(white dot) give support and
1a
selective barrier properties.
Mesothelial cell can also trap 1b
pathogens (white square),
detach (1c), phagocyte 2
pathogens and present antigen 3
(black circle) for immune
Sub- Lymphatic
induction. The sub-
Mesothelium stomata
mesothelium contains the
basal membrane, the 4
connective tissue, adipocytes
(4) and the milky spots were Milky spot Lymphatic
mainly lymphocytes (2) and vessel
macrophages are found (3).
Reproduced from [38]
After its initial description in association with peritoneal

dialysis by Gandhi [42], the condition has in the last four
decades, become recognised as a definite entity which is an
uncommon but potentially fatal complication of peritoneal
dialysis. EPS associated with long term PD is potentially the
most significant of these encapsulating conditions as it can
be associated with significant morbidity and mortality. It is a
relatively uncommon complication of PD which varies
between centres, countries and over time periods. The preva-
lence of EPS varies from 0.4% to 8.9%, its incidence rate
between 0.7 and 13.6 per 1000 patient-years. This observed
variability may be multifactorial, including genetic predispo-
sition, significant variation in practice, diagnosis, treatment
and follow up of patients [50].
Fig. 4 Photomicrograph of normal visceral peritoneum

The Pathophysiology of Development of EPS
Classification and Aetiology of EPS Due to the large number of patients on peritoneal dialysis
globally and the relatively increased numbers of PD related
Encapsulating Peritoneal Sclerosis is currently considered EPS compared to the other secondary and primary EPS, the
synonymous with the condition which is seen as a long term pathophysiology of this condition has been most studied.
morbidity of peritoneal dialysis first described by Gandhi in It is now well understood that in the vast majority of
1980 [42]. However there are a variety of peritoneal scleros- cases, development of EPS requires a predisposing factor
ing conditions described unrelated to peritoneal dialysis but and also inciting factors. There is not much literature on
associated with specific other pathology. Owtschinnikow genetic predisposition; however extrapolating from other
described a case of peritonitis chronica fibrosa incapsulata genetic fibrosing conditions, there is a strong likelihood
as early as 1907 [43]. The abdominal cocoon has been there will be a genetic predisposition in association, with
described as a specific entity, unrelated to renal failure or long term PD. While peritoneal dialysis is considered more
other causes. This presentation has mainly been described in physiological than haemodialysis, the peritoneal dialysis
China, India and the African continent with sporadic cases in solutions are hyperosmolar are have relative degrees of bio-
the temperate regions. Various infective conditions including incompatibility, which causes changes to the peritoneal
abdominal tuberculosis has also been described presenting membrane it is in contact with. Factors which cause the bio-
with cocooning of the bowel as a clinical manifestation. incompatibility and peritoneal inflammatory reactions are
Various descriptive terms have been used to describe the the glucose degradation products (GDPs) after heat sterilisa-
abdominal presentation of these different entities, including tion, the lactate content and the low pH. The pathophysio-
sclerosing peritonitis [44], sclerosing obstructive peritonitis logic process caused by these factors is similar to a sterile
[45], sclerosing encapsulating peritonitis [46, 47] and pro- chronic inflammatory process or a chemical burn. It causes
gressive calcifying peritonitis [48]. While the combination of denudation of the peritoneal mesothelial cells, epithelial to
terms are varied, they all fundamentally describe a patho- mesenchymal transdifferentiation, and cytokine release of
logic process, which is, a sclerosing and fibrosing inflamma- proinflammatory, proangiogenic cytokines, namely TGFbeta
tory condition, which encapsulates and restricts the gut, 1, IL-6, CCN2 and VEGEF (Figs. 5 and 6).
leading to bowel obstruction. Although several precipitating factors have been described
Taking into account the incidence, clinical presentations, for the development of EPS, the main factor appears to be the
associations with different aetiology and the clinical and length of peritoneal dialysis [53] and the recurrent episodes
pathologic mechanisms, of the different types of peritoneal of infective peritonitis. These processes lead to the continued
sclerotic and encapsulating conditions, it can be broadly peritoneal inflammatory changes and a cytokine cascade and
classified into three main groups. (a) EPS secondary to peri- in genetically susceptible individuals, progression to clinical
toneal dialysis, (b) EPS as a consequence of other pathology, manifestation as EPS.
unrelated to peritoneal dialysis, and the specific entity (c) The organisms grown in infected peritoneal fluid in
Primary encapsulating peritoneal sclerosis. While it can be patients who go on to develop EPS are mainly Staphylococcus
classified clearly on the basis of etiopathology, it may be dif- aureus, Propionibacterium acnes [54], Pseudomonas species
ficult to accurately classify it prior to diagnosis [49]. or Fungal Peritonitis.
Fig. 5 Peritoneal histological a b

examination: (a, b) the fibrous
components of recent
deposition, still rich in
mucopolysaccharides, is in a
pale color, while the more
ancient fibrotic component,
consisting almost exclusively
of collagen, is highlighted in
deeper blue. This staining
highlights a recent beginning
of the fibrotic process: blue is
still poorly represented
compared to the pale colour.
The thickness of the c d
peritoneal membrane is
increased (638 μm). (c) Also
in perivascular areas, the
fibrosis spreads from the
submesothelial layer towards
the inside. (d) Marked
thinning of the mesothelial
layer. (Adapted from [51])
EPS has been described sporadically after organ trans- Talc, has been known to cause fibrosis [57] Talc powder was
plantation. Lee et al. have described two cases after liver used as a lubricant for surgical gloves in the past, before its
transplantation treated with a combination of surgery, ste- detrimental effects were identified. Silica is a component of
roids tamoxifen and mTOR inhibitor [55]. talc, and causes fibrosis, with a characteristic and diagnostic
It has also been described as a rare complication of intes- histologic feature, the Maltese cross. EPS has been reported
tinal transplantation. In the case described, after confirma- in a drug abuser where it is postulated that silica got into the
tory surgery, the patient was commenced on Sirolimus, and abdomen through abdominal injections [58]. Povidone
increased steroids and tacrolimus. There was complete reso- iodine used for peritoneal lavage after surgical procedures
lution of the obstructive symptoms with recovery of intesti- has also been reported to cause EPS [59]. Dacron fibres as a
nal transit [56]. EPS presenting after kidney transplantation cause in an individual has been reported, however this patient
is quite well described. was on peritoneal dialysis, and the EPS was precipitated
While elements of the predisposing and inciting factors after change of the dialysis catheter [60].
play a part in the other secondary and potentially primary Other than externally introduced material, body fluids
peritonitis, there are other interlinked disease specific factors could precipitate EPS. Encapsulation after abdominal trauma
in addition which will be briefly touched upon. has been described [61]. It is hypothesized that subclinical
peritonitis may be the underlying cause in this case. Similarly
EPS secondary to rupture of a Dermoid cyst has been
econdary Peritoneal Sclerosing Conditions
S reported where the authors postulate the mechanism to be a
Not Related to Peritoneal Dialysis chemical peritonitis from the cyst contents [62].
Sigaroudinia et al. describe EPS as a complication of long
Secondary Peritoneal Sclerotic conditions unrelated to peri- term ventriculo-peritoneal shunts two children who required
toneal dialysis encompasses a very large and disparate group surgical enterolysis. Both of them presented with acute intes-
of conditions (Table 2). They span a spectrum of aetiopathol- tinal obstruction. The CSF was sterile in both these patients.
ogy with, the clinical manifestations caused by, both the pri- No specific mechanism is postulated other than chronic irri-
mary disease and the superimposed effects of peritoneal tation [63].
sclerosis with or without membrane formation and/or EPS has also been described as part of manifestation of
encapsulation. systemic inflammatory diseases. It is described along with
The earliest cases of encapsulation were related to foreign recurrent ascites in SLE. The mechanism may be related to
material introduced during surgical procedures. The use of the inflammation of serosal membranes, including perito-
Fig. 6 Schematic representation of a cross section of the peritoneum Reproduced from Tim Koopmans, Yuval Rinkevich: Mesothelial to
showing mesothelial-to-mesenchymal transition (MMT) as a conse- mesenchyme transition as a major developmental and pathological
quence of cancer or, for example long-term peritoneal dialysis. player in trunk organs and their cavities [52]
neum, pericardium and pleura associated with SLE. On the was thought to be enigmatic. Altman et al. have reviewed the
background of a genetic predisposition, encapsulation and linkage and identified 43 cases, and on immunohistochemis-
ascites develops [64, 65]. A similar mechanism may occur in try, vimentin+/keratin+/CD34+ was found [68].
Familial Mediterranean Fever which is associated with poly- One of the first drug related causes was reported in
serositis [66]. 1975 in association with practolol for angina [69]. The
Another group of diseases which are associated with EPS patient required surgery for obstruction, where there was
are the ovarian tumours. Leutenising thecomas are most fibrinous adhesions and cocooning of gut which required
closely associated with the condition. The link was first excision and enterolysis. Subsequently other drugs in the
described by Clement in 1994, in six patients, where leute- beta blocker class have also been found to cause EPS includ-
nizing thecomas were associated with peritoneal sclerosis ing Timolol. Antiepileptic drugs like phenytoin have also
[67]. The thickened peritoneum was made up of a prolifera- been implicated with the authors postulating that like gingi-
tion of fibroblasts and myofibroblasts separated by collagen, val hyperplasia, the mechanism might be increased collagen
fibrin and chronic inflammatory cells. The causative relation and glycosaminoglycans and peritoneal inflammations with
Table 2 Classification of encapsulating peritoneal sclerosis vascularization. Subsequently there have been several
A: EPS secondary to peritoneal dialysis reports of this condition mainly from the tropics and sub-
B: EPS secondary to other well-defined pathology tropical regions. The largest number of publications on
Drug related this condition comes from China, India, Turkey and
Practolol
Nigeria. However there have been cases also described in
Methotrexate
Antiepileptic drugs
temperate zones [81, 82].
Intraperitoneal chemotherapy No underlying cause can be ascertained in primary encap-
Infections sulating peritoneal sclerosis and hence the name and the dif-
Tuberculosis ferentiation from the secondary group of EPS. There have
Non-tuberculous mycobacteria been several hypotheses, on the aetio-pathologic processes
Bacterial peritonitis of development of this condition, including retrograde men-
Cytomegalovirus infections
struation, superadded viral infection, retrograde peritonitis
Fungal infections
Parasitic infections
via the fallopian tubes and immunological reasons [83]. The
Neoplasms condition is however also seen in men, premenopausal
Leutenising thecomas women and children. It is difficult to diagnose clinically pre-
Leutinising granulosa cell tumours operatively, but a CT scan can make the diagnosis. Careful
Abdominal trauma dissection and excision of the thick sac with release of the
Foreign bodies small intestine leads to complete recovery in the vast major-
Talcum powder
ity of cases [84].
Asbestos
Silica
Endometriosis
Dermoid cyst rupture Diagnosis of EPS
Systemic inflammatory conditions
Sarcoidosis The diagnosis of EPS requires knowledge of the condition
Systemic lupus erythematosus and index of suspicion in patients presenting under the dif-
Familial Mediterranean fever
ferent contexts referred in the classification above. It should
C: Primary EPS (the abdominal cocoon)
be considered in the differential diagnosis of an individual on
long term peritoneal dialysis who presents with abdominal
adhesions and cocooning [70]. Methotrexate has also been symptoms with progressive decline in nutritional status and
reported as an aetiological factor [71–73]. EPS associated raised inflammatory markers. The majority of patients on
with direct intraperitoneal chemotherapy has been reported long term peritoneal dialysis do not develop EPS. However
[74, 75]. EPS should be considered and ruled out in any patient who
Intraabdominal tuberculosis can also present with the has had peritoneal dialysis for a number of years (over 5),
granulomatous tissue encasing the bowel and presenting as and especially so in someone with a history of multiple epi-
an abdominal cocoon. It is important that a preoperative sodes of peritonitis.
diagnosis is made as anti-tuberculous treatment may resolve In susceptible patients it may present soon after a trans-
the problem. However if it presents as bowel obstruction not ferring from peritoneal dialysis to haemodialysis, or after
responding to treatment or an acute surgical emergency, sur- transplantation in someone who has been on long term peri-
gery has to be carried out and histological confirmation toneal dialysis. The exact mechanism of how EPS is precipi-
obtained [76–78]. tated after this modality change is unknown.
Mycobacterium fortuitum, an atypical mycobacterium It should also be considered in patients who have had pre-
has been reported, however in association with peritoneal viously had peritoneal dialysis who present with recurrent
dialysis [79]. There are several case reports of EPS associ- episodes of unexplained ascites, especially after transplanta-
ated with fungal infections, tion or after conversion to HD.
In a significant number of patients, the diagnosis is made
late after investigations for other pathology have drawn a
Primary EPS blank. If the condition is not considered early, patients often
decompensate nutritionally while being investigated for
Foo et al. in 1978 published on series of cases in young other potential pathology and in that period continue to
girls from Singapore where the gut was encased in a mem- decompensate nutritionally. In parallel with these changes, if
brane causing obstruction [80]. The condition was termed the individual is still on peritoneal dialysis reduction in ultra-
the abdominal cocoon. Histologically the membrane was filtration will be noted along with a high transporter status.
made of thickened collagenized fibrous tissue with mild The deterioration is hastened by the underlying inflamma-
tory process in the peritoneal cavity driven mainly by the Diagnostic Tests and Pathway
thickened and inflamed membrane. for Suspected EPS
In the early stages patients may present with vague
abdominal symptoms, and then develop refractory anaemia There are no specific single blood tests that point to EPS,
which does not respond to iron supplementation or erythro- however the combination of refractory anaemia, often a leu-
poietin. This is also related to the chronic inflammatory pro- cocytosis, hypoalbuminemia and a persistently raised CRP
cess, from the thickened membrane and also pockets of in the context of a patient receiving of having received PD is
loculated peritoneal collections. These collections usually suggestive.
contain debris, clots and fibrinous material and organisms. In individuals who develop post-transplant EPS, there
The CRP will be raised right from the outset and along with may be derangement of transplant kidney function from a
disease progression and there will be a downward trend in combination of inflammation, infection and dehydration
albumin levels (Table 3). from intraperitoneal fluid collections.
In the non PD group of EPS, the diagnosis may be even In the other secondary causes of EPS, the relevant disease
more difficult, and diagnosis depends on knowledge of asso- specific investigation screens along with abdominal imaging
ciation of EPS with that condition, an index of suspicion and may help make the diagnosis.
imaging.
A significant number are unfortunately diagnosed at sur-
gical exploration. There can be rare and unexpected presen- Imaging in EPS
tations [85, 86]. There are also instances, where EPS can
present without any pre-existing symptoms [87]. A plain X-ray may show areas of peritoneal calcification,
especially in long standing cases. Characteristic calcification
on the bowel surface and the peritoneum is an important
diagnostic feature which could alert the clinician to the diag-
Table 3 Symptoms and clinical features of EPS nosis. An erect abdominal film may show some evidence of
History early obstructive features, such as air fluid levels or evidence
Peritoneal dialysis, with episodes of peritonitis of frank obstruction in an acute presentation. Other than
Increased risk if peritoneal dialysis over 5 years these features which may enhance diagnostic suspicion of
Change of modality of dialysis within last 6 months or EPS, in the modern era, the role of the plain abdominal X-ray
transplantation
in these conditions may be redundant.
Symptoms of fullness, discomfort
Abdominal distension or bloating Abdominal Ultrasound is helpful in that it may show asci-
Fullness, early satiety, vomiting tes and peritoneal fluid collections and in classic cases, can
Significant loss of weight demonstrate the thickened membrane cocooning the gut, and
In late cases gross distension, obstruction dilated loops of obstructed gut (Fig. 7). For these findings to
May also present acutely with obstruction, peritonitis or be diagnostic, they should be considered along with the clini-
hemoperitoneum
cal context. Abdominal ultrasonography is important in
Clinical features
Anaemia
guiding paracentesis in some patients who present with
Weight loss and cachexia in advanced cases recurrent accumulation of ascites. It is also important in the
Abdominal distension diagnosis of postoperative intraabdominal collections after
Fluid collection as ascites or loculated abdominal fluid enterolysis and peritonectomy.
Palpable abdominal mass from the cocoon The CT scan is the modality of choice in the diagnosis of
Investigations EPS. Diagnostic features of a CT scan are peritoneal thick-
Anaemia
ening, abdominal tethering, dilated gut, fluid accumulation
Raised CRP
Leucocytosis
as loculations of fluid or frank ascites, and areas of localised
Hypoalbuminemia or generalised calcification of the peritoneum (Fig. 8). The
Imaging (X ray/US Scan/CT/MRI) CT findings depend on the stage and severity of the disease.
Thickened peritoneum In the early stage, the thickening of the peritoneum may be
Ascites subtle, however, there may be suggestive features of gut
Mesenteric retraction tethering with some localised dilatation of loops of bowel
Obstructive features with thickened bowel
[88, 89].
Calcification
MRI Scans are also as valuable or sometimes provide
The above features are primarily consistent with EPS associated with
more definitive detail of the pathology [90]. However either
peritoneal dialysis. In primary EPS and other forms of secondary EPS,
the diagnosis, is one of exclusion mainly of other causes, and consider- the CT scan or the MRI scan will provide diagnostic radio-
ing individual clinical presentations logic features that could lead to a confirmatory diagnosis of
EPS (Fig. 9). Cine MRI has been used as an experimental The critical points in laparoscopy are to ensure that there
modality [91], where pathologic features of the encapsula- is no perforation due to the cocooning (Fig. 11). An impor-
tion along with the restrictive effects of the cocoon can be tant decision when carrying out laparoscopy for diagnosing
demonstrated. EPS, is planning intervention. If EPS is definitely found on
Vadi SK et al. have reported the use of 18F-FDG PET-CT laparoscopy, it may be best for surgical intervention to be
as a modality in the diagnosis of the abdominal cocoon asso- planned at a later date.
ciated with tuberculosis (Fig. 10) [92].
Histologic Features of EPS

Laparoscopy
The diagnosis of EPS is a clinical diagnosis and not histo-
Once a diagnosis of EPS is considered, it can be arrived at by logical. Histology of the peritoneal membrane in a patient
correlating the clinical history, clinical examination, blood with EPS may show characteristic features that confirm the
tests and the radiologic imaging. However, there are situa- clinical diagnosis. It is also important in ruling out, second-
tions when symptoms will still remain unexplained and ary causes of peritoneal sclerosis or pathology including
obscure but point to an intraabdominal source. In these situ- tuberculosis or malignancies. Histologic changes reflect the
ations, laparoscopy may be useful for visualising the perito- effect on the peritoneum caused by the hyperosmolar dialy-
neal cavity for definitive diagnosis, ruling out pathology and sis fluid and is seen in both the parietal and visceral perito-
also for obtaining diagnostic samples. neum. The peritoneal membrane thickens and scleroses in
long standing peritoneal dialysis, along with mesothelial
Fig. 9 An MRI scan showing the same features in the same patient,
Fig. 7 A single static ultrasound image showing the liver with calcifi- with subtle differences. The calcification is not as prominent, and the
cation on the surface, ascites and cocooned gut with calcification on the thickening of the peritoneum is not as evident in MRI scan compared to
surface the CT scan
Fig. 8 CT scans
demonstrating free fluid,
thickening of both parietal
and visceral peritoneum with
certain areas of calcification,
mesenteric retraction and
some gut dilatation. The first
image is of a patient with
post-transplant EPS and there
is a good functioning kidney
in the left flank
Fig. 10 FDG-avid peritoneal a b e f g

thickening encapsulating
around the clumped jejunal
and ileal loops forming a
tracer-avid “cocoon” in the
abdomen as shown in the MIP
(a; arrows), axial PET (b), c
fused PET/CT (c), axial CT
(d), and corresponding
coronal (e, f; arrows and g) h i j
and sagittal (h, i, and j)
images, suggesting sclerosing
encapsulating peritonitis d
(SEP)
Fig. 11 A laparoscopic image showing early EPS in evolution. The flimsy as it is early in its formation. If left undiagnosed or untreated, it
ascitic fluid is turbid and there is encapsulation of the gut with neovas- will develop into the thick constricting collagenous membrane seen in
cularization of the surface. The membrane can been seen and is thin and advanced disease and will eventually calcify
denudation. Below the mesothelial layer, the compact zone peritoneal dialysis. Examples are peritoneal tuberculosis
thickens and is formed of myofibroblasts and fibrous colla- where typical granulomatous inflammation is seen with or
gen [93]. The vasculature in this layer undergoes changes, without necrosis and acid fast bacilli.
with medial sclerosis and hyalinization, along with neo- In malignant encapsulation, the histologic features will
angiogenesis [94]. Honda et al. have also described fibrin depend on the specific malignancy which is causing the
deposition, increase in the size of the fibroblasts, capillary pathologic manifestation.
angiogenesis and mononuclear cell infiltration were more In the primary or idiopathic cases of EPS, histologically,
common features of EPS rather than simple sclerosis [95]. the peritoneum will show a proliferation of fibro-connective
Advanced glycosylation end-products are found in the meso- tissue, inflammatory infiltrates, and dilated lymphatics.
thelial and sub-mesothelial layer of PD patients [96, 97]. There will be no evidence of granulomas, giant cells or bire-
Additional histological findings identified by different fringent material.
investigators include, positive immuno-histochemical stain-
ing for podoplanin [98] and upregulation of vascular endo-
thelial growth factor (VGEF) and downregulation of mast Treatment of EPS
cells [99, 100]. All these findings however are not specifi-
cally related to EPS, and could be seen in the different peri- As soon as a diagnosis of EPS is made in PD related cases, it
toneal fibrosing conditions. is imperative that the patient discontinues peritoneal dialysis
and is established on haemodialysis. A strategy that has been
tried in preventing the development of EPS is regular perito-
Histology of Non-renal EPS neal lavages after discontinuation of PD. Regular lavage has
been shown to help mesothelial cell repair [101].
Histologic features of secondary encapsulating peritoneal While this is a strategy that can be attempted in the very
sclerosis or peritoneal fibrosing conditions are more specific early stages without mechanical obstruction, nutritional defi-
and often diagnostic when compared to EPS associated with ciency or significantly raised inflammatory markers, it
should perhaps be carried out in conjunction with additional denatured collagens, TGF beta 1 production, which is stimu-
medical therapy. There is no robust scientific basis. lated by tamoxifen, might favour mesothelial healing by
In the group of patients presenting mainly with signifi- facilitating the removal of denatured collagen. It has been
cant and recurrent ascites, paracentesis will be required for successfully used in the treatment of retroperitoneal fibrosis
relief of discomfort. More than one attempt at paracentesis [107, 108] and long term therapy for idiopathic RPF has
will be required as the peritoneal fluid may continue to reac- been found to be effective and safe [109].
cumulate. Depending on the individual clinical context,
concomitant medical therapy may be required. In these clin- Immunosuppression
ical situations where there is no overt mechanical obstruc- Immunosuppressive agents other than steroids have been
tion, a decision on surgical intervention, may be difficult to used to good effect by different teams. Azathioprine in com-
justify. However if there is recurrent, re-accumulation of bination with steroids has been shown to be effective [110].
fluid, there may be justification in surgery with a view to a mTOR (Mammalian target of Rapamycin) inhibitors, includ-
peritonectomy of the thickened membrane. The membrane ing Sirolimus, have been used by several groups especially in
in these situations is often a strong impermeable fibrocol- patients after transplantation, including liver transplantation
lagenous membrane overboth the parietal and visceral peri- with response [111, 112].
toneum which prevents the reabsorption of peritoneal fluid.
Once stripped off, and peritoneum excised, there is the Novel Agents
establishment of fresh peritoneum which aids in Danford et al. hypothesise that while mechanical obstruction
absorption. is the main underlying factor, dysmotility may play a role
through the disruption of the myenteric plexus by fibrosis
and increased endogenous opioids from activated lympho-
Medical Therapy for EPS cytes inhibiting both propulsive motor and secretory activity
in the gut [113]. Methylnaltrexone to combat inflammation
Various medical forms of therapy have been described for associated dysmotility has been described in anti-Hu associ-
EPS, however most medical interventions are anecdotal ated intestinal pseudo-obstruction [114]. Altman et al. have
without any specific clinical trials to determine the effective- suggested targeting vimentin+/keratin+/CD34+ tissue in
ness of therapy and outcomes. It will also be very difficult to patients with leutenizing thecomas and sclerosing peritonitis
evaluate the impact of the medical therapy on the natural [68]. ACE inhibitors may make peritoneal fibrosis progress
progression of EPS. more slowly [115]. Animal studies have found hepatocyte
growth factor [116], TNP-470 [117] and antisense oligonu-
Steroids cleotides to reduce peritoneal fibrosis [118].
Corticosteroids have been used as medical therapy by differ-
ent teams at different points in the disease process. The ratio-
nale for steroid use is that it inhibits collagen synthesis and Caveats in Medically Treating EPS
maturation by suppressing the inflammatory process. The
beneficial effects of estradiol propionate was experimentally While medical therapy may be attractive for both the patient
demonstrated in nonuremic Wistar Albino rats [102]. and the treating clinician from the point of view of avoiding
Kuriyama has reported good outcomes in all patients treated a major surgical procedure with associated morbidity and
with steroids compared to poor outcomes in those not on ste- mortality, it is based on anecdotal reports and small case
roids [103]. Several other groups have also reported on the series. There is always the potential risk that the diagnosis
beneficial effects of steroids in EPS [104, 105]. may be incorrect. Steroids may mask inflammation and
cause continued progression of disease. Defining length of
Tamoxifen medical therapy may be difficult and disease progression
With a solitary case report in 1999, Tamoxifen began to be during medical therapy may cause acute obstructive, infec-
used as medical therapy largely because there was no well- tive, and haemorrhagic complications including perfora-
defined consensus strategy for therapy of EPS once diag- tions. This may require emergency surgical intervention.
nose. The rationale of the authors was that Tamoxifen, a Surgical intervention in acute situations in patients on ste-
selective estrogen receptor modulator interferes with TGF roids and mTor agents can cause significant unwanted mor-
beta 1, a probiotic cytokine [106]. Transforming growth fac- bidity. This is due to the friability of tissue and difficult
tor beta 1 (TGF B1) has a stimulatory effect on matrix metal- healing, increasing the overall chances of morbidity and
loproteins (MMP 2 and 9). MMP9 degrades Type IV and mortality.
Surgery for EPS [119, 121]. Surgical intervention is planned depending on

the overall clinical state.
There is universal consensus that in patients with encapsulat- All patients should have a full cardiovascular assessment
ing sclerosis presenting with intestinal obstruction, surgery for anaesthesia, including an echocardiogram and if possible
is the most effective treatment. The underlying problem in a cardiopulmonary exercise test. Respiratory physiotherapy
these patients, is mechanical bowel obstruction caused by a prior to surgery will improve operative outcomes. Patients
combination of the thickened inflamed peritoneum, the fibro- should be managed by experienced anaesthetists, skilled in
collagenous membrane and adhesions. Bowel is in most the anaesthesia for patients with chronic renal failure with
instances encased in this pathologic tissue. significant morbidity.
The principles of surgery are the very careful release of If patients present as an emergency with evidence of
the obstructing, sclerotic and encapsulating membrane and peritonism, where surgery is indicated immediately, it has
releasing, gut so that it remains free in the peritoneal cavity, to be carried out, although the mortality and morbidity
with the reestablishment of peristalsis. Surgery requires associated with emergency surgery in EPS is over 50%. In
meticulous attention to detail and technique and dissection, an elective or semi elective situation, all patients should
and ensuring that in the process of releasing obstructed gut, have a thorough nutritional assessment as a significant per-
a perforation is not made or there is bleeding from vascular centage of these patients will have evidence of poor nutri-
tissues or vascular structures. One of the main reasons for tion [122]. Anthropometrics, will identify depleted fat and
reported poor outcomes in EPS in international literature and lean body mass which can increase surgical morbidity and
the high mortality is the fact that if surgical teams do not mortality [123]. All patients undergoing surgery should
have experience with this entity, decision making and judge- have augmented and intensive preoperative nutrition
ment during acute presentations proves extremely difficult. including parenteral nutrition. Parenteral nutrition will in
With acute presentations in patients especially in renal fail- all likelihood need to be continued well into the postopera-
ure and on dialysis, who have decompensated nutritionally tive phase, as return of gut motility with the ability for oral
over long periods of time, managing a hostile encapsulated intake may be prolonged. It is of critical importance that
abdomen can prove extremely challenging. Hence best out- parenteral nutrition be given through a dedicated access
comes are achieved by teams who have experience in the line, with all the precautions and care taken to ensure asep-
management of the condition. sis and sterility. An infected access line could cause signifi-
There are only a handful of centres in the world which cant morbidity and mortality. In a significant majority of
have significant experience in the surgical management of these patients, there will need to be alternate access for
the condition. Clinical outcomes from these centres have haemodialysis.
improved. Various different terms are used for surgery, As perioperative fluid management is critical, and inade-
including peritonectomy and enterolysis (PEEL) procedure quate dialysis can lead to fluid retention and increase periop-
[119]. Another limited procedure which has been described erative morbidity, it is imperative that all patients have
is Capsulotomy [120]. optimum haemodialysis prior to surgery, and ideally daily
dialysis.
The aims of surgery in EPS are fundamentally to relieve
Preoperative Preparation and Planning the mechanical gut obstruction which is contributing to the
symptoms and malnutrition and also clear as much as possi-
Once a definitive diagnosis of EPS has been made, therapy ble of the thickened and inflamed membrane which is con-
has to be tailored to the individual patient. A risk benefit bal- tributing to the chronic inflammatory process and the
ance decision has to be critically made after, a thorough anaemia. Both the parietal and visceral peritoneum will be
evaluation of the patient, investigations and imaging. If the thickened and where there is obstruction, the gut proximal to
CT scans show cocooning of the gut, surgery is indicated as the obstruction will be thickened (Fig. 12). The surface of the
it is highly unlikely that any medical therapy will reverse the bowel below the membrane will be tanned and of the thick-
gut problems. Surgery is the gold standard treatment for the ened and encapsulating membrane however has to be bal-
condition except for the most early of cases. There are anced on the requirement to relieve intestinal obstruction and
numerous individual case reports and small series reports on the need to avoid iatrogenic gut perforations which can pre-
surgery and outcomes. A small number of international cen- cipitate enteric fistulas and exponentially increase postopera-
tres have consolidated experience in surgical management tive mortality.
Surgical Technique
Abdominal entry is through a long midline incision, after

recent cross sectional CT images have been reviewed. It is
important to first enter an area of the peritoneal cavity where
gut is not adherent to the anterior abdominal wall, to avoid a
perforation. If a perforation occurs during surgery, primary
closure almost invariably fails due to the thickened and dis-
eased tissue, leading to an enteric fistula and significantly
increased mortality. The technique used in the author’s cen-
tre is to develop a plane outside the abdominal cocoon, bilat-
erally. Once that plane has been developed, the cocoon is
entered in an area where there is fluid (Fig. 13). Progress of
surgery is dictated by findings on abdominal entry. Once the
peritoneal cavity is entered in a suitable area, all fluid and
Fig. 12 Dilated proximal gut with released tanned, distal encapsulated debris is aspirated, after samples are taken for culture and
segment, during enterolysis sensitivity, biochemistry and for acid fast bacilli.
a b
c d
Fig. 13 The encapsulated gut with dense sclerotic adhesions between membrane from gut and d after completed enterolysis). The extremely
loops of bowel and also the encapsulated gut and the liver (a on entry thickened and almost calcific parietal peritoneum can also be seen and
outside the cocooned bowel, b after some dissection, c releasing fibrotic adhesions also between the sclerotic mass and the abdominal wall
The peritoneal cavity is then inspected and the exact ing fixing the bowel with a long intestinal tube, to maintain
degree of the encapsulation understood. Dissection is then patency, and the use of the Noble Plication technique [129].
commenced in an area and then meticulously extended, The management of recurrent disease is exactly the same
releasing loops of bowel, which are clumped together by the with repeat surgery and further enterolysis and
membrane. The membrane is adherent to the gut surface, by peritonectomy.
a firm interface. With careful blunt and sharp dissection the
membrane can be dissected off, however it is critical that
there are no perforations made. If perforations are made, the Encapsulating Peritoneal Sclerosis in Children
propensity for post-operative leaks and fistulation, increases
significantly. A decision is made about simple closure or a EPS has been described in children who have had long term
stoma formation. Dissection is then carried out, releasing the PD. The prevalence of EPS in European children on PD is
entire gut, right from the DJ flexure till the ileo-caecal junc- comparable with that of the adult patients. A high index of
tion. The terminal ileum is one of the most important areas as suspicion is required for diagnosis in children with longer
it is the most common area affected by the sclerotic dialysis duration, peritonitis rate and UF failure [130, 131].
membrane.
ietary Therapy (to Avoid Obstructive

D
Localised EPS Symptoms with Adhesions and EPS)
While EPS is in most situations generalised, there are situa- Occasionally a completely liquid diet is required to avoid
tions where cocooning can be entirely localises to a segment obstructive type pains in patients with adhesions or
of gut, especially the terminal ileal region [124]. EPS. Review by an experienced dietitian should be provided
for all patients with chronic symptoms.
he Management of Advanced Cases Where

T
Enterolysis and Peritonectomy Is Not Possible Definitions
Cases may present acutely from time to time where at sur- Dietary fibre has been defined as carbohydrate polymers
gery the abdomen is too rigidly encased in sclerotic tissue, or with ten or more monomeric units, which are not hydrolysed
badly calcified, where enterolysis and peritonectomy is tech- by the endogenous enzymes in the small intestine of humans
nically impossible. Attempting lysis in these situations may and belong to the following categories [132]:
cause perforations, bowel fistulae and mortality. In these sit-
uations, the most appropriate course of action would be to • Edible carbohydrate polymers naturally occurring in the
close the abdomen and considering long term parenteral food as consumed
nutrition. However, there are several case reports in literature • Carbohydrate polymers, which have been obtained from
where individual cases have been managed with different food raw material by physical, enzymatic or chemical
techniques including a loop jejunostomy in a case of recur- means and which have been shown to have a physiologi-
rent EPS where the original presentation was a uretero-ileal cal effect of benefit to health as demonstrated by gener-
fistula [125]. The same group has also described placement ally accepted scientific evidence to competent authorities
of a percutaneous gastrostomy tube with jejunal extension, • Synthetic carbohydrate polymers which have been shown
to drain gastric and proximal gut secretions while providing to have a physiological effect of benefit to health as dem-
total parenteral nutrition [126]. Combined bowel and kidney onstrated by generally accepted scientific evidence to
transplantation has also been reported [127]. It demonstrates competent authorities
the feasibility of the technique, and where renal failure too is
addressed by the transplanted kidney. Plants often contain a mixture of soluble and insoluble fibre.
Soluble fibre increases the viscosity of bowel contents, slow-
ing down digestion and the absorption of nutrients. Insoluble
Recurrent EPS fibre has a high water binding capacity which results in softer
and bulkier bowel contents to aid the acceptable functioning
In spite of the best surgical treatment, there may be a signifi- of the gut. Cereal fibre is reported to have the greatest bulk-
cant risk of recurrence of up to 25% [128]. The Japanese ing effect [133]. It is these effects which has led to the use of
group which has one of the largest international experiences low fibre diets in the treatment of adhesions and
with the condition, have utilised different techniques, includ- obstruction.
In 2014 the British Dietetic Association published a sys- from two episodes during their life to monthly episodes, 90%
tematic review on the management of Crohn’s disease. This of patients reported an impact on their diet [138]. There are
review was unable to identify any trials to recommend the many case reports in the literature regarding different types
use of low fibre diets in structuring disease to minimise the of food causing bowel obstruction in both patients who have
risk of bowel obstruction or reduce symptoms [134]. The had previous abdominal surgery and those with a virgin
opinion of the group, which consisted of expert Dietitians, abdomen (Table 4).
was that fibre should be avoided in stricturing Crohn’s dis- Due to the intermittent nature of bowel obstruction, dif-
ease to reduce the possibility of a mechanical obstruction. In ferent levels of restriction may be required depending on
addition, a low fibre diet may be helpful in reducing peristo- symptoms and the degree of obstruction. Radiological
mal pain from excess gas production. The lack of scientific images may help ascertain the degree of obstruction and
evidence to support the use of a low fibre diet does not negate inform the dietary restrictions required. Patients with severe
their use in clinical practice as it is difficult, from an ethical adhesions or strictures may require a liquid diet whereas
perspective, to conduct clinical trials where dietary fibre patients with partial obstruction may be able to manage some
could result in a mechanical obstruction. The BOUNCED fibre containing foods. The BOUNCED study from the
feasibility study at the Royal Surrey County Hospital NHS Royal Surrey County Hospital NHS Foundation Trust is
Foundation Trust is aiming to investigate the use of dietary investigating the use of a 4-step bowel obstruction diet in
manipulation in bowel obstruction (see below). It is envis- patients with cancer (step 1 clear fluids, step 2 all thin liq-
aged the results will be influential in establishing a consen- uids, step 3 smooth or pureed foods only low fibre, step 4
sus and provide the standard for dietary guidelines for bowel soft sloppy foods low fibre) [139].
obstruction. Each patient will have different tolerance levels which
may change over time Therefore, it is important that restric-
tions are reviewed regularly and if possible lifted to allow
Low Fibre
Table 4 Foods reported to have caused bowel obstruction
There are no clear definitions in the literature on what consti-
Foods
tutes a low fibre diet. One study investigating the effect of a
Fruit
low fibre diet in patients with IBS aimed for 10 g of fibre per • Cherry tomato
day [135]. Another study used <10 g of fibre as bowel prepa- • Dried apricot
ration 1 week pre surgery [136] and therefore not applicable • Dried fruit
in the long term setting of bowel obstruction. • Persimmon
• Dates
• Grapes
• Orange pith
Low Residue
• Peach stone
• Plum stone
To date there are no agreed definitions of what constitutes • Apricot stone
residue and in 2012 the American Academy of Nutrition and Vegetables
Dietetics removed the term “low residue diet” from the • Artichoke
Nutrition Care Manual [137]. This is because the amount of • Mushrooms
residue produced during the passage of food through the gut • Shitake mushrooms
• Olives
cannot be quantified as includes undigested food, microor-
Nuts
ganisms, gastrointestinal secretions and cells from the intes- • Brazil
tine. Therefore, for the purposes of this chapter the term low • Chestnut
fibre will be used. Seeds
• Prickly pear
• Granadilla
Causes of Bowel Obstruction • Medlar
• Sunflower
Other
There is limited literature describing the dietary intake of • Bran
patients with bowel obstruction but patients with recurrent • Oat bran
bowel obstruction are known to have a reduced quality of life • Ginger
and their condition has an impact on their dietary intake. In a • Egg yolk
study of 48 patients with recurrent bowel obstruction ranging • Rice cakes
Table 5 Principles of a low fibre diet General Advice: Chew and Teeth
• Wholemeal bread to white bread
• Brown rice to white rice Many case studies have also identified the issues of poor
• High fibre breakfast cereals to low fibre versions dentition and mastication as a contributing cause of bowel
• Wholewheat pasta to white pasta
obstruction [142–144]. Patients should have any dental
• No skins on potatoes
• One portion of fruit a day
issues identified and referral to a dentist if poor dentition is
• One portion of vegetables a day an issue.
• Meat, fish, cheese, eggs, tofu to be recommended to meet protein
requirements
Medications
as normal a diet as tolerated to minimise symptoms. The Many medications can cause a reduction in saliva production
principles of a low fibre diet (Table 5) include reducing and therefore a review of medications can be helpful to
fibre containing carbohydrates to lower fibre or fibre free ensure only essential medication are prescribed. It is known
alternatives. Fruit and vegetables will need to be peeled, no that pharmacobezoars can form from the ingestion of drugs
skins, no pips, no seeds, no pith, no stalks. It is often rec- such as cholestyramine and antacids and so their continued
ommended that only one portion of fruit and one portion of use should be evaluated [145]. Furthermore, reports of
vegetables are taken daily. Beans are high in fibre and
obstruction resulting from the use of guar gum-containing
therefore should be limited unless vegetarian or vegan diet pills have been reported [146] which is why a detail drug
when other low fibre protein substitutes should be encour- history is essential.
aged (e.g. tofu).
Fibre Containing Enteral Nutrition

Fluid and Electrolytes
Whilst there is no evidence to support the view that enteral
Patients with bowel obstruction are at risk of dehydration feeds containing fibre are contraindicated, some authors sup-
and electrolyte abnormalities due to a reduced oral intake port this view due to the potential risk of obstruction in those
and vomiting [140]. Therefore, careful attention should be with structuring Crohn’s disease [147]. A review of enteral
paid to ensuring patients are meeting fluid and electrolyte nutrition bezoar formation [148] found 14 cases of obstruc-
requirements as the risk of acute kidney injury (AKI) is high. tion of which at least eight occurred during feeding with a
The National audit of small bowel obstruction in UK found fibre containing enteral formula. Other compounding factors
22% of the patients were admitted with an acute kidney included anatomical changes post operatively, reduced pH,
injury [141]. Patients should be educated about the most dysmotility, dehydration and medication and therefore the
appropriate fluids (+/− electrolytes) to drink (if not vomit- enteral feed may not be the sole causative agent. However, it
ing) to maintain hydration and electrolyte status especially seems prudent to avoid fibre containing enteral nutrition in
during an acute episode. cases of severe strictures and adhesions until further research
is published.
In conclusion the recommendation to follow a low fibre
Micronutrients diet will be determined by the level of the bowel obstruction
and likely resolution. Patients will require a Registered
There is no data available on the micronutrient status of Dietitian to provide education and ensure that the diet is
patients with bowel obstruction. The low fibre diet which is nutritionally complete and that reintroduction of fibre con-
inherently low in fruits and vegetables, a significant source taining foods can occur when it is safe to do so.
of micronutrients, means that deficiencies may develop if the
obstruction is prolonged and appropriate supplementation
will be required. A clinical examination to identify deficien-
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Bone Marrow and Haemopoietic Stem
Cell Transplantation
Jennifer Clay, Maria Gilleece, and Clare Donnellan
Key Points
1. Haematopoietic stem cell transplantation (HSCT) may be Introduction
autologous (using the patient’s own cells) or allogeneic
(using HLA-matched donor cells). The utility of chemotherapy alone to provide long term
2. Autologous HSCT almost always uses peripheral blood remission in some forms of haematological malignancy is
stem cells and does not result in Graft versus Host limited, with higher doses of chemotherapy or radiotherapy
disease. being restricted by organ related toxicity, in particular the
3. Allogenic HSCT may use peripheral blood, aspirate from bone marrow. Stem cell transplant is utilised both to facili-
the bone marrow or, more rarely, umbilical cord blood tate the use of higher dose cytotoxic therapy with stem cell
4. The most common indications for HSCT remain haema- rescue, whilst in the case of allogeneic transplant also pro-
tological malignancies; however it can be performed in viding a ‘graft vs. tumour’ effect and therefore the potential
patients with autoimmune conditions (multiple sclerosis, of long term remission or cure.
scleroderma) and has limited use in some solid malignan- Both of these mechanisms have the potential to cause sig-
cies (e.g. germ cell tumours) nificant gastrointestinal toxicity, with the gastroenterology
5. The most common side-effects affect the GI tract and and nutrition team frequently involved with the management
therefore nutritional status may be compromised. of such complications. The aim of this section is to provide
6. The two situations in which nutritional support is com- an understanding of the process of stem cell transplant, its
monly needed are patients with severe mucositis or those primary gastrointestinal complications and their manage-
with GVHD affecting the gastrointestinal tract. ment. Further details regarding stem cell transplant are avail-
7. Regular dietetic assessment is vital—oral and enteral able in specialised texts and reviews [1, 2].
support should be preferred over parenteral, if this is
possible
Terminology
Bone marrow and haematopoietic Stem Cell Transplants

(HSCTs) can be broadly categorised into two main classes,
autologous and allogeneic.
Autologous
Maria Gilleece has died before the publication of this book. In autologous stem cell transplant the recipient’s own stem
cells are used to facilitate haematopoietic recovery following
J. Clay · M. Gilleece (Deceased) high dose chemotherapy/radiotherapy (referred to as condi-
Department of Haematology, Leeds Teaching Hospitals Trust, tioning). This is undertaken following several cycles of stan-
Leeds, UK
dard chemotherapy to debulk and control disease in the case
C. Donnellan (*) of haematological malignancies. There is increasing use of
Department of Gastroenterology, Leeds Teaching Hospitals Trust,
autologous transplant for non-malignant conditions (e.g.
Leeds, UK
e-mail: [email protected] multiple sclerosis), and in this setting no preceding chemo-

122 J. Clay et al.
therapy is necessary, however conditioning remains essen- ing conditioning with chemotherapy/radiotherapy. The
tial. Stem cells are harvested from the peripheral blood source of the stem cells may be a relative (full matched or
following mobilisation using haematopoietic growth factors half matched (haplo-identical)), an unrelated living donor
(granulocyte colony-stimulating factor (GSCF)), with or or cryopreserved cord blood unit identified from interna-
without additional chemotherapy, allowing collection from tional registries. The mechanisms of action of allogeneic
the peripheral blood by apheresis. The cells are cryopre- transplant also includes high dose chemotherapy/radiother-
served, and then thawed and infused following the condition- apy (conditioning), but in addition whilst certain matching
ing regimen (Fig. 1). As the patient’s own cells are used there criteria need to be met there is always a degree of immuno-
is no immunological mismatch, therefore the procedure is logical mismatch between donor and recipient (except in
not associated with graft versus host disease (GvHD) or the case of a syngeneic twin used as a donor), which results
immune mediated graft rejection, there is no requirement for in a ‘graft vs. leukaemia’ effect thought to be essential for
post-transplant immunosuppression and immune reconstitu- long term disease remission. The other side to this effect is
tion is relatively rapid. Transplant related mortality is 3–5%. ‘graft vs. host disease (GvHD)’, where the donor’s immu-
The stages of autologous stem cell transplant are summarised nological cells recognise recipient tissues as immunologi-
below [3]. cally different and cause an inflammatory reaction. GvHD
can be classified as acute (aGvHD) or chronic (cGvHD).
The reverse of this is graft rejection which occurs in
Allogeneic approximately 5% of transplants. Due to these potential
immunological interactions patients require immunosup-
In allogeneic transplant stem cells are sourced from an pression for 3–12 months following transplant, and poten-
HLA matched donor and infused into the recipient follow- tially longer if GvHD develops. Due to the combination of
Fig. 1 The process of haematopoietic stem cell transplants (HSCT)

Bone Marrow and Haemopoietic Stem Cell Transplantation 123
complications including slow immunological reconstitu- Umbilical Cord Blood

tion, prolonged immunosuppression and GvHD the trans-
plant related mortality (TRM) associated with allogeneic Cryopreserved umbilical cord blood units can be used as a
transplant is typically 10–50%. stem cell source when other donor options are not available.
In the paediatric setting single cord units can be used, how-
ever in the adult setting 2 units are generally required to pro-
Sources of Haemopoietic Stem Cells vide adequate cell dose. Whilst a lesser degree of HLA
matching is required for transplant of cord blood units com-
Peripheral Blood Stem Cells pared to that required for other cell sources, the drawbacks of
this cell source include slower neutrophil and platelet
Peripheral blood stem cells (PBSC) are the most com- engraftment and delayed immune reconstitution.
monly used source of stem cells. The cells are obtained via
peripheral blood apheresis following mobilisation using
recombinant haematopoietic growth factors (granulocyte- Indications
colony stimulating factor (GCSF)). The circulating stem
cells are then collected from the peripheral blood through Haematologic malignancy is the most common indication
a process called apheresis with blood filtered through a for HSCT. Factors considered when deciding between allo-
cell separator. PBSC have advantages over bone marrow geneic and autologous stem cell transplants include the
harvested stem cells including typically a larger cell dose underlying disease, response to previous treatments, fitness
and faster neutrophil and platelet engraftment. of the patient, and donor availability. Allogeneic HSCT is
performed for a number of non-malignant conditions includ-
ing aplastic anaemia, thalassaemia and severe combined
Bone Marrow immunodeficiency. There is increasing interest in the utility
of autologous transplant in patients with autoimmune condi-
Bone marrow is collected by aspiration from the iliac crest. tions including multiple sclerosis, scleroderma and inflam-
This procedure requires to the donor to have general anaes- matory bowel disease, along with limited use in some solid
thetic but does not involve exposure to haemopoietic growth malignancies (e.g. germ cell tumours) (Fig. 2).
factors. Advantages to bone marrow stem cell source include The British Society of Marrow and Stem Cell Transplant
lower rates of GvHD, and for this reason it is now most fre- produce a comprehensive table of approved indications for
quently used in the setting on of transplant for non-malignant transplant in the UK [5]. Table 1 summarises the principles
conditions such as aplastic anaemia. of the HSCT procedure.
a b
Fig. 2 Relative proportion of disease indications for HCT in Europe neoplasms, ALL acute lymphocytic leukaemia, CLL chronic lympho-
2018. (a) Allogeneic HCT. (b) Autologous HCT [4]. PID primary cytic leukaemia, PCD plasma cell disorder, HL Hodgkin’s lymphoma,
immunodeficiency, IDM inherited disorders of metabolism, AID auto- NHL Non Hodgkin’s lymphoma, BMF bone marrow failure, HG hae-
immune disease, AML acute myeloid leukaemia, CML chronic myeloid moglobinopathies, PCD plasma cell disorders, ST solid tumours, NMD
leukaemia, MDS myelodysplastic syndrome, MPN myeloproliferative non malignant disorders
124 J. Clay et al.
Table 1 Principles of HSCT procedure Gastrointestinal Complications

1. Consideration of the patient for HSCT including MDT review.
2. Patient assessment The gastrointestinal complications of transplant can be
(a) Disease status: In general transplant outcomes are better for broadly separated in to pre-engraftment (during conditioning
patient in a complete or partial response. Outcomes for those with
refractory or progressive disease are universally poor.
and until 2–3 weeks post cell infusion), early (up to day 100)
(b) Assessment of fitness including assessment of and late (day 100 onwards) post engraftment (Fig. 3). Pre-
cardiorespiratory function engraftment complications are predominantly related to the
3. Donor availability (allogeneic transplant only) toxic effects of the conditioning protocol and medications
(a) HLA-tying (commonly called tissue typing) of patient and any used to manage early complications (e.g. antibiotics, anti-
potential related donors.
emetics). Post-engraftment complications are most com-
(b) Searching of international donor registries where a suitable
related donor is not available monly associated with GvHD and delayed immune
(c) All donors undergo medical assessment by an independent reconstitution and therefore more frequently encountered
clinician to assess fitness to donate. following allogeneic transplantation than autologous.
4. Transplant conditioning therapy
(a) Combination of chemotherapy/radiotherapy determined
depending on disease and patient factors.
(b) The role of conditioning includes:
• Reduction or eradication of any residual disease present at the
time of transplant
• To ‘make space’ to allow engraftment of infused stem cells
• Immunosuppression to prevent graft rejection and reduce the
rate of GvHD
5. Transplant protocol
(a) A personalised schedule detailing conditioning, date of stem
cell infusion and relevant prophylactic medications along with key
donor/recipient details (e.g. HLA match, blood type, CMV status)
6. Patient undergoes transplant procedure as an inpatient or
outpatient depending on local protocol.
7. Posttransplant care—initial intensive monitoring, ongoing care
dependent on individual complications and disease monitoring
requirements. All transplant patients will undergo long term late
effects follow up.
Nausea and vomiting - chemotherapy Nausea and vomiting - drug/infection, acute

induced GvHD Nausea and vomiting - chronic GvHD
Diarrhoea - chemotherapy, infection Diarrhoea - drugs, infection, acute GvHD Diarrhoea - chronic GvHD, malabsorbtion
Tephlitis/ileus
Bleeding
Mucositis/oesophagitis Xerostomia, stomatitis - chronic GvHD
Poor nutrition
Infection - Baterial, viral, fungal Infection - Baterial, viral, fungal Infection - Baterial, viral, fungal
Transaminitis - chemotherapy, infection Transaminitis - drugs, infection, acute GvHD Transaminitis - Iron overload
Veno occlusive diseae of the liver (VOD)
Cholestasis - drugs Cholestasis - Drugs, acute GvHD Cholestasis - chronic GvHD
Reduced/altered taste - chemotherapy, drugs Reduced/altered taste - chronic GvHD
Conditioning Pre-engraftment Post-engraftment (Early) Post-engraftment (late)

Day 0- ~21 Day 21-100 Day 100 onwards
Fig. 3 The pre, early and late gastrointestinal complications of HSCT

Pre-engraftment Complications common toxicity criteria for grading of stomatitis’, which

grades mucositis as follow:
Nausea and Vomiting
• Grade 1—Painless ulcers, erythema or mild soreness
Nausea and vomiting are almost universal in the early stages • Grade 2—Painful erythema, oedema, and ulceration but
following stem cell transplant due to the use of chemother- is able to eat
apy/radiotherapy in the conditioning regimen, the severity • Grade 3—Unable to eat
varies depending on the combination of chemotherapy, • Grade 4—requiring enteral or parenteral support
radiotherapy and the intensity of doses used. Preventative
antiemetics should be used in all cases. Standard combina- Where ulcers are present these should be swabbed to exclude
tions generally include a 5-HT3 antagonist (e.g. Ondansetron) infection, particularly of viral origin. Bleeding may occur
along with metoclopramide, typically given orally, intrave- locally in the mouth or throughout the GI tract; therefore
nously or subcutaneously, depending on the patients’ needs. platelet support is a key aspect of supportive care. Tranexamic
Dexamethasone may be added to control delayed emesis acid can also be beneficial either systemically or dissolved
associated with drugs such as cyclophosphamide and may be and used as a mouthwash for oral bleeding.
continued for several days [6]. Management of mucositis is predominantly aimed at
In addition to the impact of chemotherapy/radiotherapy symptomatic control, prevention of infection and provision
other pharmaceutical agents commonly used such as antimi- of nutrition when patients are unable to eat. Prevention in the
crobials including co-trimoxazole and -azole antifungals form of good oral hygiene and mouth washes such as saline
along with agents used for GvHD prophylaxis such as cyclo- and chlorhexidine are used before mucositis occurs. When
sporine and mycophenolate mofotil (MMF) may contribute patients become symptomatic analgesic mouth washes along
to nausea. with topical measures such as lignocaine lozenges can be
Infection, most commonly oesophageal candidiasis, can helpful, however patients frequently require opioid analge-
cause nausea and vomiting and should be considered and sia, initially orally while able to swallow but ultimately often
investigated with upper GI endoscopy in cases of intractable subcutaneously or intravenously. Subcutaneous administra-
nausea and vomiting. Due to the risk of viral reactivation tion through a syringe driver with a combination of opiates
staining for CMV of biopsies should be requested in all cases and antiemetics is commonly used. Diarrhoea can be man-
alongside the standard testing, this complication can occur in aged with anti-diarrhoeal agents such as loperamide when
the absence of detectable CMV viraemia in the peripheral infection has been excluded. There is a significant risk of
blood. infection with the breakdown of mucosal barriers, and most
units use prophylactic anti-biotics when patients become
neutropenic along with antiviral and antifungal prophylaxis.
Mucositis Whilst a number of agents have been used to modify locally
the effect of cytotoxic therapy such as ice, prostaglandins
The degree of mucositis experienced by patients varies dra- and interleukin II benefit has not been proven.
matically depending on the intensity of conditioning used, The time to recovery from mucositis depends on the pres-
and in particular the use of high dose total body irradiation ence of infection, nutritional status and most importantly
(TBI), with these patients almost universally experiencing haematopoietic recovery. Whilst most patients experience a
severe mucositis. This complication should be considered as rapid improvement with neutrophil engraftment allowing
‘mucosal barrier injury’ [7] with potentially the entire gas- them to start to eat and drink again many will experience
trointestinal tract being involved. Pain is predominantly persisting mucosal sensitivity, for example to spicy foods
related to oral/pharyngeal and oesophageal involvement, and loss of taste for weeks to months. In those who have
while diarrhoea, bloating abdominal pain and less commonly been treated with TBI reduced salivary secretion may persist
ileus are caused by lower GI involvement. Mucositis as a long term.
cause of diarrhoea is a diagnosis of exclusion, and faecal cul-
ture to exclude an infective cause should be undertaken in all
cases. Infective and Neutropenic Colitis
Oral mucositis progresses in four phases: Phase 1—vas-
cular/initial inflammatory, Phase 2—Epithelial, Phase 3— Diarrhoea in the early post-transplant period is frequently
Ulcerative, Phase 4—Healing. Multiple scoring systems multifactorial. Infection should always be considered and
exist to enable consistent documentation of the severity of investigated. Due to the implementation of infection control
mucositis [8]. One example is the ‘National Cancer Institute measures, isolation and neutropenic diet in these patients the
126 J. Clay et al.
rates of organisms traditionally associated with ‘food poi- hepatomegaly and reversal of hepatic flow considered con-
soning’ is low. The evidence surrounding ‘neutropenic diets’ sistent with the condition. Liver biopsy is the gold standard
is limited, however most units will implement restrictions for diagnosis, however due to the risks associated with the
such as those recommended by the British Dietetic procedure is very rarely undertaken. Whilst additional diag-
Association [9]. Due to the use of broad spectrum antibiotics nostic investigations including biomarkers are under devel-
both as prophylaxis and treatment Clostridium difficile is opment, they are currently only available in clinical trials.
common, with symptoms including profuse watery diar- The diagnosis of VOD remains a clinical one, and treatment
rhoea, abdominal pain and frequently fever. Treatment should not be delayed whilst awaiting investigations.
should be instigated depending on severity score, metronida- Treatment comprises a combination of supportive care and
zole, vancomycin and fidaxomicin are all included in NICE defibrotide, an anti-thrombotic agent for treatment of VOD
recommendations. Whilst viral reactivation is rare in the [14]. The mortality rate from untreated severe VOD with mul-
early stages post-transplant this should be considered, cases tiorgan failure is around 90%, therefore recognition and
of CMV negative peripheral blood PCR but biopsy proven prompt treatment in the early stages of the condition is essen-
CMV colitis have been reported, therefore specific testing of tial. Whilst other strategies including heparin anticoagulants
biopsy samples for CMV should be undertaken. and steroids have been used historically the evidence to sup-
Neutropenic colitis, also known as typhlitis is a rare com- port their use is not robust. Supportive care includes diuresis,
plication thought to be caused by direct invasion of the salt restriction and in severe cases organ support.
colonic or caecal mucosa resulting in toxic mucosal necrosis.
The diagnosis is predominantly radiological (colonoscopy
should be avoided due to a heightened risk of perforation). Infection
Patients may complain of right iliac fossa pain. Treatment is
predominantly with broad spectrum antibiotics and support- Reactivation of both fungal and viral infections can occur in
ive measures including bowel rest and analgesia. Severe the early post-transplant stage. The widespread use of pro-
cases can result in megacolon or perforation, in this circum- phylactic -azole antifungals has resulted in a marked fall in
stance surgical intervention with subtotal colectomy and systemic candida infections, with aspergillus species being
defunctioning colostomy may be considered, however due to the most common cause of fungal infections [15]. Presentation
the high risks associated with surgical intervention in early with liver dysfunction, hepatic tenderness and fever refrac-
post-transplant patients due to pancytopenia and immuno- tory to standard antibiotics should prompt consideration of
suppression surgical intervention is deferred whenever pos- fungal infection. Combined modality investigation with
sible [10]. imaging, fungal biomarkers (Aspergillus antigen, Beta-d-
glucan), peripheral blood cultures and where possible direct
sampling of any discrete lesions should be undertaken.
Hepatic Complications Whilst CMV reactivation and other viral infections typi-
cally occur later post-transplant they should also be consid-
Veno-occlusive disease of the liver (VOD) is a potentially ered in the early phase.
life-threatening complication following allogeneic stem cell
transplant, with rates estimated to be around 8–14%. Whilst
it can be seen following autologous transplant it is much less Drugs and Therapeutics
common, estimated around 3% [11]. The diagnosis is based
on a clinical triad of jaundice, weight gain and tender hepa- There is an extensive list of medications, both prophylactic
tomegaly, with the potential to progress to multiorgan failure and those used to treat symptomatic and infective complica-
if left untreated. The pathogenesis of this condition relates to tions. Many of these have the potential to cause hepatic
endothelial damage in hepatic venules resulting in disruption abnormalities and comprehensive review of medications and
of fenestrae, inflammation and thrombus formation [12]. potential interactions should be undertaken in all cases of
Historically several different scoring systems have been used post-transplant hepatic dysfunction, with modification of
(for example Seattle and Baltimore criteria), more recently agents or doses where possible.
the European Bone Marrow Transplant Society have devel-
oped a severity scoring system which incorporates diagnosis
of late cases (after 21 days post-transplant) which are increas- Complications Beyond 2–3 Weeks
ingly recognised to make up a significant minority of cases
[13]. Investigations predominantly focus on exclusion of The majority of post engraftment gastrointestinal complica-
other causes. Liver ultrasound scan including Doppler is rec- tions occur in the allogeneic population due to protracted and
ommended in all suspected cases, with findings including complex immune reconstitution which is variable depending
on donor-recipient factors along with stem cell source (i.e. Table 2 Classification and features of Graft vs. host disease (GvHD)
cord vs. related donor). Following autologous transplanta- Days after Features of Features of
tion there is generally rapid resolution of pre-engraftment Classification SCT acute GvHD chronic GvHD
complications, and whilst full immune reconstitution can Acute GvHD
Classic acute <100 days Yes No
take up to 12–18 month this rarely results in gastrointestinal
Persistent, recurrent >100 days Yes No
manifestations. or late onset
Chronic GvHD
Classic chronic No time No Yes
Infection limit
Overlap syndrome No time Yes Yes
limit
Following allogeneic transplant both humoral and cellular
mechanisms of immunity are impaired, with the process of
immune reconstitution being complex and prolonged. A
number of variables can impact this reconstitution, includ- Acute Graft Versus Host Disease (aGvHD)
ing donor-recipient compatibility, the age of the patient,
presence and severity of GvHD. In addition, the use of Acute graft versus host disease principally affects the skin,
T-cell depletion in conditioning and the need for prolonged gastrointestinal tract and liver, with the majority of cases
immunosuppression for treatment of GvHD impact immune occurring within the first 100 days post-transplant. Histologic
reconstitution. As such patients can be at risk of both stan- appearances within the GI tract include lymphocytic crypt
dard and opportunistic infections for prolonged periods of infiltration, with epithelial cell necrosis. Severity ranges
time. from individual cell necrosis to crypt loss, ulceration and
CMV reactivation can occur in the initial months post- epithelial denudation. The most common pattern seen in
transplant, with the risk dependent on the serostatus of the hepatic involvement is small bile duct damage [17].
recipient and donor, recipient positive but donor negative Whilst aGvHD can affect any part of the GI tract it rarely
representing the highest risk combination. Most centres will involves the mouth and oesophagus. Stomach and duodenal
employ a pre-emptive strategy with regular PCR monitoring involvement cause nausea, vomiting, anorexia and dyspepsia.
and treatment at a pre-defined level. A novel agent, Bowel involvement causes diarrhoea which is characteristi-
Letermovir, is now available for use in CMV positive recipi- cally green and watery. The severity is graded predominantly
ents to prevent reactivation [16]. CMV disease can present based on diarrhoea volume (Table 3). Whilst the diagnosis of
with a broad spectrum of organ involvement but can affect gastrointestinal aGvHD is sometimes made based on clinical
any part of the GI tract causing pain, protein losing enteropa- characteristics along with proven GvHD at other sites, endo-
thy, ulceration, bleeding and occasionally perforation along scopic biopsy should be undertaken where possible to allow
with fever and rarely hepatitis. exclusion of infective causes. Hepatic aGvHD has a predomi-
Other organisms to consider include herpes simplex, adeno- nantly cholestatic picture due to small bile duct destruction,
virus, enterovirus, cryptosporidium and candida. The differ- and whilst other liver functions tests are commonly deranged
entiation of these organisms and GvHD requires endoscopic staging is based solely on bilirubin [18].
biopsy, and differentiation of infection from GvHD is essen- Treatment of acute GvHD requires a combination of sup-
tial due to treatment implications. Treatment of viral or bac- portive care and immunosuppression as first line, with the
terial infections with appropriate antimicrobial agents should degree of treatment dependent on severity and range of organ
occur, as per local guidelines. involvement. First line treatment is with corticosteroids
equivalent to 1 mg/kg methylprednisolone, escalated to
2 mg/kg in refractory cases. Budesonide can be used effec-
Graft vs. Host Disease tively as a steroid sparing agent. In addition, optimisation of
calcineurin inhibitors, and sometimes addition of other
Graft vs. host disease (GvHD) is classically separated into agents, for example MMF in those with liver GvHD can be
acute occurring within the first 100 days post-transplant, considered. Evidence for second line treatments is sparse,
and chronic occurring after that time (Table 2). With whilst numerous agents have been investigated evidence of
changes to transplant protocols this boundary has become response is lacking in most cases. The exception is extra
blurred with recognition of situations where acute GvHD extracorporeal photopheresis which does have evidence of
can occur later than 100 days (for example following donor effectiveness in steroid refractory aGvHD [19]. Supportive
lymphocyte infusion). Table 2 outlines the current criteria care is essential, gastrointestinal GvHD often requires gut
used [1]. rest with parenteral nutrition to support nutritional require-
128 J. Clay et al.
Table 3 Glucksberg criteria important to maintain dental health, along with surveillance
Gastrointestinal for oral malignancies which this patient population are at
Stage skin based on Liver based on based on quantity of increased risk of. Assessment for malabsorption and treat-
maculopapular rash bilirubin diarrhoea
ment of any underlying cause such as pancreatic insuffi-
+ 25% of surface <34– 500–1000 mL
50 μmol/L
ciency should be considered in those with intestinal
++ 25–50% of surface 51– 1001–1500 mL cGvHD. Due to the complex and often multisystem nature of
102 μmol/L cGvHD a multidisciplinary approach is essential.
+++ Generalized 103– >1500 mL
erythroderma 255 μmol/L
++++ Generalized >255 μmol/L Severe abdominal
erythroderma with pain with and
Other Late Effects
bullae and without ileus
desquamation Iatrogenic iron overload is common and can be associated
with transaminitis. It is managed with venesection on recov-
ery of erythropoiesis [20]. In cases with chronic anaemia
ments. In cases of severe gastrointestinal GvHD electrolyte post-transplant synthetic erythropoietin can be used to stim-
imbalance can be severe and challenging to manage. Due to ulate erythropoiesis to facilitate venesection. If this is not
unpredictable absorption drugs often need to be given successful, or in those requiring on going transfusion iron
intravenously. chelation should be instigated.
Post-transplant lymphoproliferative disorder, driven by
Epstein-Barr virus, is a rare but serious post-transplant com-
Chronic Graft Versus Host Disease plication. Whilst the majority of cases manifest with rapidly
progressive lymphadenopathy some may present with gas-
Chronic graft versus host disease (cGvHD) can evolve from trointestinal or hepatic involvement. Diagnosis is histologic.
aGvHD (cross over) or occur de novo after 100 days. It fre- Treatment involves B-cell directed monoclonal antibodies
quently manifests as a multisystem disorder, along with the (alemtuzumab) with or without systemic chemotherapy.
gastrointestinal tract other organ systems commonly involved
include the skin (with sclerodermatous changes), eyes, lung
and endocrine system. Treatment depends on both severity Nutritional Support
and organ involvement, with targeted local therapy along
with systemic immunosuppression when indicated. There are two situations where nutritional support may be
Gastrointestinal tract involvement commonly presents needed—patients with severe mucositis or those with GVHD
with upper tract features such lichenoid changes, erythema affecting the gastrointestinal tract. All patients should be
along with ulceration and mucoceles. Involvement of the assessed by appropriately trained dietitians, ideally working
salivary glands can also result in sicca symptoms. These as part of a nutrition support team. This allows early detec-
manifestations can cause significant pain and dysphagia tion of patients struggling with nutrition as being under-
leading to weight loss. Oesophageal involvement results in weight (Body Mass Index <18.5) is associated with poorer
dysmotility, dysphagia and reflux. Chronic GvHD of the gut outcomes from HSCT [21, 22].
is less common, but can cause mucosal atrophy, malabsorp- As with other clinical indications for nutrition support,
tion and fibrosis which can progress to strictures. Hepatic management should consist of optimisation of oral diet first
cGvHD ranges from mild abnormalities of liver function (typically trying soft, moist foods if mucositis is present).
tests to fulminant hepatic failure. Investigation aims to There appears to be no role for a ‘neutropaenic’ or ‘low bac-
exclude infective and other cases (such as iatrogenic hepatic terial’ diet [22]. Enteral nutrition (EN) support can be offered
iron loading) to ensure appropriate treatment is instigated. if oral intake is inadequate. Unfortunately some patients find
The treatment of cGvHD must be tailored to manifesta- any nasoenteral tubes too uncomfortable, due to severity of
tions in individual cases, where possible targeted topical the inflammation.
treatment should be utilised, with systemic immunosuppres- Parenteral nutrition (PN) should only be used when the
sion used in refractory or multiorgan involvement due to the first two approaches have been unsuccessful and should be
risks associated with long term immunosuppression. Topical stopped as soon as nutrition has stabilised [22]. PN does not
therapies include steroid mouth wash, tacrolimus mouth appear to provide additional benefits to EN and brings with it
wash and artificial saliva. Regular dental assessment is additional infective and metabolic complications [21, 22].
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12. Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic
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Cham: Springer; 2019.
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14. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of
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Non-surgical Cancer Treatments
Mary Booth, Fiona James, Andrew Viggars, Clare Shaw,

and Mark Teo

1. Cancer treatment may be curative, adjuvant (reduce
chance of metastases), neoadjuvant (reduce size of Malignant cells exhibit several hallmarks that distinguish
tumour) or palliative. them from normal cells [1].
2. Chemotherapy is usually given as combination therapy. These hallmarks are:
3. After bone marrow toxicity chemotherapy primarily
affects the gut mucosa. 1. genomic instability,
4. Nausea and vomiting after chemotherapy usually only 2. sustained proliferative signalling,
last up to 48 h. 3. an ability to evade growth suppressors,
5. Mucositis occurs with antimetabolites and anthracycline 4. resistance of cell death,
antibiotics and commonly occurs between 5 and 14 days 5. replicative immortality,
after treatment. This may cause acute intestinal failure 6. induction of angiogenesis,
needing parenteral nutrition. 7. cancer-related inflammation,
6. Some chemotherapeutic drugs (e.g. vincristine, adriamy- 8. activation of invasion and metastatic spread,
cin) may cause an irreversible enteric neuropathy. 9. the ability to re-programme energy metabolism, and
7. Newer targeted molecular treatments (e.g. immunother- 10. an ability to evade immune destruction.
apy, tyrosine kinase inhibitors) have direct and indirect
side-effects on gut mucosa and nutrition requiring spe- Cancer treatments aim to target these hallmarks and prefer-
cialist input. entially eliminate cancer cells over normal cells. The avail-
8. The toxicity from acute irradiation typically starts ability of newer more potent cancer treatments, intensified
1–2 weeks following the start of radiotherapy treatment combination multimodality regimens and earlier cancer
and depending on dose, can last for a few short weeks detection has improved survival rates such that 69.3% of all
following completion and can result in the breakdown of cancer patients will be alive 5 years after diagnosis [2].
epithelial surfaces. However, despite rapid developments in improved targeted
cancer treatments, all treatments produce side effects varying
in severity and according to the predominant types of target
normal cells. Toxicity limits both the dose and the frequency
of administration and may reduce the potential to cure some
patients.
M. Booth · F. James · A. Viggars · M. Teo (*) Each different cancer treatment modality can be delivered
Leeds Cancer Centre, Leeds, UK
with different treatment intent (Table 1), which alters the
e-mail: [email protected]; [email protected];
[email protected]; [email protected] strategy of managing treatment toxicities of complications.
For example, for treatment with curative intent the focus is to
C. Shaw
Therapy Research, The Royal Marsden NHS Foundation Trust, maintain treatment intensity and dose by tackling toxicity
London, UK aggressively with supportive measures including enteral or
Therapy Research, NIHR Cancer and Nutrition collaborative, parenteral nutritional support, versus treatment with pallia-
Southampton, UK tive intent where there is a lower threshold to lower dose or
e-mail: [email protected] halt treatment.

132 M. Booth et al.
Table 1 Cancer treatment intent and cancer site examples Sites of Action of Cytotoxic Agents
Treatment Purine Pyrimidine
Synthesis Synthesis
intent Aim Cancer site examples
6-Mercaptopurine
Curative Cure cancer Chemotherapy: 6-Thioguenine
Haematological and germ Ribonucleotides
cell tumours Methotrexate
5-Fluorouracil
Radiotherapy (often with Hydroxyurea
concurrent chemotherapy Deoxyribonucleotides
as a radiosensitiser): Lung
cancer, head and neck Cytarabine
Alkylating
cancers Agents
DNA
Adjuvant Reduce chance of local Chemotherapy: Breast and Antibiolics
and/or distant recurrence colon cancer
Endocrine: Breast and
prostate cancer Etoposide RNA
irinotecan, Topotecan
Monoclonal antibodies:
Breast cancer Proteins L-Asparaginase
Immunotherapy: Lung
cancer
Neoadjuvant Prior to curative Chemotherapy: Breast and Enzymes Microtubules
treatment, to reduce size oesophageal cancers
of cancer and/or to Radiotherapy: Rectal Taxanes Vinca Alkaloids
improve chance of cure cancer
Palliative To improve quality and/ Chemotherapy: Most
or quantity of life by tumour types Sites of Action of Cytotoxic Agents
reducing the disease Radiotherapy: Most Cellular Level
burden, improve tumour types
DNA Synthesis
symptoms and extend Immunotherapy: Lung,
life in palliative setting kidney and melanoma
cancers Antimetabolites
Small molecule inhibitors:
Lung, kidney and DNA Alkylating Agents
melanoma cancers
DNA Transcription DNA Replication
Intercalating Agents Mitosis

Although bone marrow suppression is a key toxicity fol-
Topoisomerase
lowing chemotherapy, the advent of haemopoietic growth Directed Agents Antomicrotuble Agents
factors, stem cell support and improved anti-microbial man-
agement protocols have reduced concerns about myelosup- Fig. 1 Sites of action of cytotoxic chemotherapy agents
pression. By contrast, gastrointestinal toxicity remains a
significant clinical problem frequently limiting the amount
of systemic therapy that can be given, and is a common side- motherapy administration will thus lead to a steady reduction
effect in most of the newer targeted therapies. in the malignant population while, it is hoped, leaving the
This chapter describes the general issues associated with population of normal cells relatively unchanged [3].
non-surgical cancer treatments specifically cytotoxic chemo- Most cytotoxic drugs interfere with DNA or protein syn-
therapy, hormone (endocrine) treatments, monoclonal anti- thesis, but other mechanisms of action are increasingly uti-
bodies and small molecule inhibitors, immunotherapy and lised as rational drug development attempts to target specific
radiotherapy; and the role of the gastroenterologist and nutri- differences in malignant cells but leave normal cells rela-
tion team in supporting patients on these treatments. tively spared (Fig. 1).
A review of all the individual cytotoxic drugs and their
effects on the gut is beyond the scope of this book. Cytotoxic
Cytotoxic Chemotherapy chemotherapy drugs are often classified into several groups
according to their mechanisms of action (Table 2).
Cytotoxic chemotherapy exerts its effects in a limited number Chemotherapy is rarely prescribed as a single agent, but usu-
of ways, leading to damage to cellular DNA. Due to the rapid ally takes the form of combination regimens. When combi-
proliferation and genetic instability of cancer cells, cancer nations are used, individual agents are chosen on the basis of
cells are unable to repair chemotherapy-induced DNA dam- having different mechanisms of action and, preferably, dif-
age as robustly and quickly as normal cells. Intermittent che- ferent patterns of toxicity [4].
Non-surgical Cancer Treatments 133
Table 2 Cytotoxic chemotherapy drug classes and mechanism of drugs (Fig. 2a). The effects on normal tissues may be repre-
action
sented in similar graphs (Fig. 2b). The respective position of
Class Mechanism of action Example agents organs changes for different drugs. For tumour cell types in
Alkylating and Bind covalently with Mustard gas which cell death can be significantly increased with doses
Platinum agents DNA, causing derivatives:
cross-linking of DNA Cyclophosphamide. not limited by gut or other organ toxicity, the use of haemo-
strands, and DNA Hydrazines and poietic sparing techniques may offer significant improve-
strand breaks, Triazines: ment in survival rates (Fig. 2c). In cancers where tumour
interfering with cell Procarbazine, sensitivity is less than gut sensitivity to cytotoxic drugs, little
replication. Temozolomide.
benefit will be seen (Fig. 2d). The haemopoietic sparing
Nitrosoureas:
Carmustine, techniques currently in use include treatment with haemo-
Lomustine. poietic growth factors, such as granulocyte colony-
Platinums: stimulating factor (G-CSF) and granulocyte-macrophage
Carboplatin, Cisplatin, colony-stimulating factor (GM-CSF), and haemopoietic
Oxaliplatin.
stem cell transplantation, which is discussed in the next
Antimetabolites Block metabolic Folic acid antagonist:
pathways involved with Methotrexate. chapter.
DNA synthesis. Pyrimidine antagonist:
5-Fluorouracil,
Capecitabine, ffect of Cytotoxic Chemotherapy
E
Gemcitabine.
Purine antagonist:
on the Gastrointestinal Tract
6-Mercaptopurine.
Adenosine deaminase Anorexia, cachexia and malnutrition may be prominent pre-
inhibitor: Fludarabine. senting features of malignancy, causing morbidity and mor-
Cytotoxic Have pleiotropic effects, Anthracyclines: tality in patients who have advanced disease [5]. Treatment
antibiotics including alkylating Doxorubicin,
activity and inhibition Epirubicin. of the malignancy with chemotherapy can worsen the
of topoisomerases. Other: Mitomycin C, cachexia and malnutrition, further compromising the health
Bleomycin. of the patient [6].
Agents that Exert their action Vinca alkaloids: The gastrointestinal tract is widely recognised as an
target the mitotic through alteration of Vincristine, essential organ and is involved in vital life functions such as
spindle microtubule function Vinorelbine.
and thereby interfere Taxanes: Paclitaxel,
nutrition, waste excretion and protection from external
with mitosis Docetaxel. microbes and toxins. It is a complex organ, involving mouth,
Topoisomerase These agents inhibit Podophyllotoxins: oesophagus, stomach, small intestine, large intestine, anus
inhibitors either topoisomerase 1 Etoposide. and the enteric nervous and lymphoid system. All of these
or 2 and thereby prevent Camptothecan
crucial components are vulnerable to the effects of
DNA replication analogues: Irinotecan,
Topotecan. chemotherapy.
Miscellaneous Ribonucleotide Hydroxyurea The effects of chemotherapy on the gastrointestinal sys-
reductase inhibitor tem are wide-ranging, frequent and can be long-lasting, even
Miscellaneous Retinoids Isotretinoin, Tretinoin beyond the cessation of chemotherapy.
(ATRA)
Chemotherapy related GI side-effects can affect 50–80%
of patients with standard chemotherapy regimens with up to
30% developing severe side-effects [7].
ffect of Cytotoxic Chemotherapy on Normal
E The main symptoms experienced by patients include:
Tissues
1. Nausea and vomiting
Cytotoxic agents generally have greater toxicity for cells that 2. Mucositis
have higher rates of proliferation. Cell turnover varies 3. Diarrhoea
between normal tissue types and is particularly high in the 4. Constipation
haemopoietic system, hair follicles and gastrointestinal tract.
The effect of most cytotoxic drugs is not limited to malignant Nausea and Vomiting
cells but is also seen in those normal cells that are undergo- The nausea and vomiting induced by chemotherapy occurs
ing division. It is the toxicity profile of individual drugs that when the vomiting centre in the medullary reticular forma-
is dose-limiting and governs how the agent is used. tion is stimulated by the chemoreceptor trigger zone (CTZ)
The kinetics of chemotherapeutic agents frequently fol- in the area postrema of the fourth ventricle or tractus soli-
low a dose-response curve similar to that seen with many tarius [8, 9]. Stimuli to the vomiting centre may also arise
134 M. Booth et al.
Fig. 2 (a–d) Schematic a b

representation of the effects 100% 100%
Percentage tumour
of cytotoxic chemotherapy on
Cell toxicity
normal and malignant tissue Bone Gut Heart Lungs
cell death
marrow
50% 50%
Dose drug Dose drug
c d
100
Percent cell death
Percent cell death

Bone Tumour Bone Gut Tumour
marrow marrow
Toxicity
gut
0
Dose drug Dose drug
from afferent fibres located in the cerebral cortex, gastroin- vomiting they may develop similar anticipatory symptoms
testinal tract (particularly the duodenum), heart, and vestibu- before subsequent courses of treatment.
lar apparatus. The CTZ is the predominant site of action The management of emesis caused by chemotherapy has
initiating emesis caused by cytotoxic agents. The major neu- improved dramatically in the last 10 years. The availability
rotransmitters known to be involved in the emetic process are of selective 5-HT3 receptor antagonists, such as ondansetron
dopamine, serotonin, and tachykinins such as substance P. and NK1 receptor antagonists, such as aprepitant, alongside
Nausea and vomiting are the most common early mani- more traditional anti-emetic drugs, such as; metoclopramide,
festations of the toxicity caused by chemotherapy, and cyclizine and corticosteroids has resulted in excellent control
repeated studies have shown them to be the most distressing in the majority of patients, even with the most emetogenic
side effects—more so than alopecia, for example [10]. If the regimens [11]. The aim of therapy should be to prevent eme-
patient is fit, there may be no serious consequences, but in sis from the first course in order to avoid subsequent antici-
those who are already debilitated or malnourished following patory symptoms.
surgery and/or radiotherapy the addition of drug-related
emesis may cause further marked deterioration in the clinical Mucositis
condition unless intensive nutrition support is provided. Most GI mucositis and ulceration is caused by a direct toxic
Different chemotherapy drugs vary markedly in their effect of chemotherapy on mucosal cells. A direct effect on
emetogenic potential [11]. Nitrogen mustard, cisplatin, mucosal cells can affect any part of the bowel and may
dacarbazine and streptozotocin induce vomiting in nearly all severely compromise dietary intake. The antimetabolites and
patients, whereas oral chlorambucil, melphalan and busulfan anthracycline antibiotics are the agents that most commonly
usually produce little nausea and vomiting. Nausea and vom- damage the gastrointestinal mucosa. Symptoms usually
iting induced by antimetabolite drugs often depends on dose occur 5–7 days after exposure and may last for 1–2 weeks.
and schedule. Methotrexate given in conventional doses The degree of damage varies according to the dose and
rarely produces vomiting whereas high-dose infusions given schedule of administration of many of these drugs. The tox-
to patients with osteosarcoma or to prevent CNS disease in icity of methotrexate to the gastrointestinal epithelium, for
lymphoma and leukaemia cause vomiting in the majority of example, depends on the duration of exposure rather than on
patients. peak concentrations [12]. Toxicity can be reduced if folinic
In most patients, emesis commences within 1–6 h of acid rescue is given within 42 h of administration [13]. With
administration and subsides after 24–36 h. Occasionally, 5-fluorouracil, toxicity is dependent on peak concentration
delayed emesis may occur 24 or more hours after administra- with higher toxicity rates seen in bolus regimens compared
tion and may persist for up to a week (for example with cis- to continuous infusions [14]. Even when mucosal damage is
platin chemotherapy). Less frequently, chronic nausea and relatively mild, serious morbidity may ensue. Local infection
vomiting may follow chemotherapy and can be particularly with organisms such as Candida and herpes virus, particu-
difficult to treat. Once patients have experienced nausea and larly in the mouth, may cause pain and reduce subsequent
oral intake, further compromising the patient’s nutritional used alongside chemotherapy regimens. The vinca alkaloids
status [15]. It is essential that the clinician is aware of this (particularly vincristine), thalidomide and cisplatin cause
and that advice is given about topical mouth care with the autonomic nerve dysfunction leading to constipation in up to
provision, where appropriate, of antifungal, antibacterial and 90% of patients and can even cause an ileus [18–20]. The
antiviral prophylactic therapy. For some patients, intrave- onset of symptoms usually occurs soon after drug adminis-
nous nutrition support or early NG/NJ feeding may be indi- tration, frequently within 3 days, and may be associated with
cated if pain prevents swallowing. peripheral neuropathy. It is important to provide prophylac-
tic laxatives. Patients who develop an ileus should be man-
hemotherapy Induced Diarrhoea
C aged conservatively with careful monitoring of fluid
Diarrhoea is one of the most common side effects of chemo- balance.
therapy which can range from mild (with an increase in stool
frequency up to 4–6 per day more than baseline) to severe
with life-threatening complications. Although the underlying Hormone (Endocrine) Therapy
pathophysiology remains unclear, it is heavily associated
with the development of mucositis due to direct cell toxicity Hormones are substances that work as chemical messengers
and malabsorption. Studies in animal models have shown in the body. They affect cells throughout the body, often trav-
increased apoptosis in crypts within the jejunum and colon, elling through the bloodstream. The growth and proliferation
and excessive secretions leading to diarrhoea [16]. of some cancers, such as breast and prostate cancers, are
Different chemotherapeutic regimes produce differing stimulated by hormones, and hence blocking these pathways
severities of diarrhoea, in particular those containing can be an effective anticancer treatment. Hormone therapy is
5-FU and irinotecan are correlated with incidence of diar- used on its own or in multi-modality treatment regimens in
rhoea as high as 80% [7]. Management of chemotherapy the neo-adjuvant, adjuvant and palliative settings. Hormone
induced diarrhoea involves identifying any infective therapy falls into two broad groups; (1) those that block the
causes, and contributing factors such as medications body’s ability to produce hormones, and (2) those that inter-
alongside supportive management and pharmacological fere with how hormones behave in the body (Table 3).
treatment [17]. Loperamide, an oral opioid with no sig- Glucocorticoid steroidal hormones, such as prednisolone
nificant absorption from the gastrointestinal tract, is the and dexamethasone are frequently incorporated into cyto-
anti-diarrhoeal agent of choice. Dosing requires an initial toxic chemotherapy regimens for its anti-emetic and anti-
dose of 4 mg, followed by an additional 2 mg after each inflammatory effects in managing chemotherapy toxicities.
loose stool, up to a maximum of 16 mg/day. In severe or Steroids also have a direct anti-tumour effect in most lym-
persistent diarrhoea, octreotide, a somatostatin analogue phoid malignancies and reduce cancer-related
may be used. inflammation.
These agents have a favourable therapeutic ratio causing
hemotherapy Induced Constipation
C typically mild toxicity; many hormone agents can cause
Chemotherapy induced constipation is a common issue menopausal-like side effects including weight gain and sar-
which can also be exacerbated by antiemetic (e.g. 5-HT3 copenic obesity, as well as gastrointestinal side effects such
receptor antagonists) and other medications traditionally as diarrhoea and nausea.
Table 3 Classes of hormone therapies and their mechanism of action

Hormone modulation Mechanism of action Cancer type Example agents
Gonadotrophin releasing Interferes with pituitary gland stimulation of the ovaries and testicles to Breast Goserelin
hormone agonists produce oestrogen or androgens respectively Prostate Leuprolide
Triptorelin
Aromatase inhibitors Blocks non-ovarian production of oestrogen Breast Anastrozole
Letrozole
Exemestane
Oestrogen receptor blockers/ Interferes with oestrogen binding to its receptor on cancer cells Breast Tamoxifen
modulators Endometrial Fulvestrant
Anti-androgens Interferes with oestrogen binding to its receptor on cancer cells; or Prostate Enzalutamide
suppress androgen production Bicalutamide
Abiraterone
Synthetic progesterones Stimulates progesterone receptor Endometrial Medroxyprogesterone
Megestrol
136 M. Booth et al.
mall Molecule Inhibitors and Monoclonal

S receptor (EGFR) family and the vascular endothelial growth
Antibodies factor (VEGF) family respectively.
In addition to the EGFR and VEGFR pathways, there are
Targeted therapies interfere with molecular targets involved a growing number of other classes of targeted monoclonal
in the sustained proliferative signalling of cancer. This is in antibodies or small molecule inhibitors used in anti-cancer
contrast to non-selective cytotoxic chemotherapy which tar- agents (Table 4).
gets all rapidly dividing cells. Many targeted agents have
been developed via rational drug design where targets are
selected and drugs designed based on their key role in inhib- Effect of Targeted Therapies
iting uncontrolled cancer growth. Targeted agents may be on Gastrointestinal Tract
monoclonal antibodies targeting cell surface receptors or
small molecules designed to bind and inhibit specific signal- Despite their targeted action, monoclonal antibodies and
ling proteins. Common targets of small molecule inhibitors small molecule inhibitors exhibit toxicities of the gastroin-
are tyrosine kinases, hence the use of a broad class of agents testinal tract as despite being “targeted”, these agents often
called tyrosine kinase inhibitors (TKIs). show activity on similar kinase classes on normal cells that
Small molecule inhibitors may focus on extracellular and express the target receptor. Table 5 shows common and
intracellular targets as they are able to translocate through uncommon gastrointestinal toxicities of targeted agents and
the cell membrane. Monoclonal antibodies are antibodies their management. Below, two specific examples of toxici-
with antigen binding domains, which have been engineered ties are detailed, and the management explained.
to bind with high specificity to the target of interest, typically Diarrhoea is a common side effect of many targeted
membrane receptors. Modern immunotherapy agents which agents, and frequently occurs within the first 2 weeks of
affect the immune response to cancer (described further commencing therapy [25]. Diarrhoea may be particularly
below) are predominantly monoclonal antibodies though severe in cases where targeted agents are combined with con-
small molecule inhibitors are in development. The complex- ventional chemotherapy. Anti EGFR family agents are com-
ity of the pathways involved in cancer initiation, survival and monly associated with diarrhoea. EGFR is expressed in the
propagation is reflected by the increasing number of targeted normal colonic mucosa, involved in regulation chloride
agents that are clinically available, in clinical testing, or in secretion and sodium inhibition, and therefore EGFR inhibi-
development. tors may result in secretory diarrhoea [26]. Other causes of
The mechanism of action of small molecule inhibitors diarrhoea should be excluded, including concurrent medica-
and monoclonal antibodies is dependent upon the receptor tions and infection (in particular Clostridium difficile infec-
targeted and the pathway in which that receptor has a function). In addition to the impact on quality of life, diarrhoea
tion. The specificity of such targeted agents varies, therefore may also lead to fluid and electrolyte loss, subsequent renal
some agents may have more than one site of action. Figures 3 impairment, and malnutrition.
and 4 show the various targets of action of small molecule Management is dependent upon the Common Terminology
and monoclonal antibody on the epidermal growth factor Criteria for Adverse Events (CTCAE) grade [27].
Fig. 3 Action of small

molecule inhibitors and
monoclonal antibodies
targeting EFGR family, MET,
and downstream cellular
pathways, including example
agents. Cancer sites agents
used in shown in brackets.
Mab monoclonal antibody,
TKI tyrosine kinase receptor
inhibitor, HCC hepatocellular
carcinoma. (Adapted from
Stone et al. [21])
Fig. 4 Effect of on VEFG VEGF

VEGFRC
Bevacizumab VEGFRD
signaling pathways in cancer. (colorectal; breast; Activation
renal; lung; gynae Inhibition
Binding of VEGF ligands to
VEGF receptors leads to VEGFB VEGFR2
downstream intracellular
pathways resulting in VEGFR1 VEGFR3
angiogenesis, migration and
survival. Cancer sites agents
used in shown in brackets.
GIST gastrointestinal stromal
Pl3k Cell membrane
tumour; HCC hepatocellular PKC
carcinoma
TKI with anti VEGF activity
Sunitinib (GIST, renal)
Sorafenib (HCC) Akt
Regorafenib (colorectal, GIST, renal) ERK
Pazopanib (renal)
Axitinib (renal)
Cabozantinib (thyroid, renal) Cellular migraion
Levatnibib (renal) and survival
Angiogenesis, cellular
migration and survival
Table 4 Targeted therapy classes with example target, cancer type this agent is used in and the potential gastrointestinal toxicities
Example agent
Target pathway Example agents target Cancer type Gastrointestinal toxicities
DNA repair Olaparib PARP Gynaecological cancers Diarrhoea, nausea, vomiting, decreased
appetite [22]
Cell signalling Crizotinib, ALK and ROS1 ALK or ROS1 mutated non-small cell Diarrhoea, vomiting, constipation [23]
Alectinib lung cancer
Cell cycle Palbociclib CDK4 and HER2 negative breast cancer Nausea, diarrhoea [24]
regulation CDK6
Table 5 Gastrointestinal (GI) toxicities of small molecule inhibitors A serious potential toxicity of anti-VEGF treatments is
and monoclonal antibodies gastrointestinal perforation [28] most commonly bowel per-
Targeted therapy class foration. Bowel perforation may lead to peritonitis, fistula
Gastrointestinal Common formation, abscess and sepsis. Management of bowel perfo-
toxicity toxicity Uncommon toxicity ration should involve the multidisciplinary team including
Diarrhoea EGFR
oncology, surgery, and radiology. Conservative, non-
inhibitors
Constipation All operative management options include bowel rest, antibiot-
Nausea and vomiting All ics and parenteral feeding. The decision of whether or not to
Abdominal pain All operate is complex, and such decision-making should take
Stomatitis All into account the severity and sequelae of the perforation, the
Dyspepsia All patient’s comorbidities, likely outcome of the operation, and
Gastrointestinal VEGF RAF inhibitors; the patient’s wishes.
perforation inhibitors temsirolimus; crizotinib
Gastrointestinal VEGF
haemorrhage inhibitors
Fistula formation VEGF Immunotherapy
inhibitors
Pancreatitis RAF inhibitors; VEGF “Immunotherapy” is a broad term encompassing any therapy
inhibitors
that up-regulates the immune system to target cancers. Over
the years, various different methods of “switching on” the
Uncomplicated diarrhoea, that is patients with grade 1 or 2 immune system have been used including vaccine therapies,
diarrhoea, with no additional complications, may be man- intra-tumoral injections and cytokine therapies. This section
aged conservatively with oral hydration and loperamide ther- focuses on the currently most commonly utilized immuno-
apy in an outpatient setting. In cases of grade 3 or 4 diarrhoea therapy; the family of drugs referred to as the immune check-
fluid replacement should be via the intravenous route, which point inhibitors (ICPIs). These drugs are monoclonal
may include potassium replacement. Management is the antibodies, which target the ‘checkpoints’ the immune sys-
same as previously described on chemotherapy induced diar- tem has in place to regulate autoimmunity. Examples of
rhoea [17]. ICPIs include the anti-CTLA4 directed therapy (ipilimumab)
138 M. Booth et al.
Stimulation roids or immunosuppressive agents, which themselves can

cause long term side effects.
Antigen
Presenting T-cell ffect of Immunotherapy on the
E
Cell
CTLA-4 Gastrointestinal Tract
ICPIs can impact the GI tract and nutrition in a multitude of

Inhibition
actions, either through direct action on the mucosa itself, or
by the effects on supporting organ systems or through toxic-
ity from supportive agents. Table 6 gives a list of example
toxicities:
Stimulation
I nvestigation and Management of Patients

Cancer on ICPIs
T-cell Cell
PD-L1 PD-1 The most important initial step is recognition that the pre-
senting complaint could be secondary to the ICPI. This is
often easy if the patient is still receiving the drug, however,
Inhibition
toxicities of ICPIs can occur late even months following ces-
Fig. 5 Mechanism of Action of CTLA-4 and PD-1/PD-L1 inhibitors;
adapted from [29]. For an immune reaction to take place there must be Table 6 Toxicities from ICPI and the effect on nutrition
stimulation between a cell displaying abnormal proteins (either the
antigen presenting cell or a tumour cell) and the T-cell via a receptor Site/cause of
pathway (in black). The interaction between CTLA-4 (green pathway) toxicity
and PD-1/L1 (blue pathway) blocks immune activation, which in nor- (frequency) Impact on nutrition
mal cells prevent inappropriate immune activation but in cancer cells is General drug Nausea is a common side effect of ICPI therapy
used to evade immune destruction. When anti-CTLA-4 or anti-PD1/ adverse effects and therefore can impact on nutritional intake
PD-L1 antibodies (dark red) are present, they block CTLA-4 or PD-1/ (very common)
L1 interaction respectively, thus allowing immune activation Immune-related Diarrhoea, abdominal pain, bloating, urgency of
colitis (common) defaecation and possible malabsorption. Can
cause severe inflammation of the colon with a
syndrome of symptoms similar to inflammatory
or the anti-PD-1/PD-L1 directed therapies (e.g. pembroli- bowel disease;
zumab, nivolumab, atezolizumab and durvalumab). Immune-related Similar to colitis but with inflammation within
The indications for checkpoint inhibitors are growing enteritis the small bowel; can cause nausea/vomiting,
exponentially with ever increasing trials testing these agents (unknown) bloating, malabsorption
Immune-related Causing a syndrome similar clinically to type 1
in different cancers at different disease stages with different
diabetes diabetes mellitus; dysregulation of glucose
treatment objectives; given as monotherapy or in combina- (uncommon) homeostasis requiring management with insulin
tion multi-modality treatment regimens. One of the hall- Immune-related Failure of the pancreas to produce enzymes to
marks of cancer is the ability to evade detection by the pancreatic allow digestion of macronutrients; presents with
immune system through these immune checkpoints. ICPIs insufficiency diarrhoea, steatorrhoea, bloating, weight loss
(uncommon)
are used to allow the immune system to ‘recognize’ cancers Steroid-induced Steroids cause altered glucose homeostasis which
again (see Fig. 5). This can lead to dramatic responses of diabetes can cause a picture similar to type 2 diabetes, but
cancers to treatment and has revolutionized the treatment patients can present acutely with hyperglycaemic
and survival of some cancers. hyperosmolar syndrome
The side effects of ICPIs, however, are incredibly broad GI infection Either as an effect of the ICPI or secondary to
immunosuppression, patients are at risk of GI
and either originate from the effect of having a systemic ther- infection; recent safety signals were released
apy (fatigue, nausea) or due to the effect of direct immune about the risk of reactivation of cytomegalovirus
attack on specific organs of the body. ICPIs can lead to causing colitis with ICPIs [30].
immune adverse effects on any organ; three of the commonly Endocrine Immune-related endocrine adverse effects are
insufficiency well recognized with ICPIs most commonly
affected organ systems include the colon (colitis), liver (hep- (from common to thyroid dysfunction. Less common conditions
atitis) and endocrine organs including the thyroid and pan- uncommon) include hypopituitarism, and hypoadrenalism.
creas. Whilst this auto-inflammatory response can often be Potential effects of these conditions include
managed, this can require long-term use of high doses ste- weight loss, nausea and anorexia.
sation of immunotherapy, which can make diagnosis difficult resulting in DNA damage and if unrepaired, initiating cell
especially if patients did not present at an oncology unit. death pathways. RT ionization events and cancer cell death
There are published international guidelines (for example follow a probabilistic model, hence DNA damage (and can-
by the European Society of Medical Oncology [31]) on the cer cell death) escalates with increasing RT dose. Thus, with
management of ICPI-induced toxicity based on the severity high enough radiation doses, localized cancer eradication
of the toxicity using the Common Terminology Criteria for and cure can be achieved. However, in metastatic disease, RT
Adverse Events (CTCAE) grading system [27] to guide the has an important role in localized palliation of symptoms
subsequent requirement for admission, investigations for such as pain, obstruction and bleeding.
alternative causes and management options, typically the RT is becoming increasingly more targeted and sophisti-
consideration of oral or intravenous steroids. In the event of cated owing to significant developments in technology
lack of response to steroids, other forms of immunosuppres- allowing the delivery of higher RT doses to cancers with
sion are then considered. improved cure rates while sparing normal tissue with reduced
toxicity. RT continues to evolve with developments in parti-
cle therapy, such as proton therapy, which delivers radiation
Specific Examples dose in a more confined manner compared to conventional
photon RT, allowing greater sparing of normal tissue from
Immune-Related Colitis low/intermediate doses especially to organs adjacent to the
Patients on ICPI frequently present with diarrhoea or a cancer, and potentially reducing long-term morbidity in
change in bowel habit, often mild and relating to the consis- some situations.
tency of stools. Presenting features are often similar to
inflammatory bowel disease (IBD). For mild CTCAE grade
1 toxicity, treatment may involve just the use of simple anti- ffect of Radiotherapy on the
E
motility agents such as loperamide and exclusion of infec- Gastrointestinal Tract
tion. In severe CTCAE grade 3+ toxicity, inpatient admission
for high dose intravenous steroids and rapid further investi- Ionizing radiation beams travel in straight lines. Therefore,
gation including cross-sectional imaging, endoscopy and either on the way toward the tumour or after passing through
biopsy of the colon may be required. In patients with unre- it, radiation may damage the surrounding normal tissues of
sponsive severe symptoms, therapies often used in IBD are the body. This damage causes cessation of normal cellular
considered such as infliximab or vedolizumab. Specialist functions and can cause death of the normal body tissues.
gastroenterology review is strongly recommended for these This effect of radiation on normal structures causes both
patients with severe toxicity. Early pre-treatment screening acute and late toxicity. It is important to note that the major-
tests for eligibility for anti-TNF monoclonal antibody thera- ity of curative RT regimens are often multi-modality, typi-
pies (such as tuberculosis, viral hepatitis and HIV infections) cally combined with concurrent chemotherapy as a
should be considered for any patient presenting with severe radiosensitizer to improve cure rates but exacerbating acute
immune-related colitis to allow prompt escalation of RT toxicity onset and severity in addition to the chemotherapy-
treatment. related toxicity.
Immune-checkpoint inhibitors are being used in an Acute RT toxicities (those seen during a course of treat-
increasingly broad range of cancer therapies in both the adju- ment or in the short weeks following completion) relate to
vant (following completion of definitive management, either the cell death of rapidly dividing cells (for example skin and
surgical or concurrent chemo-radiotherapy) and metastatic mucosal surfaces) causing breakdown of epithelial surfaces.
setting with good outcomes and therefore these patients may As the GI tract is lined by an epithelial membrane, any part
have excellent survival outcomes from their cancer therapy of this receiving a dose of radiation can be affected. Acute
however, the effect on quality of life in the long term due to toxicity typically subsides within a couple of months of
immunotherapy can be profound. Prompt consideration and treatment as normal tissue cells regrow and restoring the epi-
management of ICPI toxicity is therefore paramount. thelial surfaces.
Late RT toxicities are related to multiple different factors
including normal tissue hypoxia, inflammation, stem cell
Radiotherapy death, fibrosis and angiogenesis (formation of new vascula-
ture). Its late onset is related to the cells of the stroma
Radiotherapy (RT) has been used in the management of responding more slowly to radiotherapy damage. These pro-
malignant diseases for over a century. Conventional RT uses cesses can result in tissue necrosis (e.g. osteoradionecrosis
high energy X-rays or photons to cause ionization events of the mandible), stenosis (e.g. oesophageal strictures), tel-
(removal of orbiting electrons from atoms) within cells angiectasia (the development of new, fine fragile blood ves-
140 M. Booth et al.
sels prone to bleeding), and functional changes in the gut, Table 8 Late-effects of radiotherapy on gastrointestinal tract
dependent on the site affected (e.g. bile acid diarrhoea when Site of
the terminal ileum is irradiated). treatment Effect on GI function/nutrition
The most common cancer sites with likely acute and late Head and Long term xerostomia—may affect choice of diet
effects of RT affecting gastrointestinal (GI) function include neck and fatigability of chewing, poor dentition
Oesophagus Disordered motility, strictures
treatment for gynaecological organs (endometrium, cervix),
Small Bacterial overgrowth, bile acid diarrhoea, strictures
lower GI (rectum, anus) and urology (bladder, prostate)— intestine
persistent symptoms have now been termed ‘Pelvic Radiation Large Proctopathy, radiation colopathy, rectal
Disease’. Other sites affected can be the pancreas, liver, intestine telangiectasia
oesophagus and head and neck. In addition to acute and late Pancreas Exocrine dysfunction, stricture of pancreatic ducts
Vascular Vessel damage, calcification, reduced splanchnic
toxicity, due to the direct action of radiation on the gut, there
system blood flow and reduced absorption.
are a multitude of other effects that RT has on intestinal func-
tion and nutrition. The supportive organs can also be affected;
for example salivary glands, pancreas, liver or surrounding cancers commonly develop acute mucositis of the orophar-
bloods vessels. In general, the effects of RT are localized to ynx or oesophagus. It usually presents with odynophagia
the area being treated (e.g. salivary glands affected in head (pain on swallowing) and if uncontrolled, worsening dyspha-
and neck RT, oesophagitis in oesophageal or lung RT). gia. Symptoms typically develop 2 weeks into RT treatment,
A common side effect of RT is nausea which is believed progressing over the course of RT and peaking 1–2 weeks
to be related to 5-hydroxytryptamine 3, neurokinin-1 (NK- following completion of treatment.
1), and dopamine neurotransmitter release affecting the eme- Patients often require a change in diet to aid swallow
togenesis centres of the brain. RT induced nausea is most function, changing from solid to a soft or liquid diet. The aim
typically related to irradiation of the GI tract or brain. of treatment is supporting nutrition and controlling symp-
Management of RT induced nausea is as discussed earlier toms until recovery of the normal tissues and side-effect
with chemotherapy induced nausea. resolution, typically 4–6 weeks post treatment but can be up
The acute and late toxicities affecting different regions of to several months with head and neck cancers.
the GI tract are detailed in Tables 7 and 8. Supportive medical therapies are focused on symptom
Below are two examples of acute and late RT toxicities control to aid swallowing and manage pain, for example
respectively. topical lubricants (carboxymethylcellulose), oral coating
solutions, oral local anaesthetics and analgesics with strong
Oropharyngeal/Oesophageal Mucositis opiates often required. Active prevention and management of
Patients receiving high RT doses to the oropharynx or conditions likely to exacerbate mucositis recovery such as
oesophagus in head and neck, oesophageal and central lung acid reflux (especially with concurrent chemotherapy-related
emesis) with antacids and anti-emetics, and oropharyngeal/
Table 7 Acute toxicities of radiotherapy on gastrointestinal tract oesophageal candidiasis (due to loss of the protective muco-
Site of sal surface from RT treatment and chemotherapy-related
treatment Effects on GI function/nutrition immunosuppression) with good oral hygiene and a low
Head and Xerostomia, dysphagia potentially leading to threshold to commence anti-fungal treatment.
neck aspiration, decreased enjoyment of food, alterations If nutritional intake is inadequate, consideration has to be
to consistency of the diet, mucositis/ulceration
given to enteral feeding (typically nasogastric tube feeding).
Gustatory Change in tastes/cravings and decreased enjoyment
system (taste) leading to food avoidance In high risk head and neck or oesophageal cancer patients,
Oesophagus Mucositis/oesophagitis, odynophagia, dyspepsia, prophylactic percutaneous enteral tube insertion is often
gastro-oesophageal reflux, requirement for altered considered prior to commencing treatment. Multidisciplinary
dietary consistency, dysphagia and risk of aspiration support of patients on treatment with specialist speech and
(in cervical oesophageal treatment). See worked
example
language therapists and dietitians is vital to ensure weight
Stomach Nausea/vomiting, dyspepsia, early satiety, ulceration loss is minimized due to its impact not just on patient malnu-
Small Bloating, nausea/vomiting, borborygmi, pain/ trition but also on RT treatment dosimetry and accuracy.
intestine cramping, enteritis, poor absorption of nutrients,
bacterial translocation, oedema leading to subacute elvic Radiation Disease
P
obstruction
Large Diarrhoea, pain/cramping, dehydration, proctitis
Pelvic radiation disease can be defined as “transient or
intestine leading to food avoidance to reduce need to longer-term problems, ranging from mild to very severe,
defaecate, oedema leading to subacute obstruction arising in non-cancerous tissues resulting from radiotherapy
Liver Nausea/vomiting treatment to a tumour located in the pelvis” [32, 33]. This
Pancreas Acute pancreatitis disease can present with multiple different GI symptoms and
can have a wide range of implicated aetiologies with the the time of diagnosis compared with those who have retained
underlying cause often secondary to more than one diagnosis their previous weight [42]. Cancer cachexia is not simply due
and may not directly relate to the effects of radiotherapy to lack of adequate oral intake; rather, its pathophysiology is
itself. complex and includes a combination of systemic inflamma-
Diagnosis is often the first problem for patients, as the late tion and hyper-metabolism alongside decreased intake.
GI effects of radiation are often underdiagnosed or perceived Metabolic abnormalities in patients with cancer cachexia
to be untreatable by healthcare professionals, or patients may have been reported to include marked alterations of lipid,
not mention them, wrongly thinking they are expected to carbohydrate and protein metabolism [40]. Energy stores are
“just live with it”. However, the underlying aetiologies are diminished and total body water is increased. Of particular
often treatable with good symptomatic benefit for patients. interest is the marked reduction of glutamine levels in
Referral to a radiotherapy late effects specialist team or gas- patients with cancer cachexia [43]. Malignant cells extract
troenterologist is recommended. For further guidance on the glutamine with higher efficiency than any other cell in the
management of pelvic radiation disease, please refer to col- body and this may affect normal protein synthesis. Recently,
laborative guidance by Andreyev et al. [34]. sarcopenia has been shown to be an important prognostic
factor in cancer patients undergoing chemotherapy, with
many recent studies showing that loss of lean body mass loss
ffects of Chemotherapy on Radiation
E is an independent risk factor for chemotherapy toxicity, che-
Toxicity motherapy dose reductions, hospital admissions, and a
decreased survival in these patients [44].
Chemotherapeutic agents are often given concurrently in This evidence has emphasised a role for nutritional sup-
curative radiotherapy regimens often as a radiosensitizer by port in cancer patients to attempt to combat this reversible
binding to radiation-induced DNA damage and inhibiting poor prognostic factor. This has been incorporated into many
DNA repair thus enhancing cancer cell kill [35]. Common cancer therapy guidelines, with recent guidelines by the
concurrent chemoradiotherapy agents used include plati- European Society of Enteral and Parenteral Nutrition
num agents, 5-fluorouracil, capecitabine and taxanes. (European Society of Clinical Nutrition and Metabolism)
However, radiosensitization from concurrent chemotherapy having advocated increased attention to nutritional support
also impacts irradiated normal tissue with higher incidences in all patients with cancer [45] and United Kingdom National
of severe acute radiotherapy toxicity including acute gastro- Institute for Clinical Excellence best practice guidelines
intestinal radiotherapy toxicities as listed previously in advocating early nutritional screening to identify malnour-
Table 6 [36]. ished patients for consideration of interventions [46].
Although enhancement of toxicity is greater when both Nutrition support in cancer patients should always be
chemotherapy and radiotherapy are given concomitantly, dietetic-led. Initially oral nutrition should be optimised if
docetaxel, paclitaxel, gemcitabine, capecitabine and doxoru- possible. If this fails to meet nutrition requirements, supple-
bicin, and EGFR tyrosine kinase inhibitors have been mentary nutrition can be offered to patients via the gut
reported to produce a ‘radiation recall phenomenon’ [37, (enterally), or using intravenous (parenteral) nutrition (PN)
38]. This may occur at a site that has previously been irradi- in selected patients (Table 9).
ated when one of these drugs is given weeks or months later.
Gastrointestinal tract recall phenomenon reported include
mucositis, oesophagitis, gastritis and colitis reported. Effect of Cancer on Nutritional Status
The presence of cancer can have a profound effect on nutri-

Nutrition Support tional status through its effect on nutrition impact symp-
toms, food intake and body composition. The term disease
Under-nutrition (protein–energy malnutrition) is a common related malnutrition refers to malnutrition along with the
issue in patients with malignancy, and studies have demon- activation of systemic inflammation by underlying disease.
strated a relationship between weight loss and a lower chance The resulting inflammatory response contributes to loss of
of responding to treatment [39, 40]. Malnutrition can con- appetite and has a metabolic impact on tissues and organs. It
tribute to morbidity in cancer patients by many mechanisms, can result in a loss of body weight, changes in body compo-
including: increased infection risk, delayed wound healing, sition with a loss of muscle mass and fat along with a dete-
muscle weakness, depression, worse quality of life, reduced rioration in physical functioning or performance status [47].
chemotherapy and radiotherapy response, increased surgical Metabolic abnormalities in patients with cancer cachexia
complications and worse survival rates [41]. Five-year survival have been reported to include marked alterations of lipid,
rates may be up to 50% lower for patients with weight loss at carbohydrate and protein metabolism. Energy stores are
142 M. Booth et al.
Table 9 Reasons for giving parenteral nutrition to patients with malig- neck, pancreas and lung are associated with an increased risk
nancy (a predicted ‘long’ survival with a good quality of life is desirable of malnutrition. Overall the reported range is from about
before starting parenteral nutrition)
20–70% [47, 55]. Nutritional screening should be mandatory
Indications for parenteral nutrition at diagnosis and at key points during the treatment pathway
Gastrointestinal toxicity (mucositis/enterocolitis)
using a validated screening tool [55]. As the weight of popu-
Bowel obstruction
Prolonged ileus
lations is increasing it is essential that a normal body mass
High-output enterocutaneous fistula index or weight to height ratio is not used as the only method
Malabsorption of assessment. This can hide changes in weight, body com-
Graft-versus-host-disease (GVHD) position and food intake. Anorexia and other nutrition impact
symptoms are recognised as important early indicators as a
risk of malnutrition [47].
Table 10 Terminology used to describe physiological changes occur-
Following nutrition screening those identified as having a
ring in cancer
moderate or high risk of malnutrition should be referred for
Term Description
specialist dietary advice with the aim of meeting estimated
Cachexia A multi-factorial wasting syndrome characterised by
involuntary weight loss, loss of skeletal muscle mass nutritional requirements.
and fat mass [51].
Pre- Early clinical and metabolic signs which precede loss ystemic Anti-Cancer Treatment and Nutritional
S
cachexia of body weight and muscle. Status
Refractory Cancer cachexia which does not respond to
Tolerance to systemic anti-cancer treatment (SACT) is influ-
cachexia conventional nutritional support [51]
Sarcopenia Low skeletal muscle mass and low muscle function enced by nutritional status and body composition. Early stud-
[52]. Fatigue is common and physical function is ies demonstrated that people who had lost weight generally
limited. experienced more side effects of chemotherapy during treat-
Sarcopenic Low skeletal muscle mass in obese individuals. Often ment [56, 57]. This association is now recognised to be closely
obesity overlooked as body weight may appear normal,
overweight or obese. Associated with poorer outcomes
linked with low lean mass. Calculation of dose of SACT is
in relation to systemic anti-cancer treatment as based on body surface area derived from measurement of
associated with increased risk of toxicity and potential body weight. This estimate does not take into account body
dose reduction of treatment [53, 54] composition and the amount of lean mass and fat mass. Studies
have shown that people who have a low lean, as measured by
diminished and total body water is increased. The metabolic dual-energy X-ray scans or measurement of muscle mass from
changes are mediated by systemic and tumour related cyto- computed tomography scans (CT) have a high risk of toxicity
kines including tumour necrosis factor-α (TNF-α), interleu- of treatment and dose adjustment of SACT [53, 58].
kin 1 (IL-1) and IL-6. Cytokines can impact on the
neuroendocrine control of appetite leading to anorexia, in utrition Support During Systemic Anti-Cancer
N
addition to causing wasting of skeletal muscle and reduced Treatment
performance status [47]. Individualised dietary advice is required for anyone deemed
Cancer cachexia is often not diagnosed or mentioned in a to be at risk of malnutrition following a diagnosis of cancer.
full medical assessment as there is often confusion as to its Continual and ongoing screening should identify people who
definition [48]. Percentage weight loss over time is often the develop toxicities of treatment that impact on their dietary
main criteria with more recent definitions including a combi- intake or nutritional status. Nutritional support should be part
nation of factors, for example, weight loss, a simple ques- of a comprehensive approach that provides supportive care
tionnaire of sarcopenia (SARC-F), Eastern Cooperative in a holistic way (Table 11). This may include psychological
Oncology Group performance status, appetite loss and support, pain control, symptom control, physical activity and
abnormal biochemistry [49]. The Glasgow Prognostic Score other aspects of daily life identified by the person themselves
(GPS), based on serum albumin and levels of C-reactive pro- [60]. Increasingly physical activity in the form of both aero-
tein are also predictive tools used for the assessment of bic and resistance exercise is recognised as an important strat-
inflammation in cancer which are associated with prognosis egy to improve upper and lower body muscle strength [61].
and mortality [50]. The European Society of Enteral and Parenteral Nutrition
A number of terms are used to describe the physiological (European Society of Clinical Nutrition and Metabolism)
syndromes that occur and these are described in Table 10. recommend the use of indirect calorimetry to predict resting
The prevalence of malnutrition in the people with cancer energy expenditure; however, this is often not performed in
varies depending on tumour type, tumour stage and the per- routine clinical care [47]. In the absence of this measurement
son’s age with increasing age conferring a greater risk. it is recommend to estimate energy requirements as
Cancers affecting the upper gastrointestinal tract, head and 25–30 kcal/kg/day with 1.2–1.5 g protein/kg/day with higher
Table 11 Assessment for the provision of nutrition support [59] More intensive nutrition support should be considered for
Category Examples patients with cachexia and increasing weight loss if aggres-
Anthropometry Weight sive therapy is to be offered [47]. For patients who are mark-
Height edly malnourished and, as a result, are felt to be poor risks
Body mass index for chemotherapy, the use of enteral nutrition should be con-
Weight change—actual and percentage body sidered as the improvement in nutritional status may allow
weight from normal over 1, 3 or 6 months
Mid upper arm circumference
its subsequent use. Enteral nutrition is the preferred form of
Biochemistry Electrolytes, Urea, Creatinine, Albumin and feeding if the gastrointestinal tract is functional and may be
C-reactive protein (to determine modified achieved by the use of nasogastric tubes or gastrostomy or
Glasgow Prognostic Score) jejunostomy feeding catheters if oral intake is insufficient or
Clinical Type of SACT, expected side effects, patient not possible due to tumour or the effect of treatment. Post
reported symptoms preferably using validated
symptom scores or scales. pyloric feeding may be preferable in those who have ongoing
Dietary intake Current intake of food and fluid/nutritional intake or uncontrolled nausea and vomiting although placement
Habitual food intake and retention displacement of naso-jejunal feeding tubes
Meal pattern may present a challenge in such cases. For longer-term EN
Texture of food consumed support (particularly in patients with head and neck cancers
Foods not tolerated undergoing radiotherapy) a gastrostomy tube (PEG or RIG)
Dietary supplements consumed
can be considered, often placed prophylactically prior to
Environment Social circumstances
Primary carer treatment.
Arrangements for shopping, cooking Concomitant use of SACT and radiotherapy, for example
Behavioural Food related behaviour, physical activity in head and neck cancer, may exacerbate the toxicity of treat-
Psychological Self efficacy, self-management, mental health ment. It is paramount that the provision of appropriate nutri-
status tional support is part of the treatment pathway to avoid
Health care Hospitalisation, treatment planning
delays in tube placement which in turn may influence ability
utilisation
to continue with treatment. The risks and benefits of appro-
priate feeding tubes should be discussed with people early in
amounts of protein being required when depletion is severe the treatment pathway enabling them to make an informed
[47]. Severely depleted patients should be managed with a decision on the most suitable method of feeding.
slow, gradual introduction of nutrients with concurrent
monitoring of electrolytes and tolerance to reduce the risk of Multi-Modal Interventions
refeeding syndrome [50]. Increasingly it is recognised that improvements in sarcope-
Nutrition counselling is the first and most commonly nia, cachexia and poor nutritional status require a multi-
utilised intervention for people with cancer who have a modal approach that incorporates nutritional support and
functioning gastrointestinal tract. This must include ade- physical activity. The European Society of Enteral and
quate symptom control particularly with respect to nausea Parenteral Nutrition (European Society of Clinical Nutrition
and vomiting. Nutritional care should be undertaken within and Metabolism) (ESPEN) recommend maintenance or
a framework of the nutrition care process taking into increased level of physical activity to support muscle mass,
account multiple clinical, nutritional, sensory and social physical function and metabolic pattern [47]. The role of
factors. For people who are struggling to maintain an ade- drugs such as non-steroidal anti-inflammatory drugs
quate dietary intake, expertise from a Registered Dietitian (NSAID) to increase body weight and androgens to increase
has been shown to help improve intake of protein and muscle mass are not supported by a sufficient body of evi-
energy intake [62, 63]. Some symptoms such as taste dence to be used routinely in clinical practice. Appetite stim-
changes are particularly challenging to manage and can ulants such as progestins and steroids have studies to
lead to a decrease in oral intake [64]. demonstrate their efficacy; however, their use is associated
Oral nutritional supplements may also be appropriate to with potentially serious side effects such as thromboembo-
use and these have been demonstrated to improve protein lism in the case of progestins [47].
and energy intake [65]. Although many trials on the use of It is hoped that this multi-modal approach early in the
nutritional support have not demonstrated a clear benefit for treatment pathway will support optimisation prior to and
enteral nutrition in cancer patients, some of these have, during SACT resulting in reduced toxicity of treatment and
unfortunately, been poorly designed. Increasingly studies are improved outcomes. This has yet to be demonstrated in clini-
providing support for the early provision of dietary advice cal trials and requires appropriate planning and support
and nutrition support to influence the ability to withstand rather than waiting to identify those who have become
SACT [66]. malnourished.
144 M. Booth et al.
pecific Nutrients and Their Influence in Cancer

S neutrophil counts below 0.5 or 2.0 × 109/L and whether these
The use of specific nutrients to improve nutritional status are both necessary and effective at reducing food borne
have met with varying degrees of success. Amino acids have infections [71–73]. Increasingly hospitals are reviewing their
been studied to determine their ability to increase fat free policy and in many cases are relaxing the previous restric-
mass, however, these studies have failed to demonstrate suf- tions that were imposed.
ficient benefits to warrant their use in routine nutritional sup- Parenteral nutrition (PN) should only be used in people
port. Fish oil derived eicosapentaenoic acid (EPA) has been who have a non-functioning gastrointestinal (GI) tract or in
administered for its anti-inflammatory properties with the whom it is not possible to access the GI tract. Some patients
purpose of dampening the inflammatory changes that occur may develop diffuse intra-abdominal malignancy and this
in cachexia. Whilst some studies have failed to demonstrate may cause malabsorption or obstruction. Use of PN should
a clinical benefit from their administration, others have also be considered for people in whom enteral nutrition has
reported improvements in appetite, energy intake, body been commenced but failed to become established (for
weight, lean body mass and prognostic benefits from fish oil example, in immunotherapy or graft versus host disease
enriched nutrition [67, 68]. More definitive evidence is where symptoms and intestinal failure may result in reduced
required before fish oils can be recommended for use during tolerance to enteral nutrition). PN may also be considered for
SACT. patients whose severe cachexia is the primary reason for fail-
The role of glutamine in cancer continues to be controver- ure of restoration of performance status and in whom
sial. It has been suggested that glutamine is semi essential in treatment-associated toxicities prevent the use of enteral
catabolic states and that glutamine depletion is linked to can- nutrition. There should be a reasonable expectation that anti-
cer related fatigue, performance status, poor nutritional sta- tumour therapy will produce a response, improve survival
tus and inflammation in patients with solid tumours [69]. and may reduce the severity of intestinal failure so that PN
Glutamine has also been trialled as a treatment for SACT may be stopped.
induced mucositis although studies have not provided suffi- Some patients may develop diffuse intra-abdominal
cient evidence for it to be recommended for this use [47]. malignancy, and this may cause malabsorption or obstruc-
tion, with death due to nutritional failure, rather than cancer
an Diet Influence Gastrointestinal Symptoms
C progression. The decision to provide home PN for such
of SACT? patients depends primarily on the underlying tumour type
The effect of SACT on gut mucosa is well known with diar- and the likelihood of it responding to chemotherapy. Chemo-
rhoea being a common side effect of treatment. It has also responsive diseases such as germ cell tumours, lymphomas
recognised that this may have temporary implications for and ovarian cancers may reduce rapidly in volume with che-
digestion and absorption of nutrients, including lactose, vita- motherapy, and recovery can be enhanced by a period of
mins and minerals. Lactose intolerance during chemotherapy PN. Similarly, patients who have developed severe, pro-
has been demonstrated with the use of lactose hydrogen longed mucositis and enterocolitis as a result of radiotherapy
breath tests demonstrating a rate of lactose intolerance higher may benefit from support with PN. For patients who are
than the normal population [70]. However, it is important to markedly malnourished and, as a result, are felt to be poor
note that not all patients were symptomatic from lactose risks for chemotherapy, the use of enteral nutrition should be
intolerance and lactose restriction has not been shown to be considered as the improvement in nutritional status may
an effective method for managing gastrointestinal symptoms allow its subsequent use.
caused by SACT. Dietary restrictions during acute toxicity The consideration of PN versus EN in cancer patients
should not be imposed without evidence that they are effec- without one of the strong PN indications (Table 9) remains
tive as they are likely to further exacerbate the risk of malnu- controversial with a recent review and meta-analysis of over
trition during treatment. 43 studies show that EN and PN are equal in terms of mortal-
ity and nutritional complications, with a slight increase in
re Dietary Restrictions Required in SACT?
A risk of infection for PN support [74]. The use of PN in the
People undergoing SACT are more susceptible to infection peri-operative setting has been examined in several studies
and should be given advice to avoid foods that are a high risk and, again, conflicting results have been obtained. Patients
of containing pathogenic organisms. These include pate seem to benefit from PN after the development of a pro-
(meat or vegetarian), cheese from unpasteurised milk, raw longed ileus following an abdominal procedure: if the patient
fish (for example sushi) and uncooked eggs. Good food has been unable to resume oral intake 7 days after surgery,
hygiene is paramount and advice should be available to rein- PN may be considered. Lean body mass may be maintained
force the importance of hand hygiene, appropriate storage as a result, improving quality of life and allowing a more
and heating of food. There is an ongoing debate about further rapid return to normal activities [75]. Cancer patients who
food restrictions that may be imposed for people who have undergo multiple bowel resections may develop the prob-
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Bacterial Overgrowth and Enteric
Infections
Eamonn M. M. Quigley
Key Points terial species. The most dramatic increase in diversity and
1. Small intestinal overgrowth (SIBO) can occur due to alter- population numbers occurs on crossing the ileo-cecal valve
ations in intestinal anatomy (including diverticula), gastro- into the colon where over 1012 bacteria per mg of feces and
intestinal dysmotility, or a lack of gastric acid secretion. up to a 1000 species will be encountered. It must be con-
2. Can cause steatorrhoea and B12 deficiency (folate may be ceded, however, that the detailed composition of the gut
high). microbiota (and not just bacteria but also archaea, viruses,
3. The diagnosis of SIBO is commonly made on the basis of fungi and protozoa) continues to be defined; it is evident that
an early rise in exhaled breath H2 following the adminis- culture-based techniques had dramatically underestimated
tration of an appropriate substrate (glucose or lactulose). the size and diversity of microbial communities within the
Criteria for diagnosis vary and must take account of GI tract. As molecular techniques, such as shotgun sequenc-
accelerated small intestinal transit. Alternatively, quanti- ing, are applied to enteric communities, their full dimensions
tative cultures of aspirated small bowel contents may be in health and disease will be appreciated [1–3]. The same
used to make the diagnosis. applies to the definition of small intestinal bacterial over-
4. In clinical practice, the diagnosis of SIBO is often growth (SIBO); as we will see later, its definition has, to
assumed and empirical antibiotic treatment commenced date, relied upon culture or indirect approaches, such as the
and the effect carefully monitored. analysis of exhaled gases—we await the systematic applica-
5. Chronic SIBO may justify long-term rotating oral antibi- tion of high-throughput sequencing, metagenomics and
otics (e.g. co-amoxyclav, rifaximin, ciprofloxacin, metro- metabolomics to its assessment. The latter may prove to be
nidazole, a tetracycline or a cephalosporin) given for especially important by identifying those bacterial products
6 weeks before rotating with an intervening 1–2 weeks and metabolites that actually produce symptoms and injure
off antibiotics. There are many different regimens. the intestine in SIBO. In a similar vein, while a profile of
bacterial numbers along the GI tract has been described
based on cultures of luminal aspirates (and used as the
Small Intestinal Bacterial Overgrowth benchmark for defining abnormality), data, derived from
either sequencing or metagenomics on bacterial populations
he Gut Microbiota: A Key Player
T throughout the small intestine, in health or disease, is scanty
in Homeostasis and this remains a major obstacle to our understanding of
SIBO [4]. While there have been many studies of the human
As one passes down the gastrointestinal (GI) tract from gut microbiota in health and a variety of gastrointestinal dis-
esophagus to rectum the numbers and diversity of bacteria eases, most have been, for reasons of obvious logistical sim-
increase dramatically. Though, not as previously considered, plicity, based on the analysis of stool samples. While such
sterile, the esophagus and stomach contain relatively low studies have revealed many of the factors that influence the
numbers of bacteria but still feature quite a diversity of bac- development and maintenance of the gut microbiota through-
out life, they may be poorly reflective of those critical inter-
actions that occur between bacteria and the host at, or close
E. M. M. Quigley (*) to, the epithelial surface [4].
Division of Gastroenterology and Hepatology, Lynda K and David
We do know that enteric bacteria colonize the alimentary
M Underwood Center for Digestive Disorders, Houston Methodist
Hospital, Weill Cornell Medical College, Houston, TX, USA tract at and soon after birth. Thereafter, the infant’s microbi-
e-mail: [email protected] ota rapidly increases in numbers and diversity to reach adult

150 E. M. M. Quigley
proportions at about 2 years of age and then remains rela- levels are markedly decreased and Proteobacteria (including
tively constant throughout adulthood only to decline some- pro-inflammatory Enterobacteriaceae) emerge as the pre-
what in later years [5]. These early years may be critical, not dominant phylum, especially among those with type III SBS
only to the development of the mature microbiome but also and with intestinal failure associated liver disease (IFALD)
to shaping immunological and metabolic interactions with and central line-associated bloodstream infections (CLABSI)
the host—interactions that may play a critical role in predis- [6–9]. Lactobacilli may be increased [10]. In various studies,
posing an individual to disease in adolescence and adult- changes in the microbiota have also been linked to diarrhea,
hood. The literature is now replete with examples of the the need for parenteral nutrition, d-lactic acidosis, liver dis-
sensitivity of the developing microbiota to various interven- ease and growth failure [8–10]. The interpretation of all of
tions (diet and antibiotics, for example) that presage later ill these findings must remain guarded given the small sizes of
health. We also now have a reasonable understanding of the study populations and the multiple factors that may
some of the factors that shape the microbiota in adulthood— impact on the microbiota in these patients rendering it diffi-
here again, diet and antibiotic use loom large with certain cult to assign causality to any association between changes
medications, ethnicity, host genetics, geographic location in the microbiota and a clinical finding.
and disease itself appearing to exert impacts; ones that could
readily confound the interpretation of microbiota data.
The four dominant bacterial phyla in the human GI tract Definition of SIBO
are Firmicutes, Bacteroidetes, Actinobacteria, and
Proteobacteria. Most bacteria belong to the genera In its original usage the term small intestinal bacterial over-
Bacteroides, Clostridium, Faecalibacterium, Eubacterium, growth (SIBO—sometimes referred to as “contamination”)
Ruminococcus, Peptococcus, Peptostreptococcus, and was introduced to describe a situation where an increase in
Bifidobacterium. Other genera, such as Escherichia and the numbers and/or change in the type of bacteria in the
Lactobacillus, are present in lower numbers. It must be small intestine resulted in clinical consequences and, specifi-
stressed that a number of fungal genera are normal inhabit- cally, those associated with malabsorption and maldigestion
ants of the gut and include Candida, Saccharomyces, [11]. However, this rather narrow context has been radically
Aspergillus, Penicillium, Rhodotorula, Trametes, Pleospora, expanded in recent years to encompass a broad spectrum of
Sclerotinia, Bullera, and Galactomyces, among others. intestinal and extra-intestinal disorders often on the basis of
Archaea include important species such as the methane- imprecise methodology and/or limited data. Such studies
producing (methanogenic) Methanobrevibacter smithii. have generated considerable controversy and thrown the def-
Major differences in the distribution of bacterial taxa are evi- inition of SIBO into sharp relief. Fortunately, a discussion of
dent as one moves in an aborad direction along the gut with SIBO in the context of intestinal failure is largely concerned
lactobacilli, enterococci, oral streptococci and other gram- with SIBO as a contributor or exacerbator of maldigestion/
positive aerobic or facultative anaerobes reflecting the bacte- malabsorption where the clinical presentation is related to
rial flora of the oropharynx dominating in the upper gut; for effects of the contaminating organism on host morphology
example, coliforms rarely exceed 103 colony forming units or function which, in turn, result in the clinical consequences
(cfu’s)/mL of jejunal juice. The microbiology of the terminal typically associated with SIBO, such as steatorrhea, diar-
ileum represents a transition zone between the jejunum, con- rhea, protein losing-enteropathy and/or specific deficiency
taining predominantly aerobic species, and the dense popula- states.
tion of anaerobes found in the colon. On crossing into the In this context, SIBO can be defined as “clinical and/or
colon, the concentration and variety of enteric flora changes laboratory evidence of maldigestion/malabsorption
dramatically with obligate anaerobes such as bacteroides, related to qualitative and/or quantitative alterations in
porphyromonas, bifidobacteria, lactobacilli and clostridia the small intestinal microbiota” [11]. Here the emphasis is
dominating and outnumbering aerobic bacteria by a factor of on the clinical context and SIBO is incriminated, firstly, by
100–1000:1. documenting its presence, and, secondly, by demonstrating a
clinical response to its eradication.
In IF, especial caution should be exercised in the diagno-
he Gut Microbiota in Short Bowel
T sis of SIBO and its treatment by antibiotics given that the use
and Intestinal Failure of antibiotics must be balanced against the benefits to the
individual patient of energy salvage due to colonic bacterial
There have been relatively few studies on the intestinal metabolism of unabsorbed carbohydrate to short-chain fatty
microbiota in SBS and/or IF. Bacterial diversity and acetate acids [12].
Bacterial Overgrowth and Enteric Infections 151
Pathogenesis of SIBO prominent examples of dysmotility-related SIBO [15–17].

In diabetes, SIBO is especially common among those with
An appreciation of the factors that protect against the devel- long standing, type I diabetes who exhibit other target organ
opment of SIBO in health helps to predict the likelihood of pathologies, such as nephropathy, retinopathy and, most
its occurrence in disease (Table 1). Of these, gastric acid and notably, autonomic neuropathy [15, 16]. Intestinal pseudo-
intestinal motor activity seem to be most important. In the obstruction, whether based on myogenic of neurogenic
stomach, acid kills and suppresses the growth of most organ- intestinal dysmotility, though an uncommon cause of SIBO,
isms that enter from the oropharynx. In the small bowel, the in general, looms large in any IF population [18]. Dysmotility
cleansing action of aborad propulsive forces and, especially, may also be relevant to the pathogenesis of another rare
phase III of the interdigestive migrating motor complex cause of SIBO, jejunal diverticulosis. Morphological stud-
(MMC), limits the ability of bacteria to colonize the small ies suggest that disorders of intestinal motility such as pro-
intestine [13]. Other protective factors include the integrity gressive systemic sclerosis, visceral myopathies and
of the intestinal mucosa, including its protective mucus layer neuropathies play an important role in the formation of
and intrinsic anti-bacterial mechanisms, such as defensins small bowel diverticula [19]. Disruption of the MMC
and immunoglobulins; the enzymatic activities and bacterio- appears to be an important factor leading to the develop-
static properties of intestinal, pancreatic and biliary secre- ment of SIBO in patients with radiation enteropathy; a not
tions; the protective effects of the commensal flora; and the infrequent cause of IF [20].
mechanical and physiological properties of the ileocecal
valve [14]. One can readily appreciate that many of these Altered Anatomy
protective factors may be missing or impaired in the indi- A variety of surgical procedures that alter gastrointestinal
vidual with short bowel syndrome or intestinal failure. Let us anatomy have been associated with SIBO. A number of
now examine the contribution of these various factors to pathophysiological factors may be operative in this setting,
SIBO in the individual with intestinal failure (IF). including hypochlorhydria, formation of blind loops
(depending on the nature of the surgical procedure), lack of
Dysmotility contact between chyme and bile and/or digestive enzymes
Virtually every condition that has been linked to small intes- and disruption of intestinal motility. Stagnation and/or recir-
tinal dysmotility has been associated with SIBO with dia- culation of intestinal contents resulting from strictures, fis-
betic autonomic neuropathy and scleroderma being tulae, enterostomies and anastomoses also predispose to
SIBO; all relevant to IF, in general, as well as to two com-
mon causes of IF, Crohn’s disease and radiation enteropa-
Table 1 Factors involved in the pathogenesis of SIBO
thy. Loss of the ileocolonic junctional region, as well as
• Dysmotility direct anastomoses between the proximal small intestine
– Intestinal pseudo-obstruction
and colon, will also predispose to and promote SIBO in
– Scleroderma and related disorders
– Autonomic neuropathy some IF subjects. The distinction between the ileocecal
– Jejunal diverticulosis valve and the ileocolonic junctional region is important.
– Radiation enteropathy While the ileocecal valve forms a physical barrier to reflux
• Altered anatomy of colonic material from the colon into the small bowel,
– Blind loops results from both experimental animal models and human
– Strictures studies have failed to identify a major effect on either bacte-
– Fistulae
rial translocation or SIBO following resection of just the
– Entero-colonic anastomoses
– Loss of the ileo-cecal valve valve [14]. These findings would lend support to the hypoth-
• Hypochlorhydria esis that specialized motor patterns in the distal ileum, and
– Vagotomy not the valve itself, are the critical elements in sustaining the
– Gastric resection propulsive functions of this region [21].
– Acid suppressive medications
• Immune deficiency Hypochlorhydria
– Hypogammaglobulinemia
Initially described in relation to surgical procedures that
– Combined variable immune deficiency (CVID)
• Multifactorial
reduced gastric acid secretion, hypochlorhydria has, more
– Crohn’s disease recently, been invoked in the development of SIBO among
– Radiation enteropathy individuals on long-term treatment with proton-pump inhibi-
– Chronic pancreatitis tors (PPIs). Though some studies suggested that long-term
– Chronic liver disease PPI therapy was associated with SIBO [22–24], others have
– Celiac disease failed to confirm this [25]. Furthermore, though their meta-
analysis revealed a pooled odds ratio of 2.82 for SIBO among Table 2 Consequences of SIBO
PPI users versus non-users, Lo and Chan found that this • Symptoms and signs
association held true only for studies employing intestinal – Diarrhea
culture rather than breath tests for the diagnosis of SIBO – Steatorrhea
– Edema
[23]. Interestingly, Ratuapli and colleagues, who failed to
– Weight loss
identify a relationship between PPI use and SIBO, based
– Malnutrition
their analysis on breath tests [25]. In IF it seems prudent to – Anemia
exert some caution in the use of PPIs. – Encephalopathy
• Laboratory findings
Immune Deficiencies – Steatorrhea
SIBO has been described in association with hypogamma- – Hypoproteinemia
globulinemia, both in inherited and acquired forms, as well – Anemia
– Vitamin B12 deficiency
as with disorders of cellular immunity, such as human immu-
– Elevated levels of Folic acid
nodeficiency virus infection. – Elevated levels of Vitamin K
– Deficiency of other fat-soluble vitamins
Impact of Co-morbidities – d-lactic acidosis
From the above it is clear that multiple factors will contribute – Hyperammonemia
to the pathogenesis of SIBO in IF. Diseases that may occur in
the IF patient (such as Crohn’s disease, radiation enteropathy Table 3 Complications of SIBO
[26] and diabetes, for example) may also predispose to • Malnutrition
SIBO. It is likely that multiple factors also contribute to the • Protein-losing enteropathy
pathophysiology of SIBO associated with chronic renal fail- • Mucosal injury
ure, chronic pancreatitis and liver disease; all may occur in • Encephalopathy
the IF patient. The cause of SIBO in chronic pancreatitis is – Hyperammonemia
multifactorial and includes the loss of pancreatic enzymes, a – d-lactic acidosis
• Bacterial translocation
decrease in intestinal motility resulting from the inflamma-
– Gut-derived sepsis
tory process, the effects of narcotics on gut motility and the – CLABSI
presence, in some instances, of intestinal obstruction. Of • Liver disease
these the association with chronic liver disease is, perhaps,
the best documented. SIBO has also been frequently docu-
mented in association with liver disease and it is in this con- fatty acids that, in turn, increase the osmolarity of intestinal
text that relationships between SIBO and systemic sepsis fluid and promote motility. Direct mucosal injury may also
have been most extensively explored [27, 28]. In liver dis- result from bacterial adherence or increased conversion, by
ease and of great relevance to IF, SIBO has been linked to enterotoxins, of the enzyme xanthine dehydrogenase to xan-
systemic endotoxemia, spontaneous bacterial peritonitis and thine oxidase; indirectly, morphological changes may occur
both overt hepatic encephalopathy and minimal hepatic secondary to cobalamin deficiency. Regardless of mecha-
encephalopathy [29–31]. Just as an altered intestinal micro- nism, enterocyte injury leads to both a loss of activity of
biota has been linked to non-alcoholic fatty liver disease brush border disaccharidases and altered permeability, the
(NAFLD) [32], there is some evidence to link a disrupted later predisposing to the development, in the most severe
microbiota, in IF, with, not only poor outcomes [10, 33], but cases, of a protein-losing enteropathy. The former will result
also IFALD [6, 10, 34, 35]. in the presentation of more unabsorbed carbohydrates to
intestinal bacteria for fermentation and could also contribute
to lactose intolerance. Mucosal injury by bacterial toxins
IBO: Consequences and Complications
S may also trigger an inflammatory response with the genera-
(Tables 2 and 3) tion of inflammatory cytokines such as tumor necrosis factor
α which may contribute to hepatic and systemic
SIBO may influence gut function through direct and indirect complications.
mechanisms. Deconjugation of bile acids in the proximal Bacterial digestion of luminal protein will leave the
small bowel will disrupt fat digestion and lead to the produc- affected individual susceptible to malnutrition and will also
tion of lithocholic acid, which is poorly absorbed and may be contribute to hypoproteinemia and edema. Although some
directly toxic to enterocytes. Carbohydrate malabsorption, degree of hypoproteinemia is common, severe malnutrition
due to SIBO, can contribute to diarrhea due to metabolism of is rare in SIBO. Bacterial metabolism of protein can also
malabsorbed carbohydrates by bacteria to form short-acid lead to the production of ammonia. In the context of an
impaired mucosal barrier, encephalopathy may result. of sepsis syndrome and multiple organ failure, recent studies
Moreover, short bowel syndrome patients, especially those have shown that gut-derived-bacteremia, even when due to
with an intact colon, may suffer d-lactic academia and asso- potent nosocomial pathogens, is an event of low proinflam-
ciated encephalopathy as a result of the production of d- matory potential and, is of itself an insufficient stimulus for
lactic acid by certain Gram-positive anaerobes [36, 37]. the systemic inflammatory response and organ failure state
A number of phenomena combine to make SIBO an typically seen after severe and prolonged catabolic stress. It
important cause of B12 deficiency. These include the con- seems much more likely that alterations in the gut’s immune
sumption of cobalamin by anaerobes, malabsorption of the function and interactions between the gut-associated immune
vitamin as a result of competitive binding with cobalamin tissue and the rest of the body form the basis for this
from bacterially-generated metabolites of cobalamin at the syndrome.
ileal receptor and, in instances of more severe overgrowth, Central venous infection is the most frequent complica-
actual mucosal damage involving the binding site. Bacterial tion during parenteral nutrition and in IF. Although catheter
utilization of vitamins, in SIBO, has also been invoked in the sepsis is often associated with enteric organisms, Reimund
development of thiamine and nicotinamide deficiency. et al. found that, in their 42 adult patients, Staphylococcus
Deconjugation of bile acids and consequent depletion of epidermidis was detected in 51% [44]. Moreover, the pres-
the bile acid pool will lead to maldigestion of fat and fat ence of enteric organisms in the bloodstream does not neces-
soluble vitamins. Here there is one particular paradox: bacte- sarily mean bacterial translocation caused by bacterial
rial production of vitamin K, combined with enhanced overgrowth, because of diarrhea episodes, patients often
absorption of the vitamin, due to greater permeability, may have colonization of skin and their immediate environment
serve not only to sustain but even increase vitamin K levels with enteric flora.
to a degree that warfarin dose may need to be adjusted to
maintain therapeutic anticoagulation [38]. Bacterial synthe-
sis of folic acid may result in the rather unusual combination Diagnosis of SIBO
of high folate and low B12 levels in the circulation.
Although aspiration and direct culture of jejunal contents are
regarded by many as the gold standards for the diagnosis of
Bacterial Translocation and Sepsis SIBO, these methods have several limitations, such as the
potential for contamination by oropharyngeal bacteria dur-
The possible contribution of SIBO to bacterial translocation ing intubation, and the fact that bacterial overgrowth may be
and sepsis is an important issue in intestinal failure, a disor- patchy and thus missed by a single aspiration. Overall the
der where sepsis is an important cause of morbidity and mor- reproducibility of jejunal aspiration and culture have been
tality. Bacterial translocation is defined as the passage of reported to be as low as 38% in comparison to 92% for breath
viable bacteria or bacterial products, such as lipopolysaccha- tests. In addition, these methods may be regarded as cumber-
ride, from the gastrointestinal tract to extraintestinal sites, some and invasive for patients who may require repeated
such as the mesenteric lymph node complex, liver, spleen, testing.
kidney, and bloodstream [39–41]. Experimental animal For this reason, a variety of noninvasive diagnostic tests
models have shown that bacterial translocation may be pro- have been devised for the diagnosis of SIBO based on the
moted by mucosal inflammation, intestinal obstruction, isch- excretion, in exhaled breath, of hydrogen generated by the
emia and hypo-perfusion injury, acute pancreatitis, liver metabolism of carbohydrate by luminal bacteria. In these
disease, prematurity, burns and trauma. SIBO, increased breath tests, the diagnosis of SIBO is established when the
intestinal permeability, and impaired host immune defense, exhaled breath H2 increases by more than 20 parts per mil-
are considered to be the primary mechanisms which promote lion (ppm) over baseline on two consecutive samplings
bacterial translocation. Indeed, this model of an altered lumi- within 90 min of substrate ingestion [45] (Fig. 1). If methane
nal microbiota, impaired gut barrier function (“the leaky is measured, a rise of 10 ppm is considered diagnostic
gut”) and bacterial translocation has been invoked to explain (Fig. 2). These criteria assume that the small intestine is ana-
a host of hepatic and systemic disorders. However, it must be tomically intact and that small intestinal transit is normal. It
emphasized that while animal studies support this concept, it has also been suggested that a fasting breath hydrogen level
has been poorly documented in man [42, 43]. that exceeds 20 ppm is indicative of SIBO; in short bowel
The term gut-derived sepsis is used to describe a state of patients where the small bowel remnant is in continuity with
systemic inflammation and organ dysfunction associated a functioning colon, breath test interpretation may be diffi-
with severe catabolic stress; it has been hypothesized that cult as the baseline breath H2 level may be very high.
this syndrome is initiated and perpetuated by the intestinal Even though double peaks (SIBO and colonic peaks) have
microbiota. Although the gut plays a role in the development previously been defined as representing an abnormal lactu-
Fig. 1 Breath Hydrogen and

Methane levels for 180 min Breath Hydrogen Curves following ingestion of Lactulose
following ingestion of 200
lactulose (time 0). Note: early
(>20 ppm) rise in breath 180
hydrogen between 20 and
160
40 min illustrating an “early”
peak and very suggestive of 140
SIBO
120
ppm 100
80
60
40
20
0
0 20 40 60 80 100 120 140 160 180
Hydrogen Methane
Time - minutes
Fig. 2 Breath Hydrogen and

Methane levels for 180 min Breath Hydrogen Curves following ingestion of Lactulose
following ingestion of 90
lactulose (time 0). Note:
“double peak” in methane 80
excretion, the first at 40 min
(indicative of SIBO) and the 70
second at 120 min (consistent
with arrival of the substrate in 60
the colon)
50
ppm
40
30
20
10
0
0 20 40 60 80 100 120 140 160 180
Hydrogen Methane
Time - minutes
lose breath test (Fig. 2), they may also result from rapid oro- carbohydrate malabsorption and a resultant increase in
cecal transit resulting in the premature delivery of fermentable colonic fermentation. However, in support of a role for
substrate to cecal bacteria. Indeed, the reliability of these bacterial overgrowth in symptom pathogenesis, studies have
diagnostic techniques has been criticized in patients with reported a parallel improvement in gastrointestinal symp-
intestinal failure, and especially those with short bowel syn- toms and breath tests after antibiotic therapy among intesti-
drome, because of the rapid intestinal transit that accompa- nal failure patients with positive breath tests [46, 47]. It must
nies these disorders. Interpretation of breath tests may also also be borne in mind that false-negative or “flat” responses
be complicated, in patients with short bowel syndrome, by to lactulose administration may be found among those whose
bacterial flora has been altered by antibiotic therapy or diar- with SIBO, bacterial translocation and intestinal failure are
rhea or in whom motility disorders coexist, situations com- not readily reversible. Nontransplantation surgical proce-
monly present in patients with intestinal failure. Finally, dures and medical treatment have the same emphasis, which
between 15% and 27% of the population do not generate is to reduce the requirement for total parenteral nutrition and
hydrogen, following the ingestion of this substrate, but, to reach a normal weight, height and lifestyle. Non-
rather produce methane (as illustrated in Fig. 2); the mea- transplantation surgical approaches (see elsewhere in this
surement of hydrogen alone will clearly underestimate the volume) can improve intestinal function and increase nutri-
prevalence of SIBO among such individuals. ent and fluid absorption by either slowing intestinal transit or
The diagnosis of SIBO remains problematic [48]. Jejunal increasing intestinal absorption.
aspiration is cumbersome and open to confounders while
breath tests are fraught with problems of interpretation. We
await the application of nucleic acid amplification techniques Nutrition
and metabolomics to SIBO; approaches that have revolution-
ized the study of the microbiota elsewhere. The nutritional support of the IF patient is dealt with exten-
In the IF patient, SIBO should be suspected based on the sively in this volume; if SIBO is present attention should be
symptomatology described above but breath tests interpreted paid to the correction of deficiencies, such as hypoprotein-
with caution. A therapeutic trial may also be considered but emia and B12 deficiency resultant from, or exacerbated by,
mindful of the negative aspects of indiscriminate antibiotic SIBO.
therapy.
Prokinetics
Therapy of SIBO (Table 4)
Prokinetics that accelerate intestinal transit and improve
SIBO should be suspected in patients with intestinal failure postprandial small-intestinal motility may be attractive adju-
whenever they are not progressing in a normal manner, espe- vants to the treatment of SIBO and intestinal failure. In spite
cially if patients require additional calories, lose weight, or of this, there are few studies about the effect of prokinetics in
regress in their growth. Control of SIBO can be expected to this group of patients and the majority have been performed
improve absorption when significant enteritis has occurred in gastrointestinal motility disorders per se. Options are lim-
due to severe bacterial proliferation. ited; cisapride, perhaps the most extensively studie drug in
this context, was withdrawn due to cardiovascular effects.
Although new prokinetic drugs, without cardiovascular
Surgery adverse effects, such as prucalopride [49], are now available
in some countries, controlled studies are needed to establish
Clearly, the primary goal should be the treatment or correc- the efficacy of these drugs in the treatment of SIBO.
tion of any underlying disease on defect when possible.
Unfortunately, several of the clinical conditions associated
Antibiotics
Table 4 Management of SIBO
In most instances the therapy of SIBO rests exclusively on
• Correction of predisposing abnormalities the use of antibiotics. The ESPEN guideline recommends
• Correction of nutritional deficiencies
“that short bowel syndrome (SBS) patients who have motility
• Prokinetics
• Antibiotics disorders, including those with dilated segments of residual
– Rifaximin small bowel, blind loop etc., and who suffer from symptoms
– Norfloxacin of bacterial overgrowth, benefit from occasional antibiotic
– Amoxicillin-clavulanic acid treatment. (Grade of evidence: very low). We do not recom-
– Co-trimoxazole mend the routine use of antibiotics in SBS patients with a
– Tetracycline preserved colon, given the benefit of the energy salvage due
– Metronidazole
to colonic bacterial fermentation of malabsorbed carbohy-
– Ciprofloxacin
Single course—7–14 days drate to short-chain fatty acids, in spite of a potential reduc-
Intermittent therapy tion in the production of gases and consequent symptoms
Rotating antibiotics (4–6 weeks on, 2 weeks off) related to this fermentation. (Grade of evidence: very low)”
Continual [12]. They concluded that very little is known about the pres-
ence of small bowel bacterial overgrowth in patients with Probiotics

SBS; a situation confounded by the aforementioned lack of
consensus regarding its definition and the lack of consensus Probiotics, a word is derived from the Greek and meaning
on indications for treatment. “for life”, are defined as live organisms that, when ingested
The objective of antibiotics in SIBO should not be to in adequate amounts, exert a health benefit on the host [53].
eradicate the bacterial flora but to alter it in a way that leads Several experimental studies have suggested that the
to symptomatic improvement. Although, ideally, the choice mechanism of probiotic activity is likely multifactorial.
of antimicrobial agents should reflect in vitro susceptibility Competitive metabolic interactions with pathogens, produc-
testing, this is usually impractical as many different bacte- tion of bacteriocins, inhibition of bacterial translocation,
rial species with different antibiotic sensitivities typically enhancement of mucosal barrier function, and signaling with
coexist. Antibiotic treatment remains, therefore, primarily the epithelium and immune system have been reported as
empirical. Effective antibiotic therapy must cover both aero- possible modes of action of probiotics strains [54].
bic and anaerobic enteric bacteria and different schedules There is also a paucity of data on probiotics in SIBO
have been suggested. Although in general, a short single (7- related to IF. In an isolated case of d-lactic acidosis in a
to 10-day) course of antibiotic may improve symptoms for patient with short bowel syndrome and recurrent encepha-
up to several months in between 46% and 90% of patients lopathy, Uchida et al. showed that a probiotic associated with
with SIBO and render breath tests negative in 20–75%, oral kanamycin was effective in ameliorating these episodes
patients with SIBO and intestinal failure due to short bowel [55]. While some lactobacilli can generate d-lactic acid, oth-
syndrome and/or gastrointestinal disease are more refrac- ers do not and the latter have actually been used to treat
tory to antibiotic therapy and may require either repeated d-lactic acidosis [37].
(e.g. the first 5–10 days out of every month) or continuous Vanderhoof and colleagues suggested that, in their chil-
courses of antibiotic therapy. For the latter, rotating antibi- dren with bacterial overgrowth associated with short bowel
otic regimens are recommended to prevent the development syndrome, Lactobacillus plantarum 299v either prevented or
of resistance. Decisions on management should be individu- delayed the recurrence of symptoms following antibiotic
alized and consider such risks of long-term antibiotic ther- treatment [56]. In a randomized, double-blind trial, Gaon
apy as diarrhea, Clostridium difficile infection, intolerance, and colleagues found that, in their 12 patients with bacterial
bacterial resistance, and cost. In the past, antibiotics such as overgrowth-related chronic diarrhea, both Lactobacillus
norfloxacin, amoxicillin-clavulanic acid, and metronidazole casei and acidophilus strains cerela were effective for bacte-
for 7 days were a good option. More recently and given its rial overgrowth-related chronic diarrhea, and suggested that
minimal systemic absorption and favorable safety profile, probiotics should be used continuously [57]. In contrast,
rifaximin has emerged as an important option [50]. Rotating Saccharomyces boulardii did not significantly influence the
regimens are especially valuable in patients with visceral evolution of chronic diarrhea and breath test results [58].
myopathy, scleroderma and jejunal diverticulosis and com- Stotzer et al. showed that, in their patients with long-standing
monly feature 4–6 weeks on one antibiotic followed by a bacterial overgrowth, Lactobacillus fermentum did not ben-
2 week “holiday” off antibiotic followed by 6 weeks with efit symptoms or normalize breath tests [59]. Data remains,
another antibiotic, and so on. therefore, inconclusive.
Prebiotics and Synbiotics Enteric Infections and Intestinal Failure
A prebiotic is defined as a substrate that is selectively uti- uman Immunodeficiency Virus (HIV)
H
lized by host microorganisms conferring a health benefit Enteropathy
[51]. They are, typically, non-digestible but fermentable food
ingredients that selectively stimulate the growth and activity In the previous edition of this textbook an entire chapter was
of one species or a limited number of species of bacteria in devoted to HIV infection; it is a testament to the dramatic
the colon. Though the science behind prebiotics continues to progress in treatment of this once fatal condition that HIV
develop, there is less clinical data and little in relation to enteropathy merits a mere footnote in this edition. Indeed, as
SIBO and IF. One study found that the addition of the prebi- the incidence of opportunistic enteric infections has
otic preparation guar gum enhanced the efficacy of rifaximin decreased due to more effective anti-retroviral therapy
[52]. (ART), the incidence of noninfectious diarrhea (such as that
occurring as an adverse consequence of therapy and HIV 4. Blaser MJ. The microbiome revolution. J Clin Invest.
2014;124:4162–5.
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5. Quigley EM. Gut microbiome as a clinical tool in gastrointesti-
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should now be an extreme rarity among those who have Hepatol. 2017;14:315–20.
access to effective anti-viral therapy [60, 61]. Once opportu- 6. Wang P, Wang Y, Lu L, Yan W, Tao Y, Zhou K, Jia J, Cai
W. Alterations in intestinal microbiota relate to intestinal failure-
nistic infections have been excluded, therapy becomes pri-
associated liver disease and central line infections. J Pediatr Surg.
marily symptomatic and supportive with careful attention to 2017;52:1318–26.
choosing ART agents with minimal diarrheagenic effects. 7. Huang Y, Guo F, Li Y, Wang J, Li J. Fecal microbiota signatures
While a number of medications are used on an off-label of adult patients with different types of short bowel syndrome. J
Gastroenterol Hepatol. 2017;32:1949–57.
basis, crofelemer is the only therapy currently approved in
8. Piper HG, Fan D, Coughlin LA, Ho EX, McDaniel MM,
the US for symptomatic relief of non-infectious diarrhea in Channabasappa N, Kim J, Kim M, Zhan X, Xie Y, Koh AY. Severe
patients with HIV on ART. gut microbiota dysbiosis is associated with poor growth in patients
with short bowel syndrome. JPEN J Parenter Enteral Nutr.
2017;41:1202–12.
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10. Neelis E, de Koning B, Rings E, Wijnen R, Nichols B, Hulst J,
In a manner similar to HIV, a variety of opportunistic enteric
Gerasimidis K. The gut microbiome in patients with intestinal fail-
infections, such as giardiasis [62], have been reported among ure: current evidence and implications for clinical practice. JPEN J
those who suffer from common variable immunodeficiency Parenter Enteral Nutr. 2018;43:194.
(CVID). CVID is diagnosed on the basis of levels of IgG and 11. Quigley EMM. Bacterial overgrowth. In: Camilleri M, Fitz
JG, Kalloo AN, Podolsky DK, Shanahan F, Wang TC, editors.
IgA more than two standard deviations below normal in the
Yamada’s textbook of gastroenterology. 6th ed. Chichester: Wiley;
absence of any other cause for hypogammaglobulinemia. 2016. p. 1294–304.
Though rarely meriting the diagnosis of intestinal failure, 12. Pironi L, Arends J, Bozzetti F, Cuerda C, Gillanders L, Jeppesen
chronic diarrhea in CVID can result from chronic norovirus PB, Joly F, Kelly D, Lal S, Staun M, Szczepanek K, Van Gossum
A, Wanten G, Schneider SM, Home Artificial Nutrition & Chronic
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Intestinal Failure Special Interest Group of ESPEN. ESPEN
logical remission can result from effective clearance of the guidelines on chronic intestinal failure in adults. Clin Nutr.
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been reported to cause IF, however, in children who have 13. Vantrappen G, Janssens J, Hellemans J, Ghoos Y. The interdiges-
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Extensive Mucosal Disease: Coeliac
Disease and Eosinophilic Enteritis
Suzanne C. Donnelly
Key Points Coeliac Disease

1. Coeliac disease, the most common disease affecting the
small intestine in the Western world, can be found in most The most common cause in the Western world of small intes-
countries tinal disease is coeliac disease which is also known as coe-
2. Coeliac disease is treated with a life-long gluten-free diet. liac sprue or gluten-sensitive enteropathy. It is a small
3. More severe metabolic complications of coeliac disease intestinal disorder caused by an inappropriate immune
occur in refractory coeliac disease, ulcerative jejunitis response to dietary gluten. Ingestion of wheat, rye or barley
and enteropathy-associated T-cell lymphoma proteins in susceptible individuals triggers an inflammatory
4. The development of treatment to allow gluten transgres- response particularly in the proximal small intestinal mucosa
sions in coeliac disease is slow to come to market causing damage to the villous architecture. In a small minor-
5. Eosinophilic enteritis is a rare condition affecting the gas- ity of patients this also happens with oat proteins. The dis-
trointestinal tract ease manifests itself as a generalised malabsorption which
6. Treatment for eosinophilic enteritis currently involves typically presents as weight loss, diarrhoea or disorders asso-
oral corticosteroids ciated with specific nutrient deficiencies such as anaemia or
osteoporosis. However, since the advent of highly sensitive
serological screening tests, less well-defined forms of the
Introduction disease are being increasingly recognised and the terminol-
ogy has changed. Treatment, at present, is the life long, com-
The small intestine has a role in both secretion and absorp- plete avoidance of gluten from the diet.
tion. Small intestinal disorders can be predominantly malab-
sorptive or secretory in nature but often the two co-exist with
most small intestinal mucosal disease having malabsorption Epidemiology
and excess secretions. Diarrhoea due to small intestinal dis-
ease is often non-inflammatory and of high output. The Early estimations of the prevalence of coeliac disease indi-
larger the surface area of small intestinal mucosa affected, cated that it was an uncommon disorder. A study in 1950
the higher the outputs. Improvement of diarrhoea after fast- estimated the incidence of coeliac disease to be 1:8000 in
ing suggests an osmotic component to the diarrhoea and both England and Wales and 1:4000 in Scotland [1]. Since then
may co-exist. Malabsorption symptoms include steator- the diagnostic process has vastly improved with the advent
rhoea, malodorous flatus, bloating and postprandial of endoscopic small bowel biopsy in the 1960s and highly
diarrhoea. specific serological screening methods, such as the anti-
endomysial or the tissue transglutaminase antibodies. This
made it possible to evaluate the true prevalence of coeliac
disease showing an unsuspected frequency of clinically atyp-
ical forms of coeliac disease. A UK study screened over
7000 serum samples for anti-endomysial antibody and found
S. C. Donnelly (*)
Gastroenterology and Intestinal Rehabilitation, London North West that, in England, undetected coeliac disease affects approxi-
University Healthcare NHS Trust, Harrow, UK mately 1% of the adults aged 45–76 years [2]. A large, inter-
e-mail: [email protected] national, multicentre study investigated a wide population

162 S. C. Donnelly
sample in four different European countries [3]. On average status of whole Chinese population may yield some interest-
the overall prevalence of coeliac disease was 1% with large ing results.
variation between countries: 2% Finland, 1.2% Italy, 0.9% There is no data about the prevalence of coeliac disease in
Northern Ireland, 0.3% Germany. This study also confirmed Sub-Saharan Africa. There are however reasons to believe
that many coeliac disease cases would be missed without that coeliac disease is not common in these countries. Staple
active serological screening. Biagi et al. [4] cautioned that cereals such as millet and rice are mostly naturally gluten-
the prevalence of coeliac disease can be over-estimated if tis- free and the HLA-related predisposing genes DQ2 and DQ8
sue transglutaminase is the only diagnostic tool. are much less frequent in these areas than Western countries.
Similar rates have been reported from the US population, Coeliac disease is rare in individuals of Afro-Caribbean ori-
1:133 [5] and from developed countries mostly populated by gin [25].
individuals of European origin, Australia 1:251 [6] and New Evidence suggests that the pattern of disease is changing.
Zealand 1.2% [7]. The presence of coeliac disease is long A multicentre study found the average age of diagnosis in
established in many South American countries that are children had risen from two years in 1975 to four years in
mostly populated by individuals of European origin. Among 1990 [26]. This probably reflects changes in feeding prac-
Brazilian blood donors, the prevalence of coeliac disease tices, for example, a prolonged breastfeeding period is high-
ranged between 1:681 [8] and 1:214 [9], however these may lighted by a well-documented phenomenon that occurred in
be artificially low as blood donors represent the “healthiest Sweden in the mid-1980s. At this time there was a sharp
segment” of the population. In Argentina an overall preva- increase in the incidence of symptomatic coeliac disease in
lence of coeliac disease was found to be 1 in 167 in 2000 children under two years of age [27]. Retrospective analysis
adults involved in a prenuptial examination [10]. of this epidemic found that there had been a two-fold increase
Recent epidemiological studies performed in areas of the in the average daily consumption of flour in formula feed.
developing world show prevalence rates overlapping Furthermore, at this time only 50% of infants were breast-
European figs [11, 12]. The prevalence of coeliac disease in fed. The incidence rates fell in 1995. This coincided with an
North African countries was found to be 0.53% in Egypt increase in the proportion of infants being breast fed at
[13], 0.79% in Libya [14] and 0.6% in Tunisia [15]. In the 6 months and lower quantities of flour in the formula feed. A
Middle East the prevalence was found to be 0.88% in Iran study found breastfeeding to be protective against the onset
[16] and 0.47% in Turkey [17] while in India the rate was of symptomatic coeliac disease [28]. The reason for this is
0.7% [18]. unclear, although other studies have also shown a protective
This widespread diffusion is not surprising at all given effect of breast-feeding against autoimmune diseases.
that the causal factors, HLA predisposing genotypes (DQ2 However, a prolonged period of breastfeeding is not likely to
and DQ8) and consumption of gluten containing cereals prevent the later occurrence of coeliac disease in an individ-
show a worldwide distribution [19]. ual who is genetically predisposed [29].
The highest prevalence of coeliac disease is to be found in
the Saharawi population of Arab-Berber origin living in
Algeria and is 5.6% [20]. High levels of consanguinity, high Manifestations of Coeliac Disease
frequencies of HLA-DQ2 [21] and heavy gluten ingestion
are potential explanations for this phenomenon. The clinical manifestations of coeliac disease vary greatly
In the Far East, there are a few recent reports of coeliac and although this was perceived as a purely paediatric dis-
disease where previously coeliac disease was thought not to ease, the diagnosis is increasingly being made in adult life.
exist. Coeliac disease was found in 14% of symptomatic The classical syndrome of diarrhoea, abdominal distension,
children with diarrhoea in four major cities in China [22]. In muscle wasting and failure to thrive is usually seen in infants
another study, 2.6% of adults tested in the Jiangsu province, between the age of 9 and 18 months of age following the
with high gluten ingestion, who had either type 1 diabetes induction of gluten into their diet. Generally, the earlier intro-
mellitus or diarrhoea-predominant irritable bowel syndrome, duction of gluten into the diet, the sooner the onset of symp-
had positive tissue transglutaminase serology. These adults toms, and therefore prolonged breastfeeding may postpone
declined endoscopy but improved symptomatically as well symptoms [30]. Anaemia is a common presenting feature of
as clinically on a gluten-free diet. The HLA-DQ2 molecule paediatric coeliac disease, and the disease can go undiag-
was also found in 17% of the individuals tested [23]. With nosed where this is the only presenting feature [31]. Anorexia
rising gluten consumption in China and a high level of con- and vomiting are also common. Dental enamel defects have
sanguinity, increasing the prevalence of HLA-DQ2, in some also been reported [32, 33]. Milder forms of the disease are
of the population it may be that coeliac disease is more com- becoming more common and children now tend to present at
mon than first thought [24]. Genetic screening of the HLA a later age and often with only minor symptoms [30].
Extensive Mucosal Disease: Coeliac Disease and Eosinophilic Enteritis 163
In adults, coeliac disease can manifest as a variety of Pathogenesis of Coeliac Disease

symptoms presenting to almost any hospital department. The
presenting symptoms may be varied including gastrointesti- The pathophysiology of coeliac disease is not fully
nal, metabolic, neurological or psychological. The most understood.
common presenting gastrointestinal symptom is diarrhoea Coeliac disease occurs in genetically susceptible individ-
which can be continuous, intermittent or alternated with uals in possession of particular human leucocyte antigen
periods of constipation. It may be accompanied by weight (HLA) class II molecules with approximately 95% of
loss, bloating, anorexia or abdominal pain. Isolated increase patients expressing HLA-DQ2 and the remainder HLA-DQ8
in serum aminotransferase level caused by mild, non- [38]. The HLA-DQ2 or DQ8 molecule is responsible for
progressive liver inflammation is also a common presenta- antigen recognition [39].
tion [34]. There are two mechanisms involved in the pathogenesis
Approximately 50% of coeliac patients do not have clini- of coeliac that may be interlinked. What is not clear is the
cally significant diarrhoea and present with less severe symp- link between the epithelial response and the lamina propria
toms such as lassitude, weakness or weight loss. Anaemia is response. There is an adaptive T cell response predominantly
a frequent finding in coeliac disease and may be the in the lamina propria as well as the innate response poten-
presenting feature [35]. Microcytic anaemia, secondary to tially driven by IL-15 and intraepithelial lymphocyte- entero-
iron deficiency anaemia is highly prevalent and is frequently cyte interaction. It is perhaps this response that is the initiator
the sole manifestation of the disease; oral iron supplementa- of the pathological process with the adaptive T cell response
tion will prove useless in these cases. Macrocytic anaemia maintaining the inflammation. Pathological changes in the
may occur as a result of folate or B12 deficiency. This defi- mucosa of coeliac individuals start to occur one hour after
ciency was previously thought to be unusual in coeliac dis- ingestion of gluten [40, 41] which is too early for an acti-
ease because B12 is absorbed in the terminal ileum and vated T cell response. Tissue transglutaminase is an intracel-
coeliac pathology primarily occurs proximally. Studies have lular enzyme that requires active secretion into the lamina
reported low serum vitamin B12 levels in untreated patients propria to deamidate gluten peptides. The more peptides are
[36]. Low calcium and vitamin D absorption may give rise to deamidated the greater the available antigens for presenta-
osteomalacia and bone pain, with an increasing risk of devel- tion to T cells. It may be that the innate response initiates the
oping osteoporosis. inflammatory cycle that is maintained by the adaptive T cell
response.
Oslo Classification of Coeliac Disease
The true prevalence of coeliac disease within a population is Diagnosis of Coeliac Disease
difficult to estimate as many affected individuals will not dis-
play any symptoms; the disease is therefore undetected. Serology
Experts met, in Oslo, to agree nomenclature for the different
forms of coeliac in Table 1 [37]. The diagnosis of coeliac disease has changed recently in the
paediatric population with the advent of improved coeliac
immunological markers. Serum IgA and IgG antibodies
Table 1 Oslo nomenclature of coeliac disease against gliadin, reticulin, endomysium (components of con-
Term Description nective tissue), tissue transglutaminase and deamidated glia-
Classical coeliac presents with signs and symptoms of din peptides are detectable in individuals with coeliac
disease malabsorption: diarrhoea, steatorrhoea, weight disease. The expertise in immunofluorescence technique for
loss/growth failure EMA is being lost due to time constraints in modern immu-
Non-classical presents without signs and symptoms of
nology laboratories. The ease of using an ELISA based test
coeliac disease malabsorption
Subclinical coeliac is below the threshold of clinical detection. means that IgG tissue transglutaminase antibodies are mea-
disease They have clinical or lab signs (IDA, enamel sured first line in individuals. Screening for serological
defects, osteoporosis, incidental VA) with no markers is initially used for individuals who are at increased
symptoms risk of coeliac disease: patients with non-specific symptoms;
Potential coeliac normal small intestinal mucosa but increased
disease risk of CD-positive serology
those with a family history of coeliac disease or patients with
Coeliac disease for those who have not had a biopsy but have at an associated condition such as Type 1 diabetes mellitus.
autoimmunity least two strongly positive tTG or EMA Approximately 2–3% of coeliac patients are IgA defi-
Genetically at risk family members with CD that have HLA DQ2 cient [42] which can produce false negative EMA results.
of coeliac disease or DQ8 positivity: 2–20% risk For this reason, it is recommended that serum IgA levels
164 S. C. Donnelly
be measured in those individuals at a higher risk of coeliac These features form a continuum with normal mucosal
disease, those with symptoms or with a family history. IgA architecture at one end and the classical flat lesion at the
deficient individuals should be screened using an IgG other end, which may take many years to develop. Marsh 1 is
based test. an increase in IELs counted per 100 enterocytes, the first and
most sensitive index of the effects of gluten on the mucosa.
Infiltration of gluten-dependent lymphocytes into the lamina
propria is also seen. However, it is not pathognomonic for
Histology coeliac disease as they may be raised in infections for exam-
ple. Marsh 1 is often seen in dermatitis herpetiformis, in
The coeliac lesion predominantly affects the proximal small treated coeliac disease, and in family members of those
intestine with lessening damage occurring towards the distal affected by coeliac disease. Figure 1 shows the histological
small intestine. The pathology spans a spectrum of severity changes of Marsh 3c lesion.
that has been classified into five stages by Marsh [43]: the pre- However, villous atrophy is not pathognomonic for coe-
infiltrative, infiltrative, hyperplastic, destructive and hypoplas- liac disease as it can occur in the context of other disorders
tic (atrophic) lesions. These were subsequently modified by such as cow’s milk allergy, giardiasis, rotavirus infection and
Oberhuber [44] to be able to use the classification for diagnos- autoimmune enteropathy [45].
tic purposes. The classification is summarised in Table 2. The Type 4 is a very rare hypoplastic lesion which is charac-
parameters assessed in the diagnosis of coeliac disease on terised by a flat mucosa but normal crypt depth and normal
mucosal small bowel biopsy specimens include villous or IEL count. It is probably a historic lesion seen in severely
crypt architectural changes as well as lamina propria cell den- emaciated small children and most likely signifies malnutri-
sity and intra-epithelial lymphocyte (IEL) cell counts. tion parallel findings in kwashiorkor [46].
Table 2 The modified Marsh classification

Type 0 Type 1 Type 2 Type 3a Type 3b Type 3c
IEL/100 enterocytes <40 >40 >40 >40 >40 >40
Crypts normal normal hypertrophic hypertrophic hypertrophic hypertrophic
Villi normal normal normal mild atrophy marked atrophy absent
Fig. 1 Histological changes Marsh 0 Marsh 3c

of coeliac disease. H + E stain
second part of duodenum low
power (×100) courtesy of Dr.
Chang, St Thomas Hospital
Criteria for Diagnosis of Coeliac Disease age group. The algorithm proposed by the ESPGHAN work-
ing group on the diagnosis of coeliac disease is complicated
The required criteria for a diagnosis of coeliac disease were but it aims to reduce the need for endoscopy which requires
first proposed by the European Society of Paediatric anaesthesia in the paediatric cohort. The new ESPGHAN
Gastroenterology and Nutrition (ESPGHAN) in 1970 [47]. diagnostic pathway in children who have classical symptoms
The original statement proposed that a diagnosis should be of coeliac disease, with HLA-DQ2 or -DQ8, the genetic pre-
based on three criteria: disposition, and strongly positive tTG and EMA serology
should not undergo endoscopic evaluation of the small intes-
1. Structurally abnormal jejunal mucosa when taking a tine. Those who have the genetic predisposition and equivocal
gluten-containing diet serology should proceed to a biopsy of the small intestine, as
2. Clear improvement of villous structure when taking a in those patients in whom the diagnosis in unclear [53].
gluten-free diet
3. Deterioration of the mucosa as a result of a gluten
challenge. Treatment
A patient underwent a minimum of three endoscopies for a Gluten-Free Diet

definite diagnosis of coeliac disease. The criteria were
revised in 1990 [48] after it was found that many gastroenter- Once a diagnosis of coeliac disease has been established,
ologists were not recommending a gluten challenge and a patients are advised to start a lifelong gluten-free diet. This
third biopsy. The revised criteria continue to emphasise that involves the exclusion from the diet of any cereal that con-
an initial biopsy is paramount. Histological examination tains wheat gluten and prolamins from rye and barley or its
showing the characteristic abnormalities, that is, lympho- derivatives, such as malt, or hybrid wheat varieties, such as
cytic infiltration, villous atrophy and crypt hyperplasia, on a spelt. The place of exclusion of oats from a gluten-free diet
gluten-containing diet provides the first step towards a diag- remains controversial. A typical gluten containing diet con-
nosis. In children under the age of 2 a gluten re-challenge tains an estimated 10–20 g of gluten, derived from multiple
and small intestinal biopsy is still required for the diagnosis sources and therefore a gluten free diet necessitates a calcu-
of coeliac disease. lated avoidance of many foods. A strict gluten-free diet is
A definite symptomatic improvement within a few weeks low in dietary fibre and folate, niacin and vitamin B12 [54–
of commencing a strict gluten-free diet would be consistent 56]. Complying with a gluten-free diet is difficult for a num-
with a diagnosis of coeliac disease. A second biopsy may be ber of reasons:
carried out 3 to 6 months after commencement of the diet to
confirm that there has been histological improvement as well 1. Gluten may contaminate food during harvesting, food
as symptomatic relief [49]. If there is a symptomatic improve- preparation or processing [57, 58]
ment but no histological recovery the gluten free diet should 2. Gluten-free products are more expensive than gluten con-
be verified and continued and a further biopsy taken after taining products and may be more difficult to source [59]
three months. It has been shown that complete mucosal 3. Dietary compliance is poor particularly in adolescents
recovery can take up to two years [50, 51]. Where there is [60]
still no histological response or symptomatic improvement it 4. There is no agreed consensus on the minimal amount of
is recommended that patient compliance should be gluten permitted in food: in Australia “no detectable glu-
examined. ten” is <5 mg/kg [61] whereas in Europe “gluten–free” is
Those patients who do not respond to a strict diet may 20 mg/kg [62]
have refractory sprue, ulcerative jejunitis or intestinal lym- 5. A wide variety of gluten sensitivities exist between
phoma. A third endoscopy after gluten challenge is no longer patients: 50% of patients experience symptoms with an
a compulsory diagnostic step. It may be required however at acute challenge whilst 50% do not
a later date if the original diagnosis of coeliac disease is 6. To improve palatability, many gluten-free products con-
brought into question. tain purified wheat starch which invariably contains
ESPGHAN decided in view of the improved serological residual gluten [57]
testing available as well as the HLA DQ testing availability 7. A gluten-free diet does not resolve the problems associ-
that there should be revised paediatric diagnostic criteria. ated with the rare complication of refractory coeliac
This was precipitated by only 12% of paediatric gastroenter- disease
ologists, who responded to a postal survey, adhered to the
then current ESPGHAN guidelines [52]. The main transgres- Patients not adhering to a gluten-free diet are predisposed to
sion was the omission of gluten re-challenge in the under 2 numerous sequelae such as short stature [63], nutritional
166 S. C. Donnelly
deficiencies, early osteoporosis, secondary autoimmune dis- Novel Therapies

orders [64, 65], malignancies [66], infertility and poorer out-
come of pregnancy [67]. However, a gluten-free diet has few A greater understanding of the pathogenesis of coeliac dis-
side effects. ease has allowed alternative treatments to be designed to act
Naturally gluten–free cereals include rice, millet, maize either as an adjuvant to a gluten-free diet, allowing for minor
and sorghum [68]. Quinoa, an Andean grain from Peru, has transgressions, or replace it all together through potential
many benefits for a gluten-free diet as it is the only plant to blocking of various postulated mechanisms [80]. The options
have all essential amino acids as well as being high in miner- include:
als and vitamins. However, quinoa has similar prolamin con-
tent to wheat [69]. A recent study demonstrated that not all 1. Modifying wheat in an attempt to reduce the toxic gluten
cultivars of quinoa are safe for coeliacs to eat as evidenced epitope content
by T cell activation [70]. 2. Degrading gluten to smaller peptides, not able to be pre-
Products labelled as gluten-free have to adhere to strict sented to gluten-sensitive T cells, either in vivo or in vitro
permissible levels of gluten in Europe [62]. This standard 3. Targeting tight junction proteins to ensure that they do
was amended in 2008 to reduce permissible level of gluten in not allow gluten to pass through
gluten-free foods. The change was ratified in January 2009 4. Tissue transglutaminase 2 blockade to reduce the deami-
however manufacturers had until January 2012 to comply. dated peptides presented to gluten-sensitive T cells
Foods labelled as “gluten-free” must now contain no more 5. Reducing HLA-DQ peptide presentation to gluten-
than 20 mg/kg of gluten whereas foods labelled as “very low sensitive T cells by amino acid substitution of gluten T
gluten” can contain between 21 to 100 mg/kg. cell stimulatory sequences
6. Immune system modification either by naturally occur-
ring gluten peptide sequences or helminth infection
Oats in Gluten-Free Diet 7. Targeting inflammatory cytokines with biological thera-
pies, such as anti-IL15
Oats are more distantly related to wheat and are thought to be 8. Vaccination with gluten peptides in order to induce
less toxic to coeliac patients. Several studies suggest that immune tolerance
oats are safe for coeliac patients to eat [71–73] however, 9. Intra-nasal administration of T cell immunostimulatory
there are high dropout rates in both the Janatuinen studies gluten epitopes to induce tolerance
[71, 72] in the oats group of patients. Janatuinen in his five
year follow up study [72] only had 23 out of the original Many of the options above are a long way off from market as
recruited 35 coeliac patients left, and in his study in 1995 they are in the early stages of development and testing in
[71] there was a 10% drop out rate in the group eating oats. animal or human subjects. However, this is a rapidly-
Many commercially available oat products are contaminated expanding, market-driven, in part, by the wish of coeliac
with wheat, rye or barley [74]. Studies from Norway suggest individuals for an alternative to a gluten-free diet. The main
that in a small minority of patients’, non-contaminated oats drawback facing researchers is that a gluten-free diet has few
are toxic [75, 76]. Avoidance of oats in the first year after side effects. Therefore, for a treatment to be recommended in
diagnosis may help improve histology but an attempt should the treatment of coeliac disease, it has to have an acceptable
be made to reintroduce into the diet to help broaden the range low number of side effects.
of gluten-free foods.
omplications and Associations of Coeliac

C
Nutrient Replacement Disease
Nutrient deficiencies should recede on commencement of Non-responsive Coeliac Disease

gluten free diet but dietary supplements may be necessary.
Recovery from anaemia can take between 6 and 12 months Approximately 30% of individuals with coeliac disease fail
as intestinal mucosa reverts to normal [77]. After a diagno- to improve symptomatically with a gluten-free diet [81].
sis of CD patients should undergo a dual-emission x-ray Non- responsive coeliac disease is defined as continued
absorptiometry scan to assess bone mineral density. Patients symptoms in patients on a gluten free diet. A study published
found to have a low BMD should be advised to strictly demonstrated that 45% of non-responsive coeliac patients
adhere to a gluten free diet, to avoid smoking and excessive continued to ingest gluten, either inadvertently or deliber-
alcohol intake, and take calcium and vitamin D supple- ately. Eleven percent of non-responsive coeliac disease
ments [78, 79]. patients had concomitant microscopic colitis, 9% had small
bowel bacterial overgrowth (SBBO), 7% had evidence of accumulate, such as the association with HLA-DQ2 and
inflammatory bowel disease as well as coeliac disease and DQ8, the presence of circulating Purkinje cell antibodies and
6% also had lactose deficiency. Some patients had more than the presence of antitissue transglutaminase antibody in the
one reason for continued symptoms. Eight out of 100 patients gut and brain. Moreover, 60% of patients have evidence of
were found to have refractory coeliac disease (see Refractory cerebellar atrophy on MRI scanning and proton MR spec-
coeliac disease below). Overall in 90% of non-responsive troscopy may also be abnormal, indicating abnormal cere-
coeliac disease a remediable cause could be found [82]. bellar function [91]. The authors observed that improvement
of these conditions may occur on a gluten-free diet.
The reason why some patients develop these neurological
oeliac Disease and other Immunological
C problems could revolve around a newly identified tissue
Disorders transglutaminase, transglutaminase 6. Antibodies to tTG6
have been detected in a group of patients with idiopathic spo-
The raised prevalence of the DR3/DQ2 haplotype in patients radic ataxia [93]. This work further extends the concept of
with specific autoimmune disorders indicated a common gluten sensitivity beyond the bowel, coeliac disease, and the
genetic factor may confer a susceptibility to autoimmune skin, dermatitis herpetiformis, to involve the nervous
disease. There is a well established association between coe- system.
liac disease and a number of autoimmune disorders, particu-
larly type 1 diabetes mellitus (T1DM). 3–6% of the patients
with T1DM have coexisting coeliac disease [83, 84] and Refractory Coeliac Disease
share similar genetic variants [85]. Autoimmune thyroid
disease (Grave’s and Hashimoto’s) and Sjögren’s syndrome A rare complication of coeliac disease is refractory coeliac
are also recognised associations. Evidence indicates that a disease, when clinical symptoms and histological changes
gluten free diet may protect against the development of auto- persist or recur after a good response to a gluten-free diet,
antibodies; adolescent patients not compliant with a gluten after other causes of villous atrophy having been excluded.
free diet have been found to have raised serum levels of anti- Intestinal mucosal recovery on commencement of a gluten
bodies against endocrine tissue [86]. A study in 1999 reported free diet can take up to 2 years [50] and it may therefore be
that a longer duration of exposure to gluten may give an necessary to delay a diagnosis of refractory coeliac disease
increased risk of developing autoimmune disorders [87]. until at least one year on a gluten free diet.
However, a subsequent study contradicted these findings Refractory coeliac disease can be classified according to
[88]. This was a similar study but accounted for additional the immunophenotype of intra-epithelial lymphocytes.
factors such as patient compliance to a gluten free diet. No Abnormal clonal lymphocytes with loss of surface markers
correlation was found between duration of gluten exposure CD8 and CD3 occur in type 2 RCD whereas in type I RCD
and onset of autoimmune disorders. the majority of lymphocytes have normal surface markers
and T cell receptors are polyclonal [94]. Differentiation
between the different types of refractory coeliac disease is
Neurological Manifestation important as the reported five-year survival rate varies
between 40% and 58% for type 2 RCD [95–98], and 93% in
Neurological manifestations have been reported in coeliac type 1 RCD [97]. The main cause of death in type 2 RCD is
patients for a number of years, but it is only recently that progression to an enteropathy associated lymphoma with a
these neurological associations have been studied in depth. 5-year survival rate of 8–20% [96, 99] as well as progressive
Peripheral neuropathy, myopathy, myelopathy, dementia, malnutrition. Some of these patients are on parenteral nutri-
migrane and epilepsy are all associated with coeliac disease. tion to help with the management of their malnutrition and
A group in Sheffield, reported gluten sensitivity, based on their small bowel histology do improve.
the presence of anti-gliadin antibodies, in patients with neu-
rological disorders of unknown cause. The majority of these
patients had ataxia or peripheral neuropathy [89]. The terms Ulcerative Jejunitis
gluten ataxia and gluten neuropathy have been coined to
describe these disorders. Duodenal biopsy showed coeliac Ulcerative jejunitis is another cause of non-responsive coe-
disease to be present in only a third of patients [90, 91]. The liac disease. It is a rare disorder characterised by ulceration
concept is still controversial as gluten sensitivity has also of the jejunum and ileum. Scarring often occurs, leading to
been found in hereditary ataxias, and response to a gluten- stricture formation with alternating areas of dilated small
free diet in many patients is lacking [92]. Nevertheless, sup- bowel. Ulcers can be of varying depth and can extend through
porting evidence for idiopathic gluten ataxia continues to the entire thickness of the bowel leading to perforation [100].
168 S. C. Donnelly
Like type 2 refractory coeliac disease, ulcerative jejunitis risk was only significant for those diagnosed clinically
is characterised by non-lymphomatous monoclonal T cell prior to the study and not those with silent coeliac
population in the epithelium. These intraepithelial lympho- disease.
cytes from Type 2 refractory coeliac disease and ulcerative Survival from EATL is abysmal, with a five-year survival
jejunitis have been shown to share an identical aberrant rate of 8–20% [96, 99]. As these cancers are particularly rare
immunophenotype to those found in enteropathy associated (0.5 to 1 in 1,000,000 annual incidence), their actual inci-
T cell lymphoma [101]. They are therefore considered to be dence in coeliac disease remains low, in the order of 1 case
part of a spectrum of neoplastic T cell disorders. As a result, per 5500 patient years or less with a relative risk of 4.27
the mortality is high due to obstruction, bleeding and perfo- (2.36–7.74) [64]. EATL has a peak incidence in the jejunum
ration. Steroids are commonly used to treat the ulceration in the sixth decade and is associated with refractory gastroin-
and a strict gluten-free diet is essential. In patients with testinal symptoms, although it can present at extra-intestinal
ulcerative jejunitis, their small bowel often allows easy trans- sites. It is probable that refractory coeliac disease and ulcer-
location of gut bacteria and sepsis is an early feature of this ative jejunitis are the precursors to EATL with identical aber-
condition. rant immunophenotype IELs [101]. Treatment options for
these conditions are being evaluated to try to prevent pro-
gression to EATL.
Malignancy Adenocarcinoma of the small intestine is a rare cancer,
over represented in coeliac disease. In a British Society of
Early reports suggested a large increase in risk of gastroin- Gastroenterology survey published in 2003, details of 175
testinal cancer in coeliac disease. With relative risk ration of cases of small bowel adenocarcinoma were collected over
10 for oesophageal and 40 for non-Hodgkin’s lymphoma, two years and 13% were found to be associated with coeliac
with a higher risk if non-compliant with a gluten-free diet disease, with two thirds presenting in diagnosed coeliac
[66]. Several other studies seemed to confirm the high rela- patients with a median length of diagnosis of 8 years. These
tive risk of all site lymphoma in the range 30–100. Some of patients had a 58% survival at 30 months, which equated to
this data has managed to infiltrate and perpetuate itself in the the absence of metastasis at presentation [107].
literature. Most of the above data was based on cancer case- A recent publication suggests that patients with non-
finding and inherently includes major acquisition bias. Later symptomatic coeliac disease have no increased risk of lym-
data suggests a more conservative doubling of risk for all phoproliferative malignancy [112].
cancers and, in particular, a relative risk of 6 for lymphoma However, there can be some protective effects of coeliac
[102]. Population-based studies have provided more con- disease. The reason behind a reduced risk of lung and breast
vincing estimates of overall cancer risk and indicate only a cancers are not clear [64, 104, 113–116]. A population-based
small increase above the background population. This risk is survey suggested that there are potentially adverse as well as
negated if the first year after diagnosis of coeliac disease is favourable breast cancer risk profiles in coeliac disease com-
excluded, which again accounts for a degree of acquisition pared to the general population [117].
bias.
The risk of both enteropathy associated T cell lymphoma
and small bowel adenocarcinoma are elevated, the later many Eosinophilic Enteritis
fold. A wealth of collected data exists as the incidence of
cancer is one of the leading causes of concerns for coeliac Eosinophilic enteritis is a rare primary eosinophilic gastroin-
patients as well as their gastroenterologists [64, 103–111]. testinal disorder of unknown aetiology which is character-
The Italian Working Group on Coeliac Disease and ised by the rich infiltrate of eosinophils on histological
Non-Hodgkin’s lymphoma gathered data from 693 patients examination of the mucosa [118–120]. It is part of a group of
with Non-Hodgkin’s lymphoma and found only 0.92% had eosinophilic disorders of gastrointestinal tract involving the
a diagnosis of coeliac disease, with a calculated relative oesophagus, small intestine and colon. Eosinophilic enteritis
risk of 3 for Non-Hodgkin’s lymphoma for coeliac patients, causes a wide array of symptoms such as abdominal pain,
although the figure was 19 for EATL [105]. Mearin et al. nausea, vomiting, diarrhoea, bloating or ascites. Table 3
[111] have reported on a prospective review in 10 European shows the array of symptoms for each of the diseases. As
countries of 1446 Non-Hodgkin’s lymphoma adults and these symptoms are non- specific, a high index of suspicion
matched controls, which indicated an odds ratio of 2.6 need to be maintained in order to diagnoses eosinophilic
(1.4–4.9) for Non-Hodgkin’s lymphoma. Importantly this enteritis.
Table 3 Primary eosinophilic gastrointestinal disorders Table 4 Secondary causes of eosinophilia

Eosinophillic Eosinophillic Eosinophillic Diagnosis How to investigate
oesophagitis enteritis colitis Hypereosinophilic syndrome • Clinical observation with
Forms Atopic Mucosal Atopic Persistently elevated eosinophil count testing for involvement of
Non-atopic Muscular Non-atopic ≥1500 eosinophils/mm3 for at least either the heart, nervous
Familial Subserosal 6 months system or bone marrow
Definition Eosinophillic Gastrointestinal Children • Testing for mutations
infiltration of symptoms and Eosinophillic involving the PDGFRA and
the oesophageal eosinophilic infiltration of FIP1L1 genes
mucosa without infiltration of one the colon • T cell clonality
other intestinal or more intestinal Atopy or Gut infections
segment segment cow’s milk Intestinal parasites Patient medical history, stool
involved protein Ascariasis, toxocariasis, trichinosis, parasite examination,
allergy schistosomiasis, teniasis, serology (toxocariasis,
Main clinical Dysphagia Abdominal pain Diarrhoea ankylostomiasis, trichuriasis, trichinosis, schistosomiasis,
characteristics Vomiting Diarrhoea Rectal stronglyoidiasisenterobiasis teniasis), antiparasitic
Food impaction Obstruction bleeding treatment
Ascites Helicobacter pylori, Escherichia coli, Gastric biopsies, stool and
From ref. [121] Pineton et al Shigella blood cultures
Drugs and toxic substances Patient medical history
Gold therapy, oral hypoglycaemiac
agents, psychotropic drugs,
antibiotics, NSAIDs
Diagnosis Inflammatory bowel disease Upper GI endoscopy and
colonoscopy
Coeliac disease Anti-tissue transglutaminase
Eosinophils normally reside in the lamina propria of the gut antibody and distal duodenal
apart from the oesophagus. The eosinophil count of the lam- biopsy demonstrating villous
ina propria increased from duodenum to caecum and reduces atrophy
from caecum to rectum. This means that the cut off values Vasculitis and autoimmune diseases ANCA, anti-nuclear
for the diagnosis rely on the accurate location of the tissue Periarteritis nodosa, eosinophilic antibodies, vascular biopsies,
granulomatosis with polyangiitis, clinical examination
sample. In the duodenum, most studies quote a level of 20 scleroderma
eosinophils per high power field (×400) for the diagnosis of Malignancy Imaging studies, histology
eosinophilic enteritis [122]. Apart from eosinophils in the
lamina propria, other signs on histology in favour for eosino-
philic enteritis are eosinophils in the epithelial or muscle lay- linical Characteristics and Natural History
C
ers, degranulation of eosinophils, villous atrophy, crypt of Patients with Eosinophilic Enteritis
hyperplasia or abscesses, and epithelial degenerative or
regenerative changes. Patients with eosinophilic enteritis can present with a variety
The diagnosis of eosinophilic enteritis requires patho- of non-specific symptoms [122, 123]. Common symptoms
logic eosinophilic infiltration of at least one part of the would be abdominal pain, diarrhoea, bloating and nausea
intestinal wall and the exclusion of secondary eosinophilia. whereas jaundice, ascites, rectal bleeding and vomiting are
Eosinophils could be seen in any segment of the small less frequently seen. They often present with a complication
intestine but were most commonly seen in the stomach and of their disease as the index presentation [124]. The clinical
duodenum. They could also be seen in any layer within the presentation depends on the depth of intestinal wall involved.
small intestine: Klein et al. [119] described three anatomi- This was classified by Klein et al. [119] into three different
cal variants based on the eosinophilic infiltration of the forms of the disease according to the layer of intestinal wall
mucosa, intestinal muscle or. Thus, the diagnosis of eosin- involved:
ophilic enteritis requires the symptoms associated with a
pathological eosinophilic infiltration of the small intestine • The mucosa form characterised by predominant mucosal
with the exclusion of secondary causes of eosinophilia (in inflammation causing diarrhoea, abdominal pain, signs of
Table 4). malabsorption or protein losing enteropathy
170 S. C. Donnelly
• The muscular form characterised by intestinal strictures remained in remission, with the many patients presenting
with abdominal pain, nausea and vomiting which can lead with a persistent or progressive disease course.
to obstruction
• The subserosal form characterised by an eosinophilic-rich
ascites with bloating and abdominal pain. Treatment
The occurrence of these forms varies in the literature, in part The treatment of eosinophilic enteritis can be challenging as
due to less surgical specimens being sent to help diagnose there are no clear recommendations and very little evidence
the muscular form of the disease [122, 125]. base in the literature [129]. Treatments which have been
Patients with eosinophilic enteritis may vary in their pre- already used and evaluated are discussed below however,
sentation depending on how extensively the gut is involved. 40% of patients will have a spontaneous remission of eosino-
The most common sites to be involved would be the stomach philic enteritis.
and proximal small intestine, seen between 40–80% of
patients with eosinophilic enteritis. The more extensive the
disease the more likely to have protein losing enteropathy, Diet
malabsorption and iron deficiency anaemia. Biopsies of all
parts of the gastrointestinal tracts are required to diagnose Several dietary strategies have been proposed. If there is a
the enteritis. clear and limited precipitant, identified on food allergen test-
An elevated peripheral eosinophil count can be seen ing, then this should be avoided. When many or no allergens
[125]. More than 70% of patients with eosinophilic enteritis have been identified, a more aggressive empiric elimination
will have a transient high (>500/mm3) eosinophil count dur- diet or elemental diet can be tested. There is not enough evi-
ing a flare. If the eosinophil count is >3000/mm3, then the dence in the literature to recommend these in routine
patient is likely to have predominantly subserosal involve- management.
ment. An absence of peripheral eosinophilia should not
exclude the diagnosis of eosinophilic enteritis.
Elevated IgE levels can also be seen in approximately 505 Corticosteroids
of patients. In eosinophilic patients with protein losing enter-
opathy, malabsorption or intestinal inflammation hypoalbu- The use of corticosteroids is one of the main treatments of
minaemia, iron deficiency, steatorrhoea and a high CRP can the patients with eosinophilic enteritis [130, 131]. Most case
be seen [124]. series have reported good efficacy of corticosteroids with
Imaging studies are often non-specific and only intestinal clinical remission achieved in 50–90% of patients with
biopsies will lead to the diagnosis. Upper gastrointestinal eosinophilic enteritis [128, 132].
endoscopy and ileo-colonoscopy may be macroscopically Treatment should be started at 0.5 to 1 mg/kg for a few
normal or show slight erosions, oedema, erythema or nodules weeks before tapering the dose over 6 to 8 weeks [129]. After
[126]. Capsule endoscopy can be used to examine the whole this approximately 20% of patients will have steroid depen-
small intestine but does not allow biopsies of the areas [127]. dency requiring low dose prednisolone to maintain clinical
The natural history of the disease follows three courses remission. To avoid the side effects of corticosteroids,
[125]: Budesonide could also be used. Budesonide is effective at
9 mg per day for the induction and maintenance of clinical
• A single flare (42%) remission in patients with eosinophilic enteritis [133–140].
• A recurring course with multiple flares and period of full The dose can be tapered to 6 mg and then 3 mg per day for
remission from 2 months to several years (37%) maintenance therapy, if required.
• A continuous course (21%)
Pineton de Chambrun et al. [125] found patients with pre- Azathioprine

dominantly mucosal disease accounted for 80% of patients
with continuous course to their disease. Over 50% of the Azathioprine can be used in patients with eosinophilic enter-
cases of patients with a single flare, without disease recur- itis who are either refractory to or dependent on corticoste-
rence, had subserosal forms of the disease. There was also no roids. The usual dose of eosinophilic enteritis patients is
occurrence of myeloproliferative disorders. Reed et al. [128] similar to the dose used in inflammatory disease patients at
found that only a third of patients with eosinophilic enteritis 2–2.5 mg/kg [141].
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Intestinal Failure in Critical Care
Moran Hellerman Itzhaki and Pierre Singer
Key Points support in the critically ill with emphasis on nutritional tar-
1. Nutritional assessment and requirements on an intensive gets, macronutrients and the place of supplements in nutri-
care unit (ICU) can be difficult to determine. Weight tional therapy. Specific populations, such as those with
changes, indirect calorimetry (measuring CO2 produc- sarcopenia, diarrhea and the refeeding syndrome will be dis-
tion) and a CT scan at L3 are helpful. cussed in detail, along with current topics in intensive care
2. It is estimated that 1% muscle mass is lost per day on such as COVID-19.
ICU.
3. In acute injury (trauma/major surgery) nutritional support
aims to provide 70% of the nutritional target by day 3 and Definition and Etiology
increase further in the post-acute phase.
4. Glutamine and Ω3 fatty acid supplements may be benefi- Intestinal failure has been defined as “the reduction of gut
cial especially glutamine for burns (>20%) and trauma function below the minimum necessary for the absorption of
patients. macronutrients and/or water and electrolytes, such that intra-
5. Relatively tight blood glucose control aims to keep the venous supplementation is required to maintain health and/
blood glucose to less than 10 mmol/L. or growth. The reduction of gut absorptive function that
6. If there is a gastric aspirate of more than 500 ml at any doesn’t require intravenous supplementation to maintain
time (often occurs with sepsis) then postpyloric feeding health and/or growth, can be considered as “intestinal insuf-
and prokinetic drugs should be considered. ficiency”” [1]. The estimated prevalence of acute intestinal
7. Opiate drugs, cyclizine and many other drugs can inhibit failure in the acute hospital setting varies between 1.3% and
gastrointestinal motility. 61% [2]. In the intensive care unit (ICU) about 8% of the
8. Enteral nutrition (EN) is preferred but if it fails to provide patients suffer from intestinal failure [2]. Intestinal failure is
the target amount, supplementary parenteral nutrition classified into three types. Type 1 is an acute and self-limit-
may be given. ing condition associated with critical illness or postoperative
period. Type 2 is a less common form of acute intestinal fail-
ure following catastrophic abdominal events combined with
Introduction sepsis and metabolic complications. It usually requires
intense management with prolonged intravenous support.
Intestinal failure is a common condition in critically ill Type 3 is a chronic form of intestinal failure, either as a con-
patients that may lead to severe morbidity or even death. sequence of type 2 acute IF or of a chronic medical condition
Early diagnosis and proper treatment are mandatory to pre- [1]. Acute IF in critically ill patients was graded by Blaser
vent such complications. This chapter will discuss the recog- et al. according to severity of the symptoms and the interven-
nition of malnutrition and the complex planning nutritional tions required (Table 1) [3]. The clinical manifestations of
intestinal failure in critically ill patients vary according to
M. H. Itzhaki (*) · P. Singer specific pathophysiologic processes. The short bowel syn-
Department of General Intensive Care, Institute for Nutrition drome most commonly develops following extensive bowel
Research, Rabin Medical Center, Beilinson Hospital,
Petah Tikva, Israel resection, either as part of an acute exacerbation of a chronic
disease or due to abdominal catastrophic events (trauma,
Affiliated to the Sackler School of Medicine, Tel Aviv University,
Tel Aviv-Yafo, Israel ischemia, perforation, etc.). It will usually manifest as exten-
e-mail: [email protected] sive intestinal loss of fluids and electrolytes. Intestinal fistu-

178 M. H. Itzhaki and P. Singer
Table 1 Classification of acute gastrointestinal injury (AGI) Screening and Assessment of Malnutrition
AGI
Grade Definition Clinical presentation In order to identify critically ill patients at risk of acute IF that
NO No GI malfunction No GI symptoms may benefit from nutritional support, nutritional screening
AGI
AGI Risk for GI failure • Nausea and/or vomiting (Post
and assessment must be performed. Malnutrition is a com-
grade 1 abdominal insult) mon phenomenon, with reports of prevalence rates as high as
• Absence of bowel sounds 50% among hospitalized patients, depending on their clinical
(following abdominal surgery, status, age and medical condition [4]. Critically ill patients
anesthetic or opioid therapy,
shock)
are particularly vulnerable owing to the acute nature of their
• Mild diarrhea illness and co-morbidities potentially limiting their ability to
• Abdominal distention eat and absorb food. There are many objective and subjec-
AGI GI malfunction with • Gastroparesis/large GRV tive methods of assessing the risk of malnutrition in hospital-
grade 2 symptoms requiring • Severe diarrhea (causing fluid
ized patients, with the subjective global assessment (SGA)
treatment and electrolytes imbalance)
• IAH (12–15 mmHg) being one of the few tools validated in the ICU setting [5].
• Visible GI bleeding SGA includes five anamnestic components (weight changes,
AGI GI dysfunction progress • Large GRV/Vomiting/GI nutrition intake, gastrointestinal (GI) symptoms, functional
grade 3 despite treatment with paralysis persist despite capacity and metabolic stress) and two physical components
systemic deterioration treatment
• Severe IAH (signs of muscle wasting and fluid balance). Laboratory
• Severe diarrhea parameters such as albumin and prealbumin levels are
• Abdominal sepsis extremely affected by inflammation/saline administration
• Ileus and are therefore not useful for the diagnosis of malnutrition
AGI Life threatening GI • Bowel ischemia/necrosis
grade 4 failure • GI bleeding causing
[6, 7]. Rattanachaiwong et al. compared several diagnostic
hemorrhagic shock tools for malnutrition in ICU patients and found the nutrition
• Acute colonic risk screening (NRS) to be more sensitive and specific than
pseudo-obstruction the SGA [8]. In 2019 the European Society of Enteral and
• Abdominal compartment
syndrome
Parenteral Nutrition (European Society of Clinical Nutrition
and Metabolism) (ESPEN) proposed the global leadership
Modified from Blaser et al. gastrointestinal failure in the ICU. Curr
Opin Crit Care 2016; Apr 22(2):128–141 initiative on malnutrition (GLIM) criteria for the diagno-
AGI acute gastrointestinal injury, GI gastrointestinal injury, GRV gastric sis of malnutrition. The GLIM criteria include phenotypic
residual volume, IAH intra-abdominal hypertension characteristics like unintentional weight loss, low basal
metabolic index (BMI) and loss of muscle mass, and etiolo-
lae may also occur as a complication of chronic inflammatory gies including reduced intake or absorption, inflammation
bowel disease, a persistent abdominal infection or a surgical and disease severity [9]. A paper published by Theilla et al.
complication. A fistula may cause a similar loss of fluid and found that the GLIM criteria had a high sensitivity of 85%
electrolytes as well as a systemic metabolic response that is and specificity of 79% compared to the SGA, considered to
a part of sepsis. Chronic processes, such as intestinal tumors be the gold standard in the ICU [10]. They concluded that
or chronic inflammation, are generally not acute in nature. the GLIM criteria are acceptable for use in the ICU. Reduced
However, the clinical implications of mechanical obstruction muscle mass is not only a phenotype of malnutrition but also
may be severe and life threatening, often requiring intensive a strong predictor of increased mortality, prolonged mechan-
care. Intestinal dysmotility is a common manifestation of IF ical ventilation and a protracted hospitalization course [11,
in ICUs. Many factors are associated with its development, 12]. Assessment of body composition may provide insight
the most common being medications, systemic inflamma- into patient-specific characteristics of malnutrition. Body
tion, post-operative states and metabolic disorders. It may composition may be studied using several commercially
then present as non-mechanical bowel obstruction (paralytic available methods. Bioelectrical impedance is a quick, non-
ileus) and delayed gastric empting (gastroparesis), both of invasive, low-cost technique that does not expose the patient
which will be discussed later. Malabsorptive conditions often to radiation and is performed at the bedside. Bioimpedance
manifest as diarrhea. This is common in critically ill patients, uses low voltage electrical currents to identify different com-
are often secondary to medical treatments, infection or artifi- ponents of the body. Conduction alternation allows for the
cial nutrition, and may require close monitoring and nutri- measurements of the fat mass and the fat free mass (FFM).
tional supplementation [2]. FFM is mainly composed of water, proteins and carbohy-
Intestinal Failure in Critical Care 179
drates [12]. A long-established method for assessing body [4]. Other than intense physical therapy, personalized nutri-
composition is dual energy X ray absorptiometry (DXA). tion strategies are needed. Recent guidelines recognize the
DXA was originally used to measure mineral bone density pitfall of using “ideal body weight” to calculate energy
but now can be used to measure all three major tissue com- requirements in obese individuals as it neglects the meta-
ponents of the body (fat mass, lean mass and bone mineral bolic demand of adipose tissue. It is therefore advocated by
mass) [13] DXA is well validated and requires slight radia- some to add a correction factor of 20–25% of excess weight
tion exposure. However, it is rarely used in the ICU as it (actual body weight - ideal body weight) to the ideal body
seldom available [12]. Computed tomography (CT) may be weight [18]. Another strategy is to combine a relatively low
employed to assess body composition. It offers informa- number of calories with high protein intake (2–2.5 g/kg/
tion on specific compartments, including dividing adipose day) [19].
tissue into visceral and subcutaneous and characterizing
specific skeletal muscle groups. One technique is the use of
single slice CT, usually at the level of L3, which provides
information on several muscle groups, and correlate with Nutritional Targets
whole body muscle mass [14]. In a retrospective study of
240 ICU patients, Weijs et al. examined the effect of low The importance of determining the proper nutritional targets
skeletal muscle area on mortality. A single slice CT scan for critically ill patients is well documented. In a large Cohort
showed reduced muscle area in 63% of the patients in both study, Zusman et al. showed a non-linear connection between
sex groups, with evidence of increased mortality compared the caloric intake of ICU patients and 60-day mortality. As
to those with preserved muscle area (OR 3.86 [1.8–8.26]) caloric intake increased and reached 70% of resting energy
[15]. A major disadvantage of this technique is the exposure expenditure (REE) assessment, mortality was reduced. On
to radiation, rendering it difficult to justify without other the other hand, mortality increased as caloric intake was
indications. The patient’s clinical condition and the risk of above 100% of REE [20]. The clinical course of critical ill-
mobilizing a patient outside of the ICU must be considered ness is divided in several phases. The hyperacute phase of
as well. Point of care ultrasound is an increasingly popular hemodynamic instability often leading to ICU admission.
technique used in the ICU that provides the clinician with The acute phase composed of the early period with marked
viable information at the bedside without radiation expo- catabolism and metabolic instability and the late period char-
sure. When ultrasound was studied for body composition acterized by stabilization of metabolic disturbances and sig-
assessment, it showed only moderate correlation with other nificant muscle wasting. This will be followed by the
modalities. The lack of consensus on the preferred site and post-acute phase of persistent inflammation or rehabilitation
method of measurement makes existing clinical data hard to [18]. In the acute phase there are alternation in hormone lev-
compare [12]. els such as glucagon, cortisol and epinephrine increasing
insulin resistance and gluconeogenesis. In addition, cyto-
Sarcopenic Obesity As previously mentioned, the risk of kines release including TNF-α, IL-1, IL-2 and IL-6 increases
sarcopenia in the ICU is extremely high, with a prevalence protein breakdown and insulin resistance. Increased glucose
of more than 90% and muscle mass loss of nearly 1% a day production, lipolysis and protein breakdown all lead to sig-
[16]. Accelerated catabolism, inadequate nutrition and nificant endogenous substrate production observed in early
immobilization are all major causes for sarcopenia in the phases of acute illness [21]. In order to avoid overfeeding it
critically ill. Obesity is another common condition in the is recommended to start nutritional support gradually with
ICU as worldwide prevalence increases. Although obesity the nutritional target of 70% of REE in the first three days of
holds an increased risk for co-morbidities and may limit ICU admission and gradually increase nutritional support
treatment options, there is evidence for decreased ICU upon patient’s stabilization until reaching 80–100% of REE
mortality in obese patients compared to non-obese, some- by day 5–7 [18]. Indirect calorimetry (IC) has been estab-
times referred to as the obesity paradox [17]. Muscle mass lished as the gold standard for REE measurement [18, 22–
in obese individuals is highly related to physical activity 24] and is considered the best strategy to reduce over/under
and age. In addition, characteristic muscle changes seen feeding [18, 22]. Nevertheless, this technology is not avail-
patients with obesity may impair muscle function. Given able in all intensive care units and not applicable in clinical
the impact of sarcopenic obesity on ICU patients’ out- situations such as mechanical ventilation in high oxygen
comes, specific measures should be taken to minimize it concentrations (FIO2 > 0.7), chest drains, and usage of nitric
oxide or helium. Predictive equation for REE estimation Macronutrients

such as Harris-Benedict, Faisy-Fagon or Penn State have
shown poor agreement with IC [25]. A recent large retro- The nutritional composition of macronutrients require adap-
spective study by Zusman et al. demonstrated poor accuracy tations as the clinical condition changes. Carbohydrate
of the predictive equations [26]. An alternative method is to absorption is delayed during critical illness. However, the
estimate energy expenditure from carbon dioxide production glycemic response to carbohydrate ingestion is prolonged, in
(VCO2) values obtained from the ventilator in invasively effect increasing the incidence of hyperglycemia [32].
ventilated patients [27]. Many respirators can measure VCO2 Carbohydrates are essential in nutritional formulas in order
and calculate REE by using the Weir formula and determin- to reach caloric targets, but the recommended upper limit for
ing the respiratory quotient (RQ). This approach is contro- carbohydrates is 5 mg/kg body weight/min. Low carbohy-
versial, as while some studies show high levels of accuracy, drate enteral formulas were introduced in the past to criti-
others show less encouraging results [28, 29]. One of the cally ill patients in order to facilitate ventilator weaning. The
main limitations of measuring VCO2 is the need for a pre- hypothesis that low carbohydrate would lead to low carbon-
defined RQ. RQ, defined as the division of VCO2by VO2, is a dioxide production did not translate into clinical benefit [33].
constant influenced by many factors, including ventilator Low carbohydrate formulas are mainly prescribed to diabetic
settings and acid-base balance, all of which are extremely patient for better glycemic control [34]. These formulas
dynamic in critically ill patients. In a retrospective study by failed to show significant benefit in lowering glucose vari-
Kagan et al., an RQ of 0.89 showed the best correlation ability in the general ICU population [35]. As earlier paren-
between IC and VCO2 measurement [30]. Nonetheless, it teral nutrition formulas contained mostly carbohydrates,
seems that the use of VCO2 measurement is the best alterna- hyperglycemia posed a serious concern for patients receiving
tive to IC if the latter is not available, with better accuracy them. As technology progressed and lipids emulsions became
than predictive equations. After determining the estimated more stable, the amount of carbohydrates in parenteral nutri-
energy expenditure, 70% of estimated needs should be pre- tion decreased and so did the prevalence of hyperglycemia.
scribed in the first days of ICU admission and full nutritional Glycemic control is still considered a crucial issue in the
support should be reached within three to seven days [18]. management of critically ill patients and it comprises not
only controlling absolute glucose concentration but also glu-
Non Nutritional Calories products that contain high cose variability and time in optimal glucose range. In 2001
caloric index and with little nutritional value are considered van den Berghe et al. examined the effect of tight glycemic
non nutritional calories (NNCs). In the intensive care these control (glucose between 4.4 and 6.1 mmol/L) in critically ill
are mostly derived from the dextrose, citrate and the drug surgical patients. Her group found that tight control led to
propofol. If nutritional plans do not take these “hidden” calo- improved mortality rates [36]. However, these results have
ries into account, the risk of overfeeding increases. Propofol not been reproduced. In the NICE-SUGAR 2009 study,
is a general anesthetic commonly used in the ICU. It contains intensive glycemic control led to increased hypoglycemic
soybean oil, egg phospholipids and glycerol. Propofol con- events and mortality. The authors suggested blood glucose
tains 1.1 kcal/ml which translate into several hundred daily level targets of 10 mmol/L or less, as they had better out-
calories for the average sedated patient in the ICU [31]. 5% comes compared to lower values [37]. According to recent
Dextrose contains 3.6 kcal/g, meaning a 1 liter infusion of studies there is no optimal glucose value below 10 mmol/L
5% dextrose provides around 200 kcal of NNCs. Citrate is a that shows additional mortality benefit [38]. Several studies
regional anticoagulant used in continuous renal replacement in critically ill patients have shown that high glucose vari-
therapy (CRRT). Its caloric value is difficult to calculate as it ability increased mortality independently of mean glucose
varies from between various preparations. It also depends on levels [39–41]. As previously mentioned, prognosis improved
blood flow, infusion rate and filter characteristics of the CRRT the longer patients spent within the proper glucose range,
circuit. Trisodium citrate, for example, contains 3 kcal/g and those achieving good glycemic control for more than
[31]. A retrospective study examining the relevance of NNCs 80% of the time had better clinical outcomes [42, 43].
in the ICU revealed that in the first day of ICU admission Lipids are another cornerstone of nutrition formulas.
about 31% of the patient’s caloric intake were NNCs. By day Enteral formulas are rich in lipids, either medium chain tri-
4 that number decreased to 6% [31]. It is important to know glycerides (MCTs) or long chain triglycerides (LCTs). Fish
that on day 1 patients tend to receive a very little nutrition, oil is rich in the omega-3 (Ω-3) polyunsaturated fatty acids
largely precluding the risk of overfeeding. eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA). These affect the inflammatory process, including in pared standard nutritional care of 1.2 g/kg/day protein to a
the immune response, coagulation, vasoactivity and bone goal directed group based on indirect calorimetry and nitro-
metabolism. They are also essential for neuronal, behavioral gen balance measurements that received a minimum of 1.5 g/
and visual development [44, 45]. A recent systematic review kg/day from day 1. There was no effect on morality, organ
showed the benefit of supplemental fish oil in patients with failure or infection rates [55]. In certain clinical situations
acute respiratory distress syndrome (ARDS), decreasing the such as burn victims, frail patients, cancer patients or patients
length of ICU stay and increasing ventilator-free days, but suffering from acute kidney injury it is generally recom-
had no effect on mortality. The authors noted these results mended to provide increased protein intake [56, 57]. It is still
should be interpreted with caution as the review was based unclear whether the timing of protein administration affects
on low quality trials [46]. ESPEN guidelines conclude that patient outcomes. Bendavid et al. found early protein admin-
enteral formulas enriched with omega-3 fatty acid may be istration to be associated with increased survival (HR 0.83)
safely administered, while high dose omega-3 fatty acid in patients receiving protein>0.7 g/kg/day in the first 3 days
preparations should be avoided [18]. Lipid emulsion following ICU admission [58]. On the other hand, Koekkoek
designed for parenteral nutrition have been improved, start- et al. found that early high protein intake (>0.8 g/kg/day in
ing from soybeans as a source for LCTs to MCT based emul- the first 3–5 day of admission) was associated with higher
sions, followed by olive oil based formulas and finally 6 month mortality [59].
formulas enriched with fish oil. Soybean oil contains high
levels of omega-6 (Ω-6). There is increased concern regard- Amino-Acid Enriched Formulas Glutamine (GLN) is
ing the use of omega-6 fatty acids, specifically Linoleic Acid considered a non-essential amino acid as long as it is suffi-
(LA) due to their pro-inflammatory and immunosuppressive ciently synthetized by the skeletal muscle. In certain clinical
effects [47, 48]. LA also suppresses the synthesis of EPA and conditions such as critical illness and burns, GLN levels
DHA, potentially reducing their beneficial effects. Olive oil decrease and mortality is increased [60] while the immune
based formulas are considered good alternatives. In a meta- response is decreased [61]. In the REDOXS trial published
analysis by Dai et al., the authors concluded these formulas in 2013, the administration of GLN supplements to critically
were safe, were associated with increased antioxidant levels ill patients with multi-organ failure was associated with
as well as lower Ω-6 levels while not leading to significant higher mortality [62]. In another RCT from 2014 (the
differences in most liver enzymes [49]. Pradelli et al. per- METAPLUS study), the prescription of an immune modulat-
formed a meta-analysis on the effects of Ω-3 enriched paren- ing nutrition that included GLN did not have any clinical
teral formulas and found their use was associated with lower beneficial effect and even led to an increase in 6 month mor-
infection rates, shorter ICU stays and non-significant trends tality [63]. The ESPEN guidelines conclude that GLN sup-
for reduced mortality rates [50]. The ESPEN guideline plementation should be administered in burn patients with
authors conclude that lipid emulsions enriched with fish oil burns >20% body surface area in the first 10–15 days of
based fatty acids may be safely prescribed to patients receiv- enteral nutrition and it may be considered in critically ill
ing PN [18]. trauma patients in the first 5 days of enteral nutrition, per-
Protein intake is crucial for reducing muscle loss [51]. haps longer if impaired wound healing is evident [18]. Other
Protein and calorie targets may not always go hand in hand. than these specific populations, GLN supplements are not
The ESPEN guidelines advocate a protein target of 1.3 g/kg/ recommended in the ICU. β-Hydroxy-β-methylbutyrate
day during critical illness [18]. The quality and origin of the (HMB) is a metabolite of the amino acid Leucine and its
proteins should also be taken into consideration. The amount positive effects on muscle mass by increasing protein synthe-
of essential and non-essential amino acid, protein efficiency sis and decreasing muscle catabolism have been well studied
ratio, protein utilization and absorption make animal protein [64]. In a meta-analysis on the effect of HMB in clinical
the optimal choice [52]. Nicolo et al. showed a reduction in practice, results were conflicting. Only a small number of
mortality and length of stay when achieving more than 80% studies included critically ill patients, HMB was adminis-
of desired protein intake [53]. Compher et al. showed similar tered alongside GLN and arginine and it was used in differ-
results [54]. In a retrospective observational study of criti- ent points along the hospitalization course [65]. In 2020
cally ill patients, Zusman et al. showed a linear association Nakamura et al. published a RCT examining the effect of
between protein intake and mortality [20]. For every gram of HMB, GLN and arginine supplements on muscle loss in crit-
ingested protein there was a 1% reduction in mortality. ically ill patients [66]. The study failed to show any decrease
However, the EAT-ICU prospective randomized trial com- in muscle loss.
Micronutrients nutritional support was started early (within 36 h of admis-

sion), most patients did not reach the caloric target of 25 kcal/
Vitamins and trace elements are curial for proper function of kg/day [78]. The NUTRIREA-2 study compared EN to PN
metabolic processes and micronutrients deficiency can be in critically ill patients with shock that required mechanical
life threatening [67]. Critically ill patients with decreased ventilation with similar results, finding no difference in
intake and increased catabolism are at additional risk to 28 day mortality or infection rates between the two groups.
develop such deficiency. Trace elements are also known for The risk of gut ischemia was significantly higher in the group
their anti-oxidative properties and are sometimes given in of patients receiving EN [79]. In the clinical practice guide-
higher doses in specific clinical conditions. Sepsis is one of lines by the European society of intensive care medicine
the fields were high dose selenium have been studied [68]. (ESICM), early EN was preferred over early PN. Their meta-
In an RCT by Bloos et al. administrating high loading dose analysis showed no benefit in mortality but did show a
of selenium (1000 μg) followed by continues intravenous reduced infection rates in patients receiving EN. The same
infusion of selenium to patients in septic shock or sever sep- guidelines also recommend withholding enteral nutrition
sis did not affect mortality [69]. In cardiac surgery Schmidt support in cases of upper GI bleeding, gastric residual vol-
et al. showed significant decrease in the use of vasopressors ume >500 ml/6 h, bowel obstruction, bowel ischemia,
by using high dose selenium preoperatively and during ICU abdominal compartment syndrome or high output fistula
stay but with effect of perioperative SOFA score. Patients [80]. EN is not necessarily preferred over PN, and supple-
with renal failure and renal replacement therapy suffer from mental PN in patients receiving EN is in increased use.
Selenium and Zinc deficiency. Studies however have failed Heidegger et al. showed reduced infection rates when reach-
to normalize Selenium and Zinc level by intravenous sup- ing 100% of target REE early (on day 4 of admission) com-
plements further highlighting the significant loss in these pared to late (on day 8 of admission) using supplemental
patients [70–72]. In burn victims there is substantial loss of PN. The rates of nosocomial infections were significantly
trace elements especially Copper, Zinc and selenium and lower in the supplemental PN group, with a hazard ratio of
supplements of 5–8 times the recommended dietary intake 0.65 [81]. On the other hand, a large multi-center random-
is advised [73]. Finally, bariatric patients suffer from sig- ized controlled trial by Casaer et al. compared early (within
nificant trace elements loss due to lack of absorption. This 48 h of admission) to late supplemental PN (after 8 days of
can lead to neuropathy, anemia, weakness etc.… resolution admission) in critically ill patients. Patients in the late sup-
of symptoms may occur with intravenous supplementation plemental PN group had significantly lower rates of infec-
[73]. tions, longer ICU and hospital stays and lower probabilities
of prolonged mechanical ventilation and need for renal
replacement therapy (RRT) [82]. ESPEN guidelines states
he Best Route: Enteral Vs Parenteral
T that EN is preferred over PN in patients with intact GI tracts.
Nutrition However, PN is clearly indicated if caloric targets cannot be
reached or if enteral feeding is not feasible [18].
When deciding on the best route to provide nutrition, a few
factors must be taken into consideration. Enteral nutrition
(EN) preserves intestinal function and it is the preferred Enteral Nutrition
option in a patient unable to consume sufficient oral intake
[18]. It is however associated with more gastric and intestinal There are many commercially available EN formulas. Most
complications [74]. With Parenteral nutrition it is easier to provide 100% of daily requirement of vitamins and trace ele-
reach caloric target [75] but some studies report higher rates ments when adequate calories are provided.
of infectious complications [76]. In early studies comparing
EN to PN there was significant reduction in infection rate Timing A meta-analysis of randomized control trails com-
however it was most prominent in subgroup of patients pared early to late EN in critically ill patients and showed
receiving significantly higher caloric intake resulting in more favorable outcomes in terms of mortality and the develop-
hyperglycemic events and liver function abnormalities. Also, ment of pneumonia in patients receiving early (within <24 h)
studies conducted before the implementation of programs enteral nutrition [83]. In the ESICM clinical practice guide-
for the prevention catheter related blood stream infection, lines early EN is preferred over delayed EN [71, 72]. ESPEN
reveal a significantly higher rate of PN complications [77]. guidelines for clinical nutrition in the ICU recommend start-
The CALORIES trail, an RCT comparing EN to PN in criti- ing EN within 48 h of admission, aiming to provide 70% of
cally ill patients found no difference in mortality between the REE and gradually increasing the caloric intake to no more
two groups. It is important to note that although in this study than 100% of REE [18].
Continuous Versus Intermediate Feeding There is an Gastric Residual Volume Gastric intolerance can be
ongoing debate whether to administer EN continuously or in assessed by measuring the GRV. Reignier et al. studied in a
intermittent boluses. Theoretically there are advantages for multicenter RCT the effect of not monitoring GRV on the
each method, but most studies fail to show significant differ- risk of ventilator associated pneumonia in mechanically ven-
ences. In artificially fed patients, muscle synthesis seems to tilated critically ill patients. Not measuring GRV was non
come to a halt after 2–3 h despite continuous feeding. This inferior to routine (every 6 h) GRV measurements [96]. GRV
“muscle full effect” may be due to the muscle inability to measurements are currently not recommended as a routine
continuously absorb amino acids [84]. Even though bolus monitoring tool but rather as means for diagnosing feeding
feeding helped to overcome that effect in healthy volunteers intolerance if it is suspected. Large GRV (>500 ml/6 h) may
[85], a recent RCT comparing continuous to intermittent signify feeding intolerance that requires action. Prokinetics,
feeding early in the course of critical illness failed to show either erythromycin and/or metoclopramide, are recom-
any effect on muscle loss [86]. It is not always feasible to mended by most societies and the surviving sepsis campaign
reach caloric targets in ICU patients. Prolonged feeding ces- in cases of high GRV [21, 97]. In a meta-analysis by Singer
sations are common as patients are often sent to imaging et al., erythromycin had a clear advantage over metoclo-
studies or surgical procedures, experience high GRVs and pramide and a treatment course of 48 h is recommended in
there are many potential technical difficulties such as feeding patients with GRV > 500 ml [18]. If feeding intolerance per-
tube removal or equipment failure, and feeding regimen pro- sists, post pyloric feeding should be considered. Of note,
gression is often lacking. Bolus feeding may potentially although GRV > 500 ml is traditionally defined as a marker
allow for better timing of nutritional support and help to for feeding intolerance, studies have shown increased risk
overcome many of these technical difficulties [85]. McNelly for mortality even in lower GRVs (>250 ml) [98, 99]. When
et al. found that a larger percent of critically ill patients dealing with a high GRV in a critically ill patient, contribut-
receiving bolus enteral feeding reached the 80% caloric tar- ing factors like the use of opiates, electrolyte abnormalities
get and 60% protein target [86]. On the other hand, an RCT and hyperglycemia should be addressed [100].
by Chowdhury et al. found that bolus nasogastric feeding in
healthy adults actually leads to higher GRVs and increased
superior mesenteric artery blood volume [87]. Rhoney et al. Stress Ulcer Prophylaxis Stress gastritis in critically ill
showed similar results in brain injured patients [88]. In fact, patients has been well documented for many years.
many studies have shown no clinically relevant difference Hemodynamic instability and coagulopathy can cause
between the two modalities [89, 90]. Another emerging prac- splanchnic hypoperfusion and gastric mucosa ischemia lead-
tice is deliberate intermittent fasting in order to induce keto- ing to significant complications [101]. The use of pharmaco-
genesis and encourage autophagy [91]. Ketogenesis, logical stress ulcer prophylaxis has become the standard of
ketogenic diets and ketone supplementation had some suc- care in ICUs but it is not clear whether they prevent clinically
cess in small animal and pediatric studies [92, 93] but RCTs significant GI bleeding events [102]. In fact, studies have
are required in order to assess the clinical application. The shown no added benefit to pharmacological prophylaxis over
ESPEN guidelines promote the use of continuous over bolus early enteral nutrition [103, 104].
enteral feeding in critically ill patients [18].
Diarrhoea Diarrhoea is a common symptom in critically ill

Feeding Tube Placement EN can be delivered to the stom- patients with an estimated prevalence of 14–21% [105].
ach (gastric feeding) or into the intestine (post pyloric feed- Enteral feeding has long been considered a risk factor for
ing). Some studies have shown that post pyloric feeding was diarrhea. A systemic review by Gramlich et al. did not find
associated with lower rates of pneumonia [94] and better conclusive association between EN and diarrhea [106].
feeding tolerance [95], leading the American society of par- Thibault et al. found that EN was not a risk factor of diarrhea
enteral and enteral nutrition (ASPEN) and the society of by itself, but when reaching >60% of caloric targets the risk
critical care medicine (SCCM) to recommend the diversion of diarrhea increased by 1.75 (1.02–3.01) [107]. The use of
of enteral infusion to the lower GI tract in patients who show antimicrobial treatment was also highly associated with diar-
signs of feeding intolerance or who are at high risk for aspi- rhea. It is essential to consider infectious causes in critically
ration [21]. When choosing feeding route one must consider ill patients who develop diarrhea and treat accordingly.
that post pyloric tube placement requires skills, may cause Clostridium difficile infections should be considered not
feeding delays and is not without complications. Thus, most only in patients receiving antibiotic therapy. Once infection
guidelines recommend that the majority of critically ill has been ruled out, non-infectious etiologies should be
patients receive gastric feeding [18, 21]. raised. Non-infectious diarrhea may be a symptom of the pri-
mary disease such as pancreatic insufficiency, Intoxication for nutritional support should be based on individual param-
or even lactose intolerance. In these cases, the trigger should eters. In the early stages of acute illness, large amounts of
always be treated first. Medication is another important endogenous substrates are released from tissues and risk of
cause for diarrhea in the critically ill. Laxatives and proki- overfeeding may increase [113].
netic drugs are obvious culprits, but antibiotics and antifun-
gal medications must be considered as well. Diarrhea can
also be related to the patient’s specific diet. If this occurs in
the orally fed patients, intake should consist of small meals Special Conditions
with isotonic fluids, while in tube fed patients EN should be
delivered continuously. If the diarrhea persists, consider
changing enteral formula and reducing feeding rate [105]. Shock Both ESICM clinical practice guidelines and ESPEN
guidelines for nutrition in critically ill patients recommend
delaying enteral nutrition in cases of uncontrolled shock and
Refeeding Syndrome Dramatic shifts in fluids and electro- sever hemodynamic instability [18, 114]. Clinical studies are
lytes can occur when feeding starts after prolonged starva- scarce but theoretically administering EN in uncontrolled
tion. This is referred to as refeeding syndrome and it can be shock may exacerbate splanchnic hypoperfusion and even
lethal. Malnourished patients are particularly vulnerable, lead to bowel ischemia. There is, however, evidence that
more so after initiation of artificial nutrition. This makes early EN (<48 h) in patients receiving vasopressors at stable
screening ICU patients for malnutrition crucial, as is contin- levels reduces mortality compared to delayed EN [115]. That
uous monitoring for its signs, namely hypophosphatemia. is why the use of vasopressors does not necessarily defer EN.
Diagnosing refeeding at its early stages is of key importance
in order to prevent further complications. When refeeding is
suspected or expected, slow progression in caloric intake is Sepsis The catabolic nature of this acute illness makes sep-
advised with close monitoring of electrolyte levels [18] tic patients highly prone to malnutrition. Septic patients are
(chapter “Refeeding Problems”). also likely to develop GI feeding intolerance subjecting them
to increasing energy debt. On the other hand, in the early
stages of acute illness endogenous substrate utilization sup-
plies most of the patient’s energetic needs, increasing the risk
Parenteral Nutrition of overfeeding when delivering exogenous supplementation
[18]. This phenomenon may explain the results of the afore-
PN provides intravenous nutrition to patients who are unable mentioned EPaNIC trial, where late initiation of PN
to tolerate EN or need supplemental nutrition to reach their decreased ICU mortality, hospital mortality, infection rates,
caloric targets. As previously mentioned, in the case of a mechanical ventilation days and the number of days on RRT
major GI failure (e.g. upper GI bleeding, bowel obstruction, [82]. A prospective large study by Weijs et al. found that sep-
bowel ischemia), PN should be used instead of EN [92]. tic patients did not benefit from early high protein intake
Parenteral formulas contain carbohydrates, lipids, proteins, (≥1.2 gr/kg) [116]. In contrast, non-septic patients receiving
trace elements and vitamins, optimally in a composition early high protein intake had a significant decrease in mortal-
suited to patient specific needs. In the past each of the ele- ity (OR 0.42, 0.21–0.83). To summarize, nutrition in septic
ments were delivered separately but over time the three in patients should be prescribed on a case-by-case basis after
one, or “All-in-one” (AIO) commercial admixtures where carefully evaluating patient’s individual metabolic status.
introduced. The use of AIO systems requires only one venous
access, reducing infectious complications. They also save
preparation time and prevent pharmacological mistakes Acute Kidney Injury and Renal Replacement
[108–110]. Ready to use AIO commercial bags have become Therapy Acute kidney injury (AKI) is a major health con-
extremely common since they were first introduced, but per- cern, with reported incidence of nearly 10% of hospitalized
sonalized AIO compound bags are still an option when the patients and 50% of ICU patients [117, 118]. Renal impair-
clinical condition demands specific consideration [111]. ment negatively affects metabolic characteristics. Protein
catabolism is enhanced, insulin resistance increases, lipoly-
Timing Doig et al. examined the effect of early PN (within sis is reduced, fat clearance is impaired and the anti-oxidative
24 h of admission) compared to standard treatment in criti- system is suppressed owing to a pro-inflammatory status
cally ill patients who had a contraindication for EN. No sta- [119]. Hellerman et al. retrospectively examined substrate
tistically significant different was found in mortality, utilization in ICU patients with AKI. The study showed that
infection rate and quality of life [112]. The optimal timing patients with AKI consumed less carbohydrates and oxidized
much more lipids than expected [117]. Although commercial nase (CPK) and triglycerides allows for early diagnosis
formulas contain mainly carbohydrates, the guidelines sug- [124]. EN is still the preferred route for feeding, even in
gest increasing lipid intake while decreasing carbohydrate patients in the prone position, despite the theoretical risk for
derived calories [119]. The same guidelines recommend gastroparesis and vomiting. A prospective study by Saez de
patients with AKI and an acute/critical illness gradually la Fuente et al. found no significant difference in EN feeding
receive 1.3 g/kg protein a day. Overall, there is no recom- intolerance, defined as high GRVs or frank vomiting, in
mendation for a specific EN or PN formula for patients with patients in the prone position [125]. The same applies for the
AKI. However, if there are electrolyte abnormalities or sig- use of vasopressors or paralytic agents [124]. Special consid-
nificant fluid overload, concentrated, low electrolytes “renal” eration should be made to nutritional support after liberation
formulas should be preferred [119]. ICU patients who from mechanical ventilation. It is recommended to carefully
develop AKI are at increased risk for hospital mortality that evaluate extubated patients with suspected dysphagia and
may be as high as 50%. Moreover, about 5–6% of the patients continue tube feeding if necessary. Upon initiation oral
will need renal replacement treatment (RRT) [120]. As in all intake is rarely enough to reach nutritional targets and sup-
ICU patients, patients requiring RRT should undergo IC to plemental PN should be considered [124].
determine nutritional targets. Existing evidence suggests that
the presence of RRT does not alter REE [121]. When pre-
scribing a nutrition plan, additional calories from substrates Extra Corporal Membrane Oxygenation
like citrate, glucose or lactate provided in dialysate and (ECMO) ECMO is increasingly employed in ICUs, all
replacement fluids should be taken into account. RRT can the more so since the outbreak of the COVID-19 pandemic.
increase protein loss and therefore patients on intermittent ECMO patients are the most severely ill patients, very often
hemodialysis (IHD) should receive 1.3–1.5 g/kg/day of pro- experiencing multiorgan failure, long ICU and hospital
tein and patients on CRRT should receive 1.5–1.7 g/kg/day stays and are predisposed to develop bacterial translocation
[3]. Restricting protein intake during renal failure in order to and sepsis. That being said, early EN should still be admin-
postpone RRT may be considered, but only outside the acute istered if no other contraindication exists [18]. PN is also
illness scenario. Trace elements and vitamins require special feasible in ECMO patients if so indicated, but lipid solu-
consideration in patients undergoing CRRT, as they are lost tions must not be infused directly into the circuit to pre-
on filter membranes. Monitoring and supplementing trace vent lipid deposits and clotting [126]. The ECMO technique
elements (especially selenium, zinc and copper) and vita- uses foreign materials that may aggravate the inflammatory
mins (especially vitamin C, folic acid and thiamine) levels is response and induce significant loss of micro- and macronu-
advised [119]. trients [126]. A single dose ex-vivo study by Estensen et al.
revealed a significant decrease in the levels of the amino
acid isoleucine and of vitamins A and E [127]. This suggests
COVID-19 Since the COVID-19 outbreak in 2020, there is some circuit loss as seen in other forms of extracorporeal
an increasing number of ARDS patients in the ICU, life support systems [128]. On The other hand, Lindberg
experiencing prolonged hospitalizations and often recover- et al., in another ex-vivo study, found no difference in vita-
ing slowly time [122]. COVID-19 is characterized by an min levels, lipid profile or total proteins [129]. Unlike RRT,
inflammatory burst (often referred to as “cytokine storm”), there is no recommendation to provide ECMO patients with
respiratory distress, hypercatabolism, reduced intake and any additional micro- or macronutrient supplementation. Of
prolonged immobilization, making patients extremely sus- note, the nutritional requirements during ECMO therapy are
ceptible to malnutrition and muscle wasting [123]. Recent difficult to predict. These patients have an extremely dys-
recommendations on nutrition in COVID-19 ICU patients regulated inflammatory response, are often septic and tend
emphasize a few practical aspects of treatment. Due to the to require hemodynamic support. It is not currently feasible
workload during COVID-19 pandemic, often only vital pro- to measure REE in ECMO patients via IC and the use of the
cedures are performed, and the possible risk of viral spread simple 25–30 kcal/kg/day is recommended, using the ideal
during IC measurement may pose a threat to caregivers. body weight [21].
Guidelines recommend the use of IC only after day 10 of
hospitalization or in patients receiving full PN plan [124].
The significant energy deficit of COVID-19 patients before
ICU admission makes them vulnerable to the refeeding syn- Monitoring
drome, requiring careful electrolyte monitoring. The use of
sedatives such as propofol in high doses increases the risk to Patients in the ICU suffering from intestinal failure require
develop the propofol infusion syndrome. Close monitoring intense monitoring to prevent complications, evaluate effec-
of blood lactate levels, blood gases, creatinine phosphoki- tiveness of treatment and adjust nutrition plan. Table 2 sum-
Table 2 Assesment, nutritional targets and monitoring tools in patients Definition and classification of intestinal failure in adults. Clin
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a
Ideal body weight
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Eating Disorders in Adults
Paul Robinson and David Russell
Key Points Basic Information

1. Eating disorders are common and can appear in any med-
ical context. Definitions: What are eating disorders?
2. The main types involve weight loss, binge eating ad vom- And why are they of interest to general medical
iting and intermediates occur. services?
3. Having an eating disorder is not a lifestyle choice. The Eating disorders originate in a conviction, shared by many
patients are driven by extreme concerns about weight and in the West, especially females, that one’s body weight is too
shape that they cannot control. high and body shape too large. Whereas most people with
4. Anorexia nervosa is the psychiatric disorder with the this conviction might moderately reduce their nutritional
highest standardized mortality ratio intake often with little long term impact on weight, patients
5. If you are a non-specialist and you meet an acutely ill with some eating disorders take these behaviours to extremes
patient with an eating disorder, look up “Medical emer- and add others. They may be successful in reducing weight
gencies in eating disorders (MEED)” guidelines 2022 and can end up profoundly malnourished or they may lose a
which have replaced the senior and junior MARSIPAN smaller amount and proceed to overeating (binge eating) and
ones and follow its advice. compensatory behaviours such as vomiting or laxative abuse.
6. The outcome for eating disorders is not that bad, but not This introduces two of the currently recognised eating disor-
good enough, with around half making a full recovery, ders anorexia nervosa and bulimia nervosa. The difference
more if the patient is young and has a short history. between common dieting and an eating disorder is that the
7. The literature is large. We recommend The NICE guide- patient takes dieting to such an extreme that their life can be
line [1] and the MEED guidelines1 [2]. Available on-line at risk [1–3]. The reasons they do that are not fully under-
stood, but genetic, developmental, family, social and cultural
factors are all believed to play a part [3].
Another presentation is that of the patient whose weight is
1
https://www.rcpsych.ac.uk/improving-care/campaigning-for-better- in the obesity range and who engages in binge eating, some-
mental-health-policy/college-reports/2022-college-reports/cr233. times following attempts to lose weight. In this case there are
P. Robinson (*)
Nutrition Science Group, Division of Medicine, University College
London, London, UK
D. Russell (*)
Department General Medicine, University of Melbourne, The
Royal Melbourne Hospital, Parkville, VIC, Australia
Department of Gastroenterology, University of Melbourne, The
Royal Melbourne Hospital, Parkville, VIC, Australia
Clinical Nutrition Service, University of Melbourne, The Royal
Melbourne Hospital, Parkville, VIC, Australia
Department of Medicine, University of Melbourne, The Royal
Melbourne Hospital, Parkville, VIC, Australia

192 P. Robinson and D. Russell
no compensatory behaviours and the condition is called

Binge Eating Disorder (Box 3) although this can occur at ing a similar period of time and under similar
normal weight. circumstances.
A fourth eating disorder associated with nutritional –– A sense of lack of control over eating during the
restriction but not body image disturbance is ARFID or episode (e.g. a feeling that one cannot stop eat-
avoidant restrictive food intake disorder. ing or control what or how much one is eating).
All these eating disorders have been defined in the most • Recurrent inappropriate compensatory behaviour in
recent version of the American Psychiatric Association clas- order to prevent weight gain, such as self-induced
sification, the DSM 5 [4] and the essentials of the three main vomiting, misuse of laxatives, diuretics, or other
conditions are listed in Boxes 1, 2, and 3. Pica, which is the medications, fasting, or excessive exercise.
consumption of non-nutritive substances, and Rumination • The binge eating and inappropriate compensatory
Disorder, with recurrent regurgitation of gastric contents, behaviours both occur, on average, at least once a
have also been included under eating disorders in the DSM week for three months.
5. Atypical eating disorders are now classed as Other Specific • Self-evaluation is unduly influenced by body shape
Feeding and Eating Disorder (OSFED) and Unspecified and weight.
Feeding or Eating Disorder (UFED). • The disturbance does not occur exclusively during
episodes of Anorexia Nervosa.
Box 1 DSM-5 Criteria for Anorexia Nervosa

Box 3 DSM-5 Criteria for Binge Eating Disorder
According to the DSM-5 criteria, to be diagnosed as
having Anorexia Nervosa a person must display: According to the DSM-5 criteria, to be diagnosed as
having Binge Eating Disorder a person must display:
• Persistent restriction of energy intake leading to
significantly low body weight (in context of what is • Recurrent episodes of binge eating. An episode of
minimally expected for age, sex, developmental tra- binge eating is characterised by both of the following:
jectory, and physical health). –– eating, in a discrete period of time (e.g. within
• Either an intense fear of gaining weight or of any 2-hour period), an amount of food that is
becoming fat, or persistent behaviour that interferes definitely larger than most people would eat dur-
with weight gain (even though significantly low ing a similar period of time and under similar
weight). circumstances.
• Disturbance in the way one’s body weight or shape –– a sense of lack of control over eating during the
is experienced, undue influence of body shape and episode (e.g. a feeling that one cannot stop eat-
weight on self-evaluation, or persistent lack of rec- ing or control what or how much one is eating).
ognition of the seriousness of the current low body • The binge eating episodes are associated with three
weight or more of the following:
–– eating much more rapidly than normal
Subtypes: Restricting type and Binge-eating/purging –– eating until feeling uncomfortably full
type. –– eating large amounts of food when not feeling
physically hungry
–– eating alone because of feeling embarrassed by
how much one is eating
–– feeling disgusted with oneself, depressed or very
Box 2 DSM 5 Criteria for Bulimia Nervosa guilty afterward
According to the DSM-5 criteria, to be diagnosed as • Marked distress regarding binge eating is present
having Bulimia Nervosa a person must display: • Binge eating occurs, on average, at least once a
week for three months
• Recurrent episodes of binge eating. An episode of • Binge eating not associated with the recurrent use
binge eating is characterised by both of the of inappropriate compensatory behaviours as in
following: Bulimia Nervosa and does not occur exclusively
–– Eating, in a discrete period of time (e.g. within during the course of Bulimia Nervosa, or Anorexia
any 2-hour period), an amount of food that is Nervosa methods to compensate for overeating,
definitely larger than most people would eat dur- such as self-induced vomiting.
Eating Disorders in Adults 193
Definitions Acute Nutritional Deficiency
The definitions of the main eating disorders as described in This is one of the most alarming presentations in clinical
DSM5 are listed in Boxes 1, 2 and 3. Anorexia nervosa is medicine. The front-line doctor will usually consult
characterised by self-induced low weight, avoidance of Wikipedia (check “Anorexia Nervosa”, “Admission to hospi-
weight gain and a disturbance in body image. In bulimia ner- tal”), even though respectable publications do not allow their
vosa the patient attempts to lose weight and may have some articles in a reference list. The patient is usually but not
success, but then is overcome by urges to eat and suffers epi- always a young female and the history may be fairly brief
sodes of binge eating followed often by vomiting or laxative with two or three months of severe dietary restriction some-
abuse. Binge eating and vomiting may also complicate low times with vomiting or laxative abuse, or the patient may
weight anorexia nervosa. In binge eating disorder distressing have well established anorexia nervosa of several years dura-
binge eating occurs unaccompanied by compensatory behav- tion. She may be carried into the emergency room or brought
iours. This condition is often associated with obesity and is in on a wheelchair. She will show severe muscle wasting and
commonly seen in patients seeking bariatric surgery. Usually her appearance may be reminiscent of a concentration camp
the diagnosis of an eating disorder is not difficult because of survivor. In contrast with her emaciated appearance, she may
the weight loss, unexplained by other conditions, body image be alert and bright although she may equally be cognitively
concerns, resistance to weight gain, binge eating, vomiting impaired with slurred speech, depending on central nervous
or laxative abuse. However, if the prevalence of eating disor- system nutrition. The assessing doctor in the emergency
ders within a particular environment (e.g. a diabetic or gas- room may suspect a malignancy or other wasting condition.
troenterology clinic) is sought, clinicians may use the SCOFF However, an eating disorder should be suspected from the
questionnaire [5] which is very brief and has very high sen- age and gender of the patient, and confirmed as in the follow-
sitivity (case detection) but a lower specificity (more false ing conversation in which the patient is concealing some of
positives). her symptoms:
Doctor: You seem to have lost a lot of weight. Can you tell
me how this happened?
Epidemiology Patient 1 (female age 19): I don’t know, it just went down
without me noticing.
Estimates vary in different studies but on average [6] the fig- Doctor: How do you feel about the weight loss?
ures for prevalence in the West are 0.4% of young women for Patient 1: I don’t mind it really. I still feel that I could lose
anorexia nervosa 1% for bulimia nervosa and 1–2% for binge just a little more. Although I don’t mind if it stays like this. I
eating disorder. Hence taking AN and BN together the preva- feel so weak. Can you help me?
lence of an eating disorder among young women the preva- Doctor: Well, starting to increase your food would really
lence of eating disorders is about 3–4%. Men also suffer help that.
from anorexia and bulimia nervosa at 10–30% of the female Patient 1: Can we do that later? I don’t feel ready just
data and for binge eating the sex ratio is about 3 men to 5 now.
women. Hence eating disorders are sufficiently common for The doctor will be highly suspicious that anorexia ner-
all doctors to be liable to see an affected patient in the course vosa might be the diagnosis, and attempt to contact a relative
of his or her practice. to obtain further information that might indicate recent food
refusal, body image preoccupation or evidence of vomiting.
If tests are required to exclude other disorders which might
Different Presentations of Eating Disorders present in this way such as Addison’s Disease or tuberculo-
sis, they should be done quickly and management of the mal-
Sir William Osler, one of the founders of the Johns Hopkins nutrition, with a probable diagnosis of anorexia nervosa,
Medical School coined the term “The great imitator” when should begin.
describing syphilis and its multifarious manifestations. In the history, ask about recent nutrition, excess water
These days several diseases compete for this description and drinking, a history of fractures and muscle weakening, with
eating disorders have a good case. Because eating disorders difficulty climbing stairs, overeating and vomiting. Ask if
appear (whether or not the physician is aware) in almost others have noticed and expressed concern about weight loss
every medical clinic, the most important clinical presenta- and whether anyone (relative, doctor) has mentioned
tions will be described in turn. anorexia. What does the patient think might be wrong?
Fig. 1 The SUSS test (Royal SIT UP-SQUAT-STAND TEST (TO DETECT MUSCLE WEAKNESS)
College of Psychiatrists. With
permission) [7]
1. Sit-up: patient lies down flat on the floor and 2. Squat–Stand: patient squats down and rises
sits up without, if possible, using their hands. without, if possible, using their hands.
Scoring (for Sit-up and Squat-Stand tests separately)

0: Unable
1: Able only using hands to help
2: Able with noticeable difficulty
3: Able with no difficulty
Continuing with physical examination, look for swelling

of the parotid glands (bingeing and vomiting), lanugo hair Box 4 Pathophysiological Changes of Starvation
(fine downy hair on the back, face and elsewhere) and mus- Starvation
cle atrophy. Check the dorsa of the dominant hands for cal-
luses due to induced vomiting (Russell’s sign). If the patient • Reduced carbohydrate fuel source leads to increase:
is not obviously weak, ask her to do the SUSS test (Sit Up (1) Ketosis (2) Proteolysis
Squat Stand) (Fig. 1). This is a reliable test of muscle power • Loss of lean body mass affects major organs
with the following scale: 0: unable to rise from squatting or • Atrophy of the myocardium → poor contractility
sit up from lying flat, 1: Able to rise or sit up only by using and ↓ Cardiac Output Thiamine deficiency
hands to help, 2: Able to rise or sit up but with noticeable • Gastrointestinal atrophy → malabsorption and
difficulty, 3: able to rise or sit up with no difficulty. dysmotility
Check the pulse which may be under 50 or less at low (1) Translocation bacteria (2) Gastroparesis
weight, and see if the patient gets dizzy on standing. Check • Pancytopenia – increase in infection
the lying and standing BP and see if the difference is >20 mm • Intracellular loss of electrolytes—(K+/PO4--) and
Hg. Measure the core temperature. Hypothermia occurs in intracellular water
malnourished patients who sometimes deliberately expose • Micronutrient Deficiency-trace elements and
themselves to cold in order to shiver and hence lose more vitamins
weight. • Insulin secretion, GH release and thyroid function
The pathophysiological changes attribute to starvation are are all diminished → the basal metabolic rate slows
summarised in Box 4. The clinically significant (“red flag”) down to 20% to 25% to conserve energy
manifestations of these pathophysiological changes on • Consequently, the body becomes bradycardic,
anorexia nervosa are summarised in Box 5. hypothermic, and hypotensive
The investigations that apply specifically to an eating dis-
order are urea and electrolytes, liver function tests, calcium,
phosphate, magnesium and electrocardiogram.
Hypokalaemia suggests vomiting or laxative abuse, hypona- siently during refeeding but then go back to normal. There is
traemia may indicate excess water drinking, sometimes to almost never an indication for liver biopsy. Blood glucose
conceal weight loss when on the scale and raised urea and can fall as metabolism moves from carbohydrate based to fat
creatinine may indicate dehydration or, sometimes, renal based when glycogen stores have become exhausted. The
insufficiency. Raised transaminase levels are common and patient may be alert because the brain is using fatty acids for
appear to be related to malnutrition. They may increase tran- energy. She may however require glucose and hypoglycae-
repletion [9]. The role of the emergency department is to

Box 5 Red Flag Findings in Severe Eating Disorders (See resuscitate and perhaps begin the other phases. A detailed
MEED [2]) guide to managing this clinical situation is provided in the
MEED guidelines and textbook [2, 7, 10] which readers are
System RED Finding Note
BMI <13 BMI can be higher if
advised to consult. A broad outline will be provided here.
weight loss rapid The MEED guideline, are accompanied by the MeeD check-
Weight loss >1 kg per week list (Fig. 2) applicable to all ages and this will be described
CVS HR < 40 bpm in order to highlight the essential clinical approaches in this
Standing very difficult situation.
SBP < 90 mm Hg
with syncope
The first column covers assessment: 1. Does the patient
Dehydration Clinically present have anorexia nervosa? The diagnosis may be apparent either
Core <35 °C from information from the patient or relative as described
temperature above. If there is doubt, and this will be unusual, ask the
Muscle strength SUSS test (Fig. 1) Or use Hand Grip opinion of the on-call psychiatrist. 2. Are there significant
score < 2 Strength
risk factors? a. Low BMI, <13 in adults indicate high risk. b.
Comorbidities Sepsis, bleeding
Diabetes Mellitus:
Rate of weight loss: has weight been lost at over 1 kg per
HbA1C > 10% week for two consecutive weeks? c. Little or no nutrition for
ECG Any significant Bradycardia, T wave >5 days. This predisposes to refeeding syndrome. d.
abnormality changes Abnormalities on examination, in blood tests and ECG all
Prolonged QTc contribute to risk.
Biochemistry Na K P. Ca Reduced P, K, Mg
The middle column is concerned with refeeding. 1. Is the
suggest refeeding
syndrome. Reduced patient so ill that intensive care is required? 2. Are there risk
Na suggests water factors for refeeding syndrome (RFS)? This is dealt with else-
loading and reduced where in this book. Here it should be mentioned that in
K suggests vomiting
anorexia nervosa, abnormal electrolytes, very low BMI, and
or laxative abuse
Low Glu significant co-morbidities (see checklist) all increase the risk
(<3mmol/L) or if of RFS. Advice is given to begin refeeding at low rates if the
diabetic risk of RFS is vey high, but to build up quickly in order to
HbA1C>10% avoid the equally dangerous underfeeding syndrome (UFS) in
Transaminases up to
3× ULN
which too few calories are provided with sometimes fatal
Haematology Reduced WBC results. 3. If the risk of RFS is not too high, begin with higher
Rarely pancytopenia rates of refeeding and 4. Give thiamine and 5. Monitor closely.
Food refusal <500 kcal per day The right hand column is for general management. 1. Are
Activity Compulsive exercise medics and psychs collaborating closely? This is very impor-
Purging Self induced tant. It is not acceptable for the psychiatrists to leave the scene
vomiting, Laxative
abuse until the patient is better. Equally, physicians must make sure
Self harm, Self poisoning, that the mental health staff, who could be from an eating dis-
suicide suicidal thoughts/ order service (best) or from a liaison or general psychiatry
intent service, are called and involved in treatment planning and
staff support. 2. Are the staff trained? Usually not. The senior
staff must make sure that staff on every shift, especially if
mia should not be neglected. The blood count may show from an agency, are familiar with the patient’s symptoms,
mild anaemia, usually of mixed origin (mostly iron defi- likely behaviour and potential problems and their manage-
ciency and marrow hypoplasia) and platelets can be low in ment. A one side sheet of paper detailing the treatment plan
extreme malnutrition and accompanied by a purpuric throm- and what to do if things go wrong should be given to all staff
bocytopaenic rash and pancytopenia in gelatinous transfor- working directly with the patient. 3. Are there psychological
mation of the marrow [8]. The ECG can show almost any factors that increase risk? Falsifying weight is common in
abnormality with ST and T changes which suggest isch- patients with anorexia nervosa who are afraid that weight loss
aemia, but which probably indicate reduced energy delivery or failure to gain weight might lead clinicians to increase their
to the heart, and prolonged QTc (>450 ms) which is thought calories, begin tube feeding, arrange admission to an eating
to predict serious cardiac arrhythmias. disorders inpatient unit, or begin proceedings to force nutri-
The nutritional management of a patient such as the one tion under the Mental Health Act. Methods vary and test the
described comprises three phases: resuscitation, repair and powers of observation and deduction of the clinician.
Fig. 2 The MEED Checklist (Royal College of Psychiatrists. With permission)
Fig. 3 A graph of weight 2.5

change in kg (diamonds, from
Admission
Hospital
37.5 kg) each week and the 2

Sit Up test on the same day
(squares). The weight stays
1.5
stable but the Sit Up scores
decline. The patient is
admitted (down arrow) and 1
weight immediately falls by
2 kg 0.5
Weight change
0
0 1 2 3 4 5 6 7 Sit UP
–0.5
–1
–1.5
–2
–2.5
Patient 2 was being seen in the outpatients’ department above the high risk range (<13). However, her Sit Up test
for severe anorexia nervosa. Her weight was 37.5 kg and her declined and on the basis the consultant decided to admit
BMI 13.5. Every week she was seen in the clinic she was her to hospital against her wishes. After admission her
weighed and the SUSS test (see above and [7]) was per- weight immediately fell to 35.5 kg, BMI 12.8. Her comment
formed. Her weight appeared to be stable and her BMI was was “Doctor, I’m so glad you admitted me. I couldn’t have
managed to drink any more water.” She was drinking 2 is kept on the ward, it is very difficult to prevent micro-
litres of water whenever she was weighed prior to admis- exercise. Initially, advice from a nurse who may be observ-
sion. (See Fig. 3). ing the patient one to one can be helpful, but a determined
Patient 3: This patient was being seen by a therapist in an patient may continue. Again, if it is thought to be impairing
outpatient clinic and being weighed weekly. Her BMI was her response to nutrition, it may be justified to use small
15.5 (weight 41.7 kg) so she was not regarded as very high doses of a benzodiazepine such as Lorazepam [7]. This can
risk. However, her therapist that she thought that the patient be hazardous, however, because of the potential for hypo-
was looking thinner. Two days later the patient was admitted tension these drugs bring, in a patient who may already be
to a medical ward in status epilepticus. She was treated and hypotensive. There has been some interest in the use of
woke up from the fit 24 h later. Her sodium on admission was Olanzapine [11] in the treatment of anorexia nervosa at a
119 mmol/L (normal range 135–145) and two days later she dose of around 5 mg. It may have some effect on weight,
weighed 35.1 kg (BMI 13). She admitted to massive water although this is disputed and being further investigated, but
loading prior to her therapy for fear of admission. When the drug may also have a beneficial effect on agitation and
asked how she managed to “gain” 8 kg she said that she it would not be unreasonable to use it in patients with
would go into the shower, place the shower rose in her mouth micro-exercising.
and turn on the water.
Disposing of food: This is a common practice in hospital
and at home and is sometimes evidenced by the family cat Suicidal Behaviour and Self-Harm
becoming obese! In hospital, patients have been known to
dispose of nasogastric feed in the sink, the toilet and even This is a large and very important subject and can only be
into a pillow into which a hole has been drilled. dealt with cursorily here. A proportion of patients with eat-
Patient 4: A patient with anorexia nervosa and a border- ing disorders express suicidal thoughts and some even see
line personality disorder was admitted to a general psychiat- starvation as a more acceptable way to die (e.g. for their
ric ward with a BMI of 13. She spent four weeks there and families) than other methods. 20% of patients with
appeared to be eating well. However her weight stayed anorexia nervosa who die do so by suicide [12]. Patient
exactly the same and eventually she was discharged because should be asked about suicidal ideation and psychiatric
of lack of progress. After she left a smell was noticed in her assistance obtained for patients with suicidal ideas. Self
en-suite bathroom. Investigation revealed a large amount of harm is characteristic in patients with eating disorders who
rotting food when the side panel of her bath was unscrewed. also suffer from borderline personality disorder, but it also
Secretive exercise: This is also common. Many acute hos- occurs in a proportion of patients who do not fulfil criteria
pitals have signs encouraging staff and others to use the stairs for BPD [13]. Self harm can be very difficult to deal with
rather than the lifts. Our patients need no second invitation. on a medical ward, especially if the patient is resistant to
Because they are often not confined to the ward, even though attempts to improve nutrition. A meeting between the
they should probably be confined to bed, the patients use the medical and the psychiatric team is essential and a clear
stairs as an indoor gym, sometimes with 12 floors to run up. management plan developed. Sometimes patients, usually
Other common forms of exercise are less obvious. Micro- female, may cut or burn a part of the body that they find
exercising means the use of small muscles to increase calorie most unacceptable, such as the stomach. A real danger
consumption and patients will be noticed to be wiggling their with such a patient is the possibility of escalating levels of
toes or fingers or, sometimes knitting furiously. Standing is observation so the patient can find herself with one or two
another variant and some patients refuse to sit, knowing that special nurses, sometimes with restraints on one or both
maintaining the erect posture increases calorie use. Lastly, wrists. Such treatment naturally requires a compulsory
wearing inadequate clothing in cold weather is a form of order, but even then it can be hard to justify continuing it
micro-exercise because the patient is aware that if she shivers for days or even months which has occurred in some cases.
she will use more energy. Escalating treatment can seem to be a motivating factor as
Managing exercise and micro-exercise can be a chal- in the following patient who was interviewed in an inpa-
lenge. The patient can be strongly advised not to leave the tient unit for eating disorders:
ward, and to stay in bed until her BMI has improved and Doctor: How is it that you came to need two nurses look-
this approach will work for some patients. However, keeping after you?
ing a reluctant patient on the ward when she is not detained Patient 5: Well I noticed that Jenny got her own nurse
under the Mental Health Act is not legally defensible and if when she started cutting, so I did the same. Then when Jenny
it is thought that exercise is adversely affecting her recov- started cutting the other arm, so did I and I’ve now got two
ery and she is in a dangerously poor state of nutrition, a special nurses, like her, although I don’t like it because I
discussion with the psychiatrist about the Mental Health have hardly any freedom and both my wrists are bandaged to
Act may be justified. Even if a patient is on a “section” and the bed.
Family Distress and Anxiety abuse or neglect by carers or relatives of patients with eating
disorders, although in some cases laxatives have been smug-
When a patient is admitted for care to an inpatient bed, espe- gled into the ward at the request of the patient and this could
cially in a medical unit, the family members are well aware fall under safeguarding. On discharge home, staff must be
that their loved one is in a very dangerous medical state. clear that care is appropriate and as helpful as possible,
They may also realise that eating disorders are not very well which it almost always is, so that neglect or abuse does not
understood on the unit, and that experts in the subject may take place after discharge.
not be on the scene. Their anxiety is at very high levels, and In general, the MEED recommendations are designed to
is increased by shortage of information. The combination of facilitate joint work between psychiatric and medical experts,
fear for their loved one’s survival, concern about competence and when there is doubt, the last recommendation in the right
and lack of information can lead to behaviour which may hand column should always be enacted “Mobilise psych
seem irrational. One family arranged for an uncle, a retired team to advise on management”.
anaesthetist, to come and provide a second opinion which
conflicted with the views of the consultant, leading to much
heat and little light. In another case, the mother became con- Electrolyte and Micronutrient Imbalance
vinced that the nurses were sexually interfering with her son
who was on the ward with extreme malnutrition and a para- Hypokalaemia
noid psychosis, probably of nutritional origin. Patient 6: A primary care physician referred a male patient
Such incidents are more easily prevented than stopped, of 32 to the emergency department. He was underweight,
and a number of principles can be suggested for managing had been vomiting regularly for several years and had
the relationship with relatives. recently fainted. A serum potassium level was 1.9 mmol/L
(normal range 3.5–5 mmol/L). The doctor in the emergency
1. Include at least one relative in discussions about the department noticed that his teeth were almost all worn away,
patient’s care. Most patients over 18 will agree to their with some fillings “standing proud”.
relatives being involved in treatment decisions. Low potassium occurs quite commonly in the course of
2. Rather than deal with all members of the family, it is use- eating disorders. Self induced vomiting as a form of weight
ful to ask them to nominate one member as the family control occurs in bulimia nervosa and also in the bulimic
representative, both for meetings and phone calls. form of anorexia nervosa. Among atypical eating disorders,
3. Make sure that information is available regularly; say patients of normal weight who purge without binge eating
every few days, so that the family’s knowledge is up to (termed “Purging disorder”) are also at risk. The patient may
date. or may not have relevant symptoms and although some
4. When there is clear distress which is not satisfactorily patients describe muscle cramps or episodes of loss of con-
dealt with by the above measures, designate a sensitive sciousness consistent with cardiac arrhythmia, the problem
and experienced team member to meet with the relative is most often identified in a routine blood test. Low potas-
and attempt to resolve issues by providing support and sium can also occur after loss of the ion in diarrhoea, induced
information. by extreme laxative abuse, and also sometimes because of
5. Because complaints are not unknown, staff should make very low intake in anorexia nervosa, restricting subtype.
sure that they document and justify their treatment deci- Examination may not be instructive, but the ECG may show
sions in case they are later examined. U waves and other abnormalities (Fig. 4).
6. As long as the collaboration between medical and psy-
chiatric personnel is occurring as advised above, rela-
tives can be reassured that experts in both the
psychological and medical aspects of the condition are
working together, and be invited to meet both sides, pref-
erably together.
Safeguarding Concerns
Safeguarding for adults at risk because of mental disorder

refers to the responsibility of staff looking after them to
make sure they are not subject to abuse or neglect. The inpa- Fig. 4 ECG characteristics in hypokalaemia showing ST depression,
tient medical setting does not often provide examples of such T flattening and a U wave
The cause of hypokalaemia in eating disorders varies with Managing Hypokalaemia

the patient’s behaviour. In the above case, the problem was
repeated self induced vomiting over many years. Vomitus The physician can safely assume that loss of potassium (K),
does not contain much potassium, and the mechanism of whatever the route is likely to continue. Change in attitude to
hypokalaemia appears to be mediated by loss of hydrogen body image takes time and therapy and in the short term is
ions from gastric juice, leading to a metabolic alkalosis. The unlikely. There have been reported cases of patients with
attempt to correct this and restore body pH to normal, results hypokalaemia due to bulimia being given an intravenous
in H+ being retained and K+ lost and this increases renal infusion of potassium chloride until the serum potassium is
excretion of potassium and leads to hypokalaemia. However, in the normal range and then sent home with no follow up.
the process can continue for some time while potassium, This is a very dangerous practice and can result in the death
which is primarily intracellular, leaks out of the cells and of the patient. At the very least the patient requires regular
maintains serum potassium levels. Only when total body and frequent (every few days) blood tests to monitor electro-
depletion of potassium is substantial does hypokalaemia lytes, as well as support and therapy from an expert eating
show itself. disorders practitioner. Secondly, considering that there is a
In other situations, such as laxative abuse, the cause of large total body deficit of potassium, an infusion for a day is
hypokalaemia is loss of potassium in the stool, whereas in unlikely to replenish it, and longer treatment is required.
restrictive anorexia nervosa, the most likely cause is Intravenous potassium chloride is certainly an appropriate
chronic under-ingestion of potassium. Lastly, patients with lifesaving intervention if potassium levels are very low. This
eating disorders, some of them doctors, nurses and phar- can be followed by oral potassium chloride tablets to con-
macists, may abuse diuretics in an attempt to reduce body tinue the process of repletion, bearing in mind that the patient
water and achieve weight loss, which of course does not may have resumed vomiting and potassium loss may there-
reflect any change in fat mass. The action of diuretics, fore have resumed. Monitoring should take place every few
especially the more powerful ones such as furosemide, is days to detect recurrent low levels of potassium. In clinics
to stimulate the loss of sodium and potassium, and hypo- without access to intravenous infusion (such as outpatient
kalaemia can be the result. The metabolic effects of hypo- eating disorders clinics) the following schedule can be
kalaemia are widespread and are serious and if unrecognised followed:
can be fatal.
9 am: Blood test for potassium level
10 am–4 pm: If hypokalaemic perform ECG and give potas-
sium chloride tablets every 2–4 h
Box 6 Consequences of Hypokalaemia 4 pm: Repeat Blood test for K level
Sequelae of Hypokalemia Send home if level > 3.5 mmol/L
Subsequent days: Repeat Blood test for K level
• Cardiac Send home if level > 3.5 mmol. Continue to monitor K.
–– Arrhythmias, cardiac arrest, increased digitalis If still hypokalaemic refer to emergency dept.
sensitivity, orthostatic hypotension, EKG
changes (T wave flattening or inversion, U Another approach which is theoretically interesting is to
waves, ST segment depression) give the patient (with intractable hypokalaemia due to vomit-
• Gastrointestinal ing) a proton pump inhibitor drug such as Lansoprazole [14].
–– Constipation, ileus, exacerbation of hepatic The theory is that if the stomach can be prevented from
encephalopathy secreting acid then vomiting should not lead to alkalosis, and
• Metabolic so potassium does not need to be exchanged for hydrogen in
–– Glucose intolerance, hypokalemic metabolic order to keep the body’s pH normal.
alkalosis
• Neuromuscular
–– Areflexia, hyporeflexia, paralysis, parenthesis, Hypoglycaemia
respiratory depression, rhabdomyolysis, weakness
• Renal Low blood sugar is frequently observed in patients with low
–– Decreased urinary concentrating ability, poly- weight due to anorexia nervosa. The carbohydrate stores of
uria and polydipsia, nephropathy with decreased the body, glycogen in muscle and liver, have often been
glomerular filtration rate, myoglobinuria (sec- exhausted as a result of a low calorie, especially a low carbo-
ondary to rhabdomyolysis) hydrate, diet, and sometimes by exercise, either overt or
“micro”. In complete starvation glycogen is exhausted by
24–48 h [15]. At that point energy delivery to essential organs

(brain and heart) is continued by switching to triglycerides • Muscular skeletal
and ketones produced by the liver and by day 3 some 30% of –– Rhabdomyolysis
energy needs are provided in this way. Fat cannot be trans- –– Diaphragm dysfunction
formed to glucose, but protein can, through gluconeogenesis, • Haematological
although the amounts are limited and protein breakdown –– Reduced RBC 2-3 DPG – oxygen dissociation
occurs, for example in muscle. curve to the left
Hence, the hypoglycaemia seen in severe anorexia ner- –– Haemolysis
vosa may not have the same clinical impact as the same low –– Reduced WCC function
level of glucose seen after, for example, an overdose of insu-
lin. The patient may be alert and functioning, because the
brain is being fed with energy through ketones.
Patient 7: A young woman with anorexia nervosa was an Box 8 Sequelae of Hypomagnesemia
inpatient on a medical ward. Her blood glucose, by finger-
prick, was low at 2.5 mmol/L. At around midnight the on-call • Cardiac
doctor rang the senior physician to report that the blood glu- –– Arrythmias, tachycardia, torsade de pointes
cose machine was recording a level of zero. The physician • Gastrointestinal
asked if the patient was conscious and was assured that she –– Abdominal pain, anorexia, diarrhea,
was in animated conversation with nurses and other patients. constipation
The physician concluded that the machine must be faulty. • Neuromuscular
The patient was found dead in the morning. The glucose –– Ataxia, confusion, fasciculations, hyporeflexia,
monitoring machine was found to be functioning normally. irritability, muscle tremors, painful paresthesias,
Hence, in spite of very low blood glucose the patient may personality changes, positive Trouseau’s sign,
be deceptively well. The management of this situation seizures, tetany, vertigo, weakness
demands good clinical judgement. The low glucose can, as
seen above, be fatal. However, the body has shown major
adaptation to lack of carbohydrate and the amount of glucose
required may be less than is given in an insulin overdose. It Renal Insufficiency
is probably safe to provide enough glucose to maintain serum
levels within the normal range, with a combination of oral, Eating disorders can cause renal failure by different mecha-
bolus and intravenous glucose, but each case needs careful nisms. Many patients with anorexia nervosa restrict not only
thought and closely monitored treatment. Glucose refeeding calories, but also water and after months of such deprivation,
can induce acute thiamine deficiency in patients with severe the kidneys can be severely damaged.
malnutrition. Prophylactic intravenous thiamine is strongly Patient 8: A woman of 19 who had withdrawn from treat-
recommended prior to giving any oral or intravenous ment the year before contacted one of the authors by email as
glucose. follows: “Dear Dr, I think I need help. Maybe something can
Other major electrolyte disturbances that can occur due to be done? Signed x”. An urgent appointment was arranged
severe starvation or as a result of refeeding are hypophospha- and the history obtained that for the previous year, she had
temia and hypomagnesemia. The clinical manifestations are consumed, every day, only a small pie and half a glass of
summarised in Boxes 7 and 8. water. She was severely underweight and tests showed that
she was in acute renal failure. She was admitted to a medical
ward and a glucose infusion was set up, in order to encour-
Box 7 Sequelae of Hypophosphatemia age her kidneys to begin functioning again. She noticed that
the infusion contained glucose, ie calories, and switched it
• Decreased cardiac ATP off during the night. The nurses noticed what she had done
→ CCF and restarted the drip. However, she died a few hours later.
→ arrythmias Apart from fluid restriction, the most common metabolic
• CNS problem affecting renal function is hypokalaemia, discussed
–– Delirium above. Patients who maintain very low levels of serum potas-
–– Seizures sium for long periods may sustain progressive renal tubular
–– paraesthesia damage and the result can be end stage renal failure, requir-
ing dialysis sometimes followed by transplantation.
Refeeding Syndrome infection and cardiac problems and to be fed naso-

gastrically, than those admitted to eating disorder ser-
Refeeding syndrome (RFS) is covered in chapter “Refeeding vices. They may also have had lower BMI levels, simply
Problems”. In eating disorders patients there are a few points because they had waited for treatment longer, become
worth noting (Figs. 5 and 6). more ill and hence had required an emergency medical
bed rather than a psychiatric admission. There may also
1. In discussions between physicians and psychiatrists dur- have been differences in attitude between the two types of
ing the MEED consultations, it was clear that RFS was specialist, with physicians having had more experience of
more commonly seen by the physicians than the psychia- severe RFS than psychiatrists and hence being more cau-
trists. The reasons for this are not readily apparent, but tious. In the end, the advice in MEED provides for lower
differences in practice did emerge, with patients in medi- initial kilocalorie provision for patients with the highest
cal beds being given initial rates of feeding well below risk of RFS, and higher provision for the rest. However, it
those admitted to eating disorder specialist beds. One was stressed that to avoid Under Feeding Syndrome, cal-
likely explanation is that patients admitted medically may ories should be increased rapidly while monitoring for
have had more major medical co-morbidities such as the emergence of RFS.
2. Refeeding syndrome is more likely to occur in admitted
patients, especially when enteral feeding is given.
However, RFS has been described in a patient with
anorexia nervosa who, during admission, began binge-
eating [16]. This complication has also been observed in
outpatients and the need for moderation in refeeding
should also be conveyed to community patients with
anorexia nervosa undergoing nutritional treatment in out-
patients or day care. In practice, most patients’ reluctance
to eat and gain weight makes the emergence of RFS in
patients on oral refeeding rather uncommon.
Fractures
The presence of fractures in a young person not associated

with major trauma should alert the physician to the possibil-
ity of an eating disorder. The context can be the emergency
department, where a patient may present with fracture of any
bone, and the fracture may have occurred after relatively
Fig. 5 Metabolic changes in starvation and carbohydrate refeeding
minor trauma. Patients with eating disorders who exercise by
walking for hours may present with fractures in the foot
(“march fractures”) which seem to be the result of repeated
minor trauma in a patient with osteoporosis. Other medical
services including primary care can be consulted as a result
of bone or joint pain, fractures or loss of height.
Patient 9: The man of 37 had suffered from anorexia ner-
vosa since his teens with chronically low weight and frequent
admissions. He was known to have severe osteoporosis. He
was seen in an outpatients clinic and proudly announced that
his anorexia had recovered. He explained that he had worked
out his Body Mass Index and found that it had risen to 19.
Further enquiry and examination demonstrated that his
weight had remained the same, 45 kg, but his height had
reduced from 1.74 m (BMI 14.9) to 1.54 m (BMI 19) over the
previous 3 years as a result of spinal vertebral collapse frac-
Fig. 6 Electrolyte and body water (Intracellular and extracellular) tures causing a kyphosis. The patient was advised to use his
changes in starvation and refeeding former height in order to work out his BMI.
Bone involvement in anorexia nervosa is progressive as (Mallory-Weiss syndrome) in which case the bleeding may
long as weight is low. Within a year or two of onset, many be massive and the patient gravely ill, have been described
patients are found to have osteopenia on the Bone Mineral [22]. Patients with anorexia nervosa have delayed gastric
Density “Dexa” scan. The T score in the spine and hip will emptying probably related to undereating and starvation
be between <1 and <2.5. As years go by osteoporosis in [23, 24] and this can predispose to early satiety and, if large
more frequently observed (T score ≤2.5) and the rate of quantities of food are consumed, a danger of acute gastric
fractures increases. The aetiology of osteopenia in anorexia dilatation and rarely perforation [25]. Occasionally oesoph-
nervosa is complex. Unlike post-menopausal osteopenia, ageal perforation has been reported in anorexia nervosa
bone loss cannot be slowed using sex hormones [17]. The [26]. In patients with laxative abuse, very large doses of
exception to this rule is that in adolescents with anorexia stimulant laxatives may be taken daily, initially in an attempt
nervosa bone loss may be reduced by physiological doses of to speed calories through the gut, but later in response to
oestrogen delivered transdermally [18]. Sex hormones may increasing constipation and tolerance to the effects of laxa-
therefore play a part in aetiology. Other hormones such as tives. The patient may complain of diarrhoea, but in more
cortisol, which is increased in anorexia nervosa and which chronic cases, constipation is seen and this may be resistant
can reduce bone density may be relevant while the reduction to laxative treatment. In a few instances, a “floppy colon” is
in stress on bones which accompanies chronically low seen, with severe constipation and rectal prolapse [27]
weight, in a process analogous to the osteopenia experi- which may require surgical treatment and sometimes colonic
enced by astronauts during periods of weightlessness may resection and a colostomy.
also be important. Nutritionally determined lack of calcium, Acute abdominal pain in a very underweight patient with
vitamin D and protein are also candidates. Weight loss does anorexia nervosa can be caused by pressure of the superior
seem to be the key factor, because restoration of weight mesenteric artery on the duodenum (superior mesenteric
leads to a reliable improvement in bone density [19] artery syndrome, [28]) and requires urgent surgical treat-
although it is not clear that complete bone recovery can ment. Recurrent abdominal pain and colonic symptoms may
occur. be diagnosed as being due to Irritable Bowel Syndrome. The
Treatment with bisphosphonate drugs such as alendronate possibility of an eating disorder should be borne in mind
has been suggested as treatment for osteoporosis associated before this conclusion is reached, although the conditions
with anorexia nervosa. There effectiveness is in doubt [17, can co-exist.
20]. However, they have very long half lives in the body as
they are bound to bone tissue (example half life 10.9 years
for Alendronate) and treatment of a patient who may later Amenorrhoea and Infertility
become pregnant is controversial. One approach would be to
restrict the use of bisphosphonates to patients with anorexia Loss of weight usually leads to amenorrhoea and the associa-
nervosa and severe osteoporosis in men and in women after tion of low BMI and amenorrhoea should signal the possibil-
childbearing age. ity of an eating disorder, usually anorexia nervosa.
Amenorrhoea is also common in patients with binge eating
[29] and many patients with bulimia nervosa are found to
Gastrointestinal Symptoms have polycystic ovaries on ultrasound [30]. The association
is not understood but women with bulimia nervosa in the lat-
Many symptoms of eating disorders involve the gastro- ter study who had recovered showed normal ovarian mor-
intestinal tract. It is therefore not unexpected that gastro- phology suggesting an effect of symptoms on the ovaries.
intestinal disturbances can present to different physicians at Some patients with bulimia nervosa have lost significant
varying levels of acuteness. Self-induced vomiting, which amounts of weight, even though they are within the normal
often accompanies anorexia nervosa and bulimia nervosa as weight range, and this might contribute to amenorrhoea.
well as an atypical eating disorder, purging disorder, which All patients referred for or applying for infertility treat-
is mainly characterised by vomiting as a method of weight ment should be screened for eating disorder symptoms.
control. Enlargement of the parotids occurs in patients who Providing, for example, in-vitro fertilization to a woman
vomit and also in those who binge-eat without vomiting. who is seriously underweight as a result of anorexia nervosa
The parotids are usually non-tender and the occasional his- [31] provides an ethical dilemma, because of the increased
tological examination [21] has shown sialadenosis (non- risk of pregnancy complications [32] and risks to the nutri-
inflammatory enlargement). Sore throat, sometimes with tion of the infant and child [33]. In the view of the authors,
scratches on the pharyngeal mucosa, may accompany self- such patients should receive psychological and nutritional
induced vomiting, and haematemesis due to oesophagitis treatment for their eating disorder before embarking on
related to reflux, or occasionally an oesophageal tear infertility treatment.
Psychiatric Symptoms can affect staff reactions to them. In fact the eating disorders
have a recovery rate of around 50% and that improves as
Eating disorder symptoms such as food restriction, binge patients with shorter illnesses are treated. There is evidence,
eating, vomiting and laxative abuse are of course psychiatric for example in anorexia nervosa, that treatment within
symptoms. However, here we draw attention to the comorbid 3 years of onset can substantially improve prognosis [36].
symptoms such as depression, suicidality and self-harm Treatment of eating disorders follows, in general a bio-
which often accompany eating disorders and which may psychosocial model of care. Bio: The “bio” part of this triad
present to primary and secondary care and to emergency ser- involves assessment of general medical state, of risk to health
vices. The mortality rate for patients with anorexia nervosa is and life and treatment of those medical problems, some of
one of the highest of all psychiatric conditions and a substan- which have been discussed here. This includes resuscitation
tial percentage of those deaths are by suicide [12]. Hence, of a patient in an extreme state of nutritional deficiency or
any patient with an eating disorder should be asked about electrolyte imbalance, managing refeeding safely and moni-
suicidal thoughts and intentions and appropriate referrals toring and treating some of the chronic sequelae of eating
considered if they are present. Moreover, a substantial pro- disorders such as osteoporosis and infertility. Under the
portion of patients with eating disorders [13] present with “bio” heading we also have physical treatments for psycho-
deliberate self harm, which may be part of a borderline per- logical disorder. In eating disorders, treatment of undernutri-
sonality disorder. The combination of an eating disorder and tion can be seen as such an intervention and this includes
a borderline personality disorder requires complex treatment offering and supervising meals and occasionally, if life is at
so that both conditions are taken into account. Drug and risk, imposing nutrition by oral or nasogastric feeding under
alcohol misuse can further complicate the picture and may the Mental Health Act.2 There are many drug treatments in
require attention in their own right. Recognition of these psychiatry and most of them have been tried in eating disor-
interacting problems, which are sometimes the long term ders. Antidepressants which are effective in many patients
sequelae of childhood sexual abuse, in primary and second- with depressive illness seem much less effective when weight
ary medical care, can be very helpful in triggering appropri- is low [37] perhaps because of the neuro-transmitter changes
ate referral and reducing the rate of hospitalization and that may occur at low weight. In bulimia nervosa however,
increasing symptoms that can otherwise occur [34]. antidepressants, such as Fluoxetine 20-60 mg daily, have
been found to have a significant impact on bulimic symp-
toms and are recommended in NICE for eating disorders [1,
Eating Disorders in the Clinic: Summary 38]. They are less effective than psychological treatments
and Concluding Remarks and the patient may relapse when the drug is withdrawn, and
it seems to the present authors that the role of antidepressants
From the above review, which has been far from exhaustive, in bulimia nervosa should probably be restricted to patients
it can be seen that patients with eating disorders can turn up who remain unwell after a course of psychological treatment
in almost any clinic in a health system. Acuteness of presen- such as cognitive behavioural therapy. This approach has
tation varies from the cachectic patient near death carried been tested and found to give better results than treatment
into the emergency department, to the chronically ill patient with either method separately [39]. Neuroleptic drugs such
with SEED (Severe and Enduring Eating Disorder, [35] pre- as Olanzapine [40] have been used in anorexia nervosa on
senting with symptoms due to osteoporosis, laxative abuse or the basis that they cause weight gain in patients with schizo-
social isolation, amongst many others. The task of the non- phrenia. They may have an effect on BMI, fear of weight
psychiatrist is to recognise the eating disorder and to treat the gain and general anxiety in anorexia nervosa but the treat-
medical complications bearing in mind that eating disorder ment remains controversial and large randomised trials are
symptoms often make treatment, especially if it leads to awaited. On an even more experimental basis, brain treat-
improved nutrition, very difficult. There is no doubt that ments such as repetitive transcranial magnetic stimulation
some clinical staff in all areas of work, faced with a patient (rTMS) [41] and deep brain stimulation (DBS) [42] have
who is obviously in need of treatment, but who is doing her both been tested in trials with some encouraging but not con-
best to avoid and sabotage that treatment, may lose sympathy clusive results in patients with severe intractable anorexia
for the patient, and that can affect the patient’s care. Our nervosa.
advice is to try and view the patients as in the grip of a pro- The main treatments in eating disorders are psychologi-
cess that they cannot control, which leads to these sabotaging cal. These include assessment of motivation to change using
behaviour, and to avoid blaming the patient. In addition to the methods developed in the treatment of alcohol misuse
the belief that the patient is to blame for the symptoms
“doing it to herself”, there is also a widespread belief that 2 https://www.gov.uk/government/publications/code-of-practice-
there is not very much hope for these patients and this also mental-health-act-1983.
Table 1 The 6 phases of motivation ing disorders and treatment of those problems has been
Level of included in CBT-BN. CBT has been extended (CBT-E) to
motivation Description Typical statement include other eating disorders such as anorexia nervosa [44]
Pre- Denial There’s nothing wrong and trials are awaited. Other therapies have been used which
contemplation with me. It’s everyone
primarily address emotional and relational problems
else’s problem. They need
to change (Interpersonal therapy [45] and mentalization based therapy
Contemplation Acceptance there I think my eating is [46]) and one approach, Cognitive Remediation Therapy,
might be a problem, problematic, and maybe [47] has been introduced which addresses the detail focus
but not acting to my weight, but I can and cognitive rigidity that particularly occurs in low weight
change it handle it and don’t need to
change it just yet. patients.
Preparation Preparing to take This problem is affecting Social: This is a big area and includes family based ther-
action to address the my life seriously. I’m apy, sometimes provided in multiple family groups which is
problem planning to get help to particularly indicated for younger patients with anorexia suf-
address it
fering from a relatively short (<3 years) illness [48], support
Action Acting to alleviate the I’m now in treatment and
problem am struggling to deal with and education for carers and families of patients with eating
the problem disorders [49], and attention to the major social and occupa-
Maintenance Taking steps to reduce I’m a lot better and need to tional problems encountered by patients with eating disor-
the risk of relapse remain alert to the der, especially after several years of illness [50].
possibility of relapse
Should the health worker, whether doctor, dietitian, nurse
Relapse Re-establishing My symptoms came back
management control during a and I’m putting a lot of or psychologist, be a generalist or a specialist? As in most
relapse effort into getting them areas of health, the more you know about a subject the better
under control again the likely deal is for the patient. Thus, initial treatment of a
diagnosed eating disorder should, we believe, be from a spe-
cialist in the field, or a generalist who is working closely
[43]. This essentially involves interviewing the patient in a with a specialist, for example as supervisor or collaborator.
way that elicits his or her attitude to the illness, its negative This may be in a specialist outpatient, day patient or inpa-
(and positive) aspects, and the pros and cons of change. The tient setting. When non-specialists are involved because of
patient may be asked to write a letter to “My eating disorder specific circumstances, as in the case of the patient admitted
as my friend” and “My eating disorder as my enemy” in via the emergency department to a medical bed, we recom-
order the make explicit the ambivalence about change that is mend that the medical team involves the eating disorder spe-
often present in patients with eating disorders, in preparation cialist or liaison psychiatrist as soon as feasible, and that care
for a discussion with the patient about change, including how is shared with frequent joint review and consultation, as rec-
much change and at what rate. The different levels of motiva- ommended in MEED. In non-emergency cases, as long as
tion are illustrated in Table 1. the patient has been assessed and treated by a specialist team,
The motivational sequence, which can also be seen as a follow up can reasonably come from primary care or another
cycle, can be applied to any problem in which behaviour can non-specialist health worker. It is in the early cases (less than
affect health adversely including weight loss in obesity, dia- 3–5 years from onset) that we have evidence that specialist
betic control, dietary approaches to hypertension and renal care can make the greatest difference to prognosis. After that
disease, as well as misuse substances such as alcohol and the evidence is not so strong. It should also be emphasised
other drugs. In eating disorders treatment, elements of moti- that however long the history, complete recovery, although
vational enhancement can be found in many approaches and less likely, is never impossible and all of us in the field have
rather than a stand-alone therapy it is probably better seen as seen patients recover completely after 20 or 25 years of con-
an important component of treatment. The main p sychological tinuous illness, sometimes for reasons that we cannot fathom.
treatment that has been found to be effective in controlled
trials in eating disorders is cognitive behaviour therapy for
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Intestinal Failure in Children:
A Paediatric Surgical Perspective
Alexander L. Macdonald, Hannah Thompson,

and Mark Davenport
Key Points Definition

1. ‘Surgical’ short bowel whether congenital or acquired, is
the commonest cause of intestinal failure in infancy and Normal small bowel length in term infants (derived from
childhood autopsy and multi-visceral transplant donor studies and mea-
2. Remaining intestinal length is more meaningful when sured un-stretched at the anti-mesenteric border) is typically
expressed as a percentage of the normal expected intesti- considered to be 300 cm with potential to reach 600 cm by
nal length for the infant’s age/weight adulthood [1, 2]. Traditionally the actual length of the
3. Initial surgical management should adhere to the princi- remaining bowel has been used for prognosis though agree-
ples of preservation of enteral mass and continuity by dis- ment and consensus on what constituted “short” was seldom
tal refeeding and avoidance/early closure of stomas achieved. A more recent trend has been to express the
4. Autologous intestinal reconstruction (AIR) has potential remaining functioning intestinal length in terms of a percent-
to deliver enteral autonomy. age of the expected normal length for an infant of that age or
5. Longitudinal Intestinal Lengthening and Tailoring (LILT) weight. This distinction is particularly important in pre-term
and Serial Transverse EnteroPlasty (STEP) represent the infants as in this population bowel lengths will more than
mainstay of contemporary AIR and combine increasing double in late gestation from normal physiological growth
length and improving propulsive proficiency in a single alone (e.g. ‘normal’ length between 19–28 weeks gestation
procedure is observed to be 142 ± 22 cm increasing to 304 ± 44 cm by
35 weeks [1]). This makes the finding of 20 cm of remaining
small intestine in a 27-week premature infant perhaps less
Introduction concerning than the same finding in a term infant as it still
has considerable functional reserve. So where to draw the
Intestinal failure in neonates and infants primarily results line? Recent work has suggested that infants with <10% of
from insufficient intestinal mass—i.e. a ‘short bowel’ which the expected length have demonstrably poorer outcomes [3]
is insufficient to maintain adequate nutrition to support nor- and certainly those with less than 40 cm remaining are likely
mal physiology and growth. Consequent long-term depen- to require long-term PN as well as adjuvant medical and sur-
dency upon parenteral nutrition (PN) may result in significant gical strategies to promote enteral autonomy.
morbidity and mortality from intestinal failure associated
liver disease (IFALD); catheter related bloodstream infec-
tions (CRBSI); and metabolic and renal disease. Early adop- Aetiology of Short Bowel
tion of synergistic medical and surgical strategies to augment
the natural physiological process of adaption and maximise Figure 1 illustrates the leading causes of surgical short bowel
the potential for enteral autonomy are critical to long-term in the paediatric age-group. There are two equally prevalent
survival in this population. causes in infancy with completely different characteristics:
necrotising enterocolitis (NEC) and gastroschisis. The for-
mer is almost invariably found in the preterm infant—par-
ticularly those <30 weeks gestation—with multiple other
co-morbidities (e.g. cerebral haemorrhage), whilst the latter
A. L. Macdonald · H. Thompson · M. Davenport (*)
are usually isolated anomalies in otherwise normal term
Department of Paediatric Surgery, King’s College Hospital,
London, UK infants. The usual reason for intestinal loss in gastroschisis is

208 A. L. Macdonald et al.
12%
28%
32%
Gastroschisis (n = 154) NEC (n = 132)
Intestinal Atresia (n = 58) Miscellaneous (n = 56)
IBD (n = 22) trauma (n = 3)
volvulus (n = 29)
Fig. 1 Aetiology of short bowel syndrome (n = 477). Data are taken from the British Intestinal Failure Survey (BIFS) (2005–2013)—and defined
by need for parenteral nutrition beyond 28 days. Abbreviations: NEC necrotising enterocolitis; IBD inflammatory bowel disease
remaining proximal bowel [5]. While the limited enterocyte

mass is clearly important in short bowel sometimes dys-
motility may also lead to major difficulties in achieving
enteral autonomy. The residual bowel in gastroschisis and
intestinal atresia seem particularly affected by this functional
deficit.
Initial Medical Management
Initial surgical intervention should seek to minimise disrup-

tion to physiological intestinal adaptation and further surgi-
cal intervention is indicated when medically augmented
adaptation fails to achieve enteral autonomy. It is thus impor-
tant to understand both the physiology of adaptation and to
appreciate what constitutes optimal medical augmentation.
Fig. 2 Closed Gastroschisis. Necrotic midgut and typically the only Adaptation is the physiological process by which the
viable residual bowel is an intraabdominal consisting of a short length remaining intestine increases its absorptive capacity follow-
of jejunal atresia and a corresponding segment of colon distal to the exit
colon atresia. (Reprinted with permission from [4]) ing resection. The capacity for adaptation is dependent upon
the type of bowel remaining. Loss of ileum represents the
more significant insult as ileum has the greatest potential for
due to in-utero closure of the defect with resultant ischaemic compensation. Ileum is essential for the secretion of chole-
compromise of the entire extra-abdominal midgut (known as cystokinin and secretin as well as the resorption of bile acids.
a ‘closed’ or ‘closing’ gastroschisis [4]) (Fig. 2). The third Resection of ileum thus leads to increased gastric acid secre-
most common cause of short bowel is due to a congenital tion (as a consequence of loss of hormonal secretion) and
intestinal atresia—typically jejunal atresia—which is associ- osmotic diarrhoea (as a consequence of bile salts entering the
ated with distal intestinal loss and gross dilatation of the colon) [6].
Intestinal Failure in Children: A Paediatric Surgical Perspective 209
In promoting maximal potential for adaptation medical Delivering Safe Parental Nutrition
management seeks to; augment the physiology of adapta-
tion; deliver safe parenteral nutrition; and minimise the com- Delivery of parenteral nutrition must be both safe—minimis-
plications of short bowel. ing PN associated complications—and sustainable through
preservation of venous access routes.
Enhancing the Physiology of Adaptation Liver Disease

Long-term use of TPN in infants can result in a subtype of
Intestinal adaptation is stimulated by enteral nutrients and cholestatic liver disease latterly termed Intestinal Failure
consequently a mainstay of promoting adaptation is the early Associated Liver Disease (IFALD). This in itself is probably
introduction of enteral feeding regardless of the remaining the single most important reason for mortality in the paediat-
intestinal length. Breast milk contains gastrointestinal hor- ric age-group and causes cholestasis and steatosis leading to
mones, immunogenic factors and amino acids, however it macrophage activation, liver fibrosis and ultimately liver
has a high lactose content the absorption of which may be failure. IFALD is related to the duration of PN with a fivefold
hindered by the reduced surface area and enzyme activity increase observed per week of PN administration [11] and
that is inherit with short bowel. An extensively hydrolysed the ‘immaturity’ of the liver when the PN starts. Sepsis may
formula with a higher proportion of glucose polymers is thus also have a profound detrimental effect on worsening
an acceptable alternative. Bolus feeding is often poorly toler- IFALD. The key preventative strategy is to establish enteral
ated in short bowel and continuous feeding has the advan- autonomy but it may also be minimised using ‘hepatoprotec-
tages of increased transit time, increased absorption and a tive’ PN formulations and specifically lipid emulsions
lower risk of osmotic diarrhoea. The increased rate of oral derived from fish-oil (Omegaven®) or a mixture of fish oil,
aversion in tube-fed infants should be recognised and proac- olive oil and soybean (Smoflipid®) that are less inflammatory
tive strategies (such as “tasters” and trophic oral feeds) and cholestatic [12–14].
should be employed to minimise the long-term impact.
Adaptation may be pharmacologically stimulated by atheter Related Bloodstream Infections
C
administration of exogenous trophic hormones. Human (CRBSIs)
growth hormone (hGH) combined with the amino acid glu- PN is delivered via a single lumen cuffed tunnelled venous
tamine has been show to enhance adaptation and absorption catheter of an appropriate size for the infant (suitable cathe-
improving both weight gain and lean body mass. However ters are available in sizes of 2.7Fr upwards). Nowadays, lines
in the majority of published trials the effects are short-lived should probably be inserted using percutaneous image-
with a return to baseline shortly after cessation of therapy. guided techniques as this is associated with lower rates of
At present there is insufficient evidence to support routine infection and critically—in infants that may have limited
use of hGH and glutamine regimens in children with short viable access routes—allows for considerably more uses of a
bowel [7]. given vessel [15, 16].
The proteinogenic amnio acid glucagon-like peptide-2 Short bowel patients are particularly susceptible to sepsis
(GLP-2) analogue teduglutide acts to promote growth of with rates as high as 68% [17]. Multiple factors contribute to
intestinal mucosa and has regulatory approval for use in chil- this including; reliance on central venous catheters; concur-
dren >1 year. In open-label trials, teduglutide (0.025 or rent presence of stomas; a more permeable GI epithelial bar-
0.05 mg/kg/d) was associated with trends toward reduction rier with consequent bacterial translocation [18] and a
in PN requirements with the higher dose resulting in a 52% general paucity of physiological reserve. CRBSIs result in
reduction in PN calorie requirement [8]. Reported disadvan- sepsis, thrombosis and loss of vascular access routes. The
tages include: its high cost (£260 per 1.25 mg vial—price risk of CRBSIs is increased by frequent access to the cathe-
valid in 2017); reversal of effect on discontinuation of treat- ter for administration of IV fluids or blood sampling and
ment; and concerns regarding malignancy with long-term poor aseptic technique when inserting, changing and access-
use in children [3]. ing catheters.
Short chain fatty acids (SCFAs) are the breakdown prod- A systematic focus on aseptic techniques enshrined in so-
ucts of carbohydrates and are mediators of GLP-2 release. called ‘enhanced catheter care bundles’ minimises the inci-
SCFAs can enhance absorption by up-regulating the glucose dence of CRBSIs. Comprehensive bundles comprise; the use
transporter proteins GLUT2 and SGLT-1 [9] and the addition of chlorhexidine-impregnated patches at exit sites; daily
of SCFAs to PN has been demonstrated—in animal mod- bathing; ethanol line locks; two nurses for catheter care in a
els—to both prevent TPN-associated mucosal atrophy and distraction-free environment; peripheral phlebotomy; the
enhance intestinal adaptation [10]. bundling of routine blood tests; and changing PN administra-
tion sets every 24 h. Successful implementation can lead to duction in up to half of infants with short bowel. Hyperacidity
dramatic (85%) reductions in CRBSI rates [19] and inci- may result in: peptic injury to the stomach and small bowel;
dences as low as 0.42 CRBSIs per 1000 catheter days are systemic acid-base imbalance; and inactivation of pancreatic
achievable [20]. enzymes with consequent malabsorption [28]. Acid suppres-
sion with agents such as the proton pump inhibitor, omepra-
zole, may mitigate these sequelae.
Managing the Complications of Short Bowel
isruption to Enterohepatic Circulation of Bile

D Surgical Management
Acids
Loss of ileum disrupts the enterohepatic circulation of bile The surgeon has a critical role to play both at the time of the
acids [21]. These unabsorbed bile acids irritate colonic initial finding of short bowel in an infant (the initial laparot-
mucosa resulting in a secretory diarrhea. Bile acids may be omy) and in the weeks to follow.
bound by cholestyramine and exogenous administration of The principles of initial surgical management (Box 1)
the bile acid ursodeoxycholic acid (UCDA) may be utilised comprise:
to improve the enterohepatic circulation by exchanging
hydrophobic for hydrophilic bile acids improving bile flow 1.
Comprehensive documentation of the findings at
and reducing cholestasis [22, 23]. laparotomy
In PN dependent infants with evidence of significant cho- 2. Preservation of intestinal mass
lestasis UCDA has been demonstrated to shorten the dura- 3. Facilitation of post-operative refeeding
tion of cholestasis and reduce peak bilirubin levels with 4. Early establishment of intestinal continuity
effects seen within 1–2 weeks. However discontinuation of 5. Autologous intestinal reconstruction (AIR)
UCDA results in relapse [24].
Bacterial Overgrowth
Box 1 Initial Principles in the Surgical Management of
Stasis resulting from dilatation and sumping produces an
Short Bowel
environment for bacterial overgrowth which is measurably
present in up to 60% of surgical short bowel patients [25]. Initial surgical principles
This can lead to; bacterial consumption of enteral nutrients • Document length, quality and type of remaining bowel
and vitamins; de-conjugation of bile acids; accumulation of • Preserve continuity and intestinal mass where possible
• Undertake distal refeeding and early closure of stomas
toxic metabolites (such as D-lactate); bacterial translocation
• Facilitate the creation of proximal dilatation when future
and subsequent septicaemia. Clinically overgrowth is mani- AIR is thought to be likely necessary
fest as abdominal pain, anorexia, vomiting, diarrhea, cramps,
and a metabolic acidosis from the accumulation of D-lactic
acid which can lead to the significant complication of
D-lactate encephalopathy. D-lactic acidosis may be avoided The Initial Laparotomy
by judicious management of carbohydrate intake and enteral
antibiotics. However overzealous management of symptoms The length, type and quality of remaining bowel should be
with antibiotics can contribute to further overgrowth and clearly recorded. Where viability is in question, a second
appropriate stewardship through antibiotic-free period and look laparotomy at 24–48 h should be planned to minimise
cycling of agents is important. An alternative strategy is pro- the requirement for resection. The length of bowel and the
biotic therapy with non-D-lactate producing bacteria [26]. degree of dilatation present is key to both prognosis and the
planning of future surgical interventions and so must be
Rapid Intestinal Transit accurately measured and documented. It is also important to
Where transit is rapid the judicious use of agents such as note the presence or absence of the ileocaecal valve (ICV) as
loperamide to reduce peristalsis can delay transit times and its loss has been identified by some authors as an indepen-
increase absorptive potential by increasing the duration of dent risk factor for requirement for future AIR. However it
exposure of nutrients to the available mucosal surface area simply may indicate loss of a significant part of the colon in
[27]. the pathology and the true significance remains controversial
[29, 30].
Hyperacidity At initial laparotomy the advantages and disadvantages of
Increased gastrin levels due to loss of the gastrin-metabolising the creation of defunctioning stomas as against preservation
function of the bowel results in increased gastric acid proof enteral continuity must be carefully weighed. Anastomosis
and preservation of continuity increases the potential for

early enteral adaptation by maximising the absorptive sur-
face available and prolonging transit times [31]. Preservation
of intestinal continuity should thus be aimed for as the pri-
mary surgical strategy. This is particularly important in
infants with >40 cm of small bowel and an intact ICV as this
particular group is likely to achieve enteral autonomy by
adaption alone [32]. However in those with shorter remain-
ing bowel lengths early continuity is likely to result in high
stool output and significant perianal excoriation [3]. If a
stoma is chosen then it is important to bring out the distal
bowel as a mucous fistula in order to gain the post-operative
possibility of content re-feeding.
Necrotising Enterocolitis
In the context of neonatal acquired short bowel, necrotising
enterocolitis (NEC) represents a unique surgical scenario.
Unlike congenital short bowel (e.g. intestinal atresias) the
remaining bowel isn’t prone to significant dilatation and dys-
motility [33]. Consequently outcomes are potentially rela-
tively favourable but only if measures are taken to preserve
intestinal mass from the outset. To this end when faced with
the neonate with extensive and/or multifocal disease at the
initial laparotomy the surgeon should consider either form-
ing a high de-functioning jejunostomy (up to 10 cm from the
duodenal-jejunal flexure) or undertaking a ‘clip and drop-
back’ procedure [34, 35]. With the clip and drop-back tech-
Fig. 3 Refeeding. Luminal content is aspirated and then slowly rein-
nique any clearly necrotic bowel is excised but segments that fused using a soft catheter into the distal mucus fistula
are of questionable viability are initially retained by over-
sewing their ends/sealing them with LIGACLIP®s and drop-
ping them back into the abdomen. With both approaches the be performed with a water-soluble contrast agent prior to
diseased bowel is initially left in situ and whilst this may commencement of refeeding.
place a significant septic burden on the neonate it allows for
the possibility of the recovery of a meaningful proportion of
the intestine. In the clip and drop-back technique the abdo- Autologous Intestinal Reconstruction
men is re-entered within 48–72 h, whereas when a high jeju-
nostomy has been created re-laparotomy is typically Following the initial laparotomy a significant proportion of
postponed for 4–6 weeks. infants will undergo successful enteral adaptation and
achieve enteral autonomy without the need for further inter-
vention. However for those infants who fail to achieve enteral
Refeeding autonomy despite optimal medical strategies to promote
adaptation further surgical intervention in the form of autolo-
Where stomas have been created at the initial laparotomy gous intestinal reconstruction (AIR) should be considered.
distal refeeding should be instituted as early as possible
(Fig. 3). Refeeding is undertaken by regularly recycling the
proximal effluent into the distal stoma under gravity via a Aims of AIR
soft catheter (e.g. a Jacques catheter) [32]. In addition to
‘priming’ the distal bowel prior to closure of the stomas, Intestinal dilatation which occurs as part of intestinal adapta-
refeeding provides an additional source of calories through tion leads to stasis and secondary dysmotility resulting in
the colonic absorption of short chain fatty acids [3]. In situa- bacterial overgrowth, increased risk of translocation and
tions where either the viability of the distal bowel is ques- consequently sepsis. Indeed the presence of dilatation has
tionable or the development of a distal stricture is considered been identified as an independent risk factor for prolonged
possible (e.g. in NEC) a distal contrast ‘loopogram’ should PN requirement and decreased survival [33]. While AIR can-
not increase absolute enterocyte mass it can increase avail- Timing of AIR
able bowel length and reduce the luminal dimeter. This
results in an increase in transit times and perhaps an increase Intestinal adaptation typically starts within 48 h of the origi-
in mucosal surface area exposed to luminal contents nal insult/bowel resection and whilst it occurs most rapidly
facilitating absorption. The bowel length achieved post-AIR in the first year it is a continuous process that can take up to
has been shown to correlate significantly with the percentage two years to complete [38, 39]. As a general principle AIR
requirement for PN in the first post-operative year [36]. The should be undertaken at the point where the child has shown
reduction in the luminal diameter improves the efficacy of a plateaux in their capacity to tolerate advancement of enteral
peristalsis reducing stasis and the associated bacterial over- nutrition. However, clearly there is a balance to be struck
growth that results in complications of translocation, sepsis between postponing AIR for a sufficient enough period of
and malabsorption. time as to allow medically augmented adaptation to occur
AIR should thus be considered in the setting of any infant and minimising the time for which the child is dependent on
who fails to achieve EA despite optimal medical manage- PN (and exposed to its associated complications). AIR has
ment necessitating prolonged continuation of PN or in those been reported to have been undertaken as early as the first
infants thought unlikely to ever achieve EA by adaptation day of life [40] and as late as 15 years [41] but generally
and conservative means alone. Additionally AIR should be techniques such as the LILT and STEP are undertaken in
considered in the presence of intestinal dilatation of a degree infancy at around 2–3 years of age. However some would
that is likely to be resulting in stasis/dysmotility (Box 2). now advocate that when the future need for AIR is consid-
ered inevitable then earlier intervention should be under-
taken—e.g. within the first year of life—to take advantage of
Box 2 Indications for and Contraindications to AIR in
the normal rapid growth and development that occurs in this
Children
period [42]. In predicting the eventual need for AIR the
Indications for AIR underlying aetiology of the infants short bowel should be
• Failure to achieve enteral autonomy taken into consideration. Certain pathologies like small
• Intestinal dilatation bowel atresia have been reported as being a 13-fold more
Relative contraindications to AIR likely to require AIR whereas others like NEC are eightfold
• Significant IFALD
– portal hypertension
less likely to require AIR [33].
– thrombocytopaenia and coagulopathy
– cirrhosis
• Ultrashort bowel length (<10 cm) AIR Procedures
– probably futile
A variety of procedures fall under the umbrella term autolo-

gous intestinal reconstruction. These include: intestinal
AIR is however contraindicated in certain scenarios and tapering; segmental reversal of the small bowel (SRSB);
particularly in the presence of significant IFALD manifest as colonic interposition; the Iowa procedure; the longitudinal
high-grade fibrosis and/or the presence of portal hyperten- intestinal lengthening technique (LILT); serial transverse
sion). In this context consideration should be given to liver or Enteroplasty (STEP) and spiral intestinal lengthening and
combined liver and small bowel transplantation the specifics tailoring (SILT).
of which are out-with the scope of this chapter. AIR may still Intestinal tapering [43] is relatively straightforward way
have a role in this population as a bridge to transplant for of correcting a dilated segment and facilitating anastomosis.
those infants too young/small to receive organs. Typically As it means discarding at least some mucosa it tends to be
the youngest recipient would be older than 2 years of age. reserved for situations where bowel length is not critical.
Intestinal dilatation is the sine qua non of autologous Imbrication may achieve the same effect but needs to be
reconstruction. Typically dilatation of a segment/segments done with non-absorbable sutures otherwise it tends to come
of bowel greater than 4 cm or more than twice the normal apart with time.
luminal diameter for age are quoted as necessary to under- Segmental Reversal of the Small Bowel (SRSB) [31]
take successful AIR [37]. refers to a procedure in which a segment (typically 3 cm) of
One has to be realistic about the prospects of significant small bowel is interposed distally in an antiperistaltic orien-
benefit in infants with ultra-short bowel. Clearly in a sce- tation. This acts to slow transit time, prolonging contact time
nario where the remaining intestinal length is 10 cm or less, with nutrients and increasing absorptive potential. This
then even achieving a doubling of this length following suc- procedure may also be used as a means to produce the proxi-
cessful AIR is unlikely to afford a significant nutritional mal dilation necessary for other AIR procedures. A segment
benefit. of colon may also be interposed in in an antiperistaltic orien-
tation to achieve a similar effect without the need to resect piral Intestinal Lengthening and Tailoring
S
small bowel. Alternatively, the colon may be interposed in an Spiral intestinal lengthening and tailoring (SILT) was
isoperistaltic orientation and the colon’s generally slower described by Cserni in Debrecen first on a synthetic bowel
motility and greater capacity to absorb fluid and electrolytes simulator in 2011 [50] and then in 2014 on a 3 year old girl
is relied upon to improve enteral tolerance [44]. with 15 cm of jejunum following a midgut volvulus [51], this
The Iowa procedure was described by Ken Kimura in represents the most recent of the reported AIR techniques in
1992 [45] and is a two-stage procedure whereby a dilated children (Fig. 7). Continuous spiral lines are marked between
loop is split longitudinally and the antimesenteric segment is the mesenteric and antimesenteric border of the bowel at
attached to an autologous host organ (e.g. liver) allowing for 45–60° to the longitudinal axis of a loop. These lines are
the generation of a collateral blood supply. At a subsequent incised and the bowel is stretched over a catheter and the
laparotomy this bowel is reincorporated in an isoperistaltic edges sutured in a continuous fashion to produce a tube of
manner as a ‘new’ loop. There is very little evidence of its longer length but narrower diameter. Its proposed advantages
practical use. are that it involves minimal handling of the mesentery and—
Aside from tapering, most of these procedures have failed unlike STEP—does not disrupt the orientation of the bowel’s
to find a role and are now predominately only of historical muscle fibres. To date the reported experience of this tech-
interest. At present this leaves the LILT and STEP proce- nique is limited to case reports and small case series [52].
dures as the mainstay of contemporary AIR surgery in chil-
dren, together with the newly introduced technique of SILT.
Outcomes of AIR and Choice of Technique
ongitudinal Intestinal Lengthening Technique
L
The principle of the longitudinal intestinal lengthening tech- LILT and STEP represent the mainstay of AIR in children.
nique (LILT) was first proposed by the Maltese paediatric Both techniques are attractive as they are single stage proce-
surgeon Adrian Bianchi while working in Manchester, UK in dures that result in both a lengthening of the intestine and a
the 1980s [46]; initially using an experimental animal model reduction in calibre without requiring sacrifice of intestinal
of short bowel and then first undertaken that same year on a mass. Meaningful comparison of the outcomes of these two
4 year old with 40 cm of small bowel, PN dependence and procedures (Table 1) is hindered by small numbers; heterog-
limited venous access [47]. The child achieved EA within enous patient populations and a paucity of comparable long-
10 weeks and the procedure has gone on to gain widespread term follow-up data (owing in part to the more recent
acceptance. LILT takes advantage of the anatomical observa- inception of STEP in 2003 vs 1980 for the LILT). Thus any
tion that the small intestinal blood supply separates within direct comparison should be interpreted with caution.
the mesentery to one side or the other someway short of the However published outcome data to date would suggest that
actual bowel wall. This allows the bowel to be divided along whilst LILT would appear to result in a greater proportion of
its axis and at 1800 anti-mesenterically with complete vascu- infants successfully weaning from PN it is associated with a
lar preservation (Fig. 4a). The two intestinal “halves” are higher transplant rate [37]. This seemingly conflicting data is
then tubularised and isoperistaltic continuity restored likely in part a consequence of the availability of longer-term
(Figs. 4b–d, and 5a, b). follow-up data for the LILT.
LILT is a technically more challenging undertaking but
Serial Transverse EnteroPlasty certainly not beyond the reach of most neonatal surgeons.
The serial transverse enteroplasty (STEP) procedure was first STEP however is relatively straightforward if one can get
described by Kim et al. in Boston, USA in 2003 (initially on a one’s hands on a linear stapler (preferably an EndoGIA™) and
porcine model and then on a 2 year old boy) [48]. Owing is perhaps more versatile and may be applied to any length of
largely to its ease of application it has gone on to achieve dilated bowel including the duodenum [53]. Intestinal re-dila-
widespread adoption and to date numerous centres participate tation occurs following STEP at a greater rate than is reported
in an international registry. Firstly small mesenteric “windows following LILT [37], however unlike the LILT (which cannot
“are created, then a GIA stapler is fired part way across the be repeated on the same segment of bowel as the mesentery
bowel diameter. This is repeated at equal intervals and from has already been split) STEP may be repeated as a ReSTEP
alternate sides (Fig. 6a) to create a zig-zag channel of about procedure [49]. Complications arising from STEP include
1–2 cm diameter (Fig. 6b). The STEP can be undertaken as a bleeding from staple-line ulcers (which can be life-threatening
primary procedure or applied to a segment of bowel previ- [54]), perforation and fistula formation.
ously lengthened by the LILT. Additionally STEP may be Ultimately the choice of the most appropriate AIR proce-
reapplied to bowel previously lengthened by STEP which has dure ought to be a combination of the surgeon’s experience/
re-dilated in what is termed the ReSTEP procedure [49]. familiarity with a particular procedure and the infants age
a b
c d
Fig. 4 Longitudinal intestinal lengthening technique (LILT). (a) The tubularised with each relying on half of the original mesenteric blood
bowel is divided antimestenterically along its axis at 180° (red dashed supply. (c, d) Continuity is restored by anastomosing (green and purple
lines) splitting the mesentery. (b) The two intestinal ‘halves’ are then lines) and reincorporating the ‘new’ loop in an isoperistaltic manner
a b
Fig. 5 LILT—operative picture after division of dilated jejunum. (a) Case of closed gastroschisis with grossly dilated jejunal atresia and an initial
measured length of 20 cm. (b) Post-division of jejunum showing two independently vascularised intestinal strips prior to re-tubularisation
a b
Fig. 6 Serial Transverse Enteroplasty (STEP). (a) Small mesenteric at equal intervals and from alternate sides to create a zig-zag channel of
‘windows’ are created so that a GIA stapler may be fired part way about 1–2 cm diameter
across the bowel diameter (dashed lines). (b) GIA firings are repeated
a b
c d
Fig. 7 Spiral Intestinal Longitudinal Intestinal and Tailoring (SILT): (b) After spiral incision. (c) End result of SILT.(d) Lengthened segment
experimental model in minipigs. (a) Incision line marked on the dilated 5 weeks postoperatively is viable, with normal calibre and remains
segment (dotted line: incision on the posterior wall). The scale is 15 cm. long. (Reprinted with permission from [50])
Table 1 Comparison of the Longitudinal Intestinal Lengthening (>5 cm) dilatation is achieved a STEP is performed and
Technique (LILT) and Serial Transverse Enteroplasty (STEP)
intestinal continuity is restored [56].
LILT STEP
First reported 1980 2003
Rate of 70% (4–100%) at a 58.1% (20–100%) at a
successful PN mean of 10.3 months mean of 9.4 months
Summary
weaning (5–21 months) (6–16 months)
Learning curve Technically challenging Undertaken with GIA Short bowel syndrome is the commonest cause of intestinal
requiring dissection of stapler without failure in infants and arises either as a result of congenital
mesentery and long disturbing mesenteric
malformations such as small bowel atresia and gastroschisis
hand-sewn anastomoses vessels
Limitations Minimum of >20 cm of Can be applied to any or is acquired as a consequence of intestinal loss following
dilated bowel required dilated bowel (including acute pathology such as NEC or malrotation volvulus [57].
Cannot be reapplied duodenum) though In the management of short bowel in childhood the paedi-
arguably of limited use atric surgeon is a key member of the MDT from the outset.
Can be reapplied as
ReSTEP Adopting a considered and structured approach to the initial
Complications Re-dilatation, leak, Re-dilatation, leak, surgical management of these infants can minimise the loss
stricture and necrosis stricture and bleeding of intestinal mass, maximise the potential for enteral absorp-
Reported 30%a 14% tion and aid the creation of anatomy upon which future AIR
mortality is then feasible. When adequate adaption cannot be achieved
Reference: Frongia G, Kessler M, Weih S, Nickkholgh A, Mehrabi A, by conservative means alone then the timely undertaking of
Holland-Cunz S (2013) Comparison of LILT and STEP procedures in
children with short bowel syndrome—A systematic review of the litera-
AIR may deliver enteral autonomy or at least reduce the bur-
ture. J Pediatr Surg 48:1794–1805 den of PN.
a
The reported series of LILT are much older and reflect the limited
options available for end-stage liver disease in previous eras
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Part III
Chronic (Long-Term) Intestinal Failure
Physiology and Problems of a Short
Bowel
Key Points twentieth century, a resection of more than 200 cm of small

1. A short bowel occurs when there is an insufficient length intestine, thought to be a third of the total small intestinal
of small intestine to absorb enough nutrition/fluid to length, was referred to as an ‘extensive’ intestinal resection and
maintain health/growth. was thought to be the maximum length of small intestine that
2. Due to large range of “normal” small intestinal length, it could be removed and for the patient to survive [2]. In 1935,
is important to refer to the remaining length of small Haymond used the term ‘massive’ in preference to ‘extensive’
bowel rather than the length resected. intestinal resection when he reviewed the literature of 257
3. There are two common types of patient with a short patients, most of whom had had a resection for an intestinal
bowel. Those with jejunum anastomosed to colon volvulus (Table 1); he noted an overall survival of 67% [3].
(jejunum-colon or type 2) and patients with an end jeju- In the 1960s, as an awareness developed that the outcome
nostomy (type 1). A third less common group have had a from an intestinal resection depended upon the length of
predominantly jejunal resection [jejunum–ileum. (Type small bowel remaining rather than the length resected, so the
3)], and have more than 10 cm of terminal ileum remain- term ‘short bowel syndrome’ came into use. The syndrome
ing, their problems are similar to the jejunum-colon was characterized by ‘intractable diarrhoea with impaired
patients. absorption of fats, vitamins, and other nutrients, ultimately
4. Patients with a jejunostomy have high stomal losses of leading to malnutrition, anaemia, and continued weight loss’
water and sodium and often have hypomagnesaemia. [4]. This description implies a slow chronic illness and is
Fluid balance dominates their management. adequate to describe most patients who have a short bowel
5. Patients with a jejuno-colic anastomosis do not generally and retained functioning colon; it does not describe the acute
have fluid balance problems and the colon salvages fluid balance problems experienced by patients with a jeju-
energy from colonic fermentation. However they have a nostomy (end-jejunostomy syndrome). The first report of a
high prevalence of calcium oxalate renal stones. patient surviving with a jejunostomy, 120 cm from the
6. All patient types have a high prevalence of calcium bili- duodeno-jejunal flexure, was in 1963 [5].
rubinate gallstones. Early work was on physiology first in animals after a
7. The absorption in patients with a preserved functioning large predominantly jejunal resection then work in man was
colon improves with time; this does not occur in patients initially in those with a jejunocolic anastomosis. Later work
with a jejunostomy. was with patients with a jejunostomy and a high output
Background Table 1 Reasons for a ‘massive’ intestinal resection in adults as pub-

lished in 1935 [3]
In 1880, Koberle performed the first reported successful small n = 257

Volvulus 76
intestinal resection of more than 200 cm on a 22-year-old girl
Strangulated hernia 45
with multiple intestinal strictures [1]. At the beginning of the Mesenteric thrombosis 34
Tuberculosis 16
Mesenteric tumours 14
J. M.D. Nightingale (*) Uterine perforation 11
Honorary Consultant Gastroenterologist St Mark’s Hospital, Adhesions/bands 7
Harrow, Middlesex, UK Other 54

stoma. The studies to understand the physiological changes raphy [11] or magnetic resonance scans [12]) can be mea-
in the 1990s were about motility and gastrointestinal hor- sured in short segments and give an a moderately accurate
mones. Research since the millennium has concentrated on estimate of the remaining small bowel length. This is easier
peptide growth factors, new hormones and the microbiome. to estimate if the total small bowel length is less than
200–300 cm.
Length of Small Intestine

Functional Length
The length of the adult intestine, measured surgically, radio-
logically or at autopsy from the duodeno-jejunal flexure, Citrulline is a non-essential amino acid that is almost exclu-
ranges from about 275 to 1510 cm and tends to be shorter in sively synthesized in the enterocyte by pyrolline-5-carboxy-
women than in men (chapter “Normal Intestinal Anatomy lase-synthase from glutamine. It is not derived from food or
and Physiology”). Congenital cases of a short bowel have proteolysis and is not incorporated into body proteins. Some
been reported and are usually associated with malrotation of of the citrulline made by the enterocyte passes to the liver,
the gut [6, 7]. Patients who have a small intestinal length at where it is an important intermediate in the urea cycle (urea
or below the lower end of the normal range may develop the made from ammonia) and some passes into the systemic cir-
problems associated with a short bowel after relatively little culation. All the citrulline in the systemic circulation is
small intestine has been removed. In a study of 11 patients derived from small intestinal enterocytes, thus plasma levels
with Crohn’s disease and less than 200 cm small bowel of citrulline are related to the length of the remaining func-
remaining, the median original small bowel length was cal- tional small bowel (Fig. 1) [13–16].
culated from the lengths resected and remaining to be 240 cm Apolipoprotein AIV (Apo AIV) may be an equally effec-
(range 205–315 cm), indicating a short small bowel length tive marker of functional enterocyte mass; it is exclusively
before any resections [8]. A further study has confirmed that synthesized by enterocytes. Its concentration in plasma, like
patients with Crohn’s disease have a shorter total small intes- citrulline, mainly depends on production in the small intes-
tinal length than controls (mean length at laparotomy in 279 tine and is not affected by first-pass metabolism. Apo AIV is
Crohn’s disease patients 460 cm vs. 564 cm in 77 non- incorporated into the surface of nascent chylomicrons. Upon
inflammatory bowel disease patients) [9]. entering the blood circulation, it is rapidly dissociated from
The large range of normal human small intestinal length the chylomicrons and predominates in the plasma as a
means that it is more important to refer to the length of small lipoprotein-free fraction. It shows no circadian rhythm and
bowel remaining rather than to the length removed. The term maintains stable physiological plasma levels. It has the
ultrashort bowel is occasionally used to refer to patients who advantage over citrulline of being easier to measure (smaller
have less than 20 or 30 cm small bowel remaining and are sample, simpler equipment and faster results) [17].
thus unlikely to absorb any macro or micronutrients.
60
Plasma citrulline concentration (umol/L)
r = 0.83. P<0.0001
Assessment of Residual Small Intestine 50
Anatomical Length 40
The remaining small bowel length is ideally assessed at sur- 30

gery by measuring 10–30 cm segments of bowel along the
antimesenteric border, taking great care not to over-stretch 20
the bowel. If there is no surgical measurement available and
radiographic films are available, the bowel can be measured 10
using an opisometer, a device used for measuring distances
on maps. It traces the long axis of the small bowel on a small 0
bowel meal radiograph. This technique is relatively accurate 0 20 40 60 80 100 120 140 160
if the total small intestinal length is less than 200 cm and if
the entire small bowel is shown on one film [9, 10]. As most Remnant samll bowel length (cm)
films are saved on a computer the small bowel length (on Fig. 1 Fasting plasma citrulline level and remaining small bowel
contrast follow through, computerized tomographic enterog- length. (With permission [13])
Physiology and Problems of a Short Bowel 225
natomical Considerations of Remaining

A Causes of a Short Bowel
Bowel
The four most common reasons for patients to have less than
Ileum or Jejunum 200 cm of small bowel are superior mesenteric artery throm-
bosis, Crohn’s disease, irradiation damage and surgical com-
A jejunal resection is better tolerated than an ileal resec- plications [10, 34, 44] (Tables 2, 3 and 4). Resection of an
tion. Ileal mucosa, in contrast to the jejunal mucosa, has ischaemic small intestine ultimately results in colonic pres-
tight intercellular junctions and thus can concentrate its
contents. Gastrointestinal transit is naturally slower in the Table 2 Reasons for a short bowel in adults in 1969 [44] (less than
ileum than jejunum, so allowing more time for absorption 120 cm small bowel remaining; almost all patients had a remaining
functional colon)
[18, 19]. The terminal ileum absorbs vitamin B12 [20, 21]
and bile salts. Ileum remaining after a small bowel resec- n = 123
tion can adapt in both structure and function to increase Superior mesenteric artery thrombosis/embolus 49
Volvulus 24
absorption [22–24], while the jejunum can only adapt func-
Superior mesenteric vein thrombosis 10
tionally if some distal bowel remains (chapter “Intestinal Tumours 10
Adaptation”). Non-occlusive gangrene 10
Strangulated herniae 5
Regional enteritis 1
Ileocaecal Valve Other 14
It is traditionally considered that preservation of the ileocae- Table 3 Reasons for a short bowel in adults in 1992 (less than 200 cm
cal valve is beneficial as it may slow transit and prevent small bowel remaining) [34]
reflux of colonic contents into the small bowel; however, Jejunum–colon Jejunostomy
studies of ileocaecal valve excision show no evidence that it Total (sex) 38 (26 F)a 46 (31 F)
slows transit, and small bowel peristalsis probably prevents Age (range) 46 (7–70) 42 (16–68)
reflux from the colon into the small bowel [18, 25] (chapter Median jejunal length (cm) 90 (0–190) 115 (20–190)
Diagnosis
“Normal Intestinal Anatomy and Physiology”).
Crohn’s disease 16 33
Some reports suggest that conservation of the ileocaecal Ischaemia 6 2
valve in children is beneficial in terms of survival and the Irradiation 5 3
need for parenteral nutrition [26, 27]; others show no such Ulcerative colitis – 5
benefits [28, 29]. The reports proposing benefit of ileocaecal Volvulus 5 –
valve preservation in adults may reflect preservation of a sig- Adhesions 4 1
nificant length of terminal ileum. Diverticular disease 1 1
Desmoid tumour 1 1
7 had an ileocaecal valve and 31 a jejuno-colic anastomosis
a
Colon Table 4 Characteristics of 268 adult patients receiving HPN for non-
malignant short bowel (less than 150 cm small bowel) from 1980 to
Conservation of the colon is beneficial because it absorbs 2006 [45]
water, sodium [30–34], calcium [35] and short- and medium- Total (sex) 268 (139 F)
chain fatty acids [36–38]; it also slows gastrointestinal tran- Age [mean (range)] 52.5 (18–89)
sit [39], stimulates small intestinal hyperplasia [40] and its Diagnosis
bacteria manufacture some amino acids and vitamins (e.g. Mesenteric infarction 115 (43)a
Irradiation 61 (23)
vitamin K, biotin, folic acid and thiamine) which can then be
Surgical complications 33 (12)
absorbed in the colon. Patients with an entero-colic anasto-
Soft tissue tumour 16 (6)
mosis may survive without parenteral support with a very Crohn’s disease 15 (6)
short [41, 42] or even no remaining jejunum [43]. Patients Volvulus and trauma 14 (5)
with a preserved functioning colon rarely need regular water Chronic intestinal pseudo-obstruction 11 (4)
and sodium supplements [32–34]. In terms of the need for Other 3 (1)
parenteral nutrients, preservation of at least half of the colon 93 arterial and 22 venous infarction
a
after a jejuno-ileal resection is equivalent to about 50 cm of

small intestine [34].
ervation (75%) and affects an older age group (median age 1. Jejunum–colon. (Type 2) Patients in whom the ileum has
57 years) [34]. Patients with Crohn’s disease and jejunum in been removed, often with the ileocaecal valve, to leave a
continuity with a functioning colon had undergone a median jejuno-colic anastomosis (jejunum–colon); patients who
of 3 small intestinal resections (range 2–6) over a median of have less than 10 cm of terminal ileum are included in
14 years (range 0–29), compared with 4 resections (range this group.
1–12) over a median of 11 years (range 1–26) in those with a 2. Jejunostomy. (Type 1) Patients in whom some jejunum,
jejunostomy [34]. The median time from irradiation to hav- the ileum and colon have been removed, so they are left
ing a small intestinal length of less than 200 cm in 8 patients with an end-jejunostomy.
with irradiation damage (5 gynaecological cancers, 2 carci- 3. Jejunum–ileum. (Type 3) Patients who have had a pre-
nomas of the colon and 1 seminoma) was 5 years (range dominantly jejunal resection, and have more than 10 cm
1–16) [34]. of terminal ileum and the colon remaining (jejuno-ileal)
A short bowel occurs more commonly in women (67%) [10, 34, 50]. This last group is not common (2 of 86
than in men [34, 45]; this may be because women start with patients [34]); since the residual ileum can adapt both
a shorter length of small intestine than men. structurally and functionally, these patients rarely have
The more recent causes of a short bowel in adults are major problems and they are not specifically discussed in
derived from the reported aetiology of patients receiving par- this chapter.
enteral support and additionally from those taking part in
peptide growth hormone studies. There are no studies since Patients with a jejunostomy can be classified according to
1992 of patients with a short bowel and not receiving the results of balance studies as net ‘absorbers’ or net ‘secre-
HPS. The number of patients with a short bowel and Crohn’s tors’. The ‘absorbers’ in general have more than 100 cm of
disease has reduced while the number following surgical residual jejunum and absorb more water and sodium from
resections, with mesenteric ischaemia and malignancy have their diet than they take orally (usual daily jejunostomy out-
all increased [46]. put about 2 kg); they can therefore be managed with oral
The causes of a short bowel arising in childhood and sodium and water supplements, and parenteral fluids are not
infancy usually result in colonic preservation. In infancy the needed. The ‘secretors’ usually have less than 100 cm resid-
causes include necrotizing enterocolitis, multiple jejuno- ual jejunum and lose more water and sodium from their
ileal atresia, gastroschisis, mid-gut volvulus and congenital stoma than they take by mouth (the usual daily stomal output
[26–29, 46–49] (chapters “Peritoneal Adhesions and may be 4–8 kg). ‘Secretors’ cannot convert from negative to
Encapsulating Peritoneal Sclerosis” and “Acid-Base positive water and sodium balance by taking more orally,
Disturbances in Intestinal Failure”). In children trauma, and so they need long-term parenteral supplements [51].
post-operative complications, cancer and motility disorders These requirements change very little with time [34]. The
dominate [46]. As the management and thus the survival of jejunostomy output from a net ‘secretor’ increases during the
these children improves [27–29], they are being cared for as daytime in response to food and decreases at night; any drug
adults. therapy that aims to reduce the output is therefore given prior
to food. The change from a net secretory state, in terms of
water and sodium balance, to a net absorptive state occurs at
Types of Patient with a Short Bowel a jejunal length of about 100 cm (chapter “Management of a
High Output Stoma, Jejunotomy or Uncomplicated
There are three types of patient with a short bowel (Fig. 2): Enterocutaneous Fistula”).
Fig. 2 The three types of

patient with a short bowel.
a b c
Patients with a jejuno-colic
anastomosis or a jejunostomy
are most commonly
encountered. (a) Jejuno-colic
anastomosis; (b) Jejunostomy;
(c) Jejuno-ileal anastomosis
Bowel Length and Fluid/Nutritional Support ments for a few months but in the long-term would not be
expected to need any supplements unless the remaining
• Jejunum–colon. While it is possible for a patient with no bowel was diseased. When the jejunal length is between
remaining jejunum to survive without parenteral nutri- 50 and 100 cm, some patients will need long-term paren-
tion, quality of life is poor [42]. A patient with 100– teral nutrition (PN), if it is between 30 and 50 cm most
200 cm of normally functioning jejunum in continuity will do so, and if it is less than 30 cm almost all patients
with a functioning colon may need oral nutrient supple- will need PN [34, 50] (Fig. 3). Sometimes parenteral
Fig. 3 Pie chart showing the parenteral and enteral sodium and water sodium and water supplements, but almost all jejunostomy patients
supplements given to 71 stable patients with less than 200 cm jejunum were receiving them [34]
remaining. Few patients with a colon were receiving oral or parenteral
nutrition is needed not to maintain nutritional status but to

prevent the severe diarrhoea associated with eating.
• Jejunostomy. The survival of patients with a jejunostomy
has improved since 1963 [5, 52]. If 100–200 cm normally
functioning jejunum remains, oral sodium supplements
(glucose–saline solution or sodium chloride tablets) are
likely to be needed, often with oral nutrient solutions to
which sodium chloride has been added [34, 50, 51, 53]. A
patient with a jejunostomy and less than 100 cm jejunum
remaining would be expected to need long-term paren-
teral saline. If less than 85 cm jejunum remains, long-
term parenteral nutrition is likely to be required in addition
to the saline. Patients usually need long-term parenteral
nutrition when they absorb less than a third of their oral
energy intake [51, 54].
Physiological Changes
Of the physiological changes observed after a small intesti-

nal resection, some reflect normal and some altered physiol-
ogy. Most experimental work in animals involves a
predominantly jejunal resection (jejuno-ileal anastomosis);
Fig. 4 Median peptide YY levels with interquartile range for 6 jeju-
this has a better prognosis but is not a common situation in
num–colon patients, 7 jejunostomy patients and 12 normal subjects
humans, in whom an ileal resection with or without a colec- after a pancake and orange juice meal [59]
tomy is most common.
tric emptying are normal [39]. This colonic braking

Gastrointestinal Motility mechanism may be caused by the release of peptide YY
from the colon [59] (Fig. 4). Infusions of peptide YY that
Gastric Emptying achieve similar levels in normal subjects delay the gastric
There are mechanisms (brakes) in the jejunum, ileum and emptying of liquid [60].
colon that slow gastric emptying (chapter “Normal Intestinal • Jejunostomy. The rate of gastric emptying of solids is nor-
Anatomy and Physiology”). In addition, events external to mal in patients who do not have a short bowel but have
the bowel can affect gastric emptying; for example, malnu- had a proctocolectomy and distal ileal resection [61]. In
trition and many drugs (e.g. cyclizine and opiates) delay gas- patients with a jejunostomy, barium taken orally has been
tric emptying and parenteral nutrition delays the gastric observed to pass rapidly into the jejunostomy bag. Dual
emptying of solids [55]. Studies in animals have shown that radio-isotope studies have shown that the early rate of liq-
gastric emptying of liquid is normal after a jejunal resection uid gastric emptying is rapid and that this tends to corre-
[56, 57]. late inversely with the remaining length of jejunum [39].
This is probably caused by the loss of cells secreting pep-
• Jejunum–colon. Gastric emptying of liquids is normal in tide YY in the terminal ileum and colon, and the conse-
patients who have had a distal small intestinal resection quent low plasma levels [59].
that does not result in a short bowel [58]. Studies in which
a dual isotope meal (liquid and solid components of the
meal are labelled with different isotopes) has been given Small Bowel Transit
to patients with a jejuno-colic anastomosis have shown As there is normally faster transit of chyme through the jeju-
that some liquid leaves the stomach rapidly and travels num than ileum [18, 19, 23, 61], it is not unexpected that
quickly through the short length of remaining jejunum to small bowel transit has been shown to be fast after an ileal
reach the colon. In the colon, by a neural or hormonal and slow after a jejunal resection [56, 57, 62].
mechanism, the liquid meal activates a colonic braking
mechanism by which subsequent gastric emptying is • Jejunum–colon. The first part of a liquid meal travels rap-
slowed and overall measurements of liquid and solid gas- idly from the stomach to the colon, reflecting both the
normal faster jejunal transit and the short distance it has to noted that resections of 60 cm or more of the small bowel
travel. The transit rate for solid is normal, however, sug- caused an increase in basal and pentagastrin-stimulated acid
gesting that jejunal transit has been slowed by the colonic output [85]. They related this increased gastric acid output to
brake already activated by the prior arrival of some liquid a previous terminal ileal resection rather than to active dis-
in the colon. This effect may have been mediated by pep- ease [86].
tide YY. In humans, the survival of some patients with a very short
• In the fasting state, in patients with a short bowel and a bowel has been attributed to their previous gastric surgery
retained colon, the interdigestive migrating motor com- [70, 87, 88]. The evidence for gastric acid hypersecretion in
plex (MMC) occurs more frequently but for a shorter total the long term in patients with a retained colon is not good.
time than in normal subjects, and phase 2 activity is of a Miura et al. reported three of seven patients with a short gut
shorter duration [63, 64]. The frequency and amplitude of and a retained colon who developed duodenal ulcers [89].
jejunal contraction is unaffected [64]. Windsor et al. described 19 patients in whom more than
• Jejunostomy. The rate of liquid and solid small bowel 300 cm of small intestine had been resected and noted in 8
transit is rapid in patients with a jejunostomy. This may be patients large postoperative aspirates of gastric juice of more
due to low peptide YY levels. Six hours after a meal there than 1.5 L daily which lasted for less than 14 days. The vol-
is still some meal residue within the stomach, and this ume of aspirate did not correlate with the remaining length
may result from a disorder of the MMC [39]. of small intestine. In 6 of the 19 patients the increased secre-
tion was attributed to impaired liver function, which these
researchers postulated might increase circulating histamine
Gastrointestinal Secretions levels [78].
One patient with a jejunostomy 90 cm from the duodeno-
Salivary Secretion jejunal flexure following surgery for Crohn’s disease had an
The volume of saliva produced at rest was significantly less acidic (pH 1–6) jejunostomy output of 4.8 L daily that was
in 7 jejunostomy patients (median 0.6 g/5 min, range 0.0– reduced by gastric irradiation [72]. O’Keefe et al. showed
1.4) than in 13 normal subjects (median 2.2 g/5 min, range normal pentagastrin-stimulated gastric acid secretion in nine
0.9–8.7, p < 0.005). After stimulation of salivary flow by patients with a jejunostomy (jejunal length 25–200 cm) more
chewing paraffin wax for 5 min, the volume of saliva was than a year after surgery [90].
significantly less in jejunostomy patients (median High gastrin levels have been observed [59, 91, 92] and
4.6 g/5 min, range 2.2–8.2) than in normal subjects (median may result from a reduced length of small bowel being avail-
9.7 g/5 min, range 7.0–20.5, p < 0.005). These observations able to catabolize gastrin [93, 94]. However, gastrin may not
are likely to reflect altered physiology, but a degree of dehy- be of major physiological importance as studies in the
dration was not excluded [65]. Rhesus monkey have shown that, 6 months after a distal
small intestinal resection, basal and histamine-induced acid
Gastric Secretion secretion are at their highest levels, yet serum gastrin levels
In 1914, Stassoff [66] performed experiments on six dogs in have returned to normal [95]. Another reason for gastric acid
which he demonstrated that if the distal half of the small hypersecretion may be the loss of a normal inhibitor of gas-
intestine was removed, the chyme that emerged from a duo- tric acid secretion, such as neurotensin or peptide YY, from
denal fistula was more liquid and had left the stomach more the distal small bowel/colon. In an extensive review in 1974,
quickly than before the resection. Many studies in dogs with Buxton suggested that stasis in remaining bowel segments
denervated Heidenhain pouches [67–82] and in some with allowed bacterial colonization; these bacteria then either
innervated Pavlov pouches [76] have shown hypersecretion deconjugate bile salts or degrade ‘protein’ which directly or
of gastric acid. In most studies, the colon has been retained, indirectly causes the release of gastrin or a gastrin-like hor-
though in one a colectomy alone caused gastric acid hyper- mone that causes increased gastric acid secretion [96].
secretion [83]. The larger the intestinal resection, the greater Excess gastric acid in the duodenum, in addition to
is the postoperative gastric acid hypersecretion [70, 84]. The increasing the incidence of peptic ulceration, causes bile salt
greatest rises in acid output are produced by jejunal rather precipitation [97], reduced pancreatic enzyme function and
than ileal resection [75, 81, 84] (with the exception of one increased jejunal motility; all of which impair nutrient
study [72]) and by defunctioning bowel [69, 74] rather than absorption.
resecting it. The increased secretion is prevented by antrec- The evidence indicates that gastric acid hypersecretion,
tomy [74, 79, 81, 82] but not by a vagotomy and pyloroplasty after a small intestinal resection, occurs in dogs with dener-
[79, 82]. vated gastric pouches and colons left in situ. It may be pres-
Fielding and Cooke showed an 8% incidence of peptic ent for the first 2 weeks after a small bowel resection in
ulcer among 300 patients with Crohn’s disease and they humans, but there is no good evidence that it occurs in the
long term in patients with a short bowel with or without a lowing a substantial resection (60–80% of total length) of
colon, even though high gastrin levels are observed. small intestine [107].
There are differences between the two types of patient,
Pancreatico-biliary Secretions the most significant ones being in the plasma levels of two
If a person is undernourished [98], or if no food passes hormones produced by the terminal ileum and colon, namely
through the gut [99], pancreatic function is reduced. In seven peptide YY [59, 105] (Fig. 3) and GLP-2 [108, 109] (Fig. 5).
well-nourished patients who had a mean small bowel resec- Peptide YY slows gastrointestinal transit and GLP-2 stimu-
tion of 164 cm (leaving colon) and were taking an oral diet, lates small bowel villus growth (chapter “Normal Intestinal
the post-prandial secretion of trypsin and bilirubin (mea- Anatomy and Physiology”). Patients with a colon have high
sured by jejunal aspiration after a liquid meal) was the same fasting plasma peptide YY and GLP-2 levels, and both hor-
as in normal healthy individuals [100]. However, another mone levels are low in patients with a jejunostomy [59, 108–
study in children showed reduced pancreatic volume and 110]. Low plasma peptide YY levels also occur in ileostomy
enzyme secretion, after an injection of secretin and cholecys- patients who have had a colectomy [110]. High plasma moti-
tokinin, in two of five patients; both of these had most of lin levels occur in patients with a jejunostomy, but this is
their colon remaining [101]. unlikely to be of physiological importance as the highest lev-
When more than 100 cm of terminal ileum has been els occur in those with the longest lengths of jejunum remain-
resected the increased hepatic synthesis of bile salts cannot ing who do not have rapid intestinal transit [59].
keep pace with the stool or stomal losses and thus fat malab-
sorption results [102]. The greatest lipid malabsorption (ste-
atorrhoea) occurs in patients with a jejunostomy: partly Changes in Intestinal Microbiome
because of a very reduced bile salt pool, partly due to rapid
transit, and, in a few cases, due to bacterial overgrowth in the The faecal microbiome is becoming an increasingly
remaining bowel [103]. It has not been determined if changes researched and thus increasingly understood. Unabsorbed
occur in the volume of bile produced each day after an intes- nutrients (especially polysaccharides) within the colon are
tinal resection. metabolised by bacteria to form short chain fatty acids (chap-
ter “Normal Intestinal Anatomy and Physiology”) which in
turn may enhance mineral absorption, promote enteroendo-
Gastrointestinal Hormones crine secretions, stimulate epithelial cell growth and differ-
entiation in the small and large intestine and may also
There are differences in the systemic plasma gastrointestinal promote the motility across the ileocaecal junction [111].
hormone profiles after a meal in patients with a short bowel Additionally the colonic microbiome manufactures (in addi-
compared to normal subjects. However, it is only as studies tion to short chain fatty acids) some amino acids (especially
are performed in these patients, using the hormones, specific when undernourished), micronutrients (e.g. vitamins: folate,
agonists or antagonists, that the physiological importance of K, biotin, thiamine, riboflavin and panthothenic acid). It may
the observations can be understood; until then the signifi- detoxify some chemicals and manufacture others that are
cance of many observations remains a matter for important for messaging/that aid absorption and it may help
speculation. regulate the immune system and promote intestinal adapta-
Parenteral nutrition itself does not affect the gastrointesti- tion [112].
nal hormone response to food [104]. The levels of some The faecal bacteria composition is different from healthy
plasma hormones (e.g. enteroglucagon, pancreatic polypep- individuals in that anaerobic bacteria are reduced (e.g. bacte-
tide and somatostatin and gastric inhibitory polypeptide) roidetes). Firmicutes (includes the lactobacillus and chlos-
before and after a meal in patients with a short bowel (with tridium geni) are the most abundant phylum, Proteobacteria
or without a colon) are the same as in normal subjects. is second, followed by Bacteroidetes, and lastly by
Plasma levels of vasoactive intestinal peptide in patients with Actinobacteria (includes bifibacterium). The lactobacilli are
a colon were normal in one study [105], but high in another the largest genus and are responsible for manufacturing l
[106]. High plasma gastrin and cholecystokinin levels and and d lactic acid which in some patients may accumulate in
low plasma neurotensin, GLP-1 and insulin levels occur in the stool. This may be promoted by lactate-consuming bacte-
both types of patient. The plasma neurotensin levels corre- ria (Veillonellaceae, Bacteroidaceae, Sutterellaceae, and
late with the length of residual jejunum [59]. The high Acidaminococcacea) being under-represented [113, 114].
plasma cholecystokinin levels could cause satiety in some When the d isomer dominates then d-lactic acidosis can
patients with a very short gut [59]. Ghrelin (the “hunger” result. Healthy individuals do not accumulate faecal lactate
hormone) levels have been found to be low in patients fol- as it is readily absorbed or metabolised by other commensal
Fig. 5 Median GLP-2 levels with interquartile range in 7 jejunum–colon patients, 7 jejunostomy patients and 7 normal subjects after a continental
breakfast [108, 109]. Courtesy of P. Jeppesen and P.B. Mortensen
bacteria or converted to other metabolites (e.g. SCFAs) 100 cm ileum has been removed, the enterohepatic circula-
[115]. It has been suggested that patients with jejuno-colonic tion will be disrupted and diarrhoea is likely to be due to
anastomosis are stratified according to the presence or steatorrhoea [102]. If less than 100 cm has been resected,
absence of lactate in their faeces [114]. diarrhoea may result from unabsorbed deoxybile salts (sec-
A lack or reduction of the Gram-negative anaerobic bac- ondary bile acids) causing colonic sodium and water secre-
terium Oxalobacter formigenes which both interacts with the tion [102].
colonic mucosa to induce active secretion of endogenously
produced oxalate and also degrades oxalate in the intestinal
tract may be partly responsible for the high prevalence of Clinical Problems and Their Treatment
calcium oxalate renal stones in patients with a short bowel
and a retained colon [116, 117] (chapter “Nephrolithiasis The problems experienced by patients with a short bowel
and Nephrocalcinosis”). depend upon the type and length of remaining small bowel
The changes in bacterial content of patients with a jeju- and the presence or absence of a functioning colon (Table 5).
nostomy or indeed an ileostomy are poorly investigated and Most of these problems are dealt with in specific chapters
due to a fast transit time may not be of major significance. and only a brief summary follows here.
Changes in Absorption Presentation
In addition to absorption of nutrients, there are some special- The presentation and long-term outcome from a resection
ist functions that are particular to the ileum. The ileum has can be predicted from knowledge of the remaining small
the unique functions of absorbing vitamin B12 and bile salts. bowel length and the presence or absence of a functioning
Vitamin B12 deficiency is likely to occur if more than 60 cm colon. In both types of patient, treatment is aimed first at
of terminal ileum has been resected [20, 62]. If more than maintaining fluid balance. Nutritional supplements are usu-
Table 5 Problems of a short bowel they are selfconscious about their wasted appearance.
Jejunum–colon Jejunostomy Apathy, depression and irritability associated with under-
Presentation Gradual, diarrhoea and Acute fluid losses nutrition may stop the patient from being motivated to
undernutrition recover (chapter “Consequences of undernutrition and
Water, sodium and Uncommon (in the Common
magnesium depletion long-term)
dehydration”). Short bowel patients who can be main-
Nutrient malabsorption Commona Very common tained on an oral diet need to consume more energy than
d(-) lactic acidosis Occasionally None normal subjects because as much as 50% of the energy
Renal stones (calcium 25% None from the diet may be malabsorbed. Patients can achieve
oxalate) this by eating more high-energy food, having oral sip-
Gallstones (pigment) 45% 45% feeds, or receiving high-energy enteral feeds at night
Adaptation Functional adaptation No evidence
through a nasogastric or gastrostomy tube. Once weight is
Social problems Diarrhoea High stomal
output regained, the daily energy requirements may decrease,
Dehydration especially in those with a retained colon. Only if these
Dependency on measures fail and the patient continues to lose weight, or
treatment fails to regain lost weight, is parenteral nutrition given.
a
Bacterial fermentation of carbohydrate salvages some energy, but d(-) Even then, parenteral supplements may be needed for only
lactic acidosis can occur if the diet is high in mono- and a limited period of weeks or months, and thereafter oral
oligosaccharides
supplements may be adequate.
In the long term, parenteral nutrition is needed if a patient
ally started 24–48 h after the surgery, to prevent loss of lean absorbs less than one-third of the oral energy intake [51, 54],
body mass. This may entail a period of parenteral nutrition, if there are high energy requirements and absorption is about
which is gradually reduced as the patient takes more food 30–60%, or if increasing the oral/enteral nutrient intake
orally. causes a socially unacceptably large volume of stomal output
or diarrhoea. In addition to consumption of a high-energy
• Jejunum–colon. These patients are often deceptively well diet, the dietary advice given to the two types of patient is
after the resection except for diarrhoea/steatorrhoea, but different (chapter “Dietary Treatment of Patients with a
in the succeeding months they may lose weight and pres- Short Bowel”).
ent as severely undernourished (classical ‘short bowel
syndrome’). • Jejunum–colon. In order to increase energy absorption
• Jejunostomy. These patients have immediate problems and to reduce the risk of renal stones, patients with a
after surgery due to the large volume of stomal output, retained colon need a large total energy intake with a diet
which increases with food and drink. This high-volume high in carbohydrate (polysaccharides) [37] but not
output results in patients rapidly becoming depleted in increased in fat (long-chain triglycerides); the diet should
water and sodium. Recognition of this high output means also be low in oxalate. D(-) Lactic acidosis may occur if a
that clinicians are often aware that nutritional problems diet is high in monosaccharides [118]. If oxalate is not
will follow; hence nutritional care is often addressed at a reduced there is a 25% chance of the patient developing
much earlier stage than in patients with a retained colon. symptomatic calcium oxalate renal stones [34] (chapter
Jejunostomy patients are highly dependent on treatments “Nephrolithiasis and Nephrocalcinosis”). Long-term par-
to compensate for water and sodium losses. If they miss enteral nutrition is likely to be needed if less than 50 cm
their treatment for 1 day they are likely to become unwell jejunum remains [34].
from sodium and water depletion. Their requirements for • Jejunostomy. Jejunostomy patients need a diet high in
water and sodium supplements change little with time energy. It does not matter whether this is as carbohydrate
(chapter “Intestinal Adaptation”). or lipid so long as the osmolality is kept low by using
large molecules (polysaccharides, protein and triglycer-
ides) [119, 120] and thus allowing extra sodium chloride
Undernutrition to be added to give the meal/liquid feed a total sodium
concentration of 90–120 mmol/L and an osmolality of
Loss of muscle leads to weakness and early fatigue. Loss about 300 mOsm/kg. An elemental diet has a high osmo-
of body fat results in feeling cold, a gaunt facial appear- lality and little sodium and should therefore be avoided as
ance, dry and wrinkled skin, and dull hair. These features, it may increase water and sodium losses. A high-lipid diet
together with a stooped posture, give an impression of pre- may increase stomal calcium and magnesium losses
mature ageing. Patients may dislike looking in the mirror (chapter “Dietary Treatment of Patients with a Short
and weighing themselves, and may avoid company because Bowel”).
Water and Sodium Losses greater than normal urinary losses of potassium [32] or by
magnesium depletion [121] (chapter “Dietary Treatment of
Clinical Assessment/Monitoring Patients with a Short Bowel”).
Deficiencies of water and sodium (most common in those
without a retained colon) are common and result in a loss of reatment of Water and Sodium Depletion
T
extracellular fluid volume, hypotension and, if severe, pre- Jejunostomy. Intravenous fluid is given initially while the
renal failure. Daily body weight and an accurate fluid bal- patient takes no oral food or fluid. This will reduce the high
ance (to include stomal effluent) are essential measurements output dramatically; food is then gradually reintroduced.
during the initial stages of management. Acute sodium and Parenteral nutrition/saline is likely to be needed in the long
water deficiencies are detected by a rapid fall in body weight, term if less than 100 cm jejunum remains. Oral hypotonic
postural hypotension, low urine volume and, if very severe, fluids are restricted and a glucose–saline solution (sodium
by a rising serum creatinine and urea. A useful guide to concentration 90–120 mmol/L) is given to sip during the day.
sodium depletion is measurement of sodium concentration in Some clinicians suggest that liquid and solids be taken at dif-
a random urine sample: lack of body sodium is suggested by ferent times although there is no published evidence that this
a concentration of only 0–5 mmol/L. It is ideal, though not reduces stool/stomal output [122]. Drugs that reduce gastro-
always possible, to achieve a daily urine volume of at least intestinal secretions or motility may be used; often both
800 mL with a sodium concentration greater than types of drug are administered. In general, patients who are
20 mmol/L. In addition to relatively normal haematological net ‘secretors’ have the greatest reduction in their stomal out-
and biochemical measurements, it is desirable (though again put when drugs that predominantly reduce gastrointestinal
not always possible with oral medication) to have a plasma secretions are given, for example omeprazole 40 mg daily,
magnesium level greater than 0.6 mmol/L (chapter ranitidine 300 mg twice daily, cimetidine 200 mg every 6 h
“Management of a High Output Stoma, Jejunotomy or or 300 mg continuously over 6 h or, if there is insufficient gut
Uncomplicated Enterocutaneous Fistula”). to absorb these (less than 50 cm), subcutaneous or intrave-
nous octreotide 50 μg twice a day. However, these treatments
• Jejunum–colon. The colon has a large capacity to absorb rarely completely alleviate the need for parenteral supple-
sodium and water; thus patients with a short bowel and a ments. Patients who are net ‘absorbers’ have the greatest
preserved colon are rarely in negative water and sodium reduction when drugs that predominantly reduce gastrointes-
balance and rarely need water or sodium supplements [31, tinal motility (e.g. loperamide 4 mg four times a day and
34]. If sodium deficiency does develop, a glucose–saline codeine phosphate 60 mg four times a day) are given half an
drink can be sipped during the day, as for patients with a hour before food (chapter “Management of a High Output
jejunostomy. Although the colon secretes potassium, a Stoma, Jejunotomy or Uncomplicated Enterocutaneous
low serum potassium level is rare [34]. There is an Fistula”).
exchange mechanism of chloride absorption/bicarbonate
secretion in the colon; thus, if much sodium chloride is
consumed, bicarbonate may be lost in the stools and give Magnesium and Other Micronutrients
rise to a metabolic acidosis similar to that occurring in
patients who have an ileo-conduit following a The clinical syndrome of magnesium deficiency in man was
cystectomy. described in 1960 [123, 124] and in the same year was
• Jejunostomy. Patients with a jejunostomy have a large reported as occurring after a massive intestinal resection
volume of stomal output that is greater after eating or [125]. It has subsequently been reported after jejuno-ileal
drinking. Each litre of jejunostomy fluid contains about bypass for obesity [126] and after ileal resections of more
100 mmol/L of sodium [51]. This high-volume output is than 75 cm [127]. Its features include fatigue, depression,
mainly the result of loss of the normal daily secretions jerky and weak muscles, ataxia, athetoid movements, cardiac
produced in response to food and drink (about 4 L/day) arrhythmias and, if severe, convulsions [123, 124, 128, 129].
although gastric acid hypersecretion and rapid liquid gas- Carpopedal spasm and positive Chvostek and Trousseau
tric emptying and small bowel transit may contribute. signs generally occur if there is a concomitant hypocalcae-
mia [124, 128, 130].
The effluent from a jejunostomy or ileostomy contains rela- Low serum magnesium levels are more common in
tively little potassium (about 15 mmol/L) [32, 51]. Potassium patients with a jejunostomy than in patients with a retained
balance is not often a problem, and net loss through the colon. Of short bowel patients who were not receiving paren-
stoma occurs only when less than 50 cm jejunum remains teral nutrition, 11 of 27 (41%) of those with a colon were
[51]. A low serum potassium level may be caused by sodium receiving magnesium or had low serum magnesium levels,
depletion with secondary hyperaldosteronism and thus compared with 19 of 28 (68%) with a jejunostomy [34].
Patients with a preserved colon require less magnesium and Table 6 Treatment of hypomagnesaemia
have higher serum values than those without a retained 1. Correct water and sodium depletion (and thus secondary
colon. This, together with reports that magnesium poisoning hyperaldosteronism)
can occur after a magnesium sulphate enema, provides fur- 2. Give oral magnesium preparation (e.g. 12 mmol magnesium oxide
or 10 mmol magnesium aspartate at night)
ther evidence that the colon absorbs magnesium [131]. 3. Reduce lipid in diet
Most clinicians use a serum magnesium measurement of 4. Give 1α-cholecalciferol (1–9 μg daily)
less than 0.6 mmol/L as their guide to magnesium depletion; 5. Give intravenous magnesium (occasionally subcutaneous or
however, urine, skeletal muscle, mononuclear cell or ionized intramuscular magnesium sulphate)
magnesium levels [129] are more sensitive indicators.
There are several reasons for magnesium deficiency.
Magnesium is normally absorbed by passive diffusion in the Most magnesium salts are poorly absorbed and may worsen
distal small bowel and colon. Bowel resections reduce the diarrhoea/stomal output. Magnesium acetate causes less
absorptive area and may increase stool losses [132]; how- diarrhoea than magnesium gluconate [139]. Magnesium
ever, this does not occur in an easily predictable manner and oxide is commonly given and contains more elemental mag-
balance studies have shown that magnesium balance does nesium than the other salts. It is insoluble in water and alco-
not relate to the length of small bowel remaining [65]. The hol but soluble in dilute acid. In the stomach it is converted
composition of the diet consumed may be another cause of to magnesium chloride. It is given as gelatine capsules of
stool losses of magnesium. Fatty acids, derived either from 4 mmol magnesium oxide (160 mg of MgO) to a total of
digestion of dietary fat or from bacterial fermentation of 12–24 mmol daily or magnesium aspartate 10 mmol daily.
malabsorbed carbohydrate, combine with magnesium, cal- Magnesium diglycinate (chelate) is absorbed as well as mag-
cium and zinc and prevent their absorption, increasing fae- nesium oxide as an intact dipeptide in the proximal jejunum
cal or stomal losses [133]. A third reason, occurring and after an ileal resection it results in the passage of fewer
particularly in patients with a jejunostomy, is stool/stomal stools than magnesium oxide [140]. Oral magnesium treat-
loss of salt and water and the consequent secondary hyper- ment is usually given at night when intestinal transit is
aldosteronism. Aldosterone increases renal excretion of assumed to be slowest and there is more time for absorption.
magnesium in rats and man and the faecal excretion of mag- This regimen does not appear to increase stomal or stool out-
nesium in rats [134, 135]. put. Magnesium may also be given as a topical spray [141].
A low serum magnesium level reduces both the secretion A low-fat diet decreases stool/stomal magnesium losses,
and function of parathormone [136]. Thus parathormone especially in patients with a retained colon [133]. If oral
cannot promote magnesium absorption in the ascending limb magnesium supplements, dietary advice and correction of
of the loop of Henle or activate renal 1α-hydroxylase to water and sodium depletion do not bring the magnesium
make 1,25-hydroxycholecalciferol. The failure to make level into the normal range, oral 1α-hydroxycholecalciferol
1,25-hydroxycholecalciferol results in reduced magnesium in a dose of 1–9 μg daily may improve magnesium balance
and calcium absorption from the gut [137]. Na+/K+-ATPase [142, 143]. It may exert its effect by increasing both intesti-
activity, which normally keeps potassium within a cell and nal and renal magnesium absorption [143].
sodium out, depends upon magnesium. When the serum Magnesium can occasionally be given as a subcutaneous
magnesium level is low, activity of this enzyme is impaired. injection of 4 mmol magnesium sulphate every 2 or more
Potassium is therefore lost from cells and renal potassium days, but can cause skin ulceration. Intramuscular injection
excretion is increased, resulting overall in hypokalaemia. of 10 mmol/L is an alternative, but is painful. Regular intra-
This hypokalaemia may not respond to the administration of venous infusions of 12 mmol or more can be given, usually
oral or intravenous potassium, but does to magnesium sup- in a litre of saline over 1–2 h, but can cause flushing.
plementation [138].
The treatment of hypomagnesaemia is outlined in Table 6. Selenium
Patient hydration and, thus, secondary hyperaldosteronism Patients receiving parenteral nutrition are commonly defi-
must first be corrected. Serum magnesium levels can usually cient in selenium [144–146] and need larger amounts of sele-
be improved by oral supplements, however the data on mag- nium than are required in the diet of normal subjects [146].
nesium absorption from different preparations are often This suggests a loss of selenium from the gastrointestinal
derived from normal volunteer studies. Tablet dissolution secretions. Patients with a jejunostomy also have a reduction
and magnesium availability may be different in patients with in selenium absorption, the amount by which absorption is
a short bowel. Various magnesium salts have been given as reduced correlating with residual jejunal length [147]. The
oral treatment including magnesium sulphate, chloride, kidney can conserve selenium but often not to a sufficient
hydroxide, acetate, carbonate, gluconate, lactate, citrate, extent. Selenium deficiency is therefore common and may
aspartate, pyroglutamate, oxide (magnesia) and diglycinate. cause weak muscles, a tendency to infections, a dilated car-
diomyopathy and symptoms of hypothyroidism (it is a cofac- sepsis, hypoglycaemia, thiamine deficiency, alcohol or other
tor for the conversion of thyroxine to the more active drugs), other specific causes should be sought in a patient
triiodothyronine) [148]. with a short bowel. Hypomagnesaemia may cause mild con-
fusion. In patients with a preserved colon, severe confusion
Vitamin B12 Deficiency can result from d-lactic acidosis (in lactate accumulators), in
Both groups of patients have had more than 60 cm of the which a metabolic acidosis with a high anion gap will be
terminal ileum removed and need long-term hydroxycobala- observed (chapter “Dietary Treatment of Patients with a
min injections, Traditionally 1 mg intra-muscularly every Short Bowel”). Hyperammonaemia may cause confusion in
3 months though may be longer depending on serum levels both types of patients with a short bowel because ammonia
[20, 62]. cannot be detoxified. The small amount of intestine remain-
ing cannot manufacture adequate citrulline to detoxify the
ther Vitamin and Mineral Deficiencies
O ammonia created in the urea cycle. If there is concomitant
There may be impairment of absorption of the fat-soluble renal impairment, the increase in blood ammonia causes a
vitamins A, D, E and K and essential fatty acids. Essential problem as the kidney will not be able to excrete the excess
fatty acid deficiency may be treated by rubbing sunflower oil ammonia. Hyperammonaemia can be corrected by giving
into the skin [149]. Zinc deficiency is not common unless arginine (an intermediary in the urea cycle) [154, 155].
stool volumes are large, when zinc sulphate may be given
(15–45 mg orally one to three times a day) [150]. In patients
receiving parenteral nutrition the deficiencies depend on the Drug Absorption
regimen used, but deficiencies of iron, vitamin D and biotin
[151–153] occurred with some regimens in the 1990s. Drug absorption can be predicted from knowing the time to
peak levels and the biopharmaceutical classification (chapter
“Drug Absorption in the Short Bowel”). Omeprazole can be
Diarrhoea (Jejunum–Colon Patients) absorbed in the duodenum and upper jejunum; problems are
likely to occur only if less than 50 cm jejunum remains.
The oral intake determines the amount of stool passed. Warfarin [156] and thyroxine may need to be given orally in
Diarrhoea may severely limit a patient’s lifestyle; limiting high doses. Loperamide circulates in the enterohepatic circu-
food intake can reduce diarrhoea but may increase the prob- lation, which is disrupted, and higher doses than usual may
lems of undernutrition. Rarely, a patient requires parenteral need to be given (chapter “Management of a High Output
nutrition to allow him or her to eat less and so reduce the Stoma, Jejunotomy or Uncomplicated Enterocutaneous
diarrhoea. Fistula”).
Diarrhoea may be treated with loperamide, 2–8 mg, given
half an hour before food. Loperamide is usually given in
preference to codeine phosphate (30–60 mg half an hour Adaptation
before food), as it is non-sedative and non-addictive; occa-
sionally, however, both are needed. If tablets/capsules Intestinal adaptation (chapter “Intestinal Adaptation”) is the
emerge unchanged in stool/stomal output, they can be process, following intestinal resection, that attempts restore
crushed, opened, mixed with water or put on food. If less total gut absorption of macronutrients, macrominerals and
than 100 cm of terminal ileum has been resected, bile salt water to that occurring before the intestinal resection (chap-
malabsorption may contribute to the diarrhoea. This may be ter “Intestinal Adaptation”).
helped by cholestyramine (or colesevelam) which has the In a classical paper in 1959, Pullan described three phases
additional advantage of reducing oxalate absorption but may that related to the changing situations in patients after a
be detrimental by reducing fat absorption and by further ‘massive intestinal resection’ leaving a functioning colon in
reducing the bile salt pool [102]. Gastric anti-secretory drugs situ (i.e. ‘short bowel syndrome’) [157]. These changes
may reduce diarrhoea shortly after surgery but are not usu- reflect structural and functional adaptation.
ally effective in the long term.
• Stage 1. As intestinal motility returns in the first few days
after the resection, profuse diarrhoea occurs and is maxi-
Confusion mal for the first 2–3 weeks. During this stage there may be
large losses of fluid and electrolytes (up to 10 L/day).
In addition to the many common general medical causes of These losses have been attributed to gastric acid
confusion (e.g. hypoxia, hepatic, renal or cardiac failure, hypersecretion.
• Large volumes of saline (sometimes with magnesium) pump inhibitor may have ceased by the end of the first
may be needed to maintain fluid balance, especially when year and the drug can be stopped.
the patient first starts to eat. A protein pump inhibitor or • After a large resection of small intestine, improvement in
H2 antagonist, loperamide and often codeine phosphate absorption of macronutrients, macrominerals and water
are empirically given. If the residual bowel length is less may occur by:
than 100 cm, parenteral nutrition may be started on the –– The patient eating more food than normal
second postoperative day. Anal soreness and excoriations (hyperphagia);
may be a problem. This phase ends as the diarrhoea –– The remaining bowel increasing in size and absorptive
lessens. area (structural adaptation); and
• Stage 2. The problem changes from that of fluid and elec- –– Reduction in bowel transit rate to allow more time for
trolyte balance to that of progressive undernutrition absorption (functional adaptation).
requiring nutrition support. If untreated, the patient may
rapidly lose weight and, despite a large oral energy intake, An increased oral intake has been observed [158]. After
not absorb enough to maintain weight. Fat malabsorption a jejunal resection in animals, the ileal remnant undergoes
is much more significant than that of carbohydrate and structural changes which include elongation of villi, deep-
protein. Deficiencies of the fat-soluble vitamins A, D, E ening of crypts, and an increase in the number of absorptive
and K may occur, causing night blindness, bone pains, cells in a given length of villus. After a jejuno-ileal resec-
ataxia and bleeding respectively. Vitamin B and C defi- tion in man to leave a jejunocolic anastomosis, no struc-
ciencies sometimes occur and cause glossitis, angular sto- tural adaptation (except possibly hyperplasia) has been
matitis, pellagra, psychotic changes and bleeding. demonstrated even though high GLP-2 levels are observed
Anaemia and hypoproteinaemia are rare after an uncom- [109]. A degree of functional adaptation with slowing of
plicated resection. liquid gastric emptying and solid small bowel transit has
• The patient may complain of abdominal cramps, disten- been demonstrated [39] and is likely to be caused by high
sion and nausea. During this time the gastrointestinal peptide YY levels. Functional adaptation does occur, as
transit rate slows, although a large volume of fatty stool demonstrated by the findings that there is a small reduction
is still passed. Carbohydrate and protein are better in faecal weight in the 3 months after a small bowel resec-
absorbed and a state of equilibrium is reached after tion [159], and that there is increased jejunal absorption of
3–6 months. water and sodium [160, 161], glucose [162] and calcium
• Stage 3. In the final stage relative equilibrium has been [163] with time. The intestinal calcium absorption may
reached and minor adjustments are made. The dietary continue to increase for more than 2 years after a resection
regimen tries to limit the lipid intake. Long-term paren- [163]. Restoring bowel continuity after a mesenteric infarc-
teral nutrition is unlikely to be needed unless less than tion resulted in cessation of home parenteral nutrition in
50 cm jejunum remains. The beneficial effects of a proton 77% within 5 years (Fig. 6) [164].
Fig. 6 Parenteral support after mesenteric infarction in patients with blue line Jejunum-colon (re-anastomosis) (n = 57). There is a reduction
jejunostomy and in those following an anastomosis bringing the colon in the need for parenteral fluid and nutrition in the 36 months (3 years)
back into continuity [164]. Red top line Jejunostomy (n = 29) and lower after the re-anastomosis
• Although adaptation occurs in the months after the cre- acid resistant to bacterial deconjugation and dehydroxyl-
ation of an ileostomy, there is no evidence for any struc- ation, that does not itself cause colonic secretion and thus
tural [90] or functional [34, 165] adaptation at any time in diarrhoea, but does result in a variable improvement in fat
patients with a jejunostomy. and calcium absorption in patients with a short bowel, with
or without a retained functioning colon [180, 181]. Attempts
to replace colonic mucosa with small intestinal mucosa to
Gallstones increase absorption have not proved successful [182]. Tissue
engineering to make small intestine over a scaffold (decel-
Gallstones are common (45%) in both types of patient and lularized organ or synthetic biodegradable matrix) is difficult
are more common in men [34] (chapter “Gallstones in due to the complex structure of the small intestine (includes
Intestinal Failure”). It was originally thought that gallstones nerves, blood vessels, muscle and mucosa) and having to
in this circumstance resulted from deposition of cholesterol achieve a secretory, absorptive, propulsive and barrier func-
because of a depleted bile-salt pool. However, the gallstones tion [183]. Another area of importance is the prevention of
tend to contain calcium bilirubinate. Such stones probably gallstones after an intestinal resection: trials using prophy-
result from gallbladder stasis: biliary sludge develops and lactic antibiotics, ursodeoxycholic acid and cholecystokinin
this subsequently forms calcium bilirubinate stones which may be performed. An oral nutrient solution containing
often appear calcified on abdominal radiographs [166]. 100 mmol/L sodium and having an osmolality of 300 mOsm/
Calcium bilirubinate crystals within biliary sludge are more kg has yet to be commercially manufactured as an ideal
commonly found in men than in women [167]. nutrient solution to give to patients with a jejunostomy or
Cholecystokinin injections have been used to prevent gall- high-output ileostomy.
bladder stasis [168] and some units have advocated a pro- Small bowel transplantation is becoming more safe (chap-
phylactic cholecystectomy [169, 170] (chapter “Gallstones ter “Intestinal Transplantation”) and the outcome in selected
in Intestinal Failure”). patients may be as good as that of prolonged parenteral nutri-
tion though one set of problems may be changed for another
(e.g. high output stoma, dependency on HPS for rejection/
Social Problems complications of immunosuppressive drugs).
Most long-term patients with a short bowel have a body mass

index within the normal range, and most are in full-time work Preventative Measures
or look after the home and family unaided [34]. Both groups
of patients may have diarrhoea, which causes problems, espe- Post-operative monitoring of Crohn’s disease to ensure
cially if housing conditions are poor. In those with a colon the mucosal healing along with smoking cessation, immunosup-
diarrhoea is malodorous and bulky due to steatorrhoea. pressive therapy (e.g. azathioprine, 6-mercaptopurine and
The effluent from a small-bowel stoma, unlike that from a methotrexate), and/or biological medication (e.g. anti-
colostomy, is not offensive. The large volume of fluid that tumour necrosis factor antibodies) and balloon dilatation of
emerges, however, may trouble the patient; sometimes strictures may reduce the need for repeated or major resec-
3 or more litres in 24 h may be passed from the stoma. The tions of Crohn’s disease and thus the chance of developing a
bag then has to be emptied frequently and, if it becomes short bowel [184].
overfull, the adhesive flange may separate from the skin with A small bowel embolus/venous infarction may be pre-
embarrassing leakage of fluid and with the likelihood of skin vented by identification of risk factors such as atrial fibrilla-
soreness. tion, a poorly functioning myocardium, recent myocardial
infarction, coagulation abnormalities or a period of hypoten-
sion. Anticoagulation therapy may be given to a patient in
Other and Future Treatments whom a potential source of emboli is identified. The diagno-
sis of a small bowel infarction can be difficult but needs to be
New treatments are likely to be aimed at increasing the made soon after the event. Clues to the diagnosis include the
absorptive function of the remaining gut. Most are currently presence of the risk factors above, pain (usually of sudden
directed at inducing structural adaptation, for example onset and continuous), and usually a rise in the white cell
GLP-1 or 2 analogues [171], epidermal growth factor [172, count, amylase, phosphate, lactate and d-Dimers [185].
173], colostrums or aminoguanidine [174]. Studies using Ideally, contrast-enhanced computed tomography (CT)
growth hormone, glutamine and fibre have been disappoint- should be performed within 2–3 h of the onset of pain
ing [175–178]. Studies that use analogues of peptide YY especially if a plain abdominal radiograph has shown no
have yet to be tried [179]. Cholylsarcosine is a synthetic bile obvious abnormality [186]. If there is partial occlusive
obstruction to the mesenteric artery then percutaneous trans- 3. Haymond HE. Massive resection of the small intestine. An analy-
sis of 257 collected cases. Surg Gynecol Obstet. 1935;61:693–705.
luminal angioplasty or a surgical revascularization procedure
4. Conn JH, Chavez CM, Fain WR. The short bowel syndrome. Ann
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necrosis has not occurred, a bolus of a vasodilator (e.g. extensive small bowel resection complicated by magnesium defi-
ciency. Case report. Ann Surg. 1963;157:92–6.
papaverine 60 mg or tolazoline 25 mg, phenoxybenzamine,
6. Wu T-J, Teng R-J, Chang M-H, Chen C-C. Congenital short bowel
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Thrombolytic drugs, heparin and low molecular weight dex- 8. Nightingale JMD, Lennard-Jones JE. Patients with a short bowel
tran may all be infused into the superior mesenteric artery or due to Crohn’s disease often start with a short normal bowel. Eur
peripherally to try and halt and/or reverse the progression of J Gastroenterol Hepatol. 1995;7:989–91.
9. Nightingale JMD, Bartram CI, Lennard-Jones JE. Length of
the infarction or ischaemia. The outcome is best if there are
residual small bowel after partial resection: correlation between
no signs of peritonitis at the onset of treatment [186]. In radiographic and surgical measurements. Gastrointest Radiol.
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infarction.
J Parenter Enter Nutr. 1996;20:275–80.
Experimentally, the most severe problems occur after 11. Cheng W, Zhang S, Wang J, Zhou C, Li Y, Li J. Three-dimensional
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B. Post-absorptive plasma citrulline concentration is a marker
reperfused as they produce vasodilatation, reduce white cell
of absorptive enterocyte mass and intestinal failure in humans.
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Chronic Small Bowel Dysfunction
Jeremy M.D. Nightingale and Peter Paine
Key Points 9. Surgical options may be considered. These include

1. Patients with chronic small bowel dysmotility have pre- insertion of jejunal feeding tubes, venting stomas, a full
dominantly a myopathy (usually dilated gut and classi- thickness jejunal biopsy and selected bypasses/resec-
cal chronic intestinal pseudo-obstruction (CIPO)), a tions or rarely small bowel transplantation.
neuropathy or idiopathic. 10. Opioids and intravenous cyclizine should be avoided.
2. The patient’s primary symptoms/problems are listed in
order of importance to the physician and patient.
3. Contributing factors (e.g. drug therapy, psychosocial Introduction
and quality of life issues) are evaluated.
4. Mechanical obstruction must be excluded (especially if Chronic small intestinal dysmotility occurs when, for more
dilated loops of bowel are noted) usually with a CT scan than 6 months, there is a failure of coordinated intestinal
of the abdomen with oral contrast. propulsion, giving rise to the symptoms and signs of intesti-
5. The patient’s nutritional status is assessed and if poor, nal obstruction (colicky abdominal pain, nausea, vomiting
nutritional treatment is begun while taking into account/ usually with abdominal distension, and often a dilated
treating refeeding risks. bowel) in the absence of a mechanical cause [1–3]. It may
6. Tests to help establish a clinical diagnosis are performed be defined as severe when there is objective evidence of
when the patient is not taking any medications that affect malnutrition, dehydration or electrolyte disturbance (e.g.
gastrointestinal motility (e.g. opiods and cyslizine) and BMI of less than 18.5 kg/m2 or more than 10% unintentional
ideally when they have achieved a normal body mass weight loss in last 3 months) and thus clinically assisted
index. nutrition and hydration (CANH) therapy may be needed. A
7. A definite diagnosis of dysmotility should not be given classical obstructive picture with distended bowel is not
unless it is certain. Terms such as possible/probable or always the case, especially if there is a neurological
working diagnosis are preferred as a label of dysmotility aetiology.
is difficult to remove. As the clinical situation changes Normal gastrointestinal motility is determined by intesti-
the diagnosis may be reconsidered. nal smooth muscle function which in turn is influenced by
8. A plan and treatment goals are agreed to help symptoms, neural and humoral factors. A disorder of one or more of
nutritional status, psycho-social issues and quality of these systems can result in intestinal pseudo-obstruction [2].
life. This should be with a multidisciplinary team Dysmotility may occur not only in the small bowel but also
(includes psychology and pain management specialists). in other areas of the gastro-intestinal tract (e.g. oesophagus,
All members of the team should give the same agreed stomach and colon) and their involvement may complicate
information to the patient/family. diagnostic tests and treatments. There are many causes of
acute or reversible/temporary intestinal dysmotility which
J. M.D. Nightingale (*) include abdominal surgery, trauma, sepsis, metabolic (e.g.
St Mark’s Hospital, Harrow, Middlesex, UK hypokalaemia) or endocrine problems (e.g. hypothyroid-
e-mail: [email protected]; [email protected] ism); and there are other medical causes of abdominal pain
P. Paine (e.g. functional dyspepsia, irritiable bowel syndrome, cen-
Department of Gastroenterology, Salford Royal Foundation Trust, trally mediated abdominal pain, familial mediterranean
University of Manchester, Salford, UK
fever, ischaemia, angio-oedema, abdominal migraine and

244 J. M.D. Nightingale and P. Paine
lead poisoning) which are not specifically discussed in this gastroenterologist, gastrointestinal physiologist, gastrointes-
chapter but the clinician must be aware of them. tinal surgeon, pain team, psychiatrist/psychologist, rheuma-
The diagnosis of these patients can be very difficult and tologist (including a specialist in fatigue management),
may be empirical. Different diagnostic labels have been urologist, gynaecologist, neurologist, clinical biochemist,
given to these patients based upon the diagnostic test used. histopathologist, radiologist and nutritional support team.
Histology in an expert centre may be the most definitive but If there is uncertainty about the diagnosis this should be
is often not available and indeed it may be inappropriate to clearly documented and only described as working (probable
obtain it due to associated risks and lack of specific therapy or possible) and the contributing factors to this should be
implications. Histology may show abnormalities but the stated on the patient’s problem list (e.g. previous surgery,
extent they are due to malnutrition, previous surgery (includ- opioid or cyclizine use, psychosocial problems or undernu-
ing defunctioning bowel) or drug therapy is not clear. The trition). A definitive diagnosis should only be given if there
clinical features, results of investigations (e.g. manometry) is a clear cause identified. It is very difficult to remove a
and histology may not all combine to indicate one specific diagnostic label once it has been given and a premature or
diagnosis. Other factors that can give rise to the clinical pic- erroneous organic diagnosis in those with predominantly
ture or aggravate the condition are: unrecognised organic psychosocial issues or abnormal illness behavior may make
small bowel obstruction/the effects of previous abdominal the management of contributing issues very difficult. A defi-
surgery (including adhesions and neuropathic pain), drug nite diagnosis although satisfying to have, rarely affects the
usage (particularly opioids and drugs with anticholinergic patient’s clinical management.
effects), psychosocial problems including abnormal illness This document discusses the differential diagnoses, the
behaviour and malnutrition. In practice, all of these often medical and nutritional treatment of chronic small intestinal
play a part and contribute to the patient’s presentation dysmotility, which result in malnutrition. In its most severe
(Figs. 1 and 2). Untangling which of these factors gives rise form patients with small bowel dysmotility may need long-
to the dominant symptom can be challenging and needs the term PN or even a small intestinal transplant, while in a
help of a multidisciplinary team that ideally consists of a milder form dietary adjustment may suffice.
Fig. 1 Progression of Motility disorder

dysmotility
Opioid/cyclizine/ Abdominal surgery Psychosocial problems Malnutrition

anticholinergic drugs
and dependence*
Worse symptoms
*some other drugs can have similar problems (e.g. calcium channel blockers, antidepressants
etc)
Chronic Small Bowel Dysfunction 245
Fig. 2 Factors contributing/ Obstruction Functional GI Drugs Psychosocial Malnutrition

mimicking severe chronic disease Opioids/cyclizine Eating disorders
intestinal dysmotility and its
traditional classification
INTESTINAL DYSMOTILITY IDIOPATHIC

(e.g. EDS hypermobility)
Myopathy Neuropathy
Primary Secondary Primary Secondary

Hollow visceral myopathy Systemic sclerosis* Hirschprung’s Neurological diseases
Jejunal diverticulosis Amyloid* Autoimmune Paraneoplastic (thymoma)
Autoimmune Irradiation Infective Neurofibromatosis
Muscular diseases Mit ochondrial disorders
*: Systemic sclerosis and amyloid can belong to both myopathy and neuropathy.
onditions that Mimic or Can Contribute

C pain with abdominal distention, loud bowel sounds, no bowel
to the Presentation or stoma action and vomiting suggest this. A distal obstruc-
tion is suggested if the vomit is faeculent, while a more prox-
A patient with suspected small bowel dysmotility will have imal one by green/yellow vomit. During an obstructive
had basal investigations to exclude other causes; these episode the bowel secretes more fluid and when the obstruc-
include inflammatory markers (CRP, albumin, platelets and tion resolves diarrhoea follows (or a high stomal output). If a
faecal calprotectin) which, if normal, make active inflamma- patient sticks to a low residue diet or even a liquid diet, the
tory bowel disease unlikely. These may be followed, as obstructive episodes may reduce or even be abolished. This
appropriate, with the use of endoscopies and cross-sectional approach, if successful, can be a useful supportive diagnostic
imaging including with intravenous contrast to diagnose test.
structural/mucosal diseases. Several other conditions may Radiologically the clue to an organic obstruction is the
appear as severe chronic intestinal dysmotility but with no demonstration of a distinct transition point between dilated
primary bowel pathology (Fig. 1). In one series the most fre- and normal sized bowel but this may not be apparent either
quent misdiagnoses for dysmotility were volvulus, megaco- because the obstruction has resolved or the bowel is fixed by
lon and chronic constipation [4]. adhesions and thus cannot dilate. It can be helpful to obtain
an abdominal CT scan when the patient has an episode of
severe pain. Contrast follow-through studies or MRI scans
Organic Obstruction although useful when positive may not be tolerated in the
acute setting and do not always demonstrate the obstruction.
A major problem, that is often not diagnosed, is a localised Unsuspected diagnoses may be revealed (e.g. small bowel
bowel obstruction as a result of adhesion formation. This volvulus from a band adhesion or an intussusception).
may be suspected clinically when a patient has had a number Further clues to an organic obstruction are visible small
of abdominal operations (with or without extensive adhesion bowel peristalsis, worse pain after prokinetic drugs or giant
division) [5]. A history of intermittent colicky abdominal jejunal contractions on manometry [6, 7].
Multiple laparotomies themselves may result in second- Other drugs such as anti-cholinergics, anti-depressants,
ary dysmotility, especially if the bowel becomes encased in calcium channel blockers, chronic laxative abuse or some
fibrous tissue as can occur with sclerosing peritonitis. In chemotherapeutic drugs (e.g. vincristine) may also cause
addition upper gut surgery (e.g. a vagotomy, Whipple’s reduced gut propulsion.
resection, gastro-enterostomy, bariatric procedures or any
bowel anastomosis) can result in secondary small bowel dys-
motility [8]. Functional Gastrointestinal Disorders
Radiation damage can cause strictures and a localised
obstruction and/or a generalised secondary dysmotility. Many of the symptoms of small intestinal dysmotility are the
Problems caused by radiation damage tend to be progressive same as for patients with other functional abdominal gastro-
over many years. intestinal disorders (e.g. irritable bowel syndrome, functional
dyspepsia, cyclical vomiting, functional bloating/distension,
functional constipation/diarrhea and centrally mediated dis-
Opioid and Other Drug Effects on the Bowel orders of gastrointestinal pain) [17].
The differentiation and overlap with these functional gas-
Opioid-induced bowel dysfunction (OBD) can result from trointestinal disorders is difficult. They all may have genetic
both opioid withdrawal and chronic opioid usage and mani- and psychosocial influences (early life trauma, life stresses,
fests with features of dysmotility (especially constipation) coping mechanisms, lack of social support etc.). In addition
when pain is not the dominant issue. The narcotic bowel syn- bacterial flora, inflammation, visceral sensation and motility
drome (NBS) may result from chronic usage and is defined may all contribute to the symptoms. In irritable bowel syn-
as chronic, worsening or frequently occurring abdominal drome there may be an overlap with enteric neuropathy as
pain despite continued or escalating doses of narcotics in increased lymphocytes have been observed in the jejunal
addition to dysmotility [9]. The opioid usage induces a myenteric plexus [18]. However, significant malnutrition is
hyperalgesic effect. It may be becoming more prevalent but rarely a consequence of these disorders.
it is often not recognised by clinicians [10, 11]. In addition to The treatment as for all dysmotility problems is to iden-
being acknowledged to occur in patients with gastrointesti- tify and treat the main symptoms. If weight loss has occurred
nal disease (functional or organic) it also occurs in patients nutritional support is given at the same time as therapies as
with no pre-existing gastrointestinal problems who take high for intestinal dysmotility. Significant caution should be exer-
doses of the opioids for other painful conditions (e.g. joint cised to avoid escalating to more invasive forms of nutrition
problems or following surgery). support in patients with functional symptoms, especially in
The components of therapy for NBS are recognition of pain predominant presentations, in the absence of objective
the disorder, a trusting therapeutic relationship with the features (e.g. no biochemical disturbance or who having a
patient, replacement using neuropathic type pain drugs and normal body mass index). Escalation of invasive intervention
controlled reduction in the opioid dose [12]. Specific drug in these patients risks causing iatrogenic problems, and in
treatments have been tried for OBD and NBS and include clinical practice does not appear to improve global function,
clonidine (to reduce withdrawal symptoms), and peripheral quality of life or symptoms.
mu opioid antagonists (naldemidine, naloxone, methylnal-
trexone, alvimopan) [13–15].
Opioids inhibit intestinal motility and so invalidate the Psychological/Psychiatric Problems
tests of small bowel motility. They may also increase the risk
of catheter-related blood stream infections (CRBSI) in Anorexia Nervosa
patients on long term PN. The American Psychiatric Association (APA) Diagnostic
Survivors of cancer treatment may have bowel dysmotil- and Statistical Manual of Mental Disorders (DSM-5) stated
ity which may be due to chemotherapy or opioid medication. in 2013 that to diagnose a person with Anorexia Nervosa
Their management may require a wider MDT input. they must display: (1) Persistent restriction of energy intake
Cyclizine is both an antihistamine and anti-cholinergic leading to significantly low body weight (in context of what
drug that acts as a centrally acting anti-emetic. There are is minimally expected for age, sex, developmental trajectory,
many reports of it being taken for its euphoric effect which is and physical health). (2) Either an intense fear of gaining
most marked when taken intra-venously. In addition to caus- weight or of becoming fat, or persistent behaviour that inter-
ing addictive behaviour, it is of a low pH and so damages feres with weight gain (even though significantly low
veins. It is not recommended for long-term use, especially in weight). (3) Disturbance in the way one’s body weight or
patients receiving PN [16]. shape is experienced, undue influence of body shape and
weight on self-evaluation, or persistent lack of recognition of weight and reported to improve when either the patient
the seriousness of the current low body weight [19]. becomes better nourished or a duodeno-jejunostomy (bypass)
However the patients that present to gastroenterologists is formed to avoid the obstruction. The symptoms attributed
often do not have this typical presentation. Delayed gastric to this are post-prandial epigastric pain, nausea/vomiting and
emptying, especially of solid, and delayed small and large loss of weight [29–33]. Whether this is cause or consequence
bowel transit have been described in patients with anorexia of malnutrition and whether it is a radiological rather than
nervosa [20–23]. There is a report of a patient having a mega- true clinical entity remains contentious and some clinicians
duodenum and no propagating migrating motor complexes dispute its existence and think it is over diagnosed. The risks
(MMC) which both improved with an increased nutritional of any surgery should be very carefully considered especially
intake [24]. as the benefits of surgery are not always predictable or clear.
Avoidant/Restrictive Eating
Some patients who have had psychosocial problems in the ypermobile Ehlers-Danlos Syndrome (EDS)
H
past may have disordered gut motility partly due to a disor- (Joint Hypermobility Syndrome or Ehlers-
dered eating pattern, undernutrition and the drug treatments Danlos Syndrome Hypermobility Type)
which they received [25]. The Avoidant Restrictive Food
Intake Disorder (DSM 5) is an increasingly recognized con- Hypermobile EDS with its gastrointestinal associations is
dition in patients with neurogastroenterology and malnutri- difficult to classify as most patients with EDS do not have a
tion presentations and is best managed with a nutritional and dysmotility of the small bowel, but mainly visceral hyper-
psychological rehabilitation approach. sensitivity. Its symptoms may mimic dysmotility (neuropa-
thy) and the presence of EDS can contribute to dysmotility,
sychiatric Disorders and Psychological Distress
P usually if postural tachycardia syndrome (PoTS), or other
Other major psychiatric disorders can be encountered, some- associated factors such as opiates are present. According to
times masquerading as or confounding a dysmotility diagno- the 2017 classification patients previously diagnosed with
sis [26]. It is not uncommon for some of these patients to be joint hypermobility syndrome and Ehlers-Danlos Syndrome-
referred to an Intestinal Failure (IF) unit. Psychological dis- Hypermobility Type were reclassified as hypermobile
tress is common (Table 1) and so an MDT approach, includ- Ehlers-Danlos Syndrome (hEDS) if they met the strict crite-
ing both clinical psychology and liaison psychiatry expertise ria or Hypermobile Spectrum Disorders (HSD) if they had
is ideal. many but not all of the characteristics of hEDS [34]. Patients
with hEDS and HSD represent a third of patients referred to
a tertiary neurogastroenterology clinic in the UK and these
Effect of Undernutrition on Gut Function patients tended to be young, female with a poor quality of
life [35]. hEDS/HSD is associated with a range of gut disor-
Malnutrition itself can impair gut function and cause malab- ders (acid reflux, abdominal pain (especially typical is pain
sorption with mucosal atrophy, reduced gastric acid and pan- after eating or when any food arrives in the gut even from an
creatic enzyme secretion and more bacterial colonization of enteral feed) and constipation) [36]. There is often auto-
the upper gut [27, 28]. The effects of undernutrition upon gut nomic dysregulation, particularly PoTS [37], chronic urinary
motility and histological appearance are uncertain. retention due to a failure of the urethral sphincter to relax
There is a large literature on the superior mesenteric (Fowler’s syndrome), and hypoglycaemia [35]. Mast cell
artery syndrome (Wilkie’s syndrome) in which the third part activation disorder [37] is being increasingly reported (most
of the duodenum is compressed between the superior mesen- commonly in those having PoTs) but is poorly defined and
teric artery and the aorta (when the left renal vein is com- not often objectively confirmed. An increasing number of
pressed it is referred to as ‘nutcracker syndrome’). It is patients with joint hypermobility and gut dysmotility are
reported to be prevalent in patients who have suddenly lost being seen by nutrition support teams because of weight loss
and malnutrition. This group seems especially sensitive to
opioids and cyclizine both of which can exacerbate/mimic
Table 1 Contributing psychological factors
all of their symptoms [16]. It is currently unclear the degree
• Delay in diagnosis
to which the association of hypermobile EDS with gut symp-
• Poor knowledge within the medical community
• No cure toms encompasses specifically any greater degree of chronic
• Pain and problems of analgesic drugs (including addiction) small intestinal dysmotility, nor whether there are any differ-
• Anxiety, depression, somatisation, poor coping, sickness role ent treatment approaches to patients without hypermobile
• Interaction with family, carers and job leading to low self-esteem/ EDS who have the same functional symptoms and it seems
confidence/mood to be more prevalent in presenting to intestinal failure units
in the UK than the rest of Europe. The same cautions there- loss of processes and damaged intracellular cytoskeleton and
fore should apply when considering escalating invasiveness organelles as revealed by immunohistochemical analysis and
of nutrition support in this group as to that of functional gas- electron microscopy. It may be that abnormalities with the
trointestinal disorders in general, especially if there is a pain ICC are the primary event or may result from a neuropathy.
predominant presentation. In Fig. 1 these patients have been In baby’s, immaturity may result in delay in maturation of
inco-orporated into the idiopathic dysmotility group but may ICCs that can lead to the appearance of a reduction in these
represent a mainly pain sensitivity problem rather than true cells, so care needs to be taken with the histological diagno-
dysmotility. sis. (1) As conditions specifically falling into this category
are few, this chapter will only discuss conditions tradition-
ally classified as a myopathy of neuropathy. In general, a
Pathophysiology myopathy results in a dilated non propulsive gut and includes
those termed chronic intestinal pseudo-obstruction (CIPO).
The propulsive failure of pseudo-obstruction is usually a A neuropathy more generally results in hypersensitivity and
consequence of either temporary dysfunction or irreversible poorly co-ordinated bowel contactions (often increased)
damage to enteric neural networks (neuropathy), or less fre- without bowel dilatation and is often referred to as enteric
quently, to disease of the effector system (myopathy). The dysmotility (Fig. 2, Table 2).
pathophysiological basis of pseudo-obstruction is propulsive It can be hard to determine if a condition is primarily a
failure. In this context, the term ‘motility’ is confusing, myopathy or neuropathy as some secondary conditions (e.g.
because it refers to both transit and to the contractile activity systemic sclerosis, vasculitis or amyloid) may appear as
of the gut. Clearly when there is reduced transit, there is, in
one sense, ‘reduced motility’. In the small bowel, however,
the most common motor abnormality, in impaired propul-
sion, is an overall increase in the incidence of contractions; Table 2 Classification of intestinal dysmotility
this can be regarded as ‘increased motility’. The increased Myopathies
activity, probably due to a reduction in the inhibitory neural Primary
input, is obstructive rather than propulsive. This explains Familial
Hereditary myopathy (e.g. Hollow visceral myopathy)
why ‘prokinetic’ drugs, which are designed to increase con-
Acquired
tractile activity, are usually ineffective in treating propulsive Auto-immune
failure. Jejunal diverticulosis
In the small bowel, the abnormal contractile activity Secondary
results in distortion of the fasting migrating myoelectric Systemic sclerosis [and other connective tissue disorders (e.g.
complex (MMC) pattern. This is most easily seen during SLE)]
Amyloidosis
nocturnal sleep, when fasting activity is always present and
Chronic irradiation damage
consists largely, in health, of alternating sequences of quies- Muscular diseases
cence and the ‘migrating’ contractions of phase III. In pro- Muscular dystrophies
pulsive failure, the nocturnal motor quiescence is replaced Myofibrillar myopathies (e.g. Desmin myopathy)
by intermittent single or clustered contractions. Phase III Hereditary inclusion body myopathies
episodes are prolonged in duration, and ‘migrate’ more Metabolic storage disorder
slowly; phase III may even be altogether absent. In the colon, Neuropathiesa
Primary (intrinsic)
the high amplitude propagated contractions that usually
Familial/Congenital/Developmental
occur 2–6 times daily are reduced in chronic constipation. Hirschprung’s disease
Neurofibromatosis
Mitochondrial disorders (MNGIE, DNA depletion, Alpes or
lassification of Chronic Small Intestinal
C Pearson’s syndromes)
Dysmotility Neuronal dysplasia
Infant colic (Developmental)
Auto-immune
There are three major histopathological entities recognised—
Anti-neuronal antibodies
myopathies, neuropathies and mesenchymopathies depend- Ganglionosis
ing respectively upon the predominant involvement of Infective
smooth muscle cells, enteric neurons or the interstitial cells Chaga’s disease,
of Cajal (ICC). Mesenchymopathies, which involve ICC, Herpes viruses (e.g. EBV, CMV, VZV) or
which are the gut pacemakers, are being recognised. The Polyoma viruses (JC virus)
abnormalities described include a decreased ICC density, (continued)
Table 2 (continued) radiological, isotopic, manometric and histologic diagnoses

Secondary (extrinsic) may be different.
Generalised neurological disorders
Brain stem lesions
Spinal cord injury
Myopathies
Multiple sclerosis
Parkinson’s disease
Neurological effects of diabetes mellitus Primary myopathies most commonly occur in children and
Autonomic system degeneration young adults and are often familial (genetic). Myopathies
Paraneoplastic syndromes [often with anti-neuronal antibodies often have multivisceral involvement and thus a relatively
(especially anti Hu)] high mortality. They may show reduced propulsive activity
Small cell lung cancer on manometry (Fig. 3b) and in the most severe form they are
Carcinoid
associated with massive gut dilatation (CIPO). Many pre-
Neuroblastoma
Thymoma dominantly affect the circular muscle (except hollow vis-
Drugs/toxins ceral myopathy). Primary myopathies are more common in
Vincristine, adriamycin children whereas secondary myopathies are more common
Antidepressants, Ca channel blockers, anti-cholergic drugs in adults.
Opiates
Clonidine
Izoniazid
Primary Myopathies
Other
MEN IIb
Porphyria (Acute intermittent) Primary myopathies are due to abnormalities in enteric mus-
Fabry’s disease cle (e.g. hollow visceral myopathy or autoimmune myopa-
Note: in most cases an empirical working diagnosis of idiopathic dys- thy). There has been interest in reduced immunostaining of
motility will be applied alpha-isoactin in jejunal circular muscle, observed in one
a
Histology is generally inflammatory or degenerative [38] then 28 more patients (overall 24% of patients having
full thickness jejunal biopsies) [39]. However it is not clear if
both. The end result of a neuropathy is often dysfunctional this is the primary pathology or secondary to other factors
enteric muscle which occasionally can dilate, as in a myopa- (e.g. drugs, undernutrition or previous surgery) or a normal
thy. Overall a neuropathy (often a secondary one) is more anatomical variant, and therefore not a specific finding [40].
common than a myopathy in causing small bowel dysmotil- Precise information as to the location of the biopsy—jeju-
ity. The diagnosis can be difficult to define partly because the num or ileum is essential for interpretation in this context.
a b
Fig. 3 (a) Plain abdominal radiograph of a patient with visceral myopathy. Note huge duodenal loop. Kindly supplied by M.A. Kamm. (b) Dilated
small bowel in patient with visceral myopathy. Kindly supplied by N. Wyer
Familial
Hollow visceral myopathy is the best know example of a
familial visceral myopathy. It is a rare congenital disorder
that usually presents in the first or second decade of life and
in addition to gross dilatation of the gastrointestinal tract
(Fig. 3) (that often starts with a megaduodenum) there may
also be associated dilatation of the urinary tract and associ-
ated frequent urinary tract infections [41–43]. The disease
has been reported to follow an autosomal dominant mode of
inheritance [44, 45]. In infants other features may include
malrotation, pyloric stenosis and bladder atony. There is a
loss of enteric smooth muscle with vacuolar degeneration
and fibrosis [46]. The longitudinal muscle is predominantly
affected. This may be due to the transformation of smooth
muscle cells to collagen synthesizing myofibroblasts [47]. In
one study of adult patients four of six patients had urinary
tract involvement with dilatation of the ureters and/or incom-
plete bladder emptying [41].
Acquired-Autoimmune Myopathy
A few cases only of a lymphocytic enteric leiomyositis
involving the smooth muscle cells have been reported [48–
50]. Eosinophilic leiomyositis has also been reported, and in
this context must prompt investigation for parasites, includ-
ing dog hookworm.
Jejunal Diverticulosis
Fig. 4 Abdominal radiograph of a patient with progressive systemic
Diverticula in the jejunum usually result from congenital sclerosis. Kindly supplied by E.A. Quigley
abnormalities or dysmotility (e.g. disordered high pressure
bowel contractions) and may be associated with sub-clinical
systemic sclerosis. Careful examination of any respected function and fibrosis. While systemic sclerosis patients with
specimen should be carried out to examine the muscle and gross gastrointestinal involvement present in the terminal
nerve layers of the bowel wall both in the region of the diver-
phase of the illness, this is not always the case and some
ticula and adjacent bowel. present with the gastrointestinal involvement early in the dis-
ease without cutaneous involvement and the disease may not
progress for many years. The clinical outcome in elderly
Secondary Myopathies scleroderma patients is the poorest of all adult onset dys-
motility patients [54]. However, where indicated, long term
Secondary myopathies occur as part of a multi-system dis- PN can offer a safe and effective means of nutritional support
ease (e.g. systemic sclerosis, amyloid, chronic irradiation in patients with severe small bowel involvement [55]. Other
damage or muscular diseases) [51]. The problems of pseudo- connective tissue and rheumatological disorders have been
obstruction are often only clinically apparent towards the associated with dysmotility including SLE, RA and Stills
end of the illness when nutritional support may be needed. disease [56, 57].
ystemic Sclerosis (Scleroderma) and Other

S Amyloidosis
Connective Tissue Disorders The primary type distribution may be associated with gut
Most patients with systemic sclerosis do get gastrointestinal involvement. The most common underlying diagnosis is
involvement (Fig. 4) particularly of the oesophagus [52]. myeloma (often producing lambda chains). While classified
While the end result and main pathology is smooth muscle as a myopathy it can also cause neurological damage and,
atrophy and gut wall fibrosis [53] it may start with microvas- like systemic sclerosis, may cause both a myopathy and a
culature damage due to collagen deposits and inflammation neuropathy. The rectum can be spared and so duodenal sam-
which cause neural damage that progresses to muscle dys- pling should also be considered. Any full thickness biopsy
for motility investigation should also be examined for amy- tive enteric neuropathies will remain idiopathic. Inflammatory
loidosis. Genetic testing is now readily available for the neuropathies may include both plexitis and neuritis, and can
hereditary type of amyloidosis which may present more be lymphocytic or less commonly eosinophilic, the former
commonly in men and with peripheral neuropathy and car- promoting autoimmune screening, the latter investigation for
diac as well as gut involvement. parasites.
Manometry may show intense but apparently uncoordi-
hronic Irradiation Damage
C nated motor activity with no propulsive contractions (Fig. 3c)
This usually occurs after pelvic irradiation for gynaecologi- and there may be no fasting MMC.
cal cancers or genital-urinary cancers. The sigmoid and ter-
minal ileal areas are often most involved. However, the Primary Neuropathy
whole small bowel can be involved giving rise to a pseudo- The enteric neuropathies can affect both the submucosal and
obstruction picture or as discrete areas of strictures. Surgery myenteric plexuses, but the myenteric plexus is predomi-
is very difficult and has a high risk of an enterocutaneous nantly affected. The term visceral neuropathy is used for pri-
fistula(s) being created. Gut permeability, secretion, motility mary intrinsic enteric nervous damage.
and blood supply can all be affected giving rise to any or all
of the following: malabsorption, protein losing enteropathy, Congenital/Familial/Developmental
diarrhoea, perforation/fistulas, bleeding and obstruction. Familial visceral neuropathies include Hirschprung’s dis-
These problems can all occur months or years after more ease, mitochondrial cytopathies and Von Recklinghausen’s
than 50 Gy irradiation has been given. The irradiation is disease. Hirschprung’s disease can affect any part of the gut.
more likely to give problems if a patient is already malnour- Mitochondrial disorders are relatively common if specifi-
ished, has diabetes mellitus, hypertension or a vasculitis cally sought. One study showed 19% of 80 adult patients
[58]. labelled as CIPO to have this [61]. Mitochondrial cytopa-
thies such as mitochondrial neurogastrointestinal encephalo-
Muscular Diseases myopathy (MNGIE) (the most common) (also referred to as
Myopathies may occur associated with congenital muscular Thymidine Phosphorylase Deficiency) is an autosomal
disorders (muscular dystrophies, myofibrillar myopathies recessive disorder characterised by severe gastrointestinal
(e.g. Desmin myopathy), hereditary inclusion body myopa- dysmotility (including bacterial overgrowth and lactic acido-
thies) but the muscle weakness (and often cardiac problems) sis); cachexia, and neurological problems including leukoen-
dominates the clinical picture though gastrointestinal prob- cephalopathy (96%), polyneuropathy (96%),
lems if sought are common. Metabolic storage disorders can ophthalmoplegia (91%) (with ptosis) and hearing loss (55%)
have a myopathic process and occasionally can be treated [62, 63]. The disease is caused by mutations in the thymidine
with specific enzyme-replacement therapy [59]. phosphorylase (TP) gene. Gastrointestinal dysmotility is the
most prominent manifestation, with recurrent diarrhoea and
symptoms of obstruction. Patients with MNGIE present
Neuropathies between the first and third decade (mean age 18 years) [64]
and usually have a much reduced life expectancy and tend to
An enteric neuropathy may occur as a primary pathology die in early adulthood (mean 37.6 years; range, 26–58 years).
(congenital, autoimmune or infective), secondary to a gener- It, like all mitochondrial defects, can be tested for by plasma
alised neurological disorder, paraneoplastic process, meta- and urine thymidine deoxyuridine, white cell thymine phos-
bolic disorder (e.g. diabetes) or drugs/toxins or as a phorylase, the Tymp gene, MR brain scanning and muscle
developmental abnormality. Visceral neuropathy is less well biopsy.
reported in the literature than visceral myopathy. Visceral
neuropathy is commonly acquired in adulthood or in old age Autoimmune
and is associated with a high morbidity usually due to factors Auto-antibodies directed at enteric neurons, usually neuro-
other than the neuropathy. Luminal dilatation is rarely seen nal ion channels (e.g. voltage-gated potassium channels) can
except at the end stage of the disease. occur as a paraneoplastic phenomenon, when the anti-
Two forms of pathology are found either enteric neural neuronal nuclear antibody (ANNA-1 or anti-Hu) is most
degeneration (in the absence of inflammation) or inflamma- commonly found, and antineuronal antibodies can occur in
tory [60]. Degenerative neuropathies can result from mito- non-paraneoplastic motility disorders [65–67]. Other auto-
chondrial dysfunction and the pathological findings include antibodies associated with dysmotility include acetyl cholin-
neuronal swelling, intranuclear inclusions, axonal degenera- esterase receptor antibody (AchR) (ganglionic, nicotinic and
tion and hypoganglionosis. The aetiology of many degenera- M3 type), antibodies against the voltage gated potassium
channel-complex (VGKC-complex), voltage gated calcium 5 (CV2) and AchR auto-antibodies have also been associated
channel antibodies (VGCC), smooth muscle and with paraneoplastic dysmotility and should prompt a careful
gonadotropin-releasing hormone (GnRH) [57]. The pathoge- search for occult malignancy [57].
netic role of auto-antibodies is currently however unclear.
Coeliac disease has also been implicated in some cases of Drugs/Toxins
dysmotility. Vincristine is directly neurotoxic and causes a visceral neu-
ropathy. Anticholinergics (e.g. phenothiazines and tricyclic
Infective anti-depressants) have been associated with severe dysmotil-
Both herpes (Epstein-Barr virus and cytomegalovirus) [68] ity. A case series of 102 life-threatening episodes of
and polyoma viruses [John Cunningham (JC) virus] [69, 70] clozapine-induced gastrointestinal dysmotility episodes
have had their DNA isolated in the myenteric plexuses of were collated with some evidence for dose dependence [76].
some patients with visceral neuropathy. They may be caus- A number of other drugs have been associated with severe
ative agents rather than innocent bystanders, but this has yet dysmotility, which, in most cases, improves with stopping
to be proven. Chagas’ disease (South American trypanoso- the drug or reducing the dose; these include baclofen, buse-
miasis) typically causes a megaesophagus and megacolon. relin, clonidine, fludaribine, phenytoin and verapamil. Lead
Chagas’ enteropathy is common and gives rise to dyspepsia, poisoning can be a rare reversible cause [57].
intestinal pseudo-obstruction with bacterial overgrowth [71].
Lyme disease and botulism have also been reported as revers- Idiopathic
ible causes of dysmotility. In the majority of patients and in most centres, the precise
aetiology of chronic severe intestinal dysmotility is not char-
Secondary Neuropathy acterised histopathologically and remains based on the clini-
The neuropathic process may affect the nerves external cal presentation, physiological testing and exclusion of
(extrinsic neuropathy) to the gut and so indirectly affect gut obstructive and mucosal disease. This in part reflects a low
motility or may be part of a generalised illness. Indeed, most uptake of full thickness biopsies outside of the context of
cases of visceral neuropathy are part of a generalized neuro- stoma formation or other surgical intervention. In selected
logical disorder rather than a primary neuronal disorder of populations of PN dependent patients with dysmotility, high
the gastrointestinal tract. rates of full thickness biopsies were associated with high
rates of neuromuscular abnormalities of which 2/3 were pri-
Generalised Neurological Disorders mary and 1/3 secondary causes, although not all biopsies
Disorders of the parasympathetic or sympathetic nerves that yielded a diagnosis. The threshold and acceptability of full
innervate the gut (including autonomic system degeneration thickness biopsy testing, especially as most will not lead to a
and the neurological effects of diabetes mellitus (most com- change in management, has not currently achieved consen-
mon) and other endocrine or metabolic disorders) can indi- sus. There also remain some unresolved issues for gastroin-
rectly cause gut dysmotility. Brainstem lesions, spinal cord testinal neuromuscular pathology standardisation and
injury, multiple sclerosis, Parkinson’s disease (basal ganglia interpretation [57]. For the near future therefore it is likely
calcification) and leukoencephalopathy can all affect gut that the aetiology in the majority of dysmotility patients will
motility [72, 73]. A lymphocytic leiomyositis and myenteric remain idiopathic.
ganglionitis have been described in the ileum of children
with cystic fibrosis and distal ileal obstruction [74].
Myotonic dystrophy, multiple sclerosis, Parkinson’s disease hysiological Consequences of Severe Small
P
and porphyria may all be associated with an enteric Intestinal Dysmotility
neuropathy.
I mpairment of Coordinated Gut Contractions
Paraneoplastic and the Migrating Myoelectric Complex
Small cell lung cancer, carcinoid tumours, neuroblastoma
and thymoma with anti-neuronal nuclear antibodies have all If the migrating myoelectric complex (MMC) is impaired,
been described to cause an enteral neuropathy. There is often then the small bowel will not be cleared of debris predis-
a dense inflammatory infiltrate of lymphocytes and plasma posing to gut stasis and bacterial overgrowth. With enteric
cells affecting both plexuses but mainly the myenteric neuropathies gut co-ordination is disrupted and the pres-
(myenteric ganglionitis). Anti-Hu neuronal antibody is char- ence of chyme in the small bowel can cause severe painful
acteristic [75]. Removal of a thymoma may result in resolu- non-propulsive large contractions. This is one of the causes
tion of the dysmotility and the patient gaining weight. CRMP of abdominal pain shortly after eating.
Gut Stasis longed sleeping, reduced sexual function, a low body tem-
perature and a propensity to develop infections which are
The failure of forward propulsion may also cause constipa- potentially severe [78]. In the gut, malabsorption with muco-
tion, and this is often the first symptom. Gut stasis results in sal atrophy, reduced gastric acid and pancreatic enzyme
abdominal distension and if much fluid accumulates (oral secretion and more bacterial colonization of the upper gut
intake and normal gut secretions) it may produce a large vol- can occur though the experimental backing for this is inferred
ume vomit. The vomit may be faeculent and contain food from studies in patients with anorexia nervosa [20–24].
debris from several days previously.
linical Features of Chronic Small Intestinal

C
Bacterial Overgrowth and Malabsorption Dysmotility and Management Plan
The combination of a dilated gut with reduced propulsion istory, Examination and Blood Tests
H
and ineffective MMC allows anaerobic bacteria to proliferate The clinical history and examination should determine if
in stagnant loops of bowel. This bacterial overgrowth results there are associated systemic neuromuscular, connective tis-
in bile salts being deconjugated, less effective secondary bile sue, or endocrine diseases (muscular diseases, neurological
acids (e.g. lithocolic acid) being made and pancreatic enzyme disease, storage diseases, systemic sclerosis, diabetes melli-
degradation occurs so that steatorrhoea and malnutrition tus, irradiation etc.) and thus if the myopathy or neuropathy
may occur. Associated with steatorrhoea is malabsorption of is a primary or secondary disorder. Exploring the family his-
the fat-soluble vitamins A and E (less so D and rarely K) tory will detect some congenital diseases as will asking about
with deficiency symptoms (night blindness, poor colour foreign travel (Chagas disease). Examination especially
vision, dry flaky skin and ataxia). Vitamin B12 may be malab- includes the neuromuscular system and testing for joint
sorbed but both folic acid and vitamin K can be manufac- hypermobility. Autonomic neuropathy should be considered
tured by the bacteria and so may give rise to high serum if orthostatic, pupillary or sudomotor (sweating) dysfunction
levels. accompanies dysmotility. Simple clinical bed-side assess-
Occasionally the bacteria can manufacture d-lactic acid ment of orthostatic pulse rate change (lying to standing) may
(normally l-isomer) giving rise to d-lactic acidosis (high identify PoTs.
anion gap acidosis) and other bacteria can manufacture Symptoms need to be listed in order of importance to the
ammonia which may appear in high levels in the blood. patient, and a record made of all the drugs currently taken or
Small intestinal bacterial over growth (SIBO) is when that have been taken for long periods (especially opioids and
excess micro-organisms are present in the small intestine and cyclizine).
lead to a malabsorption syndrome with occasionally a pro- A basic nutritional assessment will include measuring the
tein losing enteropathy. Subtotal villous atrophy may be patient’s height and weight and asking their usual weight in
found on histology. There are several endogenous mecha- health and their weight change over the last 2 weeks, 3 and
nisms for preventing bacterial overgrowth: gastric acid secre- 6 months. From these their body mass index and percentage
tion, intestinal motility, intact ileo-caecal valve, intestinal weight loss can be calculated. In addition, they are asked
immunoglobulin secretion and bacteriostatic properties of about recent changes in their food intake.
pancreatic and biliary secretions. The aetiology of SIBO is The ideal logical sequence in the diagnosis of these
usually complex, associated with disorders of these mecha- patients is:
nisms. In some patients more than one factor may be
involved. • The confirmation that there is abnormally impaired transit
There is currently no gold standard for diagnosis of SIBO of luminal content
and the commonly available methodologies (the culture of • The identification of the region of the bowel that is
jejunal aspirates and a variety of breath tests) are limited by affected
large variations in their performance and interpretation [77]. • The identification of the propulsive abnormality
• The identification of specific pathology.
Problems of Undernutrition A management plan is made, including tests to help make the
diagnosis (Table 3). Blood tests will include routine blood
Patients who rapidly lose more than 10% of their body count, renal (including potassium and magnesium), liver,
weight frequently have demonstrable physiological changes bone chemistry, thyroid function, glucose, myeloma screen,
which include, skeletal and cardiac muscle weakness, poor anti-tissue transglutaminase (for Coeliac disease). Nutritional
concentration and mental function including memory, pro- measures if undernourished or steatorrhoea include vitamin
Table 3 Management plan for small intestinal dysmotility for amyloid. Steatorrhoea will be detected, and constipation/
1. Determine and order the primary symptoms diarrhoea confirmed. Basic tests of autonomic function
2. Exclude mechanical obstruction (CT abdomen with oral contrast) include lying and standing systolic blood pressure and heart
3. Evaluate other contributing factors: drug therapy (e.g. opioids, rate with electrocardiogram (ECG) confirmation.
cyclizine and anti-cholinergics), psychosocial (may need formal
psychological/psychiatric assessment) and quality of life issues
Diagnosis made by radiology (contrast follow through,
4. Nutritional assessment (BMI, percentage weight loss and other MRI and isotope studies), manometry and/or histology.
anthropometric tests)
5. Start nutritional treatment if necessary and consider/treat Myopathy
refeeding risks Symptoms include chronic abdominal pain, abdominal disten-
6. Perform specific blood tests to help establish aetiology and
sion and bloating, early satiety, recurrent nausea and vomiting
consider tests of autonomic function
(a) Screen for hypothyroidism, coeliac disease and diabetes. and alternating diarrhoea and constipation. Without treatment,
(b) Chest X-ray (or CT/PET CT) for thymoma or other weight loss and protein-energy malnutrition may ensue [78].
neoplastic conditions (e.g. small cell carcinoma of lung) The symptoms in 28 patients with a probable enteric myopa-
(c) Antibodies for scleroderma (anti-centromere, anti Sc170, anti thy were abdominal pain (100%), distension (82%) nausea/
M3R) and other connective tissue disorders (ANA, ANCA, anti
vomiting (79%), constipation (61%) and diarrhoea (21%);
DNA, anti SMA)
(d) Antibodies that may be associated with paraneoplastic weight loss occurred in 36%, 5 of whom were given parenteral
diseases (mainly small cell carcinoma and thymoma). These support [39]. The vomiting may be faeculent and often of
include type 1 anti-neuronal nuclear antibody (ANNA-1 “anti high-volume giving rise to a risk of pulmonary aspiration.
Hu”), anti-collapsin response mediator protein 5 (anti CRMP-5 In hollow visceral myopathy (HVM) in addition to the
also known as anti CV2), ganglionic acetyl cholinesterase
receptor antibody (AChR antibody) especially if autonomic features above patients have a very dilated small bowel. They
dysfunction [49], and anti-voltage gated potassium channel may have urological complaints including bladder-emptying
(VGKC)-complex antibodies dysfunction [41–43]. Children with HVM may present at or
(e) Test for mitochondrial disorders with plasma and urine before birth with hydronephrosis, megaureters and megacys-
thymidine and deoxyuridine, WBC thymine phosphorylase. If
there is a high suspicion then test for the TYMP gene and also
tis, or in the first year of life with constipation and episodes
screen for related diseases (e.g. “MELAS” (mitochondrial of intestinal pseudo-obstruction [41, 42]. The presence of
encephalopathy with lactic acidosis and stroke-like episodes) digital arches on fingerprint, mitral valve prolapse, joint lax-
with the m.3243A>G mutation). Muscle biopsy and sequencing ity and constipation before age 10 years all favour the diag-
of mitochondrial genome may be considered
nosis [72]. HVM may present at any age, but early adulthood
7. Therapeutic plan/objectives of care to address patient’s
symptoms, nutritional status, psycho-social issues and quality of is most common [44, 45].
life Signs of autoimmune disease (arthropathy, Raynauds dis-
8. Try to establish a clinical diagnosis (or probable one). Perform ease or proteinuria) may suggest a secondary myopathy, or
physiologic assessment of the parts of the gastrointestinal (GI) the pseudo-obstructive syndrome associated with sclero-
tract that may be involved. These are done when nutritional
status is near normal and the patient is off drugs likely to affect
derma may be declared by the cutaneous manifestations of
GI motility. Consider full thickness jejunal biopsy this disease.
9. Consider surgical options
10. Regular review and reconsider diagnosis as the clinical situation Neuropathy
changes. Treat the predominant symptom/problem Many of the features are the same as for a myopathy particu-
larly with severe abdominal pain after food however abdomi-
A, E, D, INR, iron, ferritin. B12, red blood cell folate, sele- nal distension is often absent and the plain abdominal
nium, zinc and copper. Consideration is given to requesting radiograph may appear normal [79].
auto-antibodies associated with connective tissue disorders
and neoplasia (especially anti-neuronal antibodies) and tests Radiological Tests
for mitochondrial disorders. The diagnosis is usually first suspected after plain abdominal
In MNGIE (a mitochondrial disorder) direct evidence is radiographs have shown a dilated small and large bowel.
provided by a plasma thymidine concentration greater than Once suspected, investigations aim to confirm that there is
3 μmol/L and a plasma deoxyuridine concentration greater impaired transit of luminal contents, to identify the region of
than 5 μmol/L. Thymidine phosphorylase enzyme activity in the bowel affected, ideally to identify the propulsive abnor-
leukocytes will be less than 10% of the control mean. mality and to show a specific pathology [4]. Investigations
Molecular genetic testing of TYMP, the gene encoding thy- help establish the presence of intestinal pseudo-obstruction
midine phosphorylase, detects mutations in affected and may delineate an underlying cause. In practice the diag-
individuals. nosis is often presumed after several laparotomies have
Rectal examination with an unprepared sigmoidoscopy excluded a physical obstruction, although computerised
will identify stool consistency and colour and permit biopsy tomography/barium follow through/MR enterography
excluding a transition point in a diffusely distended small Breath tests to diagnose bacterial overgrowth may be mis-
bowel suggests CIPO and may prevent unnecessary laparot- leading and produce false negative results compared to cul-
omy. Computerised tomography (CT) may also help distin- ture of small bowel aspirate [77, 85]. This has in part been
guish severe dysmotility from functional bloating due to due to broad variations in how these tests are performed and
abdomino-phrenic dysinergia [80]. Dynamic magnetic reso- interpreted. Recent work in the UK and US has taken place
nance imaging (MRI) of the small bowel is becoming to develop evidence based consensus guidelines for breath
increasingly helpful [81, 82] though is less established. MRI testing in terms of dose of substrate (75 g glucose, 10 g of
brain can be helpful in the diagnosis of MNGIE [55]. lactulose) and cut off values. In addition, whilst hydrogen
The measurement of whole gut time can be measured by only breath testing was previously used, modern testing pro-
serial X-rays of ingested radio-opaque markers (small tocols have incorporated the measurement of methane.
lengths of barium-impregnated polyvinyl tubing). Increased intestinal methane levels have been associated
Small bowel transit using a barium follow-through exami- with delayed small bowel transit as measured by scintigra-
nation will usually give some indication of accelerated or phy and therefore should be measured in patients with sus-
delayed transit and a dilated duodenal loop (megaduodenum) pected small bowel dysmotility to improve the tests utility
may be one of the earliest signs of visceral myopathy [4]. In [85]. Other tests that may indicate bacterial overgrowth
addition in HVM there may be oesophageal aperistalsis and include raised urinary indicans, blood d-lactate or alcohol
variable dilatation of the small and large bowel. levels.
Radioisotopic Investigations Manometry

Gastric emptying can be measured using gamma scintigra- Intraluminal pressure sensors incorporated into a catheter
phy to obtain serial images of labelled solid (scrambled eggs, can detect the patterns of contractile events. For the diagno-
liver or pancake), semi-solid (thick soup) or liquid (orange sis of pseudo-obstruction, the logical investigation is small
juice) meals in the stomach. Gastric emptying measurements bowel manometry. Small bowel motor activity was initially
may be helpful in determining whether the stomach is studied using multi-lumen perfused tube systems, with a
involved in a generalised disorder of propulsion or a local- pump and strain gauge transducers external to the patient
ised one (e.g. Chagas’ disease). These isotopic meals can be [86]. This gave information on motor activity in the antrum
extended to measuring the transit of the meal through the and proximal duodenum, and detected abnormal motility
small bowel and if the isotope has a long half-life oro-caecal [87] and some types of pseudo-obstruction [88, 89]. This
and colonic transit may be determined. Liquid meals may technique required the patient to remain in a laboratory
not clearly demonstrate an abnormality. attached to a machine for more than 6 h and was not good at
recording fasting, and postprandial activity (Fig. 5) [90].
Endoscopic Tests An alternative is the wireless motility capsule (WMC)
Jejunal aspirate for bacterial overgrowth is infrequently per- which is an ambulatory, minimally invasive diagnostic
formed but usually by endoscopy (or fluoroscopy with jeju- modality that allows continuous assessment of intraluminal
nal intubation). A clinically significant overgrowth is when pH, temperature, and pressure during its transit through the
counts exceed 105/mL (usual is less than 104/mL). Common gastrointestinal tract. The technology allows for both mea-
species include bacteroides, enterooccus and lactobacillus. surement of transit times in multiple regions of the upper and
But most of the bacteria likely to be relevant in causing lower gastrointestinal tract, as well as pressure profiles in the
symptoms cannot be cultured. Endoscopy also has a role in antro-duodenum. The standardised equipment and proce-
mucosal sampling and palliative venting. Capsule endoscopy dures in WMC allow the comparisons of data across multi-
examination can rarely give transit information but is seldom centers. The role of the technology has been best established
used due to the risk of the capsule being retained and some in the evaluation of a large number of healthy volunteers [91]
regard it as contraindicated. and in patients with suspected gastroparesis and suspected
chronic constipation. The worry with this is technique in
on-invasive Investigations of Gut Transit
N these patients is that the capsule may remain in the bowel
Orocaecal transit can be measured using the rise in breath and not be passed. However, a paper in patients with Crohn’s
hydrogen due to the degradation of ingested polysaccharides disease has shown that the same precautions used when con-
(e.g. lactulose), in health this is caused by caecal bacteria sidering patients for capsule endoscopy (i.e. clinical and
fermenting the ingested agent but this is unhelpful if there is radiological assessment and use of a patency capsule) can
propulsive failure as small bowel bacterial overgrowth is mitigate much of the risk in potential WMC patients [92].
common and is not a recommended test for this application Twenty-four hour ambulatory jejunal manometry [93]
[83, 84]. It is also unhelpful following a significant small uses a catheter with built-in miniature strain gauge transduc-
bowel resection or if there is an enteric fistula. ers [94] and records data to a solid-state digital recorder [95].
Fig. 5 (a) Fasting antro- a

duodenal motor activity from
a control subject.
Simultaneous recording of
antral (top three channels) and
duodenal (lower three
channels) motor activity
demonstrates the sequential
phases of the Migrating
Motor Complex (MMC). The
sequence begins, on the left,
with phase II, irregular
activity, is followed by phase
III a period of uninterrupted
phasic activity which migrates
along the intestine and b
finishes with phase I, motor
quiescence. (b) Recording
from a patient with a visceral
myopathy, at a similar
moment in an MMC cycle as
in (a); in this instance,
however, the amplitude of
individual contractions in the
antrum (top two channels)
and the duodenum (bottom
four channels) is markedly
reduced through the
organization of motor events
is preserved. (c) Recording
from a patient with a visceral
neuropathy, again taken at a
similar moment in the MMC c
cycle. The tracing features
intense but apparently
uncoordinated motor activity.
In this example the phase III
seen in the middle of the trace
appears bi-directional in
propagation and is not
followed by the expected
quiescence of phase I; the
tracing also contains a phase
III-like burst during what
should be phase II and
repeated bursts of intense
contractile activity
The digital encoding of pressure data simplifies the analysis be hyperactive with many uncoordinated and often strong
of continuous 24-h recordings by computer software [96, contractions (bursts) [89].
97]. This technique has proved useful in several conditions The effect of any drugs the patient may be taking must be
[98, 99] including pseudo-obstruction. During nocturnal taken into account in interpreting any results (for example
sleep normal stereotypic MMC activity is clearly evident opioids, anticholinergics and cyclizine). Manometry does
[100] and in some patients with pseudo-obstruction the not always produce results that are clinically helpful [89].
abnormal contractile activity of the small bowel results in
distortion of the fasting MMC pattern. Manometry of patients Pathology and Histology
with pseudo-obstruction can be difficult in the later stages of The biochemical testsrecommended are listed in Table 3.
disease because the peristaltic activity required to propel a Adequate biopsy material is not often available and few lab-
manometry catheter into position in the proximal jejunum is oratories have an experienced gastrointestinal neuropatholo-
lacking, and endoscopic assistance may be needed. A patient gist. There also remain some additional pitfalls for collecting
with a neuropathy may have a normal diameter gut but it may and analysing samples including sampling error, effects of
bowel handling, sparsity of normal data and specificity. Immunosuppressive treatment has a small evidence base
Good histological samples are needed to make a firm diagno- restricted to case series or reports. Prednisolone and cyclo-
sis. Close liaison between surgeon and pathology laboratory sporin have been reported to be of particular benefit in auto-
is crucial so that a full thickness specimen of bowel is imme- immune myopathy [103]. There is a case report of an
diately processed. The samples should be divided; in an ideal improvement with initially prednisolone 1 mg/kg and aza-
situation some is snap-frozen in liquid nitrogen, and the thioprine 2 mg/kg/day then subsequently the prednisolone
main portion fixed for routine histology and electron micros- was replaced with budesonide 9 mg/day [50].
copy, in practice the latter two may be the best option. The
immediate processing of samples is important if a detailed Table 4 Drug therapies for intestinal dysmotility
examination of the nerves, ganglia and muscle tissue is to be Laxatives (after adequate fluid in diet)
carried out. Diagnosis of a neuropathy may be difficult in Osmotic Macrogols (PEG), lactulose, magnesium
conventionally oriented and stained sections of gut, and salts
whole mount plexus assessment is a research tool. The most Stimulant Anthraquinone group (senna and dantron),
bisacodyl, sodium picosulfate, docusate
important element is to ensure that enough sections and sodium,
material is examined, in a centre with experience of phosphate enema, glycerol suppository
dysmotility. parasympathomimetics—bethanechol,
A full thickness jejunal biopsy is usually taken laparo- neostigmine, pyridostigmine
5HT4 receptor agonists—prucalopride
scopically and is often helpful diagnostically but the proce-
Bulk forming Unprocessed wheat bran, methylcellulose,
dure in centres without much experience can be unhelpful ispaghula, and sterculia
and have a significant risk. Published data from centres with Faecal softeners/ Liquid paraffin, arachis oil (ground-nut oil,
expertise suggest a median operating time of 50 min, conver- lubricants peanut oil) enemas
sion rate to open operation 2% and length of stay 1 day with Peripheral opioid- Methylnaltrexone, naldemidine
receptor antagonists
an 8% readmission rate for obstructive symptoms [101]. In
Secretagoges Linaclotide, tenapanora
myopathies the diagnosis may be established. A neuropathy Antispasmodics
in general shows either degenerative changes or Antimuscarinics Tertiary amine—dicycloverine
inflammation. hydrochloride
All full thickness biopsies should be stained with Congo Quaternary ammonium compounds—
red stains to look for the presence of amyloid. As full thick- propantheline bromide, hyoscine
butylbromide
ness jejunal biopsies may not change the clinical manage- Direct smooth muscle Alverine, mebeverine, and peppermint oil
ment and are associated with risks, they are often performed relaxant
when a laparotomy does not find an organic cause of obstruc- Prokinetics
tion or when the patient happens to be undergoing surgery Dopamine receptor 2 Metoclopramide, domperidone
for another reason (e.g. a jejunal tube placement) [102]. antagonists
Macrolides Erythromycin
MNGIE can be diagnosed with a skeletal muscle biopsy
Antidiarrhoeal drugs Loperamide, codeine phosphate,
in addition to the blood and genetic testing. diphenoxylate
Anti-emetics D2 receptor antagonists (see above)
Cyclizine, ondansetron, romosetrona
Treatments Analgesics Tricyclic
antidepressant (low dose)—amitriptyline
Selective serotonin reuptake inhibitor
The drug treatments for intestinal dysmotility are shown in
SNRI (duloxetine)
Table 4. Most of the drugs are commonly used to treat milder Gabapentin
forms of the symptoms. Treatment is occasionally directed at Pregabalin
the underlying condition but more often is targeted at a spe- Antispasmodic drugs
cific symptom. Opioids (low dose)
Antibiotics for Amoxycillin-claevulinic acid
bacterial overgrowth
Underlying Condition
Ciprofloxacin
An underlying disease may need to be treated (e.g. connec- Metronidazole, tinidazole
tive tissue disorder, enteric myositis, neoplastic disease or Cephalosporin
myotonic dystrophy). Diabetic control should be very good Tetracycline, doxycycline
and may necessitate an insulin pump. Electrolyte, mineral or Non-absorbable antibiotics—rifaxamin,
endocrine abnormalities should be prevented and treated neomycin
when detected. Not licensed in the UK
a
There must always be awareness that organic obstruction functional dyspepsia [109] but was withdrawn due to an
can be missed as a diagnosis and if a prokinetic drug [104] increased risk of heart attacks or strokes.
makes pain worse then an organic obstruction must be con- Prucalopride, a high affinity selective 5HT4 receptor ago-
sidered. Similarly, a successful trial of a low fibre or liquid nist has been used for constipation and appears not to have
diet suggests an organic obstruction. the cardiac risks of cisapride or tegaserod as it does not affect
Some metabolic storage disorders can be treated with spe- the QT interval. This is by having no significant action on the
cific enzyme-replacement therapy [59]. 5-HT1B/D and on the cardiac human ether-a-go-go K+
channels [110].
pecific Drug Treatments of Symptoms
S Erythromycin, a motilin agonist, is potentially useful
No treatment is ideal and even though some help to correct [111] if there are absent or impaired antroduodenal migrat-
physiological abnormalities, they may not affect the patient’s ing complexes but is subject to tachyphylaxis. Doses of
symptoms. Drug therapy [105] can be difficult and often 900 mg/day have been recommended [112]. Azithromycin
drugs with conflicting actions are used (prokinetic for consti- may be more effective for small bowel dysmotility [113].
pation and anticholinergic for colicky pain). Essentially the A somatostatin analogue (octreotide), is given by a rela-
drug therapy is targeted at the symptom perceived as most tively painful subcutaneous injection, may be dramatically
important by the patient (Table 4). beneficial, especially in systemic sclerosis when other treat-
Prokinetic treatments are used to try and improve the dys- ments have failed [114–116]. It can improve vomiting and
motility itself and can return some of the measured abnor- pain, partly because octreotide (in normal subjects) reduces
malities towards normal. They may especially help with the perception of volume distension due to inhibition of sen-
vomiting and constipation. Prokinetic drugs are generally sory afferent pathways [114]. Octreotide may cause low
not used after a bowel anastomosis. Some of the previously amplitude MMC’s to return [116]. Octreotide may have a
used prokinetic drugs have been withdrawn or can only be beneficial effect when erythromycin has been unsuccessful;
used with extreme caution. They include domperidone and its effect (50–100 μg once or twice a day) is apparent within
metoclopramide (D2 dopamine receptors antagonists) which 48 h and lasts for more than 2 years. It may be more effective
stimulate gastric emptying and small intestinal transit, and when combined with erythromycin [117].
enhance the strength of oesophageal sphincter contraction. The parasympathomimetics bethanechol, distigmine,
Metoclopramide also increases the release of acetylcholine neostigmine, and pyridostigmine enhance parasympathetic
from some enteric nerves. Domperidone is a selective antag- activity in the gut and increase intestinal motility. They are
onist of peripheral D2 dopamine receptors, which does not rarely used because of both their gastro-intestinal and cardio-
have the acetyl-choline like effect of metoclopramide. vascular side effects (diarrhoea and severe bradycardia).
National Patient Safety Agency (NPSA) alerts have been Pyridostigmine has however been shown to help refractory
issued for Domperidone that highlighted problems with pro- constipation (including in diabetes) and was well tolerated
longed QTc therefore long-term use should be subject to using a stepped dosing regimen [118, 119].
QTc monitoring. The extra-pyramidal side-effects of meto- Naloxone 1.6 mg given subcutaneously each day, or
clopramide (especially in children) and the potentially irre- methylnaltrexone subcutaneously alternate days may be ben-
versible tardive dyskinesia in the elderly, together with no eficial in blocking dysmotility effects of opioids or in
evidence of consistent benefit in gastroparesis, caused the improving motility through blocking endogenous opioids
European Medicines Agency’s Committee to recommend [120].
that metoclopramide is not used in the long-term [106].
Cisapride, a 5-HT4 agonist, enhances acetylcholine release in Constipation
the myenteric plexus without having anti-dopaminergic Constipation may be a problem in early stages, but is rarely
effects and may have been of particular benefit if MMCs present when IF occurs. In the early stages of these diseases’
were present on small intestinal manometry. In a 6 week constipation may be managed by diet ensuring that it includes
double-blind, placebo-controlled trial in 26 patients, cis- an adequate intake of fibre and fluid. Bulk forming laxatives
apride helped abdominal pain, improved solid gastric empty- such as unprocessed wheat bran (or oat bran), taken with
ing and the MMC [104]. Unfortunately, due to an increased food or fruit juice are effective and methylcellulose (which is
risk of fatal cardiac arrhythmias (probably relating to a pro- also a faecal softener), ispaghula, and sterculia are useful in
longed QT interval) in patients taking other medications or patients who cannot tolerate bran.
suffering from underlying conditions known to increase the Osmotic laxatives [macrogols (polyethylene glycol),
risk of cardiac arrhythmias, cisapride was withdrawn. lactulose, or magnesium salts] increase the amount of water
Tegaserod, a 5-HT4 receptor partial agonist, increased stool in the large bowel, either by drawing fluid from the body
frequency in IBS [107, 108] and improved the symptoms in into the bowel or by retaining the fluid that was adminis-
tered. Macrogols are inert polymers of ethylene glycol be used as an adjunct to existing laxative therapy.
(PEG) which sequester fluid in the bowel. Lactulose is a Methylnaltrexone does not alter the central analgesic effect
semi-synthetic disaccharide, which is not absorbed from of opioids. Naloxegol and naldemidine are oral agents and
the gastro-intestinal tract. It produces osmotic diarrhoea of have the same properties.
low pH and prevents the proliferation of ammonia-produc- Faecal softeners (Liquid paraffin), the traditional lubri-
ing organisms. Magnesium salts are useful where rapid cant, has potential disadvantages of minimal efficacy (hence
bowel evacuation is required. Sodium salts should be usually used in combination with other agents) and safety
avoided as they may give rise to sodium and water issues (aspiration of paraffin or, perianal burning). Bulk laxa-
retention. tives and non-ionic surfactant ‘wetting’ agents (docusate
If there is an inadequate response to an osmotic laxative, sodium) also have softening properties. Enemas containing
a stimulant laxative can be added. Stimulant laxatives arachis oil (ground-nut oil, peanut oil) lubricate and soften
increase intestinal motility and often cause abdominal cramp; impacted faeces and promote a bowel movement. Dioctyl
they should be avoided in intestinal obstruction. Excessive sulfosuccinate, an anionic detergent, can be used to break
use of stimulant laxatives can cause diarrhoea and hypoka- down hard stools.
laemia. The anthraquinone laxatives (senna, dantron, cas- Stimulant suppositories (glycerol) or enemas (phosphate)
cara) are converted in the intestine to active sennosides, may also be effective though are often less acceptable to the
which may function by stimulating the myenteric plexus in patient. Glycerol suppositories act as a rectal stimulant by
the colon and by inhibiting colonic water absorption. Their virtue of the mildly irritant action of glycerol. Constipation
principal effect is in the descending and sigmoid colon. Their may need regular enemas initially using low volume phos-
effect is largely local and depends upon sufficient intestinal phate preparations progressing to high volume saline wash-
motility to present them to the colon for bacterial degrada- outs or trans-anal irrigation systems.
tion to their active form. Sennosides, with prolonged use, Treatment of faecal impaction may need a manual evacu-
had been thought to damage the intestine muscle and or ation under anaesthetic if disimpaction does not occur after
myenteric neurons but there is no clinical or animal evidence oral and rectal treatment, or if there is a megarectum. The
to support this [121, 122]. Poorly absorbed diphenylmethane outcome of colectomy +/− ileorectal anastomosis is poor for
derivatives (bisacodyl, phenolphthalein, sodium picosulfate) these patients and best avoided. Sometimes a defunctioning
stimulate sensory nerves in the proximal colon and increase loop ileostomy, which is reversible, may be performed before
sodium and water movement into the colonic lumen. Castor considering a total colectomy.
oil can have a place with its principal effect on small bowel
fluid secretion. Docusate sodium probably acts both as a Pain
stimulant and as a softening agent. Pain is often poorly correlated with motor events (chapter
Dantron, cascara and castor oil are rarely used, dantron “Chronic Abdominal Pain”). A simple measure such as
because of potential carcinogenicity. reducing fibre in the diet can reduce abdominal distension by
5HT4 receptor agonists (Prucalopride) are selective sero- reducing bacterial fermentation and the production of gases.
tonin 5HT4 receptor agonists with prokinetic properties. Low FODMAP diets may also have a role but are restrictive
Prucalopride is licensed for the treatment of chronic consti- in nature and should not be used in an already malnourished
pation, when other laxatives have failed to provide an ade- individual. Peppermint oil may also help.
quate response. Headache and gastro-intestinal symptoms Anti-muscarinics that are used for gastro-intestinal
(including abdominal pain, nausea, and diarrhoea) are the smooth muscle spasm include the tertiary amine dicyclover-
most frequent but rare side-effects. The side-effects gener- ine hydrochloride and the quaternary ammonium compounds
ally occur at the start of treatment and are usually transient. propantheline bromide and hyoscine butylbromide. The qua-
It has the potential to be a useful prokinetic drug now that ternary ammonium compounds are less lipid soluble than
cicapride and tegaserod have largely been withdrawn. atropine and are less likely to cross the blood–brain barrier;
Linaclotide (a 14-amino acid peptide) which acts in the they are also less well absorbed from the gastro-intestinal
intestinal lumen on guanylate cyclase-C (GC-C) so generat- tract. Dicycloverine hydrochloride has a much less marked
ing cyclic guanosine monophosphate (cGMP), which stimu- anti-muscarinic action than atropine and may also have some
lates chloride secretion, resulting in increased luminal fluid direct action on smooth muscle. Hyoscine butylbromide is
secretion and an acceleration of intestinal transit. It also may advocated as a gastro-intestinal antispasmodic and is com-
have some visceral analgesic activity. monly tried, but it is poorly absorbed, therefore intra-
Methylnaltrexone is a peripherally acting mu-opioid- muscular preparations may be more effective and can be
receptor antagonist that is licensed for the treatment of used in the long-term at home [123].
opioid-induced constipation in patients receiving palliative Direct relaxants of intestinal smooth muscle (alverine
care, when response to other laxatives is inadequate; it should citrate, mebeverine, and peppermint oil) that may relieve
pain in irritable bowel syndrome are commonly tried and tion gut-brain neuromodulators from more than one class is
have no serious adverse effects. more effective than monotherapy although gabapentin and
Persistent abdominal pain may be a major problem and its pregabalin are classed as controlled drugs in some countries
mechanism may include central nervous system sensitisation including the UK [125, 127]. SNRI and SSRI classes how-
making it very difficult to treat. Features of neuropathic pain ever should not be combined due to risks of serotonin
should be sought and managed with neuropathic agents. syndrome.
Opioid induced hyperalgesia as part of the narcotic bowel
syndrome can also develop and needs appropriate manage- Vomiting
ment by opioid reduction and withdrawal. If other analgesics Now that domperidone and metoclopramide are no longer
prove ineffective opioids and their derivatives may be cau- used in the long-term and as cyclizine can cause psychologi-
tiously tried though they themselves have pro-absorptive/ cal dependence and addictive behaviour [16], the 5-HT3
antisecretory effects and cause slowing of intestinal transit. antagonists like ondansetron are most commonly used but
Some opioids, such as tapentadol, may have a better dys- can result in constipation.
motility side effect profile. Targinact® (oxycodone and nal- If a naso-gastric draining tube helps symptoms, then a
oxone combined) is marketed as a way of giving analgesia venting gastrostomy (ideally over 20 French gauge (FG))
without causing constipation. A small amount of naloxone usually inserted endoscopically (though may also be done
crosses the blood brain barrier to block the dependence radiologically or surgically) may reduce vomiting by decom-
action of oxycodone though when first used may precipitate pressing the stomach. The difficulty is having a large enough
some withdrawal symptoms from the previous opioid like gastrostomy tube to allow all debris from the stomach to
drug. Naloxegol is a PEGylated naloxone formulation not drain. Sometimes a tube can be inserted into the small bowel
combined with opioid and therefore should not cross the if very dilated to decompress it. These venting ostomies are
blood-brain barrier, owing to the PEGylation, to minimise often successful but are associated with many complications
withdrawal side effects. such as leakage and infection (often with candida) and gen-
Oral liquid preparations may be used but sublingual or erally need to be changed more regularly than a feeding
transdermal buprenorphine or fentanyl has the advantage of ostomy.
bypassing the abnormal gut function. It may be of value to
give a patient a “pain holiday” in hospital during which seda- Diarrhoea: Bacterial Overgrowth and Bile Salt
tion and continuous subcutaneous opiates, or even epidural Malabsorption
anaesthesia, may reduce the pain threshold so allowing a Antidiarrhoeal drugs such as loperamide, diphenoxylate, or
reduction in maintenance analgesic dosage. Escalation rarely codeine phosphate are very occasionally used for
beyond a low dose of opioid is likely to be ineffective in symptomatic benefit. Opioids with a central action, such as
managing chronic pain and is associated with unacceptable codeine, are not the first choice because of the risk of depen-
risks, including catheter related blood stream infections, and dence and sedation.
should be de-escalated or discontinued if the chronic pain Steatorrhea may be secondary to an overgrowth of anaer-
persists, even if no other effective pain medication is avail- obic bacteria in the motionless dilated loops of bowel.
able [124]. As the disease progresses bacterial overgrowth can result
There is a growing appreciation for the role in abdominal in diarrhoea. This can be reduced with oral amoxycillin-
pain management of the gut-brain neuromodulators, fre- claevulinic acid combination, metronidazole/tinidazole,
quently used in neuropathic pain management [125]. These cephalosporin, tetracycline (doxycycline), ciprofloxacin,
include a tricyclic agent which can be used at sub- cotrimoxazole, or non-absorbable antibiotics such as rifaxi-
antidepressant doses for abdominal pain or discomfort in min or neomycin. Rifaxamin is often the first choice if it is
patients who have not responded to laxatives, loperamide, or on the local drug formulary. These may be used as necessary
antispasmodics. Low doses of a tricyclic antidepressant are or in repeated courses every 2–6 weeks often rotating (some-
used (e.g. amitriptyline, initially 5–10 mg each night, times with a 1–2 week period of no antibiotic) to another
increased if necessary in steps of 10 mg at intervals of at least antibiotic for a similar period of time before repeating. If
2 weeks to max. 30–50 mg each night). A selective serotonin metronidazole is used in the long-term, the patient must be
reuptake inhibitor (SSRI) may be considered in those who do warned to stop if they develop numbness or tingling in their
not respond to a tricyclic antidepressant but they are consid- feet as an early sign of reversible peripheral neuropathy and
ered to be less effective analgesics than the serotonin- be used at the lowest dose possible. Ciprofloxacin use longer
norepinephrine reuptake inhibitors (SNRIs), of which term can cause tendonitis and rupture and again low dose and
duloxetine is the first choice [126]. The role of gabapentin vigilance are required. The risk of resistant organisms,
and pregabalin is well established for chronic neuropathic including Clostridioides difficile, should also be considered.
pain, and there is emerging evidence that the use of combina- There is no data currently about the use of probiotics.
Bacterial overgrowth is virtually inevitable and can cause dence that SNS helps any of the symptoms in patients with
cachexia without necessarily causing diarrhoea, thus antibi- chronic intestinal pseudo-obstruction.
otics, as suggested above, may be needed. Small intestinal electrical stimulation is at an experimen-
Bile salt malabsorption may occur and respond, if toler- tal stage.
ated, to bile salt sequestrants (cholestyramine and cole-
sevelam). It is most likely if terminal ileum has been resected
or if there are large areas of fluid filled dilated bowel. Nutritional Support
Octreotide occasionally used for its effects in reducing
secretions and slowing gastrointestinal motility, has also Nutritional assessment and support is an important aspect of
been used in refractory SIBO. management. With appropriate therapy, many patients with
chronic intestinal pseudo-obstruction manage to maintain
Bloating/Distension their nutritional status through the oral/enteral route, without
Bloating and distension are common symptoms and not easy the need for parenteral support.
to treat. Reducing gas forming microbes (e.g. those produc-
ing CO2, methane and hydrogen sulphide) with a low fibre ietary Adjustments/Fluid Management
D
diet or an antibiotic (rifaxamin), giving simethicone or pep- Gastric motility may be far less deranged for liquids than for
permint oil or reducing visceral hypersensitivity (antidepres- solids with the result that many patients tolerate liquid feeds
sants) or constipation may help along with increasing better than solid meals. Sometimes frequent small meals
physical exercise [126]. with a low-fat, low-fibre and liquid nutritional supplements
may be helpful.
If the patient has a stoma and a short bowel, fluid restric-
Neuromodulation (Pacemakers) tion, a sipped glucose saline solution, use of loperamide
sometimes in high dose (occasionally with the addition of
There is some limited evidence for Gastric electrical stimula- codeine phosphate) will reduce the risks of dehydration,
tion (gastric pacing) to improve vomiting symptoms where sodium and magnesium depletion. If a high net secretory
gastroparesis is prominent and small bowel function rela- output occurs, a proton pump inhibitor (or occasionally
tively intact [128–130]. Patients with diabetic gastroparesis octreotide) may be needed [139].
respond best and in general responders tend to have more Post-feeding orthostatic symptoms in partial autonomic
severe vomiting. Patients with idiopathic gastroparesis have failure may respond to dietary adjustments and drugs such as
a potentially higher rate of poor response to gastric electrical fludrocortisone, midodrine and octreotide.
stimulation [131]. Non-invasive vagal nerve stimulation has
shown some promise both for improving gastro-duodenal Vitamin/Mineral Deficiencies
motility and reducing pain sensitivity [132]. Care is needed to ensure that micronutrient deficiencies par-
The dorsal column pathways are involved in the transmis- ticularly of iron, vitamin B12 and the fat-soluble vitamins,
sion of visceral pelvic pain. Spinal cord stimulation sup- especially vitamin A, D and E, do not occur. Magnesium
presses the visceral response to colon distension in an animal deficiency is common especially if a high output stoma.
model and therefore may be an effective therapy for chronic Magnesium oxide may cause less osmotic effects than other
pelvic pain of visceral origin. There has been success preparations but is expensive.
reported in one study of 35 patients in whom the catheter tip Bone mineral density is important to address and should
was situated at T5 position for a median of 9 days (range be assessed with dual energy X-ray absorptiometry (DEXA)
4–14) [133], the Cochrane database concludes that more scanning in those with malnutrition. For patients who cannot
studies are needed [134]. take oral measures to improve bone density then parenteral
Sacral nerve stimulation (SNS) uses electrical stimulation bisphosphonates such as zoledronate should be considered.
applied to the sacral nerves, eliciting a physiological effect
on the lower bowel, anal sphincter and pelvic floor and has Enteral Nutrition
shown some success in treating faecal incontinence and con- Enteral nutrition is preferred if the gut is accessible and
stipation [135–137]. A Cochrane review concluded that from absorbing. In carefully selected patients, feeding jejunos-
three studies there was “very limited evidence that sacral tomy with or without decompression (venting) gastrostomy
nerve stimulation can improve continence in selected people may be tried. A percutaneous endoscopic or radiological
with faecal incontinence, and reduce symptoms in selected gastro-jejunostomy is preferred to a direct jeunostomy where
people with constipation” and larger “good quality ran- possible as direct jejunostomy tubes are more subject to
domised crossover trials are needed” [138]. There is no evi- leakage, retention, pain and skin problems and the gastro-
jejunostomies can achieve both post-pyloric feeding and bowel conditions are fully rehabilitated after the first year on
venting with generally easier endoscopic placement whereas HPN, only a third of those with chronic intestinal dysmotil-
direct jejunal tubes will often need to placed surgically. ity are similarly rehabilitated and it is most likely if the gut is
Invasive enteral tube insertion should be preceded where not dilated [98]. Weaning from HPN is less likely when the
possible by a trial of naso-enteral tube feeding to ensure diagnosis is idiopathic dysmotility [95, 102] and when the
absorption and tolerance prior to running the risks of mortal- post-absorptive plasma citrulline is lower than 20 mmol/L
ity and morbidity associated with invasive tube placement. [143] Impairment of strength and of wellbeing as a result of
If liquid enteral feeds are given, any excess can be aspi- undernutrition and fluid and electrolyte imbalance will be
rated by enteric tube or gastrostomy before the start of the corrected by HPN but if the patient continues to experience
next meal to ensure that excess volumes do not accumulate vomiting, diarrhoea or abdominal pain from the underlying
in the stomach. Gastrostomies can be used, therefore, to condition quality of life will remain suboptimal. The annual
aspirate liquid gastric contents (decompression of venting risk of catheter-related sepsis among HPN patients is consis-
gastrostomy) as well as a conduit for feeding, particularly tently around 0.5 per 1000 catheter days but tend to be higher
when there is a need to bypass a malfunctioning oesophagus among those with chronic pseudo-obstruction especially if
and or stomach. Pulmonary aspiration of large volume vom- they remain on opioid analgesia [102, 144]; by contrast,
its is a very serious complication that may be difficult to pre- patients with systemic sclerosis who may tend to have lower
vent. A low antral site for gastro-jejunal tube placement is opioid requirements, have lower catheter infection rates
preferred to optimise drainage/venting and stability of the [145].
jejunal extension. Over half those with pseudo-obstruction receiving HPN
will be alive at 10 years [146].
Parenteral Support
Long term parenteral support (PS) should be reserved for
patients with significant malnutrition or electrolyte distur- Surgical Options
bance who cannot tolerate enteral nutrition. Complications
associated with total PS include infections, sepsis, and cho- Surgery is to be avoided in this group of patients who are at
lestatic hepatic dysfunction. high risk of iatrogenic injury; however judicious palliative
If safe nutritional status cannot be maintained through the surgical intervention [resection, bypass (Fig. 6) or stoma for-
oral and enteral route, then home parenteral support (HPS) mation] can improve symptoms and quality of life [147,
may be required. These patients, when receiving HPS, have 148]. If constipation is difficult to manage and high-volume
more problems than do patients with a short bowel [102]. saline washouts are needed then colectomy with ileorectal
They particularly have a higher incidence of catheter-related anastomosis or ileostomy may be necessary but diarrhoea or
blood stream infection (CRBSI), septicaemia and venous continuing episodes of obstruction may remain a problem.
thrombosis. The reasons for this are not entirely clear. Adhesiolysis in the absence of a clear focal obstruction car-
Procoagulation states sometimes exist, and it is possible that ries a high risk of severe complications and morbidity with
there is increased bacterial translocation from the gut. Opioid ultimately more adhesion recurrence and worsening pain.
medication (which at high doses suppresses some aspects of Often urology input is needed to help with neuromuscular
immune function) and/or cyclizine increase the risk of disorders of the urinary tract (dilated ureters and bladder)
CRBSI partly as the care taken by the patient in the manage- and may need to insert stents and/or a supra-pubic catheter.
ment of their infusions at home [140], due to cognitive Especially in women there may be fertility problems due to
effects, is reduced. The use of feeding lines to administer any dilated non-functioning fallopian tubes. Often the pains
drug is to be strongly discouraged because of the risk of cath- experienced result in gynaecological referrals.
eter infection. Such patients test the capabilities of the best-
organized nutrition teams to the full and should be managed ypass Surgery and Enteric Resections
B
in centres with a large experience [141]. Vigilance for psy- There are several reports of surgery in adults to help patients
chopathology and ongoing involvement of psychology and with pseudo-obstruction though the clear separation into
liaison psychiatry should be offered. There may be a benefit those with a myopathy and those with a neuropathy is not
from the mutual support patients can give to each other in always made [89, 147]. After diagnostic laparotomy, bypass
these situations, although patients with significant psychopa- operations (gastroenterostomy, duodeno-jejunostomy and
thology can have a detrimental effect on others. jejuno-enterostomy) can be performed in adults to reduce
Howard et al. [142] have emphasized that clinical out- vomiting if there is dilated gut. If gastric surgery is being
come on home parenteral feeding, like mortality risk, is to a performed, a vagotomy must be avoided, as this will further
large extent a reflection of the underlying condition. While retard gastrointestinal transit. Many have an ileostomy [54,
about 70% of patients with Crohn’s disease or ischaemic 89] often to treat constipation and some develop a short
for transplantation may broaden in the future. It is vital that

all patients considered for transplantation are reviewed by an
experienced multidisciplinary team with expertise in IF, and
a transplant centre [150]. Pain is not an indication for a
transplant.
Psychosocial Treatments
Psychological support from nurses, physicians, and psychol-

ogists is important. Vigilance needs to be maintained for the
presence of psychopathology even in patients with a strong
suspicion of gastrointestinal neuromuscular disorder. In one
case series, six patients diagnosed initially with IF had sig-
nificant psychopathology requiring specialised psychiatric
unit treatment [23]. In addition to psychological distress
including anxiety and depression; other psychological prob-
lems encountered can include somatisation disorder, person-
ality disorders, substance misuse and disordered eating.
Dysmotility disorders can also be associated with a risk of
self-harm including suicide. Clinical psychology and liaison
psychiatry provide overlapping but complimentary
approaches and ideally a multi-disciplinary team involving
both specialties should be available.
Outcomes
Outcome can vary from minor symptoms consistent with

irritable bowel syndrome to problems resulting in home par-
Fig. 6 Drainage procedures (gastro-jejunostomy, duodenojejunos- enteral feeding, opioid analgesics and frequent hospital
tomy, and ileostomy) occasionally performed in patients with visceral
admissions. Causes of death in these patients include pulmo-
myopathy (after P. Hawley, St Mark’s Hospital, London)
nary aspiration, pulmonary embolism, cardiac failure and
suicide. Cardiac failure may be the terminal event in hollow
bowel from multiple resections. The reports of success are visceral myopathy. The relationship between “megaduode-
variable and any undertaking of surgery needs to be a multi- num” and upper gastrointestinal tract cancer seems tenuous
disciplinary decision and based upon each individual patient. if it exists. Death will often be related to the underlying con-
Outcome is poorer in patients with evidence of small bowel dition—obviously so in the case of pseudo-obstruction
dysmotility who undergo colectomy. occurring as a paraneoplastic phenomenon, and also particu-
larly in the degenerative neuropathies, collagen vascular dis-
Small Intestinal Transplantation orders and infiltrative conditions such as amyloid. Amiot
Dysmotility is a rare indication for intestinal transplant in et al. reported 51 patients with CIPO who required HPN,
adults with dysmotility needing HPN but since the outcomes representing 26-years of experience and found that surgery
of HPN are currently better, transplantation should be was required in 84% of patients and survival probability was
reserved for those who develop complications related to PN 94%, 78%, 75% and 68% at 1, 5, 10 and 15 years respec-
including IF associated liver disease, central vein thrombosis tively [54]. Higher mortality was associated with systemic
with reduced venous access, and recurrent catheter-related sclerosis. 20-year experience of HPN from the Mayo clinic
blood stream infections [139, 148, 149]. If other organs are found that the survival for motility patients was second worse
damaged a multivisceral transplantation may be considered. only to cancer, due to the progression of the underlying dis-
The role of small bowel transplantation solely to improve ease, which was similar in data from United Kingdom St
quality of life by ceasing PN is somewhat contentious, but as Mark’s hospital. Recently published data from the Salford IF
worldwide experience of transplantation increases with cor- Unit have demonstrated worse outcomes for patients with a
responding improvements in survival rates, the indications CIPO than non-CIPO dysmotility phenotype [140]. However,
it would appear that there is room for improved outcomes in 15. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, Shabestari OL,
Kashani AR, Farzanehgan ZM. Double-blind randomized con-
this challenging patient population by cost-effective invest-
trolled trial of baclofen vs. clonidine in the treatment of opiates
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Pelvic Radiation Disease
and the Gastrointestinal Tract
Darren Fernandes and Jervoise Andreyev
Key Points the tumour will be exposed to some radiation. The rectum
1. Radiotherapy to a pelvic tumour causes a spectrum of dis- and sigmoid are in close physical proximity to the area being
orders within and outside the GI tract which should be treated and are at particular risk. The caecum is relatively
considered a progressive condition with a defined pathol- immobile and may too receive a significant dose. The trans-
ogy which has recently been termed pelvic radiation dis- verse colon and small bowel frequently loop down into the
ease (PRD) pelvis, putting them at risk, so too is the proximal small
2. Simple “trigger” questions can be used to alert any clini- bowel and pancreas especially when para-aortic nodes are
cian to the fact that significant PRD may be occurring and irradiated [1]. The presence of abdominal adhesions may
the patient needs specialist help increase the risk to normally mobile bowel loops. Other fac-
3. Large numbers of survivors of cancer suffer from PRD tors related to the risk of toxicity are outlined in Table 1.
which is often not acknowledged or recognised by health Almost all data on development of radiation injury at a
care workers molecular level are derived from animal models. However,
4. Following published checklists and treatment algorithms animal models represent poorly what happens in humans for
are efficient and inexpensive at ameliorating the GI symp- many reasons limiting clinical relevance of the results.
toms of PRD and much more effective than relying on Indeed, adequate animal models for many aspects of late
“clinical intuition” or experience radiation enteropathy have not yet been developed.
5. The underlying ischaemia and fibrosis which develops in It was once thought that the radiation dose was entirely
the tissues exposed to radiotherapy means that endo- responsible for the damage that may develop but increas-
scopic and surgical approaches which work in inflamma- ingly, patient related factors are understood to be important.
tory or malignant tissues are potentially hazardous in The gastrointestinal immune system, the enteric nervous
patients with PRD system and the intestinal microvasculature play key roles in
6. The progressive ischaemic and fibrotic pathological
changes which are the basis for PRD offer opportunities Table 1 Factors significantly associated with the development of
to halt or reverse the changes of radiotherapy and clinical Radiation Pelvic Disease
trials to assess the effectiveness of many agents which Therapy-related factors
might do this are a priority Radiation dose
7. Identifying an objective biomarker of progressive radia- Volume of bowel irradiated
Time-dose-fractionation parameters
tion change is a key step in radiation research
Concomitant chemotherapy or biological therapy
Patient-related factors
Diabetes mellitus
Why Patients Develop Symptoms Tobacco smoking
HIV disease
Most patients starting pelvic radiotherapy will have normal Inflammatory bowel disease
gastrointestinal function apart from possible local tumour Collagen vascular disease
Previous pelvic or abdominal surgery
effects. During radiotherapy, normal tissues that surround
Pelvic inflammatory disease
Low BMI
D. Fernandes · J. Andreyev (*) Colonic microbiota
Department of Gastroenterology, Lincoln County Hospital, Genetic polymorphisms
Lincoln, UK Hypertension (protective)

270 D. Fernandes and J. Andreyev
the development of radiation enteropathy [2]. Emerging Tissue injury after radiation therapy can therefore occur
data increasingly suggest that the 100 trillion bacteria in the either quickly or after a prolonged period of time and these
gut lumen, tenfold the number of cells in the human body, processes can clinically present as [8]:
are also crucial determinants of radiation enteropathy sever-
ity [3]. 1. Damage to specific neurological, enzyme based and mus-
In the past, radiation injury was classified as “early” or cular functions (and probably also local hormonal and
“late” depending on the timing of its clinical expression that immunological regulation) of the gastrointestinal tract
was founded on two different, but not mutually exclusive, 2. Acute inflammatory processes and chronic cytokine
mechanistic models of injury—the “target cell” and “vascu- activation
lar injury” models [4]. 3. Development of chronic ischaemia within the gastroin-
However, the recognition that delayed radiation injury testinal wall, surrounding stroma and mesenteries
might develop clinically in the wake of severe acute injury 4. Progressive fibrosis within the gastrointestinal wall, sur-
was recognised by Bourne et al. [5] and Peters et al. [6] who rounding stroma and mesenteries
subsequently coined the term “consequential late effects”. In 5. Changes in preexisting conditions or the development of
2001, in a very important paper, a new terminology for clas- new conditions unrelated to radiotherapy, which also
sifying healthy tissue radiation responses was described [4]. cause symptoms indistinguishable from those arising as a
In this paper, Denham and Hauer-Jensen classified lesions result of radiotherapy.
producing radiation injury into three interacting categories:
cytocidal effects, indirect effects and functional effects.
Cytocidal effects relate to the phenomena characterised Epidemiology of Radiation Damage to Gut
by the “target cell” model, where rapidly proliferating cells
give rise to early pathology and more slowly proliferating Over 17,000 men and women are treated with pelvic radio-
target cells show delayed effects [7]. Hence, the time between therapy in the UK annually and an estimated one million
irradiation and manifestation of injury depends on target cell worldwide. While oncologists frequently report that 10–15%
characteristics (radiation sensitivity, repair capacity, prolif- develop moderate or severe GI toxicity, patient focused
eration rate, etc.) and tissue organisation. In rapid renewal research suggests that up to 50% depending on the site
tissues, such as the gastrointestinal epithelium, injury mani- treated develop permanent gastrointestinal symptoms inter-
fests itself clinically within days of first radiation exposure, fering with daily activity [9, 10]. It can be difficult to define
when cells in the “differentiated” cellular compartment are exactly when symptoms start to affect quality of life and
no longer replaced by cells from the progenitor compart- why some people seek help for specific gastrointestinal
ments. These tissues have been dubbed “early-reacting tis- symptoms when others do not. Prospective studies using
sues”. Cellular turn over, however, is much slower in comprehensive, validated methodology concentrating on
connective tissues and organs that are composed of cells bowel toxicity with adequate follow-up are very few. It is
capable of re-entering the cell cycle. Radiation injury may frequently claimed that modern techniques of radiotherapy
therefore be expressed months or even years after exposure if for pelvic malignancy have substantially reduced acute tox-
cell death occurs when cellular division is attempted, and icity but as yet there are few randomized controlled trial
these tissues are said to be “late reacting” [4]. data to support this assertion and almost no long term high
“Indirect” effects are reactive phenomena that occur in quality follow up data.
response to radiation-induced injury in other cells or tissues, Examples of the weakness and variability in the reported
and include phenomena such as parenchymal cell depletion data can be quickly exemplified by from a number of studies.
secondary to vascular damage, the “bystander” effect and tis- In one prospective study in which about two-thirds of patients
sue reactions to vasoactive, procoagulant, and inflammatory had prostate cancer and most of the rest had gynaecological
mediators, including cytokines, growth factors and chemo- cancer, 2-year follow-up was only available in 57%. Of
kines [4]. these, only 12% reported bowel problems moderately affect-
“Functional” effects from non-lethal effects on different ing daily activity [11]. In the Swedish Rectal Cancer Trial
intra- and extracellular molecules and changes in gene which helped establish short course preoperative (5 × 5 Gy)
expression in irradiated cells lead, for example, to direct radiotherapy as an important therapeutic modality, meaning-
inactivation of anticoagulant molecules, activation of latent ful follow up data were obtained from 77% of the 92% of
growth factors and activation of proteases. They include phe- survivors followed for more than 5 years. This showed that
nomena such as the inhibition of cellular replicative ability 30% of the irradiated group had a significantly impaired
and accelerated senescence that lead to decreased tissue social life because of bowel dysfunction, compared with
vitality [4]. 10% of the surgery-alone group [12]. In a third prospective
Pelvic Radiation Disease and the Gastrointestinal Tract 271
study, a small subset of surviving patients who had under- patient waiting room (Fig. 1) [18]. However, a raised aware-
gone adjuvant radiotherapy after surgery for rectal cancer ness of the potential problems that can be experienced by
were questioned and investigated in detail and compared everyone who comes into contact with a patient previously
with a small subgroup of patients randomised to surgery treated for cancer is required if we are to make significant
alone. Bowel frequency (80% vs 23%), loose or liquid stools progress with helping patients with consequences of cancer
(60% vs 23%), faecal incontinence (60% vs 8%) and the therapy [19].
need to wear a pad more often (47% vs 0%) were all signifi- There are extensive data which tell us which symptoms
cantly more frequent in the radiotherapy patients [13]. A impact patient’s most [20]. Yet, when Chen et al. assessed
large recent study confirms the continuing adverse health rectal cancer specialists’ understanding of which bowel dys-
related quality of life outcomes in patients with colorectal function symptoms truly matter to patients after sphincter-
cancer, 16% of survivors without a stoma reported having no preserving treatment, they found that there was considerable
control of their bowels, with a further 17% reporting moder- discrepancy between the specialist’s perspective and patient
ate problems. With regards to sexual matters, 15.9% of experience. For example, specialists tended to overestimate
respondents reported experiencing severe difficulties with the impact of incontinence for liquid stool and frequent
patients with rectal cancer reporting a higher percentage bowel movements, while underestimating the impact of
(25.1%) and 15.4% reported severe urinary problems [14]. urgency and clustering [21].
What does seem clear from these and other patient- The lack of incidence data may be as a consequence of
centred studies, of all the symptoms that can arise after pel- lack of information how best to assess and define abnormal
vic radiotherapy, new bowel symptoms seem to have the bowel problems and the somewhat subjective nature of
greatest effect on quality of life [15]. Studies that have chronic symptoms. A retrospective study by Tom et al. 2017
assessed ‘symptoms causing moderate or severe distress’ or demonstrated this [22] when they examined and compared
whether their symptoms prevent them doing things on a reg- patient and clinician reports of acute gastrointestinal toxicity
ular basis in patients suggest that if radiotherapy was part of during chemoradiation therapy and found discrepancies in
their treatment approximately half of all patients treated for reported symptoms. Going forwards, there needs to be better
rectal cancer, one-third of bladder and gynaecological measurement of toxicity not just within research but also in
patients and one in five of all patients treated for prostate clinical practice during follow-up visits. Furthermore, which
cancer are left with significant gastrointestinal symptoms scoring systems and tools should be used to document and
[16]. While the risk of bias in some of these studies from score the late effects of radiotherapy and how best to mea-
patients lost to follow up or because the studies are retro- sure bowel effects objectively needs to be assessed.
spective must be acknowledged, however, consistent data The scoring systems that have been used include the
suggest that unrecognised toxicity causes a significant bur- Radiation Therapy Oncology Group (RTOG) score, Late
den and is an important unmet need for large numbers of Effects Normal Tissue-Subjective, Objective, Management
patients. (LENT-SOM) scales and Common Terminology Criteria for
Adverse Events (CTCAE). However, these are not only
insensitive measures of the patient experience and frequently
I s Bowel Morbidity Adequately underestimate the amount of toxicity suffered but also can-
Documented? not explain clinical outcomes [23, 24]. We have routinely
augmented our standard medical assessment with a modified
The frequent under-reporting of chronic bowel symptoms Gastrointestinal Symptom Rating Scale that patients com-
that occur after radiotherapy raises concerns as to the assess- plete at each clinic visit, along with a Bristol Stool Chart
ment and recognition of late effects in clinical practice and [25]. This helps focus the consultation on all of the patient’s
the potential value of “trigger” questions to identify those GI issues. In addition, offering all new patients a holistic
running into significant difficulty (see Fig. 1). Symptoms can needs assessment questionnaire pays dividends. In addition
occur months to years after radiotherapy and many clinicians to their GI problems, 80% of these patients report moderate
from primary to tertiary care often fail to consider and are or severe bother from fatigue, 45% from urinary problems,
unfamiliar with the spectrum of late radiotherapy effects. 36% from nutritional issues, 35% from sexual issues, 11%
Simple “trigger” questions have been described in a paper from emotional concerns and 2% from dermatological
endorsed by all GI professional bodies in the UK that any issues. So whilst the focus is on gastrointestinal and nutri-
clinician could use to help identify patient in need of special- tional issues, these other areas cannot be ignored and require
ist help [17]. These have been validated in a subsequent thoughtful management strategies [26] albeit often by a dif-
study and the ALERT B can be a useful tool used in any ferent specialist in a different service setting.
Fig. 1 The ALERT-B questionnaire for screening for significant GI toxicity after previous pelvic irradiation [18]
Table 2 Clinicians prediction of commonly suspected causes of

Diagnosis and Management changes in gastrointestinal function following cancer based on clinical
acumen have poor sensitivity and specificity [28]
Men presenting to a gastroenterology clinic after radiother- Sensitivity Specificity

Contributing GI pathology (95% CI) (95% CI)
apy frequently have a median of 11 symptoms (range 1–16)
Small intestinal bacterial 67% (41–86%) 48% (29–67%)
while women have a median of 12 symptoms (range 4–16). overgrowth
Presenting with a cluster of “typical symptoms of radiation Bile acid malabsorption 50% (21–79%) 86% (70–95%)
toxicity” has been shown to be highly unreliable at predict- Pancreatic insufficiency 22% (3–60%) 87% (72–96%)
ing the underlying cause. These clusters can be present
before radiation and are aggravated by, or amplify, the
inflammatory symptoms that occur during radiation as well
as being related to the more permanent injuries that present multiple causes contributing to their symptoms and none of
after radiotherapy [27]. Furthermore, it is difficult even for the participating clinicians predicted the correct combination
experienced clinicians to predict how symptom clusters of diagnoses [28] (Table 2).
relate to bowel pathology. This was shown in a recent pro- The lack of accuracy of empirical treatment without ade-
spective study that assessed experienced clinicians’ predic- quate investigation perhaps explains why so many of these
tions of possible diagnoses for patients presenting with patients continue to be highly symptomatic after gastroen-
troublesome gastrointestinal symptoms compared to the terological intervention. An alternative approach, which has
actual diagnoses made following comprehensive investiga- been shown in both randomised trials and in cohort studies to
tion following a checklist. While 168 actual diagnoses were be highly effective, is to use a detailed checklist to investi-
identified, only 92 were predicted and of those only 24% gate these patients and when the investigations are abnormal
matched the diagnoses made. The majority of patients had instigate treatment following a management algorithm sys-
tematically. Indeed, patients can be significantly helped and • What was bowel function like before the cancer emerged?
need only a median of six investigations and three clinic vis- • How have the symptoms changed over time?
its [8, 29–31] and this costs approximately £1563 [32]. The • Are key features indicative of reversible underlying
benefit of this approach has been confirmed by others [31]. pathology present, for example:
The ORBIT trial also showed, in an era when there are huge –– Steatorrhoea
numbers of affected patients, is that a nurse can be trained to Is there an oily film in the lavatory water?
manage the patients following checklists and algorithm and, Is the stool ever pale/putty-like/foul smelling/diffi-
with adequate gastroenterology support, can obtain out- cult to flush/floating?
comes similar to those obtained by a senior gastroenterologist Has there been rapid weight loss?
in most cases. This algorithm is now freely available to clini- –– Nocturnal waking to defaecate
cians [33]. –– Symptoms suggestive of recurrent cancer or a new
primary?
• Is there a consistent impact of a specific component of
Physiological Model of Symptoms diet on their symptoms, especially:
–– Fibre: how much are they eating—too much/too
The real conceptual advance in the treatment of patients with little?
complex GI symptoms however, comes from the understand- –– Fat: does this promote type 6–7 stool/steatorrhoea?
ing that the aetiology of GI symptoms depends not on patho- –– Lactose-containing foods?
logical change, but rather depends on physiological change –– Gluten-containing foods?
(Fig. 2). –– Alcohol intake?
It is this realisation that symptoms are caused not by path- –– Caffeine intake
ological changes per se, but by ‘changes in the normal physi- • Is there an association between the start of specific medi-
ology’ of the GI tract, that has allowed the management of cation or increase in its dose and their symptoms—for
complex symptoms to be effective. example, metformin, proton pump inhibitor, α-blockers?
• What individual symptoms are present. We particularly
favour the use of sensitive symptom questionnaires which
Initial Assessment patients can fill in before their clinic appointment and
help everyone understand which issues are important
The first step towards diagnosing and formulating a manage- [25]. Each symptom may have a different physiological
ment plan that will improve patients’ symptoms is to take an cause and so understanding in detail which symptoms are
accurate history. This needs to elicit: present help us identify what tests need to be arranged.
Fig. 2 Physiological model

of symptom aetiology [34]
Loose Stool or Diarrhoea are urgently required. Currently available diagnostic tech-
niques include breath tests—breath tests which just look for
This common symptom may be due to multiple causes. The expired hydrogen levels and do not measure methane will
frequency of these causes during and after radiotherapy as miss 25% of patients with bacterial overgrowth—direct cul-
far as they have been reported is shown in Table 3 and then ture of small-bowel contents which is particularly helpful for
the more important causes are discussed in more detail defining bacterial sensitivity to specific antibiotics, or deter-
below. mination of bile acid products in the blood. Some patients
have low vitamin B12 levels or modestly raided CRP—
<15—which normalise once bacteria are eradicated from the
small bowel [39].
Small Bowel Bacterial Overgrowth Optimal strategies for the management of bacterial over-
growth are not defined. Appropriate antibiotics to which the
Radiotherapy has a direct effect on small bowel motility. specific bacteria are sensitive, used for 1–2 weeks may abol-
This change in motility in turn predisposes to bacterial over- ish symptoms within a few days of starting treatment.
growth and in some patients episodic pseudo-obstruction However, symptoms can recur any time after antibiotics are
[16]. Small-bowel bacterial overgrowth occurs in 25% of stopped—from a few days to many years later—because the
patients [35] during the acute phase of radiotherapy. In the underlying cause of bacterial overgrowth has not gone away.
chronic setting, motility changes caused by radiotherapy are If symptoms return, retreatment with antibiotics might help.
the main cause of such overgrowth [36]—particularly that of In patients with recurrent symptoms, use of antibiotics for a
gram-negative bacilli, which in 4–45% patients may cause a few days every month, or continually at the lowest effective
wide variety of gastrointestinal symptoms [9, 36–38]. Three dose, might be effective [1].
studies [9, 37, 38] suggest that in 8–15% of patients with
diarrhoea, the diarrhoea is caused by bacterial overgrowth
and improves after antibiotic treatment. Bile Acid Malabsorption
Reliable diagnosis of bacterial overgrowth is difficult and
better diagnostic tests using modern molecular techniques Up to half of patients who develop diarrhoea acutely dur-
ing radiotherapy will have bile acid malabsorption [40]
because of a direct effect on the mechanisms of bile reab-
Table 3 Causes for diarrhea during and after radiotherapy. It is not sorption; accelerated transit that reduces bile absorption
unusual especially after radiotherapy for several causes to coexist. [41, 42]; or colon damage that exacerbates symptoms [43].
Therefore, empirical treatment is rarely effective as it is difficult to
guess the cause(s) accurately. This list does not include other common After radiotherapy, a chronic reduction in bile acid absorp-
reasons such as excess fibre which is often poorly tolerated after radio- tion is common [44, 45] but does not cause symptoms in
therapy, excess caffeine or alcohol. Clearly many of the causes in this most patients [40, 46, 47]. Bile acid malabsorption can
list can be cured with simple interventions if they are diagnosed cause a variety of symptoms. Intermittent or constant loose
accurately
stool is universal but patients may also develop abdominal
During
cramps, frequency and/or urgency of defaecation, noctur-
radiotherapy After radiotherapy
Lactose intolerance 50% 5–7% nal defaecation or incontinence. The development of bile
Other disaccharide Not known Yes but frequency acid malabsorption should be considered in all patients
malabsorption unknown who have episodes of loose (type 6) or liquid (type 7 stool
Bile acid malabsorption 50% 1–83% as per the Bristol stool chart) and if these patients are sub-
Small bowel bacterial 25% 8–45% jected to a Selenium homocholic acid taurocholate
overgrowth
(SeHCAT) scan, consistent data suggest that approxi-
Large bowel strictures – 3–15%
Pancreatic insufficiency Not known Yes but frequency mately 50% have developed the condition across a wide
unknown range of diseases (see Fig. 3) [48].
Rapid transit 100% Yes but frequency The gold standard for measurement of bile acid malab-
unknown sorption is the SeHCAT (selenium 75 homo-cholic acid
Viral infection Not known Not known conjugated with taurine) scan. Bile acid is secreted in
Clostridium difficile Not known Not known
response to dietary intake of fat, so reducing dietary fat
Cancer relapse – 4–10%
Drug related (non 10% 5% intake, can be a useful therapeutic approach in patients with
chemotherapy) mild malabsorption. Regular use of antidiarrhoeal drugs
New GI neoplasia – 10% such as loperamide or codeine phosphate [49], especially if
New onset IBD 2% taken 30–60 min before eating, may improve symptoms.
Other Not known 5% Most patients however require bile acid sequestrants which
Fig. 3 Taken from Phillips et al [48] showing the frequency and severity of bile acid malabsorption (BAM) in 506 patients undergoing a SeHCAT
scan. Not all had been treated with pelvic radiotherapy
have been shown to be beneficial in several series [37, 46, Carbohydrate Malabsorption
49–52]. Most of these data are for use of colestyramine.
However, many people cannot tolerate bile-binding resins. De-novo lactose malabsorption occurs in 50% of patients by
An effective and well-tolerated alternative is colesevelam the fourth week of pelvic radiotherapy [53]. The severity of
[53]. As a last resort a diet where medium-chain triglycer- malabsorption correlates with the length of small bowel irra-
ides replace most of the fat can be tried [54] though this diated [55]. New-onset lactose malabsorption persists in
diet is unpalatable and is rarely required. A logical thera- about 5% of patients and frequently causes diarrhoea [44,
peutic approach which has been shown to be highly benefi- 56]. If lactose malabsorption occurs, it is likely that malab-
cial is described in Fig. 4. sorption of other disaccharides also occurs. No studies have
Fig. 4 Taken from Gupta A

et al [30] suggesting a
therapeutic approach to bile
acid malabsorption based on
the SeHCAT scan value
investigated this systematically although clinical experience debilitating flatulence. Patients with substantial fat malab-
suggests that malabsorption of other sugars does sometimes sorption especially when it occurs together with small bowel
occurs. Clinical experience suggests that many patients who bacterial overgrowth can develop severe abdominal cramps
believe they have lactose intolerance, in fact have developed and vomiting, which can sometimes be mistaken for acute
bile acid malabsorption and their symptoms arise from the obstruction.
fat found in milk containing products rather than from the In a patient who has had pelvic radiotherapy, steatorrhoea
lactose. is commonly caused by bile acid malabsorption or bacterial
Investigation for carbohydrate malabsorption can include overgrowth. More rarely, it is caused by chronic pancreatic
stool chromatography, oral-tolerance tests that measure insufficiency or by the little-recognised disorder of free
blood or breath responses, use of isotope-labelled carbohy- fatty-acid malabsorption. Very rarely it may be due to
drate, direct biopsy proof of enzyme deficiency or empirical Addison’s disease, thyrotoxicosis, the development of a hor-
trials of diet. Dietary advice to avoid the unabsorbed sugars, mone secreting neuroendocrine tumour, intestinal lymphan-
which could include one or more of lactose, fructose, giectasia or very extensive new onset small bowel
sucrose and starches is needed and should be given by a inflammatory disease.
qualified dietician because diets can be complex and lactose Steatorrhoea needs to be diagnosed by direct question-
avoidance changes calcium intake, which might affect bone ing—is the stool pale, extremely offensive, with a tendency
health a potential problem in people who have had radio- to float and difficult to flush away? Of most usefulness,
therapy and are known to suffer from an increased risk of patients sometimes describe a frequent oily film on the sur-
bone fracture [1]. face of the lavatory water.
It is now almost impossible to obtain laboratory quantifi-
cation of stool fat levels [1] so these should not be requested.
Risk of Second Cancers
Endoscopic surveillance should probably be discussed with Radiation-Induced Pancreatic Insufficiency

all patients 5 years after radiotherapy and probably should be
continued long term. Large studies have concluded that after The pancreas is thought to be fairly radio-resistant. However,
radiotherapy there is a significant risk of secondary colon chronic pancreatic insufficiency can develop after pancre-
cancer and rectal cancer [57]; rectal (but not colon) cancer atic irradiation [9, 62–68]. The pancreas frequently appears
[58–60]; or either rectal cancer or colon cancer but only in completely normal on magnetic resonance cholangiopan-
parts of the gastrointestinal tract that were included in the creatography, even in the presence of severe radiotherapy-
radiation field [61] and that risk increases over time. induced pancreatic insufficiency. Invasive tests of pancreatic
function are rarely justified. Faecal elastase levels may be
artificially lowered in patients with undiagnosed coeliac dis-
Steatorrhoea ease or small intestinal bacterial overgrowth (SIBO) but
SIBO is often present in patients with pancreatic insuffi-
Steatorrhoea is loose stool caused by the presence of exces- ciency and is not an uncommon reason why patients do not
sive undigested fat (i.e., >0.3 g per kg a day). It causes tolerate pancreatic supplements. If SIBO is eradicated then
unpleasant symptoms of frequency of defaecation, urgency, pancreatic supplements, if tried again, will usually be
faecal incontinence, perianal irritation, and severe, socially tolerated.
Free-Fatty-Acid Malabsorption incontinence after radiotherapy—especially when there is

diarrhea or steatorrhoea - have been excluded.
Malabsorption of free fatty acids occasionally occurs after
small-bowel irradiation [69] and may be related to the devel-
opment of lymphangectasia [70] (which rarely, is the only Rectal Bleeding
cause of steatorrhoea). A low-fat diet (i.e., 20–30 g a day), or
occasionally a diet rich in medium-chain triglycerides, is The natural history of radiation-induced bleeding after con-
needed in addition to optimum treatment of other causes of formal radiotherapy is that it starts to be clinically apparent
steatorrhoea. 6–12 months after radiotherapy, may get worse over the next
5 years or so and then slowly improve over the next
5–10 years. Some newer radiotherapy techniques may lead
Faecal Incontinence, Urgency, Tenesmus, to a more prolonged time to recovery and cessation of all
Mucus Discharge, and Frequency bleeding. The likelihood of bleeding is closely related to the
of Defaecation dose of radiotherapy delivered to the anterior rectal wall. Up
to half of all patients have some rectal bleeding after pelvic
Of all gastrointestinal symptoms that can occur after radio- radiotherapy [75–77], for many it will be trivial but it is
therapy, urgency of defaceation and faecal incontinence reported to impair quality of life in up to 6% of patients [78].
causes the greatest distress [71–73]; however, it is the most Incidence of transfusion-dependent bleeding is 1–5% of
difficult symptom for patients to discuss. patients [78, 79].
Changes in stool consistency, reduced rectal volume, psy- The mucosal lesion that typically is associated with
chological issues, inflammation, or neoplasia in the lower radiation- induced bleeding is angiectasia, which are a
gastrointestinal tract might increase the frequency of defae- response to radiation-induced ischaemia. All patients, within
cation. In all patients with these symptoms, rectal examina- weeks to months after treatment, develop endothelial dys-
tion with assessment of anal tone and flexible sigmoidoscopy function, with subsequent vascular sclerosis and wall fibrosis
is the minimum investigation needed. In patients with fre- [80]. This can lead to narrowing or thrombosis of small arter-
quency of defaecation or changes in stool consistency, a full ies and arterioles, progressive ischaemia to the supplied tis-
blood screen is appropriate. Local rectal or sigmoid pathol- sues, and consequent neo-angiogenesis [81, 82]. Intermittent
ogy, such as a mucus-secreting tubulovillous adenoma or bleeding can frequently follow from these fragile new ves-
carcinoma, might cause faecal incontinence, and flexible sels which it on the surface of the mucosa.
sigmoidoscopy will exclude new onset inflammation of the All patients with any rectal bleeding should be offered
lower GI tract unrelated to pelvic radiotherapy (which occurs assessment with at least flexible sigmoidoscopy; proctos-
in about 2% of patients in one series) [9]. Endoanal ultraso- copy and rigid sigmoidoscopy are inadequate. Colonoscopy
nography might define sphincter defects (e.g., after child- can be reserved for those with symptoms or signs that sug-
birth or those caused by radiotherapy). gest pathological changes to the proximal colon [83]. There
A retrospective study [74] that evaluated the management is no role for routine biopsy of typical radiation change and
of patients with faecal incontinence after pelvic radiotherapy in patients who have undergone brachytherapy there is a sig-
found that the use of phenylephrine gel benefited three quar- nificant risk of fistula formation after endoscopically guided
ters of all patients with incontinence that had not responded biopsy of the anterior rectal wall. Lower GI endoscopy can
to other treatments. be more difficult after previous radiotherapy and we recom-
As these symptoms are commonly characterised by mus- mend that only experienced endoscopists should assess these
cle spasm, several treatments exist that might help, including patients and that clinicians should consider routinely using
use of correct positioning on the lavatory, pelvic floor exer- either a paediatric colonoscope in this population or even a
cises, biofeedback, correct use of anti-diarrhoeal drugs, non- gastroscope rather than a normal colonoscope to reduce the
fermented stool- bulking agents (e.g., sterculia), and low risk of perforation around fixed loops in the sigmoid.
doses of antidepressants. Surgery to divert the faecal flow Several series have suggested that the nature of bleeding
and stoma formation might have a role in the few patients does not discriminate between the different causes and that
who have substantial loss of rectal volume and who have not radiotherapy is not the cause of rectal bleeding in 25–60% of
responded to other interventions [1]. There have been sug- patients [1]. For patients with severe bleeding, anti-
gestions that sacral nerve stimulators may be of use for fae- coagulants or antiplatelet therapies should be discontinued
cal incontinence but this very expensive device should be or reduced, if possible. Patients should be advised to main-
implanted only with great caution into tissues made isch- tain regular bowel habits and we often prescribe non fer-
aemic after radiotherapy because of the high risk of compli- mentable stool bulking agents (we favour the use of sterculia
cations and definitely only after all the other causes for faecal above all other preparations) when needed to avoid addi-
tional trauma to the rectal mucosa from hard stool. For Formalin
patients with trivial bleeding not causing anaemia or interfer-
ing with daily activities, once serious underlying pathology Formalin solutions of 4–10% are applied directly to the
has been ruled out, should be reassured that they need no mucosa, where they cauterize tissue and seal fragile neovas-
treatment [84]. culature to prevent further bleeding. However, studies pub-
lished on the effects of this approach are of poor quality, and
important outcomes, including the risk of serious complica-
Endoscopy tions, are not well defined [95].
Endoscopic cryoablation and radiofrequency ablation
Endoscopy is frequently the first treatment option considered have been proposed as alternative treatments and have shown
for patients with rectal bleeding. However, there have been initial promising results. However, results from only a few
only a very few controlled studies to evaluate its safety and pilot, uncontrolled studies have been published [96, 97].
efficacy in these patients and these rarely report symptom Additional well-performed studies are needed before the
severity adequately so it is difficult to assess whether the effects of endoscopic cryoablation can be recommended.
intervention was required. Overall, based on retrospective
and uncontrolled prospective studies, endoscopic treatment
seems to be effective for about 80% of cases; the specific Nonendoscopic Therapies
treatment given usually depends on the endoscopist’s prefer-
ence and expertise [85, 86]. However, when we worked in a Medicine
specialist centre we were referred a steady flow of patients
with serious complications of the endoscopic intervention; Patients with radiation-induced injuries have minimal
either perforation or non-healing ulceration. This is unsur- amounts of inflammation, although pelvic radiation disease
prising as there is significant risk of non-healing after the use is frequently called radiation proctitis. This misleading term
of a thermal therapy such as argon plasma in ischaemic tis- results in inappropriate treatment, such as with anti-
sue. While argon plasma and formalin therapy in small ran- inflammatory agents (steroids and 5-aminosalicylic acids),
domized controlled studies [87, 88] seem equally effective in being frequently proposed as first-line treatment for pelvic
reducing rectal bleeding our preference is to avoid argon radiation disease [98]. A systematic review of randomised
plasma if at all possible and, if there is no ulceration present, and nonrandomised, prospective, comparative trials clearly
use the technique of intra-rectal formalin instillation show that these agents have no beneficial effects for patients
described by Cullen et al. [89]. with radiation toxicity [99]. At the moment, only 2 treat-
ments have been shown (in small, non–placebo controlled,
randomized trials) to be effective therapies for chronic
Thermal Coagulation radiation-induced telangiectasias: a 4-week course of oral
metronidazole [100] and sucralfate enemas [101].
If thermal coagulation therapy is used, it should only be per-
formed by experienced endoscopists because of the fre-
quency of serious procedure-related side effects [90–93]. Antibiotics
Thermal coagulation therapy destroys bleeding vessels but
also potentially the mucosa and submucosa. It therefore can Antibiotics have been used to treat patients with radiation-
lead to ulceration, which sometimes is associated with induced bleeding. Metronidazole kills anaerobic and micro-
increased bleeding, chronic pain and slow healing (or no aerophilic bacteria, which contribute to hypoxia; it also can
healing at all), and subsequent rectal stricture and loss of act as an immunomodulator. However, it is not clear how this
function. Prospective studies showed that as many as 50% of antibiotic might reduce bleeding. Cavcic et al. [99] per-
patients develop rectal ulcers after treatment [94]. Therefore, formed a study of 60 patients with radiation-induced rectal
it is reasonable to propose reducing argon flow rates (≤2 L/ bleeding and diarrhea who were given either the combina-
min) and wattage (≤40 watt), with precise application, to try tion of metronidazole (3 × 400 mg/day orally), mesalazine
to reduce the number of complications [91]. and betamethasone, or the combination of mesalazine and
Recently, the technique of Radiofrequency Ablation has betamethasone. After 12 months of follow-up evaluation,
been proposed as an effective solution for bleeding radiation they observed significant reductions in the incidence of rec-
proctopathy. It cannot be recommended until there are pub- tal bleeding, ulceration, and diarrhoea in the metronidazole
lished data showing it is safe. group. We belive that these findings indicate that improved
bowel function may have been seen as a result of effective Table 4 Suggested steps for managing GI bleeding after pelvic
treatment of small-bowel bacterial overgrowth and as a result radiotherapy
of this improved bowel function, this is why bleeding was Step 1: Investigate with flexible endoscopy to determine the cause of
the bleeding
reduced.
Step 2: Optimise bowel function and stool consistency which may
reduce the amount of bleeding
Step 3: If bleeding is not affecting quality of life (eg, staining
Sucralfate Enema clothes, causing anaemia, interfering with daily activities), reassure
and do nothing further
Step 4: If bleeding affects quality of life, stop/reduce anticoagulants
A Cochrane review [101] has summarised the evidence for
if possible and, if very severe, start sucralfate enemas
treatment of rectal bleeding from radiotherapy. Sucralfate Step 5: Discuss definitive treatment to ablate the telangiectasia with
enemas (2 g sucralfate suspension made-up with 30–50 mL the patient; options include:
water in a bladder syringe injected twice a day via a lubri- (a) Hyperbaric oxygen therapy
cated foley catheter passed through the anus into the rectum) (b) Argon plasma coagulation
are often effective but need often to be continued long term. (c) Formalin therapy
It should be noted that systematic review suggests that corti-
costeroid or mesalazine enemas are ineffective for treating
bleeding from radiation proctopathy. reventing Radiation Injury: Future
P
Perspectives
Hyperbaric Oxygen As yet, no objective biomarkers of radiation-induced toxicity

exist; their discovery should be a very high research priority.
Hyperbaric oxygen therapy provides the best evidence that The need for these markers has intensified due to the grow-
radiotherapy morbidity can be modified. This therapy seems ing number of cancer survivors at risk for developing toxic-
to stimulate angiogenesis, fibroplasia, and tissue restructur- ity from cancer therapies and would allow us to select
ing through an increase in oxygen gradients in ischaemic tis- patients for trials of therapies to reduce that risk of toxicity
sues. A systematic review [102] has summarised the efficacy [105].
of hyperbaric oxygen in the management of radiation- A second priority is to develop treatments that are safe,
induced bleeding and other symptoms. These data (none of easily administered and effective at reducing or eliminating
which are randomised and much of which are retrospective) adverse health effects to individuals from radiation
are encouraging, but they lack consistency in scoring of exposure.
symptoms and response criteria. Two randomized controlled A number of radiation countermeasures are currently
trials have been published—one showed benefit [103]. Our under investigation; however, these must undergo further tri-
own trial did not although in patients with bleeding possibly als before being approved for use on humans. Importantly,
there was a trend to improvement [104]. Our own view is that protective or mitigating agents can only be considered for
there is a definite role for hyperbaric oxygen in patients with clinical use if they do not hamper the anti-tumour effect of
severe rectal ulceration but further studies are needed espe- the radiotherapy treatment [102]. With regard to efficacy, it is
cially as hyperbaric oxygen is expensive and has a low risk crucial that both the effects on acute and late intestinal radia-
of side-effects, including the theoretical risk of promoting tion injury are assessed as both agents that reduce acute and
the growth of occult metastases [1]. late injury are needed in order to improve the quality of life
of patients [106].
Surgery
Somatostatin Analogues
A final treatment option is surgery to defunction or resect the
bleeding area. However, these procedures have high morbid- Radiation exposure causes breakdown of the intestinal epi-
ity. In view of the potential of all interventions to cause sub- thelial barrier due to a decrease in intestinal crypt/stem cell
stantial harm to patients who may already have major proliferation and inadequate cell supplies to compensate for
problems, there is an urgent need for carefully designed mul- continuous enterocyte loss. As a result, sub epithelial tissues
ticentre randomised trials to assess the management of post- may be exposed to intraluminal pancreatic enzymes that sub-
radiotherapy bleeding [1]. sequently aggravate the injury by initiating auto-digestion of
A clinical algorithm [17] for treating problematic radia- the intestine and the induction of inflammatory processes
tion bleeding is shown in Table 4. [107, 108]. Strategies to reduce exogenous pancreatic
s ecretion, like pharmacological inhibition with somatostatin a natural agonist of toll-like receptor 5 (TLR5). Both flagel-
analogues, have been shown effective in reducing intestinal lin and the less toxic synthetic flagellin derivate CBLB502
radiation toxicity in animals [109, 110]. Human studies have been shown to be potent radioprotectors in mice and
investigating the effect of octreotide on post-irradiation diar- non-human primates [125, 126].
rhoea in patients being treated for rectal or anal cancer have Pretreatment with Toll-like receptor 5 agonist prevents
had mixed results [111, 112]. This might, in part, be because radiation-induced apoptosis of intestinal epithelial cells and
of the limited volume of small intestine in the radiation field, subsequent injury [126, 127]. A concern regarding the use of
the site at which somatostatin analogues are expected to TLR5 receptor agonist is the possible induction of systemic
exert their effect. inflammation [128]. Further research is thus needed to deter-
The recently developed somatostatin analogue SOM230 mine the safety and efficacy of the above mentioned agents
(Pasireotide) may be more effective in reducing radiation before they can be used clinically to prevent intestinal radia-
injury than octreotide. It has a more favourable pharmacoki- tion injury.
netic profile and broader receptor affinity. It was also found
to reduce radiation toxicity when started up to 48 h after
exposure [113]. Studies are now needed to determine the Endothelial Protectants
safety and potential efficacy of SOM230 in abdominal and
pelvic radiotherapy. It is thought that post-irradiation, endothelial apoptosis con-
tributes to intestinal stem cell dysfunction and mucosal
injury [129]. Treatments that reduce radiation-induced
Growth Factors and Growth Factor-Like Agents microvascular endothelial cell apoptosis may therefore be
able to prevent intestinal radiation injury [129]. The sphingo-
The use of growth factors and growth factor-like agents to lipid, ceramide, has been shown to play a crucial role in
improve post-irradiation intestinal epithelial recovery has radiation-induced endothelial apoptosis. Radiation exposure
been researched over the past several years. Glucagon-like can cause hydrolysis of cell membrane sphingomyelin by
peptide 2 as well as keratinocyte and fibroblast growth fac- acid sphingomyelase which results in the formation of
tors has been shown to ameliorate post-irradiation intestinal ceramide. Ceramide then initiates the apoptotic process via
injury in various animal models [114–119]. Moreover, the mitochondrial system [130]. Bonnaud et al. showed that
recombinant human epidermal growth factor as well as inhibition of post-irradiation ceramide production promotes
R-spondin 1, an intestinal stem cell growth factor, has been post-irradiation endothelial survival and ameliorates intesti-
shown to reduce apoptosis and improve recovery of the nal injury in mice [131]. In addition, as well as reducing
intestinal villi [120, 121]. Growth factor-like agents have endothelial apoptosis, endothelial function may be improved
also been be used to reduce radiation injury. For example, the post-irradiation with agents like 3-hydroxy-3-methyl-
growth factor-like lipid mediator lysophosphatidic acid glutaryl-
CoA (MHG-CoA) reductase inhibitors that have
(LPA) was shown to reduce post-irradiation intestinal apop- been shown to reduce intestinal radiation injury in animal
tosis through the LPA receptor 2 subtype [122]. models [132, 133].
Going forwards, it is important that these agents do not
affect radiation-induced tumour cell kill, tumour growth or
other malignant tumour properties. In the animal studies per- γ-Tocotrienol
formed, this did not appear to be the case. However, further
research is needed to confirm these results and if they are Another group of promising new agents targeted at reduc-
shown to be effective, serious discussions are required to ing intestinal radiation injury are Vitamin E analogues or
make them an affordable option. so called tocols that are powerful antioxidants with
favourable toxicity profiles. Hence, they have strong
potential to be developed as radioprotectants. γ-Tocotrienol
gents Acting on the Toll-Like Receptor 5
A may be so effective in reducing intestinal radiation injury
Pathway because tocotrienols accumulate in the small intestine and
colon to a higher level than tocopherols supplemented in
Toll-like receptors (TLR) are an important component of the the same concentration [134]. Other properties that may
intestinal innate immunity. Activation of TLRs by commen- contribute to the powerful radioprotective effects of
sal microflora is essential for the protection against intestinal γ-tocotrienol are its ability to concentrate in endothelial
injury and in the regulation of epithelial repair [123, 124]. cells to levels that are 30–50 fold greater compared to
Activation of TLRs reduces the sensitivity of enterocytes to α-tocopherol and to inhibit the enzyme MHG-CoA reduc-
radiation-induced apoptosis. The bacterial protein flagellin is tase [135, 136].
At present, little is known about the effects of OrbeShield®/Beclomethasone

γ-tocotrienol on tumour cells during radiotherapy. 17,21-Dipropionate (BDP)
γ-Tocotrienol may sensitise tumour cells to radiation expo-
sure and chemotherapeutic agents [137, 138], however, fur- BDP is a potent, topically-active corticosteroid currently
ther studies are needed to confirm that it does not protect under development as an orally-administered radiation
tumour cells against radiation. With regard to the safety of countermeasure for GI-acute radiation syndrome (GI-ARS)
γ-tocotrienol in human beings, studies from other fields [143]. It offers potent anti-inflammatory effects with mini-
have shown that γ-tocotrienol supplementation is well tol- mal toxicity compared with other systemic corticosteroids.
erated in human subjects [139, 140]. We have just com- BDP showed significant survival benefit in a canine model
pleted a randomised double blind trial of tocotrienol of GI sub-syndrome [143]. In this model, canines received
combined with pentoxifylline and its utility in treating total body irradiation (TBI), followed by autologous BM
established radiation injury not responsive to other modali- administration and supportive care. This was coupled to
ties. The results should be available soon. experimental treatments with either the test agent or pla-
cebo. The study suggested that BDP can reduce inflamma-
tion of tissues of the GI mucosa after irradiation and can
Pentoxifylline +/− Vitamin E improve survival, even when treatment is initiated as late as
24 h post-irradiation [144].
Pentoxifylline is a methylxanthine derivative originally
developed for the treatment of regional microcirculation dis-
orders and shown to have anti-inflammatory and immuno- Myeloid Progenitor Cells (MPC)
modulatory properties. Consistent with animal data, the
majority of studies published from the use of pentoxifylline MPC can improve the survival of mice after exposure to high
in humans to treat radiation-induced fibrosis including some doses of radiation. It has been evaluated for use as a bridging
randomised trials have reported improvement. The total therapy for radiation injuries and to mitigate the effects of
number of enrolled patients in these studies is 336 and look- lethal doses of 60Co γ-irradiation and X-rays in different
ing through these studies gives an impression that pentoxi- strains of mice [145]. Results from studies have demon-
fylline is more effective when used in combination with strated that cryopreserved allogeneic MPC significantly
vitamin E but that any benefits achieved may take many improved survival in strains of mice irradiated with lethal
months to become apparent. There is a pressing need for doses of 60Co γ-radiation (CD2F1, 9.2 Gy) and X-ray expo-
appropriately powered randomised studies, which should be sures (BALB/c, 9 Gy) that are known to cause ARS in hema-
double-blind placebo-controlled in view of the subjective topoietic tissues [135]. The survival benefit was
nature of most clinical endpoints to confirm these encourag- MPC-dose-dependent and significant even when MPC
ing findings. administration was delayed up to 7 day’s post-irradiation.
Additionally, MPC administration decreased deaths from
ARS at radiation doses up to 15 Gy (60Co γ-radiation, CD2F1
Interleukin-11 (IL-11, Oprelvekin) mice). Exposure levels of such magnitude can cause mice to
succumb to multi-organ failure. Even at doses of up to 14 Gy
IL-11 is a multifunctional cytokine of the interleukin-6 (IL- 60Co γ-radiation, MPC administration could be delayed up to
6) family. It stimulates maturation of megakaryocytes and 5 days in CD2F1 mice and still provide significant benefit to
has anti-inflammatory properties as well as cytoprotective 30-day survival.
effects on gastrointestinal crypt cells [102]. Administration In addition, MPC also improves the structural integrity of
of IL-11 improves crypt survival and reduces GI mucosal GI tissue after irradiaton. This has been observed in a study
injury after total-body irradiation in mice [141]. It also pro- that looked into the structural integrity of the GI tract of mice
tects the clonogenic stem cells in murine small-intestinal who had received MPC treatment after doses of radiation
crypts from impairment of their reproductive capacity by capable of causing GI injury and found that it improves the
radiation [142]. Although IL-11 is well-tolerated in animals, structural integrity of GI tissue and inhibits bacterial translo-
significant adverse effects including fluid retention, multi- cation from the GI tract [146]. These results give support to
system organ failure and pleural effusion have limited its the administration of MPC as a bridging therapy for GI tis-
clinical use in humans. sue. However, as promising as these studies are, further work
with extended observational periods are needed in order to The microbiota plays a role in determining the availability
investigate whether any potentially late-arising pathologies and production of these molecules. Fibrolytic bacteria
stem from graft versus host disease. degrade large polysaccharides into smaller carbohydrates,
which are then fermented into short-chain fatty acids [154,
155]. The Roseburia genus is an acetate consumer and butyr-
Enterade®/Amino Acid-Based Oral Rehydration ate producer, whereas Phascolarctobacterium is a propio-
Solution nate producer; they are both reduced in inflammatory bowel
disease. Faecalibacterium prausnitzii is a major butyrate
Enterade® is an amino acid-based oral rehydration solution producer and is reduced in Crohn’s disease [155]. These
recently developed by researchers at the University of effects are clinically relevant in inflammatory bowel disease
Florida. Studies in irradiated mice have shown that specific [155] and in acute radiation proctitis [156], and could also be
combinations of amino acids increase Na+ absorption via relevant in pelvic radiation disease.
amino acids-coupled Na + absorption while there is no stim- Thus, being able to characterise the gut microbiota and
ulation of Cl− secretion and, therefore, fluid secretion [147]. research its role further may allow the development of
In addition, Enterade® led to tightening of the mucosal bar- genomic and metabolomic profiles for risk assessment of
rier, increased crypt count and villus length in intestinal tis- patients and enable manipulation of the intestinal flora for
sue. The animal data are highly suggestive that Enterade® is prevention and treatment of pelvic radiation disease [3].
an effective radiation mucosal protectant [147]. Publications The development of next-generation sequencing technol-
subsequently suggest that it is palatable and safe and so the ogies and metabolic phenotyping could make stratification
results of ongoing interventional human studies are eagerly of patients at risk of radiotherapy-induced gastrointestinal
awaited. toxicity a realistic possibility. This is further supported by
studies of common bacterial traits in patients with radiation-
induced gastrointestinal symptoms [157]. A recent pilot
Human Microbiome study used an electronic nose and field asymmetrical ion
mobility spectrometry to detect selected metabolites in the
Recent research has shown how the gut microbiota interacts stool of 23 patients before and 4 weeks after pelvic radio-
with the host to promote homoeostasis. These mechanisms therapy, with promising results in risk prediction [158]. It is
could be important in our understanding of the gastrointesti- attractive to attribute this difference to changes in the micro-
nal symptoms that are seen after pelvic radiotherapy. A study biota. Nevertheless, these results should be carefully inter-
of 231 patients showed that 12% of microbial metabolic preted because at present faecal metabolomes do not stratify
pathways were changed in patients with inflammatory bowel populations according to their gut bacteria [159].
disease compared with only a 2% change in the microbial Finally faecal microbiota transplantation has recently
genera profile [148], with a shift towards a phenotype that been reintroduced as a treatment for Clostridium difficile-
allows the microbiota to cope with oxidative stress. Thus, induced colitis and evidence of its benefit is steadily growing
dysbiosis associated with intestinal inflammation promotes a [160]. It has not been tried in the context of radiation intesti-
selection of bacteria capable of withstanding a highly oxida- nal toxicity; however, its clinical potential seems exciting
tive environment, also present after radiotherapy [3]. because it could be an inexpensive, potentially effective
Additionally, anaerobic bacteria convert primary bile radiation-response modifier, possibly allowing for increases
acids into secondary bile acids. Secondary bile acids are in the therapeutic index of pelvic radiotherapy [3].
anti-inflammatory and inhibit TNFα, interleukin 1α, inter- Overall, the potential of the microbiota as a risk assess-
leukin 1β, and interleukin 6 through the bile acid specific ment and treatment instrument for radiation-induced gut tox-
receptor, TGR5. In inflammatory bowel disease, dysbiosis icity seems promising. If confirmed, this could be an
modifies this balance as it decreases the production of sec- important step forward in oncology, allowing for inexpen-
ondary bile acids, creating a proinflammatory environment sive, patient-tailored treatment to modulate toxicity.
[149]. Similar imbalances in the microbiota produced after
intestinal radiation have been observed [150], suggesting
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Problems After Gastric Surgery
Alastair Forbes and Alistair McIntyre
Key Points
1. Gastric surgery is most commonly a result of surgery for Introduction and Background
cancer (usually gastric) or as a result of complications of
peptic ulceration (bleeding or perforation). Gastric surgery is very rarely a cause of intestinal failure.
2. The anatomy and thus physiology must be understood Only when there have been substantial operative complica-
following gastric surgery (e.g. how much of which part of tions or when gastric surgery is combined with some other
the stomach was removed, how do pancreatico-biliary insult to gastrointestinal integrity is intestinal failure at all
secretions enter the system etc.). likely to occur. However, although surgery for gastric pathol-
3. Malnutrition results from reduced intake (partly due to ogy is now less often performed than in earlier decades,
early satiety), poor gastric secretion/mixing and sieving these combinations of multiple morbidity are seen and form
functions, reduced pancreatic secretions (maldigestion) a small but important part of intestinal failure practice.
and dysmotility (fast gut transit due to neural disruption) Additionally, the inclusion of gastric interventions in most
all of which contribute to malabsorption. Most patients bariatric procedures (chapter “Surgery for Obesity and Its
are chronically underweight. Consequences”) reinforces the value of an understanding of
4. General malnutrition and/or specific deficiencies (e.g. the consequences of disturbing the functions of this organ.
iron, B12, folate, fat soluble vitamins (especially vit D), Operations have been performed on the stomach to treat
thiamine, pyridoxine and copper) may result. cancer and peptic ulcer disease since Billroth’s first partial
5. Early and late dumping syndrome, small bowel bacterial gastrectomy in 1881. These operations initially disrupted
overgrowth, post vagotomy diarrhoea, bile salt malab- normal gastrointestinal physiology to a very marked degree.
sorption and osteoporosis may occur. In addition there is As surgical techniques developed, mobility and mortality
an increased risk of gastric cancer. were reduced but some patients nonetheless developed major
6. These patients need long-term follow up for general/spe- post-operative problems which were considered part of a
cific nutritional monitoring/giving appropriate supple- post-gastrectomy syndrome. These problems can be attrib-
ments, treating fast transit (high dose loperamide or uted to alterations in gastric, intestinal and pancreatic physi-
octreotide), small intestinal bacterial overgrowth (SIBO) ology, and may result directly or indirectly in malabsorption
(rotating antibiotics), bile salt malabsorption (cholestyr- and other nutritional deficiencies.
amine) and monitoring for osteopenia/osteoporosis and Elective surgery for peptic ulcer disease has become
gastric cancer. much less common because of a reduced incidence of ulcers
and improved medical therapy with acid suppression and
eradication of Helicobacter pylori. Emergency surgery for
complications such as bleeding and perforation is still
Alistair McIntyre has died before the publication of this book. required but rarely necessitates gastrectomy; consequently
there are few lasting effects on gastrointestinal physiology.
By contrast there is a continued and increasing need for gas-
A. Forbes (*)
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
tric resection for malignancy, particularly in the west, with
e-mail: [email protected] the increasing recognition of early and potentially curable
A. McIntyre (Deceased)
cancers.
Norwich Medical School, UEA, Norwich, UK

290 A. Forbes and A. McIntyre
Undernutrition Following Gastric Surgery Direct Effects of Gastric Surgery
Post-gastrectomy syndromes comprise a wide spectrum of The disruption to physiological processes depends on the
conditions, many of which are associated with adverse nutri- operation performed and also on the individual’s response to
tional consequences. Reduced intake and malabsorption that surgery. Many different procedures are or have been per-
both contribute to weight loss and are often seen together in formed on the stomach (Figs. 1 and 2) and their pathological
affected patients. consequences are determined by the anatomical and physio-
Inadequate nutritional intake can result from early satiety logical changes caused.
due to a small volume gastric remnant and/or its lack of com-
pliance. Operations which alter gastric motor function with-
out an adequate drainage procedure being performed lead to
delayed gastric emptying, which also leads to post-prandial a b
fullness and early satiety. Alterations in gastric motility
resulting in inadequate mixing, combined with surgically
induced reduction of acid, pepsin and intrinsic factor secre-
tion, contribute to a varying degree to subsequent malabsorp-
tion of the food that has been consumed.
It is common for gastric surgery to be followed by sub- d
optimal pancreatic function given that pancreatic exocrine
function is determined in part by an intact enteroendocrine
system, and because procedures that create an afferent loop
separate pancreatic secretions from the immediate outflow
from the remaining stomach (or the oesophagus when a total c
gastrectomy has been performed) (see below), thus reducing
their ability to contribute to digestion.
The gut hormone responses to food clearly differ substan-
tially from those in normal individuals, the secretion profiles
for insulin, glucagon-like peptide 1 and cholecystokinin all
being significantly different after a liquid challenge in gas-
trectomised patients [1].
The function of the proximal small bowel may be com- e f
promised by rapid transit, limiting the time available for
absorption of nutrients, and further if bacterial overgrowth
occurs (see below). Nonetheless mucosal absorptive capac-
ity appears to remain within normal limits in most cases.
Patients may dramatically reduce their intake of food in
attempts to avoid post-prandial symptoms and especially so
if they are affected by the dumping syndrome or diarrhoea
(see below). Other patients may select an inappropriate diet,
with large and insufficiently masticated particles of food,
nutrients with especially high osmolality or simply excessive
volumes. As well as contributing to unpleasant sensations of
Fig. 1 Types of gastric surgery done for peptic ulceration. (a) The
excess satiety these may also contribute to intestinal diges- vagus nerve which supplies the stomach may be divided proximally (a
tive malfunction. truncal vagotomy), or more distally (selective or highly selective vagot-
There is no doubt that impaired quality of life is strongly omy). (b) Pyloroplasty (frequently used with truncal vagotomy to pre-
associated with malnutrition and weight loss [2, 3], but it is vent delay in gastric emptying). (c) Gastroenterostomy (which enhances
emptying by bypassing the pylorus). (d) Billroth I partial gastrectomy.
more difficult to determine whether this is a causal relation- (e) Billroth II (or Polya) gastrectomy with afferent (a) and efferent (e)
ship and if so in which direction the cause operates! small intestinal limbs. (f) Roux-en-Y reconstruction with afferent (a)
and efferent (e) small intestinal limbs
Problems After Gastric Surgery 291
Fig. 2 Types of total

gastrectomy. (a) Roux-en-Y
a b c
oesophago-jejunostomy. (b)
Interposition of jejunal, ileal
or colonic loop. (c) Small
bowel pouch and Roux-en-Y
oesophago-jejunostomy
In broad terms the greater the magnitude of resection the as the various studies performed have had heterogeneous
greater the nutritional consequences, and (for example) near- criteria for entry, type of surgery and nutritional interven-
total gastrectomy gives some protection compared to total tion. This position is often aggravated by omission of base-
gastrectomy, with less severe and less persistent objective line weight (many studies start using pre-operative weight
markers of malabsorption than in the patients receiving the which, from the nature of the diseases concerned, is gener-
more radical surgery and without oncological hazard [4]. ally lower than the patient’s weight in health), and by a lack
Vagotomy reduces acid secretion by interrupting the vagal of appropriate control populations. As an example, one
simulation of the gastric parietal cells. When this is a highly study claimed to show avoidance of weight loss but did not
selective procedure there is essentially no other effect, but a take account of the normal gradual increase in weight dur-
truncal vagotomy not only cuts acid secretion but also pro- ing middle-age nor the fact that the “baseline” weight was
foundly impairs gastric motor function and compliance, that immediately before the surgery [5]. Overall more than
delays gastric emptying (but see below), and compromises 50% of patients are and remain underweight indefinitely
pancreatic function. after gastric surgery [6, 7].
Partial gastrectomy reduces the physical size of the stom- In general, patients with no symptoms after eating eat
ach, and, depending on the site removed, will reduce acid normally, while those with symptoms almost universally
secretion to a greater or lesser degree. The normal mixing respond to this by eating less roughly in proportion to the
and sieving functions will be impaired. severity of those symptoms. Weight loss indeed correlates
Drainage procedures such as pyloroplasty and forms of strongly with reduced food intake [7–9] and also with the
gastroenterostomy were introduced to overcome delayed speed of orocaecal transit [10, 11].
gastric emptying caused by vagotomy or partial gastrectomy, Patients who are underweight after partial gastrectomy
but paradoxically can also be the main cause of precipitate typically eat less than half the macronutrient intake of nor-
gastric emptying, dumping syndrome and rapid intestinal mal controls or those who have managed to maintain their
transit (see below). weight after surgery [12]. In those who can be encouraged,
Reconstructional surgery to permit continuity of the gut and are able, to consume normal amounts of food, some
for biliary and pancreatic secretions such as the Roux-en-Y weight gain can be expected. A major study of patients after
procedure yields an afferent loop which can itself be respon- various forms of cancer surgery accordingly confirmed that
sible for additional physiological disturbance. even as early as 3 months after operation differences in nutri-
Gastric surgery may also be responsible for uncontrolled tional intake can be overcome, but showed that those with
gastro-oesophageal reflux (which will often be alkaline) and more invasive procedures did indeed have more persisting
places the patient at increased risk of malignancy in the gas- weight loss [13].
tric remnant as well as at risk of the full gamut of post- Other factors contributing to weight loss are however
operative complications common to all abdominal surgery. almost certainly important, including dysfunctionally exag-
gerated satiety (Table 1). The normal response to relative
starvation (eating more) appears blunted in patients who
Weight Loss and Dietary Restriction have undergone partial gastrectomy.
The routine use of oral nutritional supplements has its
Loss of weight after gastric resection is so common as to be advocates, and there is good evidence in support of this and
considered an expectation; even with optimal nutritional other forms of artificial nutrition at the time of surgery for
support the weight lost may be substantial. The magnitude gastric cancer (e.g. [14, 15]) but evidence in favour of longer-
to be expected with best practice remains difficult to predict term support is lacking, problems with compliance perhaps
Table 1 Nutritional effects of gastric resection The study of gastric emptying using a two-phase (liquid
Reduced food intake and solid) double radio-isotopic method can provide objec-
Maldigestion tive evidence of the nature and rate of gastric emptying, but
Impaired gastric sieving its clinical usefulness is limited given the variable response
Impaired gastric secretion (acid and enzymes)
to interventions even when these are based on information
Malabsorption
specific to the patient concerned.
Impaired gastric secretion
Impaired pancreatic secretion
Impaired intestinal secretion
Blind loops and bacterial overgrowth Gastric Sieving
Specific deficiencies (e.g. thiamine, vitamin B12)
Early and late dumping syndromes The normal stomach yields duodenal access to liquids and—
Motility disorders affecting gastric emptying and intestinal transit through the process known as gastric sieving—of particles
only less than 1 mm in size [21]. This process is self-evidently
confounding possible benefit [16]. An educational approach greatly compromised by the more major gastric resections
taken in this regard may pay dividends [17]. and those with a substantial enterotomy, but vagotomy with
antrectomy or pyloroplasty can also disrupt the process and
allow entry of larger particles into the small bowel following
Gastric Emptying meals [22, 23]; only following proximal/selective vagotomy
alone does normal gastric sieving appear to be preserved
Disturbance of the stomach’s normal role in processing food, post-operatively [23].
so as to be suitable for transfer to the duodenum and optimal In one small study (n = 9) vagotomy and antrectomy per-
digestion thereafter, contributes to post-operative malabsorp- mitted the emptying of abnormally large meat particles into
tion. In health the stomach regulates the entry of nutrients the small intestine, to the extent that 37% of the meat left the
into the duodenum in quantity, particle size, and nutritional stomach while still more than 1 mm in size [22]. The effect
content, titrating efflux against osmolality and energy load in on gastric emptying was however quite variable since two of
such a way that proximal small intestinal function is facili- the nine patients had normal sieving (<2% of the particles
tated and absorption maximised [18]. reaching the small intestine >1 mm) whilst in the worst
Gastric emptying is thus not a single simple process, and affected patients 75% of particles were >2 mm in size. In a
although (for example) vagotomy is generally considered to similar small study of patients after vagotomy and pyloro-
delay emptying it is also a potential cause of rapid emptying plasty two of seven patients had abnormal sieving [23].
with precipitate “dumping” of nutrients into the small intes- Larger particles have a lower surface to mass ratio, and
tine [19]. Indeed liquids empty abnormally rapidly following when these are presented to the small intestine their hydroly-
vagotomy, with or without pyloroplasty, as well after all sis, overall digestion and absorption are slower than is nor-
forms of gastric resection and reconstruction [20]. The emp- mal [24, 25]. In a controlled experiment on dogs with Billroth
tying of solid food following gastric surgery is much more I gastrectomies absorption of 14C triolein from margarine in
variable—the initial phase often results in rapid emptying of the liquid phase was—as in controls—almost complete by
some solids, but after 30–60 min emptying of solids may the mid-gut. However when the 14C triolein was incorporated
become very slow or continue at rapid rates depending on the in steak and liver more than double the amount (50% vs
individual as well as on the procedure that has been per- 20%) was recovered unabsorbed in the mid small intestine in
formed. Following truncal vagotomy, even with pyloroplasty, the gastrectomised animals. This was attributed to a failure
emptying of solids is delayed [21] whilst emptying is abnor- of gastric sieving and to a shielding of fat from the digestive
mally rapid after essentially all forms of gastrectomy [20]. processes given the observation of many meat particles
Many patients describe particular problems with fatty exceeding 0.5 mm in diameter, whereas fewer than 2% of
foods and most dramatically so when oils (liquid fats) are particles were larger than 0.5 mm in the controls [24, 25].
ingested. This is probably because their rapid gastric efflux There are no directly comparable studies in man, but investi-
overwhelms the digestive abilities of the pancreas, which is gation of iron absorption strongly suggests a similar
attuned to relatively slow exposure to fats after meals, given phenomenon.
the usual sequence of solids leaving the stomach in which Under normal circumstances the absorption of radiola-
fats follow carbohydrate and protein. The absorptive capac- belled iron from solid phase dietary muscle myoglobin is
ity of the proximal small intestine can be exceeded for other only minimally less than its absorption from an aqueous
nutrients also, and if the more distal intestine is insufficient solution. However after Billroth I or Billroth II gastrectomy
in length or function to accommodate this then significant there is a markedly reduced absorption of iron from the solid
malabsorption may arise. phase [26]. It is thought that this reflects the failure of mixing
and sieving by the stomach, and the premature delivery of (e.g. Billroth II gastrectomy and the Roux-en-Y reconstruc-
oversized iron-containing particles to the small bowel. tions) pancreatic secretions are to some degree sequestered
in the afferent loop of the small intestine and mix with the
oesophagogastric effluent relatively late [10, 20].
The Small Intestine After Gastric Surgery The mechanisms that lead to pancreatic enzymes leaving
the afferent loop are not fully elucidated, but are thought to
Although there is some involvement of the small bowel in depend on a combination of passive filling and overflow
many gastric procedures—from the simple gastrojejunos- with some degree of active post-prandial motor function. It
tomy to more complex multi-loop reconstructions—the gen- is probable that in most patients the reduction in pancreatic
eral observation is that the small intestine remains normal enzyme secretion is less important than the loss of synchro-
macroscopically and histologically. At a cellular level the nous timing of peak enzyme contact with food, as overt fat
absorption of salt, water, soluble iron, glucose and fatty acids malabsorption can still be demonstrated in patients with
can all be shown to be normal [27]. more conservative procedures (such as Billroth I gastrec-
Nonetheless intestinal factors contribute to post- tomy) where the total integral post-cibal pancreatic enzyme
gastrectomy malabsorption, mainly as a result of excessively secretion is less affected. Maldigestion is most marked in
rapid transit and a reduced time available for intraluminal the early phases after eating when there would normally be
digestion and absorption. When the intestine itself is normal the most pronounced peak of enzyme secretion [20].
this rarely presents a major nutritional challenge given gen- These observations have led to a range of suggested inter-
erally high levels of reserve capacity [28], but if there is ventions to improve maldigestion and malabsorption of pan-
intestinal disease or if there has been small bowel resection creatic origin after gastric surgery. Patients are usually
then problems may be profound. advised to reduce the ingestion of oils and to take pancreatic
enzyme supplements with meals. While these measures can
be expected to ameliorate the pancreatic dysfunction [10,
Pancreatic Function 30], the former restriction may add to the overall nutritional
deficit. A small controlled trial of pancreatic enzymes after
The roles of the pancreas are closely aligned with those of surgery for gastric cancer showed modest improvements in
the stomach, so it is to be expected that gastric surgery com- quality of life and a range of nutritional measures when com-
promises its normal function to some extent. Selective proxi- pared with standard dietary advice alone [31]. When pancre-
mal vagotomy appears to have no impact, but all gastric atic enzymes are given it is important to prescribe preparations
resections and drainage procedures reduce pancreatic exo- which do not depend on an acidic pH in order to release their
crine function, typically by 30–50% from normal [22, 23], contents.
and a reduction of up to 70% has been reported after truncal More imaginatively (although as yet without convincing
vagotomy and pyloroplasty. data) it is suggested that asynchrony is overcome by recom-
Direct study of pancreatic secretion is now rarely done mending that gastrectomised patients with an afferent pan-
and reference data are relatively aged, but robust evidence creatobiliary loop should ingest a small quantity of fat or oil
nonetheless exists for reduction in output of trypsin, chymo- 60 min before ingestion of a meal [32]. This is intended to
trypsin and amylase in response to secretin-cerulein stimula- stimulate pancreatic secretion and to fill the afferent loop
tion. There is parallel perturbation of pancreatic endocrine thus “priming” the system for the meal that is about to be
function. Baseline and post-prandial levels of pancreatic ingested.
polypeptide and gastrin are low, whilst meal-stimulated cho-
lecystokinin is significantly increased [29], and abnormal
glucose tolerance tests are common. Overall Effects of Gastric Surgery
These reductions in pancreatic function are compounded on Absorption of Nutrients
by the loss of synchronous delivery of pancreatic secretions
(and bile) as food enters the upper small intestine. The com- Protein
bined effect is of slower digestion of all macronutrients and
especially of fat. The normal negative feedback loop that Western diets generally yield protein intakes well in excess
inhibits gastric emptying is also disrupted following many of requirements. Although some malabsorption of protein is
gastric surgical procedures adding to the problems, espe- demonstrable, along with azotorrhoea (protein in the stool),
cially in the earlier phases of digestion. in patients who have undergone total or subtotal gastrec-
Following all of the procedures in which the normal flow tomy, it is not generally a clinical problem after gastric
of nutrients across the outflow from the pancreas is disrupted surgery.
Carbohydrates In Combination
Carbohydrate malabsorption is more of a problem. It is dif- Although nitrogen balance is not especially compromised
ficult to quantify accurately but it contributes to post- after gastric resection it is clear that the many deleterious
operative malnutrition, and also to a series of symptoms effects on digestion and absorption of carbohydrates and fats
increasingly familiar to those exploring FODMAP intoler- contribute to a global tendency to malnutrition. However nei-
ance in patients with irritable bowel syndrome and other ther weight loss, nutritional status nor changes in body com-
functional disorders. The FODMAPs are Fermentable position correlate well with any individual component of the
Oligosaccharides, Disaccharides, Monosaccharides, and malfunctioning physiology [9].
Polyols, and comprise a group of poorly absorbed short-
chain carbohydrates. These are the most likely to be malab-
sorbed after gastric surgery, but to their number will be added Bacterial Overgrowth
lactose and longer chain molecules including starch [33].
Absorption of the FODMAPs and other carbohydrates by the Gastric acid normally makes an important contribution to
small intestine is compromised here predominantly through the relative sterility of the proximal small intestine so it is
the effects of excessively rapid intestinal transit. to be expected that procedures which diminish or elimi-
Malabsorption of sugars can be precipitated in completely nate acid secretion will sometimes be complicated by
healthy subjects if the ingested dose exceeds a threshold dic- small bowel bacterial overgrowth (SBBO). Bacterial
tated by the speed of intestinal transit [34], so the gastrect- counts of >104 colony forming units/ml are generally con-
omised patient can be seen always to be vulnerable. sidered abnormal and counts of above 106 to be diagnostic.
Flatulence, bloating, cramps and diarrhoea can all result and Diagnostic levels are found in patients after all types of
subclinical lactose intolerance may be unmasked [35]. gastrectomy [40, 41]. When there is a partially defunc-
Rarely, even glucose may be malabsorbed [36]. tioned/blind loop more than 50% of patients will be
affected, and only with selective vagotomy do rates remain
below 10% (British Society of Gastroenterology (BSG)
Fats Guidelines, accessible via https://www.bsg.org.uk/
resource/guidelines-f or-t he-i nvestigation-o f-c hronic-
Clinical fat malabsorption with steatorrhoea does not occur d i a r r h o e a -i n -a d u l t s % 2 D % 2 D b r i t i s h -s o c i e t y -o f -
following vagotomy alone [37] and is seldom present in gastroenterology%2D%2D3rd-edition.html). The presence
patients following vagotomy and pyloroplasty or Billroth I of bacteria (which are usually of the types considered
gastrectomies [30]. Under normal circumstances less than colonic/faecal) does not correlate closely with clinical
6% of ingested fat is lost in the faeces, but following Billroth manifestations however and in at least one study colonisa-
II gastrectomy or vagotomy with gastroenterostomy, levels tion was equally common in those with and without symp-
in the region of 8% are found. Following total gastrectomy toms [41].
15–20% of dietary fat is typically malassimilated [10, 30]. Clinical features attributed to SBBO include bloating
This correlates quite tightly with deficiency of the fat soluble and diarrhoea and/or steatorrhoea together with evidence
vitamins and especially of vitamin D (see below). of malabsorption particularly of vitamin B12. Investigation
is troublesome as, apart from direct culture of small bowel
aspirates, the available tests have very considerable false
Micronutrients positive and false negative rates, not least because of the
underlying rapid intestinal transit (BSG Guidelines:
Vitamin D in bone disease and deficiencies of haematinics in https://www.bsg.org.uk/resource/guidelines-f or-t he-
contributing to the anaemia seen after gastric surgery are i n v e s t i g a t i o n -o f -c h r o n i c -d i a r r h o e a -i n -
considered below, but there is also evidence for specific defi- a d u l t s % 2 D % 2 D b r i t i s h -s o c i e t y -o f -
ciency of thiamine in more than 25% of patients even after gastroenterology%2D%2D3rd-edition.html). SBBO is
relatively conservative surgery such as the gastric sleeve therefore often a clinical impression and one which may be
[38]. These patients also show frequent deficiencies in cop- subjected to a diagnostic trial of antibiotic therapy,
per and pyridoxine [39] and while the bariatric population although this too can result in some misinterpretation
may be at particular risk there is no reason to be confident through the possibility of a placebo effect in one direction
that these could not occur after surgery for other or the choice of an antibiotic to which there is already
indications. resistance in the other.
Dumping Syndrome 7% of a control group. In 11% the diarrhoea was continual,

and a further 22% of patients had at least one episode of diar-
Dumping syndrome has come to be considered the arche- rhoea each week [49]. In 8% of patients the diarrhoea had
typal symptomatic complication of gastric surgery. First been a serious problem because of sudden and unpredictable
reported by Hertz in 1913 [42] and given its name by Mix in onset, sufficient at times to lead to incontinence.
1922 [43], early dumping is characterised by weakness, The diarrhoea in this syndrome appears to be related to
faintness or syncope, palpitations, pallor, sweating, nausea the truncal vagotomy and not to whether patients have had a
and vomiting, colicky abdominal pain and diarrhoea, one or pyloroplasty or a gastroenterostomy. The pathogenesis rests
more of which occurs typically 20–30 min after eating. In on rapid gastric emptying and rapid upper gastrointestinal
some patients features may arise sooner but it is rare for transit which results in reduced digestion and absorption in
these symptoms to begin much later. Dumping is a direct the small intestine and delivery of an osmotic load to the
consequence of excessively rapid gastric emptying (particu- colon (confirmed by intubation studies [50]). Transit can be
larly of the liquid phase) with resultant delivery of hyper- so fast that it even overwhelms the gut’s ability to absorb
tonic fluid into the duodenum. The ensuing reduction in glucose [36, 50]. On glucose/hydrogen breath testing there is
vascular volume combined with stimulation and dilatation a rapid rise in breath hydrogen coinciding with delivery to
of the duodenum cause a marked neurohumoral response, the caecum at a mean transit time of 25 min. There may also
not necessarily with hypoglycaemia. Vasoactive intestinal be may a contribution from the cathartic action of bile acids
peptide, serotonin, neurotensin, enteroglucagon, peptide reaching the colon. A controlled study demonstrated higher
YY and kinins are all implicated [44, 45]. Their vasomotor total bile acids in the faeces (in particular chenodeoxycholic
effects are responsible for most of the distressing acid), in patients with post-vagotomy diarrhoea than in con-
symptoms. trols [51]. Results from patients who had undergone a vagot-
The so-called late dumping syndrome occurs at least an omy but did not have diarrhoea lay between those from these
hour after eating. Also responsible for faintness, palpitations, two groups. Nonetheless, in affected patients, avoidance of
perspiration and confusion, this is a consequence of the rapid food to reduce symptoms is more commonly the reason for
transit of food causing excessive release of gastric inhibitory weight loss than malabsorption. Vagotomised patients fortu-
peptide and insulin which results in reactive hypoglycaemia nate enough to avoid post-vagotomy diarrhoea are thought to
[46, 47]. have particularly efficient colonic salvage [28].
The dumping syndromes can be a major contributing Treatment of post-vagotomy diarrhoea is predominantly
cause to malnutrition if their effects are sufficient to deter the with the use of antimotility agents. In one study codeine
patient from eating. Relatively small, frequent meals should phosphate (60 mg) and loperamide (12–24 mg) delayed tran-
be encouraged with an emphasis on foods of low glycaemic sit by 58 min and 63 min respectively, and improved symp-
index. Monosaccharide-based drinks in particular should be toms dramatically in most patients [36]. It is key to give such
avoided. Measures to slow gastric emptying with pectin, glu- drugs in sufficient dose and at least 30 min before a meal,
comannan, acarbose or loperamide can be helpful in some since ingestion immediately prior to or with food may even
patients [47]. aggravate dumping.
Somatostatin acts as a natural counterweight to the gas- Treatment with Lomotil (diphenoxylate hydrochloride
trointestinal neurohumoral response, and its longer-acting and atropine sulphate) reduced stool frequency to a signifi-
analogues octreotide and lanreotide can slow gastric empty- cant degree, but did not prove useful in the prophylaxis of the
ing of liquids and solids, slow orocaecal transit, and reduce more severe attacks of diarrhoea [52]. In an attempt to reduce
the plasma levels of several of the implicated hormones. In the rapid efflux of food from the stomach to the small bowel,
patients where simpler (and cheaper) measures have failed, McKelvey et al reduced the liquid content of meals. Low
octreotide (50–100 μg) given subcutaneously about 30 min fluid meals gave complete control of diarrhoea in two
before meals is often effective in control of dumping symp- patients, and improved the diarrhoea in 12 patients, (less fre-
toms [47]; monthly injections of lanreotide may have a simi- quency: n = 12; less urgency: n = 9), only 4 failing to respond
lar effect. [19]. In patients with more resistant diarrhoea, however, such
manipulation of meal content is less successful. Some
patients will also respond to bile salt binding agents such as
Post-vagotomy Diarrhoea colestyramine [51, 53, 54] and there is a good case for
SeHCAT scanning in gastrectomised patients with diarrhoea
Diarrhoea is common after truncal vagotomy. Depending on (BSG Guidelines: https://www.bsg.org.uk/resource/
the definition it occurs in 2% [48] to 53% of patients [49]. In guidelines-for-the-investigation-of-chronic-diarrhoea-in-
a study of 102 patients studied a mean of 13 years after a d u l t s % 2 D % 2 D b r i t i s h -s o c i e t y -o f -
vagotomy and pyloroplasty, 53% had diarrhoea compared to gastroenterology%2D%2D3rd-edition.html).
Anaemia Following Gastric Surgery Vitamin B12 Deficiency
Anaemia is common after gastric surgery. Although the The incidence of overt vitamin B12 deficiency following
reported incidence after resection ranges from 3% to 77%, in gastric resection is typically in excess of 15% [55, 59]. In
most series the frequency is around 30% [55–57]. Anaemia one series of 351 patients with Billroth II anastomoses,
is more common following operations for gastric ulcer (e.g. 36% of patients had low (20%) or borderline low (16%) B12
30%) than duodenal ulcer (e.g. 9%) [58, 59], and patients levels [66], though other authors using more subtle mea-
with Billroth II anastomoses are affected more commonly sures such as red cell B12 and the presence of hyperseg-
than those with a Billroth I anastomosis [55, 58, 60]. After mented neutrophils suggest that minor deficiency may be
uncomplicated gastroenterostomy anaemia (generally iron- present in 68–l00% of patients [60]. The prevalence of B12
deficient) is more unusual, and vagotomy and pyloroplasty deficiency increases with time from surgery. These figures
alone are rarely followed by anaemia [18, 19]. are of course despite the well-recognised risks of B12 mal-
Deficiencies of iron and B12 make approximately equal absorption and reflect a failure to use prophylactic
contributions to the incidence of anaemia following partial treatment.
gastrectomy, with folate deficiency being less common [60]. Lack of intrinsic factor contributes to the deficiency in
The relative contributions are typified by Shafer et al.’s study about half of affected patients [59, 66], though elective
of 142 male patients an average of 8.3 years after surgery, 33 assessment of B12 absorption shortly after surgery suggests
of whom had Billroth I and 109 Billroth II gastrectomies it is usually normal at that stage [67]. The explanation may
[61]. Anaemia was present in 69 of the 142 patients, 32% of lie in that, although pure B12 absorption is normal when
whom were found to have predominant iron deficiency, 42% measured by conventional absorption tests, such as the
vitamin B12 deficiency, and 25% folate deficiency. In 23% of Schilling test [68], the abnormal emptying of food parti-
the anaemic patients there was isolated iron deficiency, in cles from the stomach and their subsequent impaired
20% isolated B12 deficiency and in 9% isolated folate digestion may reduce B12 availability from a normal diet
deficiency; mixed deficiencies were present in the remaining [69].
48%. It is unclear how much bacterial overgrowth in the small
Following total gastrectomy a similar frequency and spec- intestine contributes to B12 deficiency, but some bacteria
trum of anaemia is found. Anaemia is present in about half of certainly have the ability to compete for dietary B12. In
cases, with evidence of iron deficiency in half of these, the some patients with a Billroth II anastomosis, treatment
precise figures tending to increase the longer patients survive with a broad-spectrum antibiotic has been shown to correct
following surgery [62]. B12 deficiency. Similarly pancreatic insufficiency is a com-
pounding factor in patients with Billroth II anastomoses
and may too reduce the absorption of B12. The relative con-
Iron Deficiency tributions of these causes remain uncertain, but regular
treatment with parenteral B12—usually 1 mg im every
Iron deficiency thus occurs in 30–50% of patients following 3 months—is safe and highly reliable and should be the
partial gastrectomy and is the main cause of about 50% of preferred method when B12 deficiency is identified or
post-operative anaemia [60]. The causes of iron deficiency strongly predicted.
are multifactorial. Dietary deficiency may contribute but is
not found uniformly [59]. Chronic faecal blood loss, as mea-
sured by chromium-labelled red cell studies, is typically Folate Deficiency
3.2–6.5 ml/day and surely contributes to the anaemia [63]. It
has been suggested that there is an inability to up-regulate Although dietary inadequacy is common and serum folate
absorption in the iron-deficient state [64]. Reduced acid levels are often a little low after gastric resection [59], resul-
secretion from the operated stomach reduces the absorption tant anaemia is relatively rare, being the main cause in no
of inorganic iron, and there may be a contribution from high more than about 5% of patients [58]. It should nonetheless be
mucosal cell turnover. Rapid intestinal transit through the sought in any patient who is anaemic. Oral replacement
upper gut and/or bypass of the duodenum, which is the pref- should be given orally when levels are low and also for short-
erential site for iron absorption, almost certainly also con- term prophylactic cover in patients receiving iron or vitamin
tributes [65]. Replacement with oral iron is usually sufficient B12 for deficiencies of these haematinics to prevent the
treatment when iron deficiency is found, provided other unmasking of borderline folate deficiency during the rapid
causes have been adequately excluded (see below). haemopoiesis induced with treatment.
Metabolic Bone Disease warrant attention and in many cases formal endoscopic
surveillance.
Metabolic bone disease—both osteoporosis and osteomala- Anastomotic ulcers are most often seen in patients whose
cia—are commonly reported after gastric surgery with an surgery was for peptic ulcer, and with modern medical man-
incidence of up to 25% [30]. When specifically sought, bone agement of ulcer disease these patients are becoming rare,
pain and tenderness are reported by 6 times as many patients but these can be responsible for significant overt upper gas-
as age-matched controls [70]. Serum calcium levels are also trointestinal bleeding as well as for more subtle presenta-
lower in patients (though usually within the normal range), tions with iron deficiency anaemia. Endoscopic detection
associated with demonstrable reduction in calcium absorp- (and sometimes therapy) in combination with proton pump
tion [71]. Similarly, inorganic phosphate levels are low in 5% inhibitors and eradication of residual H. pylori is usually suf-
of patients and serum alkaline phosphatase tends to be ele- ficient, but revisional surgery with its attendant risks is occa-
vated. Radiological evidence of osteopenia can be found in sionally required.
24% (controls 4%).
It has been suggested that vitamin D and calcium loss
may be proportional to loss of faecal fat, which would be Neoplasia in the Residual Stomach
consistent with the general observation that bone disease
affects patients following total gastrectomy and Billroth II There is a definite increase in the risk of gastric carcinoma in
rather than Billroth I partial gastrectomy [70]. Dietary defi- the partially resected stomach, a risk which will normally be
ciency of vitamin D may contribute. In the bariatric popula- sufficient to justify long-term endoscopic surveillance. New
tion where there is a pre-operative tendency to secondary symptoms, including late deterioration from a nutritional
hyperparathyroidism the prevalence of this condition dou- point of view, between procedures should also prompt con-
bles post-operatively—again with a frequency related to the sideration of this possibility.
magnitude of the operative procedure [72].
It is reasonable to advise a higher than normal intake of
vitamin D and calcium prophylactically after gastric ailure to Regain Weight Lost in the Absence
F
resection. Regular (e.g. alternate year) monitoring of bone of any Overt Explanation
density should be considered. Those with overt bone dis-
ease should be managed actively with higher dose oral The great majority of patients loses weight after gastric
vitamin D and a low threshold for its parenteral adminis- resection, and although some younger patients can make
tration if the serum level of hydroxy-vitamin D does not good this loss over a year or so, most patients will never
respond. In osteoporosis consideration of bisphospho- regain their premorbid weight. There does not seem to be a
nates will also often necessitate parenteral dosing given single or reversible explanation for this and it is now becom-
the poor absorption and frequent oesophageal toxicity of ing conventional to think of it as a form of sarcopenia.
these drugs when given by mouth. Nonetheless, despite Progress in the management of sarcopenia in general may
the frequency of metabolic bone disease after gastric sur- yield specific new interventions, but it is probable that a
gery there is surprisingly little evidence of increases in combination of optimized nutrition with a physical exercise
fracture rates. programme offers the current best chance of success.
Other Complications of Gastric Surgery Summary
Patients who have undergone gastric surgery remain at risk Subtotal and total gastrectomy frequently lead to symptoms
of the usual hazards of previous abdominal surgery such as resulting in a change in eating habit and more rarely result in
incisional hernia and adhesions, which may occasionally malnutrition which reflects maldigestion, malabsorption and
lead to additional complications and thus a route to intestinal motility problems. The resultant malnutrition may be global,
failure through the need for further surgery and the risk of affecting all nutrient groups, or limited to specific nutritional
short bowel syndrome. deficiencies such as of lipid soluble elements or individual
Systemic infection is also more common in the post- vitamins. Established intestinal failure is most unusual unless
gastrectomy patient indicating a general level of depressed there have also been major post-operative complications.
immunity which is probably distinct from malnutrition and Less invasive gastric surgery is also associated with nutri-
independent of underlying malignancy [73]. There are also tional problems, but at lower levels of frequency and
more specific late complications of gastric surgery which severity.
The causes of malnutrition are often multifactorial and a 16. Ben-Porat T, Elazary R, Goldenshluger A, Sherf Dagan S, Mintz
Y, Weiss R. Nutritional deficiencies four years after laparoscopic
knowledge of the likely problems and an understanding of
sleeve gastrectomy-are supplements required for a lifetime? Surg
the pathophysiological mechanisms help to organize the Obes Relat Dis. 2017;13(7):1138–44.
approach for the individual patient. A combination of dietary 17. Lee HO, Han SR, Choi SI, Lee JJ, Kim SH, Ahn HS, Lim H. Effects
changes, drug therapy to slow transit or bind bile salts, or of intensive nutrition education on nutritional status and qual-
ity of life among postgastrectomy patients. Ann Surg Treat Res.
supplementation with enzymes and addition of dietary sup-
2016;90(2):79–88.
plements, usually leads to successful control of the problem. 18. McIntyre AS. Studies on the adrenergic control of upper gastroin-
Nonetheless, most patients remain underweight in the testinal function in man. MD Thesis, University of London, 1990.
long-term. 19. McKelvey STD. Gastric incontinence and post-vagotomy diar-
rhoea. Br J Surg. 1970;57:741–7.
20. MacGregor IL, Parent J, Meyer JH. Gastric emptying of liquid meals
and pancreatic and biliary secretion after subtotal gastrectomy or
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Surgery for Obesity and Its
Consequences
Cynthia-Michelle Borg and Jean Deguara
Key Points In 2016, the World Health Organization (WHO) estimated

1. Bariatric surgery is performed in patients suffering from that 13% of adults (18 years and over) worldwide suffered
obesity when non-surgical techniques have been unsuc- from obesity [1]. The Health Survey for England in 2018
cessful and the BMI is greater than 40 kg/m2 (or 35–40 kg/ reported that 26% of men and 29% of women were obese,
m2 if obesity complications). with 2% of men and 4% of women suffering from morbid
2. Laparoscopic sleeve gastrectomy and Roux-en-Y gastric obesity (BMI of 40 or more) [2].
bypass are the most commonly performed bariatric Obesity is associated with numerous medical complica-
operations. tions, worse quality of life and a shorter life expectancy [3].
3. Patients with abdominal pain and vomiting at any time In particular, excess body weight is associated with meta-
after a Roux-en-Y gastric bypass may have an internal bolic problems including type 2 diabetes (T2D), non-
(mesenteric) hernia and should be urgently investigated alcoholic steatohepatitis (NASH) as well as cardiovascular
and treated (to prevent bowel resections due to disease and some types of cancers. Central weight distribu-
ischaemia). tion with a waist circumference of more than 80 cm in
4. Patients should have lifelong annual follow up with regu- women and 94 cm in men puts the individual at higher risk of
lar blood tests depending on the operation and local development of cardio-metabolic complications [4].
guidelines. Mechanical problems like obstructive sleep apnoea and
5. Cholelithiasis is common and if suspected confirmed by musculoskeletal issues are also common in patients suffering
ultrasound. from obesity. They may also experience higher levels of
6. Some of these patients may present to IF/HPN centres depression, anxiety and low self-esteem.
due to weight loss (especially if small bowel has been Weight loss has been shown to improve cardio-metabolic
resected due to ischaemia) or if an enterocutaneous problems associated with obesity as well as increase the life
fistula(s). expectancy. A 10 kg weight loss has been found to be associ-
ated with a 10 mmHg fall in systolic blood pressure, a
20 mmHg fall in diastolic blood pressure, 10% lowering of
Introduction the total cholesterol and improvement in the lipid profile. A
fall of 30–50% in fasting blood glucose and improvement in
Obesity is a chronic, progressive and complex disease. It is HbA1c are also observed with weight loss [5].
defined as an excessive accumulation of body fat that can The regulation of food intake and body weight is complex
impact the health or the wellbeing of an individual. A body with signals from body fat, the gut and the pancreas to the
mass index (BMI) of 30 kg/m2 or more is often used to define hypothalamus and the brainstem together with signals from
obesity. the higher reward centres.
The ideal weight loss management should improve the
health, wellbeing and life expectancy of the individual, pre-
C.-M. Borg (*)
Department of General Surgery, Lewisham and Greenwich NHS vent obesity related complications, be safe and lead to sus-
Trust, London, UK tained weight loss. Although, lifestyle measures that involve
e-mail: [email protected] dietary restrictions may initially be associated with good
J. Deguara weight loss, long-term weight regain is common [6].
Department of General Surgery, Kingston Hospital Foundation Bariatric surgery leads to significant, sustained weight
Trust, London, UK
loss with improved medical issues and survival [7]. This is

302 C.-M. Borg and J. Deguara
because surgery not only induces a decrease in food intake JIB as an alternative [14]. Several variations, in terms of limb
but is also associated with changes in signals from the GI lengths and the faith of the bypassed small bowel, were
tract leading to increased satiety and fullness, decreased hun- described. JIB, though associated with excellent weight loss
ger sensation and changes in taste and smell [8]. and improvement of hyperlipidaemia, was itself found to be
Adequate patient preparation, proper choice of the pri- associated with a multitude of serious complications. These
mary procedure and long-term follow-up are very important. included hypoalbuminaemia and deficiency of calcium, fat-
The criteria and indications for the use of bariatric surgery soluble vitamins and vitamin B12 resulting in osteoporosis,
have been extensively debated in the surgical literature and osteomalacia, night blindness, anaemia and peripheral neu-
in conferences. Most bariatric multidisciplinary teams use ropathy [14]. Diarrhoea and electrolyte imbalance were also
the guidelines published by the National Institute for Health common. Migratory polyarthralgias, cholelithiasis, liver cir-
in the USA [9] or by the National Institute of Clinical rhosis and liver failure developed in some patients [15].
Excellence in the UK [10]. Other long-term complications included renal disease sec-
In its 2014 guidelines, NICE advises that patients under- ondary to hyperoxaluria with the development of oxalate
going bariatric surgery should have tried all appropriate, stones and interstitial oxalate deposition potentially leading
available non-surgical measures for weight reduction but to renal failure [16]. The bypassed small bowel segment was
failed to achieve or maintain clinically beneficial weight also prone to various problems including intussusception
loss. They should have a BMI of 40 kg/m2 or more, or and small intestinal bacterial overgrowth (SIBO). As a result
between 35–40 kg/m2 with obesity related co-morbidities. of these serious complications, JIB was abandoned by the
Patients with a BMI of 30–34.9 kg/m2 who have recent-onset 1970s and most patients had their procedure reversed, with
T2D should also be offered an assessment for bariatric/meta- or without another metabolic/bariatric operation being per-
bolic surgery. A slightly lower BMI may also be considered formed concurrently. There are still, however, some patients
in patients with T2D of Asian family origin. Patients require living well with this operation. Most bariatric surgeons will
multidisciplinary team management and should be fit for advise close, lifelong follow-up in this patient group to detect
general anaesthesia and surgery. Pre-operatively, medical or complications early and most would offer reversal of the sur-
psychological contraindications need to be excluded and gery should these arise.
patients are required to understand the need for long-term
post-operative follow-up [10].
The number of bariatric surgery operations being per- Operations Involving the Stomach Only
formed has increased over time. The International Federation
for the Surgery of Obesity and Metabolic Disorders (IFSO) Gastroplasty
Global registry collates data from around the world. In its Gastroplasty involved the partitioning of the stomach creat-
latest publication, the most commonly performed primary ing a small proximal pouch, which communicated with the
operation was the sleeve gastrectomy (46.0%) followed by distal and larger portion of the stomach via a restrictive chan-
the Roux-en-Y gastric bypass (38.2%), the one anastomosis nel. The most popular variety, developed by Mason [17],
gastric bypass (7.6%) and gastric banding (5.0%) [11]. used a vertical segment of stomach along the lesser curve for
Bariatric surgery has evolved over the years. the pouch (Fig. 1) and was thus called a vertical banded gas-
troplasty (VBG). The volume of the pouch was standardized
to 14 mL at the time of surgery and a polypropylene band
Bariatric and Metabolic Procedures was placed around the lower end of the pouch to prevent
dilatation. The band’s circumference was standardized and
Historic Operations: Jejuno-Ileal and Jejuno- fixed at 5 cm. Different variations of this procedure exist
Colic Bypass [17]. VBG was sometimes complicated with stomal stenosis
and gastro-oesophageal reflux (GORD) symptoms. It had
The concept of surgery for severe obesity was introduced in inferior long term weight loss when compared to RYGB
the 1950s. The first reported case in the literature was an end- often due to the formation of gastro-gastric fistulas between
to-end jejuno-ileal bypass (JIB) in 1954 [12]. It aimed to the two partitioned parts of the stomach thereby negating the
induce weight loss by malabsorption. Jejuno-colic bypass restrictive effect. Since the development of adjustable gastric
(JCB) was also performed with the proximal 15 cm of the banding, VBG is obsolete although again, there are some
jejunum being joined to the mid-transverse colon [13]. In patients still living with this operation.
1969, Payne et al. reported the results of 11 patients who had
JCB. These patients had developed uncontrollable diarrhoea Gastric Banding
with associated dehydration and electrolyte imbalance. The Adjustable gastric banding involves the laparoscopic posi-
authors thus advised against such procedures recommending tioning of a silicone band around the upper part of the stom-
Surgery for Obesity and Its Consequences 303
Sleeve Gastrectomy
Sleeve gastrectomy SG (Fig. 3) involves the excision of most
of the greater curve of the stomach and the fundus using sur-
gical staplers, with the remaining stomach having a tube like
appearance with a reduced volume (usually less than
100 mL). The diameter of this tube is standardized by using
Staple line to an orogastric bougie which may vary in size from centre to
partition stomach centre [19]. Besides being a restrictive operation, sleeve gas-
trectomy has also been found to be associated with accelera-
tion in gastric motility [20] and changes in gut hormones [8,
Small gastric pouch 21]. Although initially intended as the first step before RYGB
or duodenal switch (DS) operation in patients with very
severe central obesity [22], sleeve gastrectomy is increasing
Mesh to reinforce
the nonadjustable
being offered as a single stage bariatric procedure. It is cur-
pouch outlet rently the commonest primary bariatric procedure performed
worldwide [11].
Most surgeons would regard the presence of Barrett’s
oesophagus as a contraindication for SG. Post-operative
complications may include staple line bleeding, leaks, twists
and strictures. Long-term issues with post-operative GORD
may require lifelong medication or revision surgery.
Gastric Plication
Laparoscopic gastric plication is the infolding of the greater
curvature to reduce stomach volume using running sutures.
While cheaper than LSG, the long-term results and the dura-
bility of the operation are uncertain and most surgeons would
regard it as investigational [23].
perations Involving the Stomach and Small

O
Bowel
Fig. 1 Vertical banded gastroplasty VBG
Roux-en-Y Gastric Bypass (RYGB)
The RYGB has, for many years, been regarded as the gold
ach (Fig. 2) creating a small proximal gastric pouch that is standard bariatric operation (Fig. 4). It was first described in
usually calibrated to have a capacity of 15–20 mL. The 1967 by Mason et al. [24], with the first laparoscopic proce-
undersurface of the band has an inflatable inner cuff, which dure performed in 1994 [25]. It involves the creation of a
is connected by a tube to a subcutaneous port. The size of the small stomach pouch (based on the lesser curvature). A cut
pouch outlet can be adjusted by varying the volume of fluid Roux loop of jejunum (the alimentary limb) is joined to the
in the band through the port using a non-coring needle. The pouch to allow food to bypass the larger, distal part of the
amount of fluid is adjusted until the patient is in the ‘green stomach, the duodenum and the first part of the small bowel
zone’—when weight loss is achieved by inducing an early (the biliopancreatic limb). The alimentary and biliopancre-
feeling of satiety after eating smaller amounts of food than atic limb are anastomosed to allow intestinal continuation
before the surgery. and mixing of food and digestive enzymes digestion occurs
While band insertion is safe and can often be performed in the common channel. The standard length of the alimen-
as a daycase procedure, long-term complications like band tary limb is usually around 100–150 cm with the biliary limb
erosion, slippage and pouch and oesophageal dilatation can being 60–100 cm although some surgeons may use longer
occur. Between 30–40% of patients who undergo banding limbs especially in patients with a BMI of 50 kg/m2 or more
will require revision surgery by 7 years post-op [18]. [26]. The small gastric pouch restricts the amount of food
Weight loss with GB is usually slower and lower than after that can be eaten while bypassing of the duodenum induces
RYGB and the SG. Results may vary from centre to centre changes in gut and pancreatic hormone secretion leading to
depending on patient selection and the intensity of metabolic and hormonal changes that are associated reduced
follow-up. appetite and an increased feeling of satiety and fullness.
Fig. 2 Gastric banding
Small proximal
gastric pouch
Adjustable gastric
band with inner
inflatable cuff
Tubing leading
from the gastric
band to the port
Subcutaneous
port
Fig. 3 Sleeve gastrectomy

SG
Tube like sleeve

gastrectomy
Staple line
Majority of the
greater curve
and fundus of
the stomach
excised
There are also changes in gut microbiota, bile acid levels and One Anastomosis Gastric Bypass (OAGB)
composition and intestinal motility [8]. The OAGB was first described by Rutledge in 2001 [27]. It
Contra-indications for RYGB include small bowel dis- is also known as the single anastomosis or the mini-gastric
ease such as adhesions or Crohn’s disease as well as condi- bypass. A long tube-like proximal pouch of stomach is cre-
tions that require access to the stomach (eg in areas or ated from the lesser curvature side. Intestinal continuity is
families with high incidence of gastric cancers), the duode- re-established by connecting the gastric pouch to a loop of
num and biliary tree. Complications of RYGB may include jejunum bypassing up to 100–250 cm of the proximal jeju-
bleeding, anastomotic leak, anastomotic ulceration and stric- num (biliopancreatic limb). As it has one less anastomosis,
tures, dumping syndrome, internal herniation and mineral OAGB has a shorter operating time when compared to
and vitamin deficiency. RYGB.
Fig. 4 Roux-en-Y gastric

bypass RYGB
10-30 mL
gastric pouch
Gastro-jejunal
anastomosis
Alimentary limb- Bypassed

between 75-150 cm distal stomach
Small bowel-small
bowel anastomosis
Bilio-pancreatic limb
Common channel
Long-term data shows that the OAGB using biliopancre- ileostomy 250 cm proximal to the ileocaecal valve. The bil-
atic limbs of over 150 cm may result in a slightly better iopancreatic limb was then anastomosed to the alimentary
weight loss and better resolution of diabetes than the RYGB limb creating a common channel, which originally was
[28]. Some surgeons believe that long-term, OAGB has a described as around 50 cm. Most surgeons increased the
lower risk for internal herniation than the RYGB. The recent length of the common channel to at least 100 cm in an
YOMEGA trial has been however showed that OAGB with a attempt to limit the malabsorptive symptoms. BPD is more
200 cm small bowel biliopancreatic limb has more technically demanding than other bariatric procedures and
malabsorptive complications when compared to RYGB [29]. carries the morbidity of a partial gastrectomy. It has been
Bile reflux into the stomach with gastritis and oesophagitis is
reported to have the best results in terms of weight loss and
common and may adversely affect the patients’ quality of resolution of T2DM [32]. It can result in significant malab-
life [30]. The long-term effects of this are uncertain. sorptive complications and patients undergoing this proce-
dure require strict compliance, close follow-up and long-term
Other Operations nutritional supplementation [33].
The bilio-pancreatic diversion (BPD) (Fig. 5) was described Variations of BPD include the duodenal switch (DS) as
by Scopinaro [31] and involved the creation of a 200–500 mL described by Hess [34]. This involves a sleeve gastrectomy
gastric pouch and a distal two-thirds gastrectomy. Intestinal with preservation of the pylorus (Fig. 6). Like the BPD, DS
continuity was achieved by the formation of a gastro- is technically challenging and may lead to protein, mineral
Fig. 5 Biliopancreatic
diversion BPD
200-500 mL
gastric pouch
Gastro-ileal
anastomosis
Two-thirds distal
gastrectomy
Alimentary limb-
usually around
150 cm
Bilio-pancreatic
limb
Small bowel-small
bowel anastomosis
Common channel-
around 50 cm
and vitamin deficiency. A further recent modification of DS, They are generally divided into gastric and small bowel
the single anastomosis duodenal-ileal bypass with sleeve procedures.
gastrectomy SADI-S (also known as the one anastomosis The gastric therapies include intragastric balloons, the
duodenal switch), utilizes a single anastomosis. It was first gastric aspiration system and endoscopic sleeve gastroplasty
described Sanchez-Pernaute et al. and anastomoses the duo- (ESG).
denum directly to an omega loop of ileum 200–300 cm prox- The intragastric balloon (IGB) is a space-occupying
imal to the ileo-caecal valve, eliminating the need for the device. Several different types of IGBs are licensed for use
Roux-en-Y jejunal-ileal anastomosis [35]. Such an operation including ones that are liquid or air filled, some that require
may play a role in the management of patients who have a endoscopic insertion and removal (usually made of soft sili-
BMI of over 60 or for those with weight regain or poor cone), others that do not need endoscopic removal as they
weight loss after SG in the future. Both IFSO [36] and disintegrate after 16 weeks and others that are swallowable.
American Society for Metabolic and Bariatric Surgery Most of the soft silicone balloons require endoscopic removal
(ASMBS) [37] have highlighted the lack of long-term data after 12 months. While they can be replaced by a new IGB,
about SADI-S at this stage. they are not a durable, long-term solution for severe obesity
[38]. They however do result in modest weight loss and
Endoscopic Bariatric and Metabolic Therapies improvement in quality of life whilst in situ.
Endoscopic bariatric and metabolic therapies (EBMT) are a Contraindications to IGB placement include a history of
relatively new modality in the management of obesity. They gastrointestinal surgery and large hiatal hernia. Nausea is a
are important, alternative treatment options for patients suf- common side-effect especially early on after IGB insertion.
fering with obesity but who have relatively low BMIs and Although most patients will improve with time and anti-
those who are not keen to undergo surgery. They may also be emetics, some IGBs need to be removed early due to intoler-
used as a bridge to surgery in patients with severe obesity. ance. The Brazilian Intragastric Balloon Consensus
Fig. 6 Duodenal switch DS
Sleeve gastrectomy-
100-150 ml
Duodeno-ileal
anastomosis (ileum
transected 250cm
from ileocaecal
valve)
Alimentary limb
Billo-pancreatic
limb
Common Small bowel-

channel- small bowel
around 100 cm anastomosis
Statement reported on their experience of over 40,000 IGB nique results in short and medium term weight loss but long-
implantations in 2018 and showed that that implantation is term data regarding durability is lacking [38].
safe and effective [39]. The most common complications in The duodenum and proximal jejunum have been recog-
this large series were hyperinflation, deflation, migration and nized as a key metabolic signaling center. The EndoBarrier
ulceration [39]. Gastric perforation and small bowel obstruc- duodenal-jejunal bypass liner (DJBL) was developed to
tion secondary to migrated IGB are rare. avoid contact of food with the mucosal lining of the duode-
Gastric aspiration therapy involves the insertion of a gas- num and proximal jejunum. The device consists of a ring that
trostomy tube (A-tube). Together with a siphon assembly, it anchors on the duodenal bulb connected to a 60 cm Teflon
allows the patient to aspirate gastric contents 20 min after liner that covers the mucosal surface of the duodenum and
eating. Aspiration usually takes about 10 min and reportedly proximal jejunum. It has a modest weight loss effect but has
removes approximately 30% of ingested calories. It is been shown to ameliorate T2D control whilst the device is in
licensed for used in patients with a BMI of between 35–55 kg/ place [41]. It is not currently in clinical use due to a high
m2 in the setting of a multidisciplinary program to adjust eat- incidence of adverse effects especially liver abscesses
ing behavior. In motivated and compliant patients, it has safe reported during a US pivotal trial.
and durable weight loss [40]. Skin irritation around the stoma Duodenal mucosal resurfacing involves circumferential
site is common. Persistent gastric fistula requiring surgical mucosal lifting followed by hydrothermal ablation of duode-
closure may occur once the A-tube is removed. nal mucosa. It has been showed to improve glycaemic con-
Endoscopic sleeve gastroplasty (ESG) attempts to reduce trol in patients with suboptimally controlled T2D [42]. The
the volume of the stomach, recreating the gastric plication mechanism of how and why this happen is uncertain.
using a transoral endoscopic suturing platform. It is mostly Whether the effect will be sustained in the medium and long
used in patients with BMI 35.0–39.9 but it may be play a role term is also unknown. Adverse effects are common, most are
in patients who are unfit for laparoscopic surgery. The tech- mild but duodenal stenosis may occur.
Consequences of Bariatric Surgery [46, 47]. The use of high intraperitoneal pressure during lap-
aroscopy may also play a role. Patients often present with
Early Post-operative Complications non-specific abdominal pain. CT scan with intravenous con-
trast is often diagnostic. Most patients can be treated non-
Laparoscopic bariatric surgery is safe and effective. In the operatively with anticoagulation but some may require
UK, the in-hospital mortality rate is around 0.061% with the surgery if they develop bowel necrosis. Such patients may
30-day mortality being reported at 0.13% by Hospital end up with massive small bowel resection and subsequent
Episode Statistics (HES) [43]. Although early complications short-bowel syndrome. In the literature a mortality rate of
often represent to the bariatric centres where the surgery was about 4% is described with PVT.
performed, awareness of such presentations by other clini-
cians is important especially due to the rise in bariatric tour-
ism. Early complications may include leakage or bleeding Medium/Late Gastrointestinal Complications
from anastomosis and staple lines, venous thromboembo-
lism and chest, wound and urinary infections. Vomiting
Patients suffering from morbid obesity may not present Nausea and vomiting are common in the first few months
with typical signs of sepsis and peritonism and a high index after surgery and often settle as patients get used to their new
of suspicion is required. Tachycardia and tachypnoea may be eating habits. Patients may be unable to progress to a solid
the only features in this patient group. diet and persist on a liquid or soft diet. Common pitfalls
Bleeding occurs in less than 1% of cases [44] and may be include eating too fast, not chewing the food thoroughly and
intra-luminal, presenting with meleana and haematemesis, or mixed food and water. If these symptoms persist, investiga-
intra-peritoneal. Most patients settle with close monitoring tion of the post-operative anatomy with upper GI endoscopy
and conservative management with or without blood prod- and/or contrast studies is important to exclude strictures
ucts. Some however may need endoscopy or re-laparoscopy especially at the site of gastro-jejunal anastomosis or any
if unstable or having increased transfusion requirements. other intra-operative mishap eg Roux-en-O reconstruction
Leaks may occur from anastomosis sites, from staple [48].
lines or from iatrogenic bowel injuries. With improvement in Sometimes with SG a functional twist can arise in the
staple line technology and operative techniques, the risk of body of the sleeve. Although there is no anatomical obstruc-
leaks continues to decrease and the incidence is currently tion on endoscopy, this may often be demonstrated with a
quoted as less than 0.5% [44]. Leaks usually present between contrast study. Other causes on nausea and vomiting includ-
day 5–10 post-operatively. Abdominal pain may not be a fea- ing pregnancy need to also be excluded. Acute presentations
ture with patients presenting with fever, shoulder tip pain and with vomiting will require exclusion of acute band slippage
non-specific symptoms instead. A high index of suspicion in patients with gastric bands and internal hernias in patients
and early investigation with contrast imaging or a re- with operations who involved small bowel anastomosis.
laparoscopy is essential to avoid deterioration and long-term Expeditious investigation and treatment are important to
consequences. avoid ischaemia.
Venous thromboembolism (VTE) was found to have a Empirical intra-venous thiamine replacement is important
significant effect on readmission and mortality post-bariatric in patients with persistent vomiting to avoid precipitation of
surgery [44]. Longer operations, past history of VTE and Wernicke’s encephalopathy [49].
blood transfusion have been found to increase the risk of
VTE [45]. Most surgeons encourage the peri-operative use Gastro-oesophageal Reflux
of thromboembolic deterrent stockings, intermittent pneu- Several studies have shown a higher incidence of GORD in
matic compression intra-op, early mobilization, prophylactic patients who are overweight compared to the general popula-
anticoagulation and patient education for early recognition. tion [50]. The Bristol Helicobacter project reported that
Portomesenteric and splenic vein thrombosis (PVT) is a patients who suffer from obesity are up to three times more
rare yet occasionally catastrophic complication of bariatric likely to suffer from heartburn or regurgitation [51]. These
surgery. PVT is a well-recognized complication of upper GI patients are also at higher risk of developing GORD compli-
surgery including fundoplication and gastric resection. It cations including erosive oesophagitis [52], Barrett’s oesoph-
may also occur within the first month after bariatric surgery agus and oesophageal and junctional adenocarcinoma than
especially after SG. Risk factors include recent oral contra- their lean counterparts [53]. Central obesity rather than BMI
ceptive use, smoking, a history of malignancy, T2D and a itself is closely associated with these complications. The
history of pro-thrombotic genetic tendencies including pathophysiology of this may include increased intra-
Protein C and S deficiency and Prothrombin 20210 mutation abdominal and intra-gastric pressure, reduced oesophageal
clearance, increased transient relaxations of lower oesopha- Patients with ulcers may be asymptomatic or may present
geal sphincter (LOS) and abnormal gastro-oesophageal junc- with nausea, vomiting, epigastric pain and rapid weight loss.
tion anatomy with shorter, hypotensive LOS and increased They may also present with anaemia due to chronic bleeding.
incidence of hiatal hernia [54]. Increased mucosal sensitiv- Diagnosis is usually made with an upper GI endoscopy.
ity, larger gastric capacity, dietary habits and higher levels of Ulcers may be complicated by stricture formation. While
leptin, interleukin 6 and TNF and lower levels of adiponectin these often respond to endoscopic dilatation, iatrogenic per-
may also be involved [55]. Non-surgical weight loss has foration and recurrence are not uncommon. Ulcer perfora-
been associated with a decrease in GORD symptoms in sev- tion may occur spontaneously and often require laparoscopy,
eral studies [50, 56]. washout and an omental patch repair.
Pre-operative upper GI endoscopy is recommended prior Marginal ulceration may occur in 0.6–16% of patients
to bariatric surgery [57] but not universally performed. A with RYGB [64]. Most surgeons recommend PPIs for the
recent systematic review noted that only 7.6% of OGDs first 3 months post-op to try and prevent this complication.
performed prior to bariatric surgery [58] lead to a change in PPIs, together with sucralfate, form the mainstay of treat-
the operative management. However over a third of patients ment together with management of other risk factors includ-
undergoing bariatric surgery have abnormal OGD findings ing smoking cessation therapy. Up to a third of patients with
[57] and endoscopy often helps to establish appropriate oper- recurrent or refractory ulceration after RYGB may need revi-
ation planning, consent and follow-up. Most surgeons would sion surgery.
consider repairing the hiatus if there is a significant hiatus Ulceration in OAGB may occur in up to 10% of patients
hernia or opt for a RYGB, which has long been hailed as the and may be particularly difficult to treat as it is often the
best operation for patients with obesity and GORD [59]. De consequence of bile reflux. In these cases, conversion to tra-
novo GORD may occur after surgery especially after gastric ditional RYGB configuration is usually beneficial [65].
banding, SG [60] and OAGB [61] while the same operations
can improve GORD in patients with pre-operative symptoms Dumping
[55, 60, 62]. Studies are often difficult to interpret and com- Dumping syndrome has been reported with several bariatric
pare due to different operative techniques including manage- operations but especially with the RYGB and SG [66]. It is
ment of the hiatus, length of follow-up, medication use and often thought to be secondary to rapid post-prandial gastric
how GORD was defined (symptoms, questionnaires, endos- emptying and is characterised by gastrointestinal and vaso-
copy, biopsies, pH studies). The topic of reflux and its poten- motor symptoms. The clinical presentation is variable and
tial consequences are hotly debated in bariatric surgical symptoms are divided into early and late. Early dumping
conferences and in the literature [63] and are not the remit of symptoms usually occur within 1 h after a meal and include
this chapter. abdominal pain, loose stools, nausea, vomiting and bloating.
If patients with a history of bariatric surgery develop dys- Patients can also present with vasomotor symptoms such as
phagia or worsening reflux, 2-week wait or expedited endos- fatigue, tachycardia and facial flushing. The mechanisms
copy should be arranged. Some surgeons offer routine OGD underlying early dumping may involve the osmotic effects of
every 2–3 years after SG and OAGB [57], as poor correlation food in the jejunum, gut hormone release and autonomic
between GORD symptoms, degree of oesophagitis and the neural responses [67].
development of Barrett’s oesophagus has been shown, but Late dumping symptoms (1–3 h postprandial) relate to
this is no means the norm. Most patients who develop GORD hypoglycaemia and include perspiration, palpitations, hun-
can usually be managed with lifestyle modification and pro- ger, fatigue, tremor and confusion [67]. In one study of 450
ton pump inhibitors (PPIs) although a small proportion may patients who had undergone RYGB or SG, over a third
require revision surgery. reported symptoms suggestive of postprandial hypoglycae-
mia [68]. Spontaneous plasma levels of glucose <2.8 mmol/L
nastomotic Complications: Ulceration, Stenosis,
A (50 mg/dL) are indicative of late dumping syndrome. Late
Perforation dumping and the associated hypoglycaemia is thought to be
Operations involving anastomosis of the stomach and small secondary to an exaggerated GLP-1 response.
bowel like the RYGB and the OAGB may be complicated by Most patients with symptoms of dumping are reviewed by
ulceration, stenosis or perforation at or near the joint (mar- a multidisciplinary team including the bariatric surgeon,
ginal ulceration). Reduced blood flow and tension at the physician and dietician. Dietary changes are usually success-
anastomosis site may play a role. Other risk factors include ful in most patients. Rapidly absorbable carbohydrates
smoking, chronic NSAID use, a large proximal gastric should be eliminated from the diet to prevent symptoms of
pouch, the presence of a gastro-gastric fistula and late dumping syndrome. They should be advised to eat a diet
Helicobacter pylori. Bile reflux may play a role in marginal consisting of foods high in fibre and rich in protein, eaten
and gastric ulceration after OAGB. slowly and chewed well. Some patients therefore find symp-
toms of dumping, a timely reminder that they may be eating strictures are present. Protein malnutrition is more common
‘the wrong types of food’. with OAGB, BPD, DS and SADI. These patients require
In patients whose symptoms persist despite dietary between 60–120 g of protein per day to maintain their lean
manipulation, Acarbose and somatostatin analogues may be body mass. If malnutrition is suspected, patients should be
used. If conservative management fails, further endoscopic admitted to hospital for investigation, mineral and vitamin
or surgical techniques may be offered to attempt to slow supplementation and feeding (enteral/parenteral). Patients
down the passage of food from the stomach into the small with protein malnutrition should be assumed to have accom-
bowel [69]. panying mineral and vitamin deficiency until proven
otherwise.
Cholelithiasis Most bariatric centers recommend that their patients
Gallstone disease can be found in 10–20% of general popu- should stay on lifelong mineral and vitamin supplementation
lation. Out of these about 20% will develop symptoms due to a reduction in oral intake with food and reduced intes-
including biliary colic, acute cholecystitis and gallstone pan- tinal absorption. The dosage of these may vary depending on
creatitis. A eightfold rise in incidence has been documented the operation, the patient’s dietary habits (eg vegetarians)
in patients with BMI equal of more than 40 kg/m2 [70]. and in women with heavy periods. Routine blood tests to
Rapid weight loss induces gallbladder stasis and changes in check levels are also very important. These usually include a
bile composition with supersaturation of bile with choles- full blood count, ferritin, folate, Vitamin B12, Vitamin D and
terol and raised concentrations of mucin [71]. These changes calcium at 3, 6, 12 months post-operatively and then at least
may result in the formation of biliary sludge and gallstones. annually after that. Vitamin A, E and K1 should also be mon-
Bariatric surgery is associated with a predisposition for fur- itored after BPD and DS and may also be required after
ther development of cholelithiasis in over 35% of patients OAGB. Zinc, copper and selenium levels may be required if
[72]. Cholelithiasis is more common in the patients who oral intake is poor, patients are loosing wait rapidly or have
have lost most weight [73]. unexplained anaemia, neuropathy, cardiomyopathy, or diar-
Ursodeoxycholic acid (UDCA) is a secondary bile acid— rhea. The recent BOMSS updated guidelines should be con-
a by-product of intestinal bacteria, which helps reduce the sulted for more information about monitoring and nutrient
rate of cholesterol absorption in intestines, resulting in replacement after bariatric surgery [76].
decreased cholesterol saturation of bile and gallstone inci-
dence. UDCA has some side-effects such as diarrhoea, loose
and pale stools, and pruritis which may decrease patient
compliance to treatment. Prophylactic use of urseodeoxy- References
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Intestinal Failure in Childhood
Olivier Goulet and Cécile Lambe
1. Pediatric IF is commonly due to congenital or neonatal Intestinal failure (IF) is defined as a critical reduction of the
intestinal diseases or malformations. gut mass or its function below the minimum needed to absorb
2. Three groups of patients are identified: those with a nutrients and fluids required for adequate growth in children
reduced intestinal length (short bowel syndrome), abnor- and weight maintenance in adults [1]. As a matter of fact,
mal intestinal mucosal development, or severe intestinal severe IF, results in the need for parenteral nutrition (PN). IF
dysmotility. may be reversible or irreversible, depending on a number of
3. At birth, term-neonates have a SB length of approxi- factors such as the underlying disease and also on the treat-
mately 250 cm and their intestines lengthen substantially ment used to develop or restore intestinal capacity. Severe
during the first year of life. and even irreversible IF in children is very challenging. IF
4. IF associated liver disease (IFALD) (mainly cholestatic conditions being rare, there is not enough data to provide the
picture in children) develops frequently at an early age, scientific foundation needed to form treatment guidelines or
especially in premature infants in whom liver immaturity, for the creation of gold-standards for the care of such very
frequent sepsis and necrotizing enterocolitis (NEC) specific patients. However, guidelines for PN may provide
increase liver inflammation and severe damage. In older basic knowledge for the management of those complex
children it is associated with a dilated bowel with bacte- patients [2, 3]. In clinical practice intestinal sufficiency may
rial overgrowth. be indirectly measured by the level of PN required for nor-
5. Phytosterols contained in soybean oil are associated with mal or catch up growth [4]. Others indicators such as resid-
IFALD progression and their exclusion from lipid bags ual bowel length measured at last surgery and serum
may be beneficial in children receiving PN. citrulline, though helpful, have not proven to be always reli-
6. The major indications for HPN are SBS secondary to able prognostic factors in children with short bowel syn-
necrotizing enterocolitis, midgut volvulus, gastroschisis, drome (SBS) [5–7]. Therefore, PN requirements or PN
long segment Hirschsprung Disease and intestinal atresia. dependency index (PNDI) remain the best measure of the
Other conditions are congenital enteropathies, chronic degree of intestinal sufficiency in this setting [8].
intestinal pseudo-obstruction. Due to technical refinements and steady advances in the
development of highly sophisticated nutrient solutions con-
sisting of optimal combinations of macronutrients and
micronutrients, PN plays an important role in patient man-
agement [2, 3]. PN has become a safe and efficient feeding
technique. However, IF that requires long-term PN may be
associated with various complications including catheter
related blood stream infections (CRBSIs), growth failure,
metabolic disorders, and bone disease [9]. Cholestatic liver
O. Goulet (*) · C. Lambe
Division of Pediatric Gastroenterology and Nutrition, National disease (CLD) was rapidly identified as one of the limita-
Reference Center for Rare Digestive diseases, Pediatric Intestinal tions of long term IF management while CLD related factors
Failure Rehabilitation Center, Hôpital Necker-Enfants Malades, are mostly related to IF rather PN supporting the wording
University Paris-Cité, Paris Descartes Medical School,
“Intestinal Failure Associated Liver Disease” (IFALD) [10–
Paris, France
e-mail: [email protected]; [email protected] 13]. Severe liver disease may lead to the so-called “nutri-

314 O. Goulet and C. Lambe
tional failure” which is considered as a major indication for Table 1 Causes of intestinal failure
intestinal transplantation or combined liver-intestinal trans- Short bowel syndrome
plantation [9]. • Prenatal disease
– Intestinal atresia
– Apple peel syndrome
– Gastroschisis
Causes of Intestinal Failure • Post-natal disease
– Necrotizing enterocolitis
In industrialized countries pediatric IF is most commonly – Mid gut volvulus
due to congenital or neonatal intestinal diseases or malfor- – Vascular thrombosis
mations that can be divided into three groups (Table 1): (a) IF – Tumor
with a reduced intestinal length and consequently reduced – Traumatism
absorptive surface, such as in SBS or extensive agangliono- Congenital enteropathy
• Microvillous inclusion disease/microvillous atrophy
sis (Long segment Hirschsprung disease); (b) IF related to an
• Intestinal epithelial dysplasia/tufting enteropathy
abnormal development of the intestinal mucosa such as con- • Syndromic diarrhea/trico-hepato-enteric syndrome
genital diseases of enterocyte development (CDED); (c) IF Neuromuscular intestinal disease
with intact length but with extensive motility dysfunction • Chronic intestinal pseudoobstruction syndrome
such as pediatric intestinal pseudo-obstruction syndromes – Neuropathy
(PIPOS). – Myopathy
– Mesenchymopathy
• Long segment Hirschsprung disease/total or subtotal
aganglionosis
The Short Bowel Syndrome
Definition and Etiology In children the conditions most commonly leading to

extensive small bowel resections are necrotizing enterocoli-
SBS is characterized by a compromised bowel absorptive tis (NEC), midgut volvulus, gastroschisis, intestinal atresia
capacity due to a severely reduced mucosal surface resulting and extensive aganglionosis (eg: long segment Hirschsprung
in malabsorption with subsequent diarrhea, water-electrolytes disease, the last one leading to SBS without a functioning
imbalance, and malnutrition. SBS is the leading cause of pedi- colon (SBS type 1) (Table 1 and Fig. 1).
atric IF, usually following extensive surgical resection leaving
the SB length below a critical value for adequate nutritional
supply [9]. Exact measurement of the remnant intestine Management of SBS
remains difficult even with the help of radiographic assess-
ment [14]. At birth, term-neonates have a SB length of approx- Bowel adaptation after small intestinal resection is a physi-
imately 250 cm and their intestines lengthen substantially ological process resulting in bowel lengthening and villous
during the first year of life [15]. Preterm infants have a greater hyperplasia (Fig. 2) [27]. The management of SBS patients
potential for bowel growth since their intestines lengthen sub- aims at promoting this physiological process by using as
stantially during the last trimester of gestation [16]. much as possible the GI tract especially by oral feeding (OF)
The cut-off length for SBS is related to a number of fac- which is more physiological than enteral tube feeding (ETF)
tors. In general, SBS occurs after a massive resection leav- [27]. ETF early in life, has been shown to promote oral feed-
ing less than 40 cm of viable small bowel. A residual bowel ing disorders [28].
length of only 15–40 cm has been associated with bowel PN itself aims in promoting normal somatic growth dur-
adaptation, intestinal autonomy and PN weaning, but, most ing the time bridge for achieving full intestinal autonomy.
of the time, unfortunately with littleinformation regarding PN should not be stopped until adequate intake and growth
the long-term growth and the final stature [17–26]. can be achieved with only OF and/or ETF.
Numerous factors determine SBS prognosis: the underlying The optimal strategy for enteral feeding, OF versus ETF
diagnosis, the type of segments preserved, the presence of and continuous versus bolus, remains debated [27]. OF
the ileo-caecal valve (ICV) and the colon, a long-term stoma allows the maintenance of sucking and swallowing func-
versus a primary anastomosis, the number of surgical proce- tions along with the psychological interest and enjoyment
dures, as well as the age of the patient at the time of surgery associated with eating, thus helping to prevent eating disor-
[17–26]. Classification of SBS in three type is helpful for ders. It is important to point that OF promotes the release of
the understanding of different outcomes (Fig. 1). Other fac- epidermal growth factor (EGF) from salivary glands and
tors are relevant to the development of SBS such as the increases GI secretion of trophic factors [29].
functionality of the residual bowel, especially the motility Sialoadenectomy in animals significantly attenuates ileal
disorders [24]. villus height, total protein and DNA content after small
Intestinal Failure in Childhood 315
Fig. 1 Classification of short bowel syndrome (SBS) according to anatomy of the remnant intestine and different causes of intestinal resection
Fig. 2 Consequences of
over-feeding a dilated and Nausea
Poor intestinal motility
poorly motile intestine vomiting
Abdominal distention
leading to intestinal stasis, Abdominal pain
Abundant/rare stools
small intestinal bacterial
overgrowth (SIBO), mucosal
injury, bacterial translocation, Intraluminal
bacterial
portal inflammation,
overgrowth
cholestasis and fibrosis Translocation Mucosal injury
Entero-toxins Villous atrophy
Gram-negative Malabsorption
sepsis Permeability
Cholestasis
Fibrosis Food allergy
Cirrhosis Eating disorders
Poor growth
bowel resection that is reversed by the administration of Enteral - preferentially oral - feeding must be started as
both systemic and oral EGF [30]. Moreover, the stimula- soon as possible after surgery. Breast feeding should be
tion of hormones released by the GI tract promotes adapta- encouraged [31]. Human milk (HM) contains a number of
tion whereas alternating fasting and feeding periods along factors supporting the developing neonate’s intestinal micro-
with cyclical PN avoid permanent release of insulin and biota and immune system including human milk oligosac-
excessive fat synthesis and deposition (steatosis, fat body charides (HMOs), nucleotides, immunoglobulin A, and
mass). leucocytes [32–34]. HM also contains glutamine and growth
factors, such as EGF, which promote bowel adaptation [32]. improved adaptation of the small intestine and colon in SBS
Interestingly, polymeric diets containing whole protein, lac- [41]. In piglets, the supplementation of PN with SCFAs or
tose, and long chain triglycerides (LCT), are not usually used their intra-caecal infusion reduced mucosal atrophy and
while extensively hydrolyzed formulae (EHF) are preferred. intestinal immune dysfunction following massive small
The latter have the advantages of containing short peptides, bowel resection [42].
better absorbed than free amino acids, as well as medium- In addition to their local effects, systemic SCFAs, in ani-
chain triglycerides (MCT) [27]. Amino acid based formulas mal studies, can affect the motility of both the stomach and
(AABF) are generally used in the treatment of food allergies the ileum through neuroendocrine mechanisms, probably
or in case of milk protein hydrolyzate intolerance [35]. True through the expression of enteroglucagon family peptides
food allergies have been rarely documented in children with and peptide YY [43]. Furthermore, both systemic and enteral
SBS [36]. Andorsky reported less intestinal allergy by using SCFAs exert a trophic effect on the jejunum by increasing
AABF, without clearly defining the criteria for the diagnosis mucosal mass, DNA and villus height [44]. Since SCFAs
of allergy [18]. Two retrospective studies reported that the are the preferred energy source for colonocytes, in patients
use of an AABF was associated with earlier weaning off PN with SBS the colon becomes an important organ for calories
and also a reduced rate of allergies [37, 38]. However, the salvage. Unabsorbed carbohydrates are metabolized by the
very small sample sizes and the lack of control groups in intestinal microbiota to SCFAs [40]. In turn, SCFAs may be
these studies do not support the recommendation of using considered as trophic factors directly by developing colon
AABF in SBS patients. Moreover, commercially available mucosa trophicity [45] or by promoting the release of
AABF contain lower levels of MCT than EHF. GLP-2 [42].
Feeds should be increased gradually as tolerated. Restoration of intestinal continuity, such as an anastomo-
Tolerance is evaluated by measuring stool number and vol- sis of the small intestine to the colon, should be done when-
ume and by the observation of vomiting, irritability and ever possible. With improved colonic water and electrolyte
abdominal as well as intestinal distension. Many factors can absorption, PN can then be discontinued or at least decreased.
affect stool volume in SBS, including the length of the resid- In addition, anastomosis enables colonic fermentation of
ual intestinal segment and the type of segment (the more unabsorbed carbohydrates from the small intestine to occur,
proximal the resection the larger the fluid and sodium losses), being an important source of energy assimilation. In spite of
the mucosal and endoluminal variables (residual enzymatic small intestine malabsorption in patients with SBS, both
activity and absorptive capacity, bacterial overgrowth). hyperphagia and adaptation of the remaining colon improve
Forced continuous ETF may worsen fluid, minerals and patient outcomes. A study evaluated morphology, prolifera-
nutrients malabsorption and may result in severe perianal tion status and transporters’ expression level in the epithe-
skin lesions. Bile salts malabsorption may be suspected in lium of the remaining colon of SBS adult patients compared
children without ICV and/or colon, presenting with high to controls [45]. It seems that in hyperphagic SBS patients
stool volume and perianal injury that can be improved by with severe malabsorption, adaptive colonic changes include
using cholestyramine. Fluid losses in these patients are often an increased absorptive surface with an unchanged prolifera-
accompanied by sodium and zinc losses with subsequent tive/apoptotic ratio and well-preserved absorption NHE2,
risks of severe depletion; supplements should therefore be NHE3 and PepT1 transporters mRNA levels [46]. As men-
provided. tioned before, the preservation of the colon and its associated
microbiota is essential for energy salvage, in reducing the
need for PN and in improving the outcome of SBS patients.
he Many Faces of Intestinal Microbiota
T Bacteriological analysis based on culture-dependent meth-
in Short Bowel Syndrome ods has found that the microbiota of SBS patients is mainly
composed of Lactobacilli, but neither qualitative nor quanti-
Colonic Bacterial Metabolism tative information is available regarding the other main bac-
terial groups [47]. Few data have been reported in pediatric
he Trophic Role of the Colon
T SBS but have mostly shown low intestinal microbiota diver-
When preserved, the colon, by hosting the largest part of sity and dysbiosis [48, 49].
intestinal microbiota plays a predominant role in the physi-
ological adaptation of the intestine after large small intestinal olonic Hypermetabolism and D-Lactic Acidosis
C
resection. Colon is capable of reducing loss of energy and Clinical manifestations such as abdominal distension, bloat-
producing trophic factors [39, 40]. In animal models, supple- ing and nausea - due to colonic microbiological hyperme-
mentation of an elemental diet with pectin, which is fer- tabolism - may impair daily life and should be monitored.
mented to short chain fatty acids (SCFAs) in the colon, They are the consequences of the intestinal malabsorption
leading to huge load of undigested CHO reaching the colon. or sepsis and occurred within 1 year from the date of surgery.
This condition may be worsened by hyperphagia or aggres- More recently, the US IF consortium reported a large cohort
sive tube-feeding. One rare complication of colonic hyper- involving 272 infants [58]. Overall, they have a gestational
metabolism, which is clearly different from small intestinal age of 34 weeks and birth weight of 2.1 kg (range: 1.2–
bacterial overgrowth (SIBO), is D-lactic acidosis. 2.7 kg) and were followed up for 25.7 months (range: 11.2–
D-lactic acidosis, also referred to as D-lactate encepha- 40.9 months). Residual small bowel length in 144 patients
lopathy, is a rare neurologic syndrome that occurs in indi- was 41 cm (range: 25.0–65.5 cm). Diagnoses were NEC
viduals with SBS or following jejuno-ileal bypass surgery (26%), gastroschisis (16%), atresia (10%), volvulus (9%),
[50, 51]. Fortunately, this complication is very rare. combinations of these diagnoses (17%), long segment
Symptoms typically present after the ingestion of high- Hirschsprung disease (LSHD) (4%), and other single or mul-
carbohydrate feedings. Neurologic symptoms include altered tiple diagnoses (18%). Prescribed medications included oral
mental status, slurred speech and ataxia, with patients often antibiotics (76%), H2 blockers (69%), and proton pump
appearing drunk. Onset of neurologic symptoms is accompa- inhibitors (57%). Enteral feeding approaches varied among
nied by metabolic acidosis and elevation of D-lactate plasma centers; 19% of the cohort received human milk. The cohort
concentration. L-lactate concentration, which is reflected by experienced 8.9 new catheter-related blood stream infections
serum lactate concentration is normal. Thiamine deficiency per 1000 catheter days. The cumulative incidences for enteral
should be excluded [52]. autonomy, death, and intestinal transplantation were 47%,
When present, Lactobacilli and other bacteria, including 27%, and 26%, respectively. Enteral autonomy continued
Clostridium perfringens and Streptococcus bovis, ferment into the fifth year after study entry. Interestingly, Finnish
unabsorbed carbohydrate to D-lactic acid, which cannot be pediatric surgeons reported a link between bowel dilatation,
metabolized by D-lactate dehydrogenase so it accumulates sepsis and cholestatic liver disease [59].
in the blood and may cause neurological symptoms. These It is generally accepted that continuous ETF offers the
organisms may proliferate in an acidic environment that may advantages of optimal digestion and absorption rate [31].
be promoted by the metabolism of unabsorbed carbohydrates However, continuous infusion changes the intestinal motility
to SCFAs. The mechanism for the symptoms with the high pattern by missing fasting period [60]. Significant dysmotil-
anion gap acidosis is unknown. They have been attributed to ity - impairing intestinal bacterial clearance - leads to small
D-lactate, but it is unclear if this is the cause or whether other intestinal bacterial overgrowth (SIBO) with subsequent
factors are responsible [45]. Treatments described in case Gram-negative sepsis. SIBO and cholestasis are common
reports have included nothing (with spontaneous resolution especially in patients without ICV and those having abnor-
after reducing enteral feeding), oral metronidazole, neomy- mal motility (eg: intestinal atresia, gastroschisis, NEC).
cin, vancomycin, (for 10–14 days) and avoidance of “refined” Aggressive continuous ETF is often attempted for mimick-
carbohydrates [53, 54]. Probiotics, prebiotics and synbiotics ing “hyperphagia” with the aim of weaning the child off PN
have been used but without clear efficacy [55, 56]. that is thought to be the cause of liver injury. These patients
Finally, one should consider the intestinal microbiota as a present with dilated loops of bowel containing residual non-
major factor for achieving intestinal adaptation and should absorbed nutrients. This strategy results in increasing SIBO
be always respected and not be destroyed by unnecessary that can cause mucosal inflammation and increased permea-
and/or inappropriate use of oral antibiotics worsening the so bility leading to sensitization and allergy as well as bacterial
called SBS related intestinal dysbiosis [48, 49]. translocation, sepsis and cholestasis [9, 58, 61, 62] (Fig. 2).
In addition, aggressive ETF may also result in such a over-
loaded gut syndrome with abdominal discomfort, intestinal
Small Intestinal Bacterial Overgrowth distension and loss of self-regulation of intake leading to eat-
ing disorders.
Cholestatic liver disease (CLD) has been shown to be more Factors that link infection to cholestasis are either cyto-
frequent in the SBS patients than in any other IF conditions kines (mainly TNFα, IL-1β, IL-6) or microbial TLR2 or
[57]. Out of 175 neonates with abdominal pathology requir- TLR4 agonists [63]. Liver targets primarily include hepato-
ing surgery, the patients with SBS (n = 40) suffered signifi- cytes, but also extend to Küpfer cells, cholangiocytes,
cantly more morbidity than the group without SBS in all endothelial cells, and stellate cells. There are no direct
categories of investigation (surgical complications, septic studies of bile flow in humans given endotoxin, but there is
events, CRS, PN weaning delay, liver disease, and duration sufficient indirect evidence to link endotoxin and endo-
of hospitalization). The case fatality rate was 37.5% in toxin-induced cytokines, to cholestasis. During severe sep-
patients with SBS versus 13.3% in patients without SBS sis, including septic shock, hyperbilirubinemia is usually a
(P = 0.001). Most of the deaths were caused by liver failure central clinical finding, often out of proportion to typically
mild elevations in serum transaminase. Interestingly, TNFα on-transplant Strategies for Enhancing
N
administered in humans has shown significant hyperbiliru- Intestinal Capacity
binemia, further supporting a link between cytokines and
cholestasis [64]. utologous Bowel Reconstruction
A
Surgical approaches aimed at maximising gastrointestinal
digestive and absorptive function are crucial to the manage-
Peri-Anastomotic Ulcerations ment of SBS. These include stoma closure and restoration of
bowel continuity together with resection of strictures and
Peri-anastomotic ulcerations (PAU) is a rare but severe com- closure of fistula. There are situations where surgical inter-
plication after intestinal resection and anastomosis. It is ventions aimed at reducing stasis in very dilated bowel, pos-
described mostly in children [65, 66]. The main symptom is sibly decreasing SIBO (with its negative effects on digestion,
bleeding, leading to iron-deficiency anemia, which is life absorption and a factor of IFALD) in the process and increas-
threatening. A series of 11 patients (7 boys) with PAU after ing contact time between luminal nutrients and mucosa
an intestinal resection and anastomosis in infancy was might improve overall absorption. Indeed, these procedures
reported [65]. The study focuses on predictive factors, med- aim not only to enhance the intestinal length and reduce the
ical and surgical treatment options, and long-term outcomes diameter of the distended intestinal loop with subsequent
[65]. The diagnosis of PAU was often delayed for several reduction of SIBO. The most common procedures are
years. No predictive factor (including the primary disease, Longitudinal Intestinal Lengthening and Tapering (LILT)
the length of the remnant bowel, and the loss of the ileocae- developed by Bianchi in Manchester, UK [68] and Serial
cal valve) could be identified. Numerous treatment options, Transverse Enteroplasty (STEP) developed by Kim et al. and
including antibiotics, probiotics (Saccharomyces boulardii) mostly used in North America [69] (Fig. 3a, b).
and anti-inflammatory drugs, proved to be ineffective to The precise indications and the potential benefits of these
induce prolonged remission. Even after surgical resection, procedures remain a matter of debate [70, 71]. Classical con-
relapses were observed in 5/7 children. The mechanism ditions and indications for bowel-lengthening surgery
leading to PAU remains unknown. Another series reported include the presence of a large intestinal diameter (>3–4 cm)
14 cases revealed by severe anemia, diarrhea, abdominal for at least 20 cm of small bowel and a minimum total bowel
pain and growth failure in average 11.5 years after surgery length of 40 cm.
[66]. Ulcerations were most often multiple (n = 11), located LILT involves longitudinal splitting of the small bowel
on the upper part of ileocolonic anastomoses (n = 12) and remnant along its mesenteric and anti-mesenteric border,
difficult to treat. No granulomas were seen but lymphoid ending up with two tubes of bowel of identical length each
follicules were frequent. In addition, either ASCA or ANCA with their own blood supply which are then joined together
were positive in 4/9 tested patients and 8/11 genotyped [68]. The advantages of the LILT procedure (Fig. 3a) include
patients exhibited a NOD2 mutation (P < 0.0002 when com- the conservation of the normal orientation of the muscular
pared to French healthy controls). A recent multicenter fibers allowing more physiological peristaltic contraction,
study involved 51 patients (29 boys) identified from 19 cen- and the possibility to further perform a STEP procedure on
ters in 8 countries [67] Most patients were followed after the operated segments. The disadvantages are the risk of vas-
necrotizing enterocolitis (n = 20) or Hirschsprung disease cular complications during surgery making LILT more tech-
(n = 11). The anastomosis was performed at a median age nically demanding as compared to the STEP procedure [68,
(interquartile range) of 6 [1–23] months, and first symptoms 69]. However, results after STEP and re-STEP procedure are
occurred 39 [22–106] months after surgery. Anemia was the not as performant as expected [72–75].
most prevalent symptom followed by diarrhea, abdominal The STEP procedure involves the use of a surgical stapler
pain, bloating, and failure to thrive. Hypoalbuminemia, ele- applied sequentially from alternating and opposite directions
vated CRP, and fecal calprotectin were observed. Deep to the dilated loop, in a transverse, partially overlapping
ulcerations were found in 59% of patients usually proxi- fashion creating a zigzag–like channel of approximately
mally to the anastomosis (68%). During a median follow-up 2–2.5 cm in diameter (Fig. 3b). This operation has the great
of 40 [19–67] months, treatments reported to be the most advantage of being simple and reproducible. STEP is a more
effective included exclusive enteral nutrition (31/35, 88%), recent and less complex technique [69]; unlike LILT, no
redo anastomosis (18/22, 82%), and alternate antibiotic anastomosis is needed, and the mesenteric blood supply is
treatment (37/64, 58%). Unfortunately, persistence of symp- not put at risk. If the bowel re-dilates, a further STEP proce-
toms, failure to thrive, and abnormal laboratory tests at last dure can be undertaken. Unfortunately, there are no surgical
follow-up in most of patients show the burden of PAU lack- techniques that can reliably increase small bowel surface
ing optimal therapy and incomplete understanding of the area, and by so doing rapidly achieve more than the back-
pathophysiology. ground process of gut adaptation.
Fig. 3 The longitudinal intestinal lengthening and tailoring (LILT) procedure and the serial transverse enteroplasty (STEP) procedure
Plasma citrulline is a marker of small bowel enterocyte ormonal Therapy and Other Adaptive
H
mass [5–7]. A 5-year follow-up cohort study after STEP Treatments
confirms the efficiency of this procedure. Interestingly,
both D-xylose - a marker of carbohydrate absorption and Hormonal therapy is promising in the management of infants
mucosal integrity - and plasma citrulline - a marker of small with SBS. The role of recombinant human growth hormone
bowel enterocyte mass -increased significantly postopera- (rhGH) alone or in combination with glutamine has been
tively [76]. This suggests that STEP procedure by reducing investigated. Inconsistent results have been reported in adults
SIBO, restores small intestinal mucosa integrity and receiving rhGH, with reported side effects [78]. A few stud-
improves villous size within the first weeks following the ies of rhGH alone or in combination with glutamine have
procedure. However recent data showed no adaptive muco- been carried out in PN dependent children with SBS [79–
sal hyperplasia or muscular alterations occurred between 81]. Despite some decrease in PN requirements during treat-
first and repeat STEP [75]. This suggest that persistent ment these trials showed little benefit on body composition
inflammation and lacking mucosal growth may contribute and mucosal absorption in the long-term [79–81].
to continuing bowel dysfunction in SBS children, who Glucagon-like peptide 2 (GLP-2) is produced by the
require repeat STEP procedure, especially after removal of L-cells of the terminal ileum in response to luminal nutrients
the ileocecal valve. and has a trophic effect on the intestine, promoting absorp-
A more recent described procedure is the spiral intesti- tion and adaptation [81]. GLP-2 has been shown to increase
nal lengthening and tailoring, which consists of a spiral the surface area of the gut mucosa, up-regulate nutrient
incision of the intestinal wall and in the elongation longi- absorption, improve gut-barrier function, increase intestinal
tudinally of the intestine by sliding one flap over the other blood flow and decrease bone resorption [81]. Patients with
[77]. The final intestinal lengthening is strictly dependent low levels of GLP-2 following the resection of the terminal
on a series of parameters, some of which are defined by the ileum and/or the ileo-caecal valve improved intestinal
surgeon. absorption and nutritional status after treatment with GLP-2
The gut overload syndrome may be defined as the asso- [82]. A 12-week, open-label study, enrolled SBS PN depen-
ciation of dilated intestinal loops, abdominal discomfort, dent patients aged 1–17 years [83]. It has been concluded
SIBO, cholestasis and failure to thrive in a SBS patient that Teduglutide (GLP-2 analogue) was well tolerated at
who is partially or totally enterally fed. Surgical bowel- 0.025 or 0.05 mg/kg/day and was associated with trends
tapering with or without lengthening should be consid- toward reductions in PN requirements and advancements in
ered in such setting whatever the patient is PN-dependent enteral feeding. The above pilot study validated the recom-
or not. mended dose of Teduglutide to be used as 0.05 mg/kg per
day. However, study limitations included its short-term, lidine or ethanol lock procedures [91, 92], by using the last
open-label design, small sample size and heterogeneity of generation of lipid emulsions [11] [see below]. In the mean
both patients and management because of the multicenter time, the rate of intestinal transplantation decreased with
study. An other 24-week, open-label study, has been reported these measures [93].
[84]. A 24-week, phase III trial included 59 patients with 2 Some studies have been reported, involving the long-term
randomized, double-blind teduglutide dose groups and a growth and nutrition status of children with neonatal SBS
non-blinded standard of care (SOC) arm was used; patients after weaning off PN [22, 94–96]. Improved care of patients
received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily: with SBS significantly achieved more optimal weight gain
(0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9) [84]. for age compared with decade 1980 [94]. However, the final
Safety end points included treatment-emergent adverse genetic target size is not always achieved while some defi-
events (TEAEs) and growth parameters. The primary effi- ciencies may be evidenced [95, 96]. Indeed, children with
cacy/pharmacodynamic end point was the number of patients SBS are still at risk for different nutrient malabsorption even
who achieved a ≥ 20% reduction in parenteral support (PS) after weaning off PN for a long time. They may develop such
from baseline at week 24. TEAEs were reported by 98% and an “overloaded gut syndrome” with failure to thrive requir-
100% of patients in the teduglutide and SOC groups, respec- ing, for some, PN to be restarted. Therefore, they need long-
tively. The most common TEAEs in the teduglutide-treated term, regular monitoring and intensive nutritional care to
groups were pyrexia and vomiting. The primary end point prevent various nutrient deficiencies. Too early PN weaning
was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) may be responsible for both “overloaded gut syndrome” and
patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg failure to thrive.
teduglutide, and SOC, respectively (P < 0.05 vs SOC). Both
0.025-mg/kg and 0.05-mg/kg teduglutide groups showed
clinically significant reductions in PS volume (P < 0.05 vs Neuro-Muscular Intestinal Diseases
SOC), PS calories, days per week and hours per day of PS
infusions, and increases in enteral nutrition and plasma Intestinal motility is under the control of the enteric nervous
citrulline at week 24 compared with baseline. Two (8.3%, system that is functionally independent from the central ner-
0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg vous system and is therefore efficient even in completely dis-
teduglutide) achieved enteral autonomy. In a monocenter connected bowel loops, such as intestinal transplants. Normal
open trial of 48 weeks treatment with teduglutide (0.05 mg/ motility is achieved through the transmission of the signals
kg/day) currently under submission, we report a PN weaning from the enteric nervous system to the enteric smooth mus-
rate in 8 patients (32%) a significant increased of citrulline cle generating healthy peristaltic waves. Therefore, neuro-
plasma levels (p < 0.001) (p < 0.001) and a significant muscular intestinal disease (NMID) may derive from either
decrease of the PN dependency index (p < 0.0001). enteric nerve or muscle dysfunction. Severe gastrointestinal
Monocenter trials are required for addressing recommen- conditions classified among the NMID lead to intestinal fail-
dations and extend the use of GLP-2 analog (eg: Teduglutide ure: extensive Hirschsprung Disease and chronic intestinal
Revestive®) at a dose of 0.05 mg/kg/d. Oral insulin has been pseudo-obstruction syndrome (CIPOs).
shown to be beneficial in animal models and might be
assessed very soon in infants and children [85]. Other rele-
vant treatments associated with a trophic effect on the bowel Hirschsprung Disease
mucosa such as short chain fatty acids may be beneficial in
children with SBS [82]. Finally, there is also interest in the Total or subtotal intestinal aganglionosis (TIA) leaving the
use of other trophic factors such as epidermal growth factor child with less than 50 cm normally innervated small intes-
(EGF) and insulin-like growth factor-1 (IGF-1) in children tine below the ligament of Treitz (LOT) is a rare condition. It
with IF and SBS [83]. may be considered as a SBS type 1. Appropriate manage-
ment strategies are not well established. Surgery is per-
formed as a simple jejunostomy below the LOT with or
Outcome of SBS and Long-Term Growth without or short-segment longitudinal myomectomy
[97–99].
Mortality decreased during the last decade especially fol- Nutritional management includes cyclic PN (home-PN)
lowing the implementation of the so called “intestinal reha- associated with oral feeding for reducing the risk of liver dis-
bilitation centres” (IRC) [86–90]. Multidisciplinary ease and promoting oral skills [8]. Continuous attention is
management, improved prevention of sepsis by performing needed in the daily long-term management of these unstable
autologous bowel reconstruction [68], by preventing cathe- infants and children with a permanent risk of dehydration
ter related blood stream infections (CRBSIs) with tauro- and subsequent complications such as hypercalcemia, renal
failure. ITx is undertaken according to the occurrence of congenital and present shortly after birth with episodes of
complications (water-electrolytes disorders, CRC, and intestinal obstruction. CIPOs have been conventionally
IFALD) and/or the wish of parents for another quality of life. divided into two groups, according to the pathogenesis of
In 12 patients with TIA, it was reported an outcome rate of dysmotility: neuropathies and myopathies. The former is due
62.5% in the LITx group and 75% in the ITx group, both to the involvement of the enteric nervous system and the lat-
with half colon grafting [100]. All the surviving patients ter is due to the dysfunction of intestinal muscles. CIPOs due
were fully weaned from total PN, after a median of 57 days. to muscle dysfunction are rare but seem to be more severe.
Pull through of the colon allograft was carried out in all Urinary tract disorders such as megacystis and megaureter
patients. Fecal continence is normal in all but one of the sur- can be associated both with neuro and myopathies causing
viving children. When graft is tolerated on the long-term, CIPOs. These should be managed by experienced urologists
growth is normal and quality of life is improved [101, 102]. although, surprisingly, they may be better tolerated than
A monocenter survey included 25 patients born between other more common obstructive urinary tract disorders [106].
2000 and 2015 were followed for a median of 10.9 years
[103]. Fifteen patients had less than 80 cm of ganglionic
small bowel (SB) with a median of 20 cm. Ten patients had Diagnosis
more than 80 cm of ganglionic SB with a median of 115 cm.
The median PN duration was significantly shorter for patients The diagnosis of CIPOs is based on clinical and radiological
with more than 80 cm: 0.9 versus 7.5 years in those with less analysis. Tools helpful to assess a severe motility disorder
than 80 cm (P < 0.001). No patient with less than 80 cm was include radiological and histological evaluations and, if feasi-
weaned off PN, except 1 who underwent ITx. Ten patients ble, gastrointestinal manometry [104]. However, intestinal
with less than 80 cm develop enterocolitis on the excluded manometry is not highly contributive for either the diagnosis
segment, leading to emergency entero-colectomy in 5. Liver of CIPO or its treatment. CIPOs management is mainly based
disease was more frequent in patients with less than 80 cm on clinical and radiological features. In CIPOs a plain abdomi-
(11 vs 0). Three patients required combined liver-ITx; 2 nal x-ray typically shows air-fluid levels and dilatation of the
underwent an isolated ITx. The more severe complication bowel loops. Contrast studies, such as the barium small bowel
was enterocolitis. Liver disease compromised long-term sur- follow-through study, are helpful to rule out mechanical
vival without transplantation. Both complications should be obstruction, but may not reveal motility abnormalities. The
prevented by early diversion and enterectomy of the whole presence of a systemic autoimmune disease as well as severe
aganglionic segment. Follow-up in or together with a multi- infections and endocrinopathies suggests an acquired form of
disciplinary IRC is mandatory. CIPOs that sometimes can be managed by treating the under-
lying illness. Congenital forms of CIPOs can be misdiagnosed
as Hirschsprung Disease, even resulting in surgery. However,
Chronic Intestinal Pseudobstruction surgical biopsies reveal normal enteric ganglia. In these cases,
bowel resections should be avoided [105]. When CIPO is
Chronic intestinal pseudo-obstruction syndrome (CIPOS) is strongly suspected laparoscopic full-thickness biopsies may
a condition considered as the most severe disorders of gut support the diagnosis with a minimally invasive procedure.
motility. CIPOS continue to be very challenging despite Nevertheless, histological hallmarks are scant and the sample
recent progress in the understanding of its pathophysiology, should be evaluated in referral centers by expert pathologists
resulting in a high levels of morbidity and mortality. Major who have experience in similar cases and access to specific
contributors to the disappointing lack of progress in paediat- immunohistochemistry and electron microscopy allowing the
ric CIPOS include a dearth of clarity and uniformity across recognition of immune-mediated conditions, congenital neu-
all aspects of clinical care from definition and diagnosis to romuscular disorders and mitochondrial cytopathies [107].
management. Genetics of CIPOS is complex and partially known [104,
CIPOS is a descriptive term pooling together several dis- 108]. Most patients do not show familial recurrence (spo-
orders of the enteric muscles or nerves [104]. Thus it may radic cases) but syndromic autosomal-dominant, autosomal-
have heterogeneous features but has a similar phenotype recessive and X-linked forms have been described. In
characterized by recurrent bouts of intestinal obstruction particular, an X-linked locus has been mapped to the Xq28
without demonstrable mechanical occlusion. CIPOs are the region. Although both familial and sporadic CIPOs have
cause of approximately 15% of all pediatric cases of IF [9]. been widely reported, so far only a few genes have been
Repeated surgical procedures can negatively affect the identified as responsible for syndromic CIPO: the thymidine
course of the disease [105]. phosphorylase gene (TP, also known as endothelial cell
CIPOs may be due to several diseases that can be either growth factor-1, ECGF1), the DNA polymerase-γ gene
congenital or acquired. The most severe forms are usually (POLG) and SOX10.
Management dependency and the number of surgical procedures were

associated with a poor prognosis [112]. In the most severe
Management is based on a multidisciplinary intervention by forms of CIPOs children end up with an ileostomy, a gastros-
medical, surgical and allied professionals. Children with tomy with almost permanent aspiration due to gastroparesis,
CIPOs almost invariably require some surgical intervention. frequent bowel obstructions, and total PN dependency.
The major barriers to food progression in patients with inef- Patients with such a poor quality of life may benefit from
ficient propulsive strength are the natural GI tract bottle- transplantation that should include the stomach (i.e. modi-
necks: the pylorus and the ileo-cecal valve. These can cause fied multivisceral transplantation) [113].
a functional occlusion of the gastric outlet or small bowel
clogging, which can be easily resolved by the formation of a
gastrostomy (or jejunostomy) and an ileostomy respectively. Congenital Enteropathies
The formation of a stoma can improve the quality of life and
reduce symptoms in up to 50% of children with CIPOs [105]. Congenital diseases of enterocyte development (CDED) are
It is sometimes possible to localize the segments of the bowel a group of rare disorders causing IF in early infancy. Children
the most responsible for the dysmotility symptoms: in such with these disorders have usually neonatal onset of severe
cases a loop resection can improve the intestinal transit and diarrhea that requires PN support [114].
allow enteral feeding and a return to a more normal life. Near The etiology includes defects in nutrient-electrolyte
total small bowel resection has been proposed as treatment absorption and disorders of enterocyte differentiation and
of CIPOs in some cases [109]. polarization [115, 116]. Clinically it is important to differen-
Due to the heterogeneity of the syndrome, a key issue is tiate protracted from intractable diarrhea of infancy (IDI) -
to adapt the treatment/management to each individual patient the latter being irreversible. Figure 4 proposes a simple
according to age at onset, severity, and the outcome of surgi- algorithm to approach newborns and infants with severe
cal procedures such as a primary ileostomy. These children diarrhea.
need to maintain the ability and the pleasure to eat normal
food and this can be permitted by taking small and frequent
meals with liquids or, in more severe cases, by using the gas- Microvillous Inclusion Disease
trostomy as a venting device; the known benefits of deliver-
ing enteral feeding in children with IF make it mandatory to The most common causes of IDI are microvillus inclusion
attempt intermittent gastrostomy closure and gastric or disease (MVID, also known as microvillus atrophy), con-
gastro-duodenal low-fiber feeding [110]. genital tufting enteropathy (CTE, also known as intestinal
Only a few medications have been shown to improve gas- epithelial dysplasia), syndromic or phenotypic diarrhea, and
trointestinal motility in patients with an intact enteric ner- autoimmune enteropathy. The latter is not considered to be
vous system. Erythromycin at low or full antibiotic doses intractable unless all available treatments fail. Several genes
may improve gastric emptying in children with CIPOs and responsible for these disorders have been identified by stud-
gastroparesis [111]. Several other drugs with a demonstrated ies based on genome-wide analysis of polymorphisms, add-
effect on gastric motility, such as the serotoninergic agents ing new tools for the diagnosis of intractable diarrhea of
cisapride and tegaserod, have been withdrawn from the mar- infancy [116].
ket because of the occurrence of rare but severe cardiac The first described form of MVID was related to MYO5B
adverse events including arrhythmias, heart attacks and mutation [117, 118]. Severe watery diarrhea develops in the
strokes. Colonic acute pseudo-obstruction can be managed first few days after birth and can rapidly reach a total fecal
successfully by the infusion of the anticholinergic drug neo- output of 200–300 ml/kg of body weight per day. Diarrhea
stigmine, but this drug has not been tested on a long-term does not stop during fasting and causes life-threatening elec-
regimen. trolyte and acid-base imbalances, rapid and severe dehydra-
Children with CIPOs may experience small bowel bacte- tion and hypovolemic shock. Children with MVID are
rial overgrowth and can thus occasionally benefit from a usually dependent on continuous PN infusion not allowing
course of antibiotics such as metronidazole, amino- for cyclic PN. Some patients have associated disorders
glycosides or cotrimoxazole. These drugs should be pre- involving biliary acids metabolism and some develop liver
scribed only in case of clinical symptoms rather than disease leading liver failure within the first few years of life
regularly, in order to avoid the emergence of bacterial [117, 118]. Currently, the survival rate for these children is
resistance. around 70%, including those patients (up to half) who
A French multicenter study including 105 children, 18 received intestinal or liver-intestinal graft [119, 120].
with prenatal diagnosis and 80 younger than 12 months of The second gene in which MVID causing mutations were
age at onset, showed that early age at presentation, PN identified is STX3 [121, 122]. Patients were reported with
Onset day 1-30
Persists at bowel rest (TPN) Reduced at bowel rest (TPN) Disappears at bowel rest (TPN)
Family history Family history Feeding testing

Hydramnios / prematurity Extra-digestive disease: lymphopenia, Lactose, glucose,
Watery diarrhea anemia, skin rash galactose, fructose
Familiy history Biological presentation Protein losing enteropathy
Glucose-galactose
Consanguinity Chloride diarrhea CDG syndrome Malabsorption (SLC5A1)
Abundant watery SLC26A3
diarrhea Mitochondrial disease
Sodium diarrhea Primary lactase deficiency (LCT)
Defects in enterocyte SPINT2, GLUCY2C, Neurogenin 3 deficiency
differentiation and polarization Enterokinase deficiency
Lymphangiectasia (TMPRSS15)
Microvillous atrophy Consanguinity
MYO5B, STX3, UNC45A SGA birth Bile salts malabsorption SLC10-A2
a-b lipoproteinemia (MTTP)
Facial dysmorphy
Hair abnormalities HSPG deficiency
Epithelial dysplasia
Liver disease Early IPEX /and AIE*/ Other Defects in absorption
EpCam / SPINT2
VEOIBD * and transport
Syndromic diarrhea
Other « new » THE syndrome
diseases/mutations to be *AIE: autoimmune enteropathy; VEOIBD: very early onset - IBD
Mutations : TTC37, SKIV2L
founded And other candidate genes Cow’s milk protein allergy and IPEX syndrome as well as
sucrase deficiency are rarely of early neonatal onset
Fig. 4 Clinical approach of early onset severe diarrhoea
nonsense mutations resulting in truncations of the apically Congenital Tufting Enteropathy

targeted N-ethylmaleimide-sensitive factor attachment pro-
tein receptor (SNARE) protein syntaxin3. No genotype- Neonates with congenital tufting enteropathy (CTE)
phenotype correlation with respect to MYO5B and develop a severe neonatal diarrhea persisting at bowel rest
STX3-related MVID has been reported so far, due to the [123]. Often there is a family history of consanguinity and
small number of patients with STX3 mutations. Genetic neonatal deaths related to severe diarrhea and dehydration.
counseling can be performed for this autosomal recessive Indeed CTE has been found to be associated with muta-
disorder when mutations in MYO5B, STX3 are identified. An tions in the genes encoding for epithelial cell adhesion
international registry has been set up [122]. molecule (EpCAM and Spint2) [124]. There are reported
UNC45A belongs to the UCS protein family (UNC-45/ clusters of cases in the Arabic Gulf area [125]. Infants with
CRO1/She4p). C. elegans unc-45 was first described after CTE typically experience a worsening of diarrhea during
a screening for mutations causing motility disorders (UNC continuous ETF even when given extensively hydrolyzed
stands for uncoordinated) [76]. The UNC-45 protein has or amino acid-based formula, resulting in failure to thrive
three recognizable domains: an N-terminal tetratricopep- and protein-energy malnutrition. Diarrhea is usually less
tide repeat (TRP) domain (115 amino acids), a central severe than in children with MVID; some patients may be
domain of 400 amino acids, and a C-terminal UCS domain weaned from PN. Nevertheless, most remain PN depen-
(400 amino acids). The TPR domain participates in pro- dent and sometimes require ITx [123]. Expert histological
tein-protein interactions, especially with Hsp70 and Hsp90 review of duodenal biopsies is the key to making the diag-
HSP90AA1. The role of the central domain remains nosis of this severe cause of IF. The so-called Congenital
unclear, while the C-terminal UCS domain is critical for Sodium Diarrhea (CSD) has been reported as related to
myosin binding [77]. Whether or not variants located SPINT2 mutations [126]. Clinical presentation associated
within specific domains of UNC45A lead to different func- extra-intestinal disorders and histological features suggest
tional outcomes is still unknown. UNC45A appears to be a link between CTE and CSD [127]. Thirteen patients pre-
ubiquitously expressed and has been postulated to be senting with IF, and TE histology were retrospectively
involved in cytoskeletal functions, such as cell division or reviewed for up to 30 years [128]. It was concluded that
exocytosis [78]. Data are consistent with the multi-organ IED cases have >92% chance of long-term survival and
defects observed in children, as well as the structural >50% chance of enteral autonomy by/in early adult life
pathology in the gut in a zebrafish mutants [79]. However, and 75% by 25 years. Patients with IED managed on PN at
other features of the protein are not reflected in the pheno- home by an IF rehabilitation service should avoid intesti-
type seen in humans. nal transplant [128].
HE Syndromic Diarrhea/Trichohepatoenteric
T ICR knockout mice. The molecular, cellular, and physiologi-
Syndrome (SD/THE) cal phenotypes observed in human patients and engineered
mice indicate that PERCC1 is required for normal develop-
It is a rare and multi-system genetic disorder [129, 130]. This ment of EECs and normal entero-endocrine hormone
disorder is characterized by life-threatening diarrhea starting secretion.
within the first 6 months of life, wooly and poorly-pigmented
hair, facial dysmorphism including prominent forehead and I ntestinal Failure Associated Liver Disease
cheeks and hypertelorism, hypopigmentation, cardiac Many peoples continue to talk about PN-related liver disease
defects, immunodeficiency, and liver disease. It includes suggesting that PN is the cause of liver disease. Nowadays IF
extensive hepatic fibrosis and cirrhosis, affecting about half should be considered as the main cause of cholestatic liver
of patients. SD/THE is caused by mutation in SKIV2L or in disease. The most appropriate wording should be intestinal
TTC37, two genes encoding subunits of the putative human failure associated (or related) liver disease (IFALD) [10]. It
SKI complex involved in RNA degradation [130]. There are is probably the most important complication affecting chil-
currently no specific biochemical profiles in these patients dren with IF on long-term PN. The prevalence of the disorder
although a functional T-cell immune deficiency with defec- is unknown because there is no established definition of liver
tive antibody production has been reported [131]. disease in this setting and it is unclear as to whether IFALD
Microscopic analysis of the hair shows twisted hair (pili- should be diagnosed on the basis of clinical, biological or
torti), aniso- and poikilotrichosis, and trichorrhexis nodosa. histological criteria. Indeed, there are insufficient data on the
Histopathological analysis of small intestine biopsies shows degree and type of liver involvement in patients with long
non-specific villous atrophy with low or no mononuclear cell term PN.
infiltration of the lamina propria and no specific histological
abnormalities involving the epithelium. Early management
consists of total PN. Some infants have a milder phenotype Causes and Mechanisms of IFALD
requiring partial PN or only enteral feeding. Prognosis of
this syndrome is poor but most patients now survive and The main factors contributing to liver injury in these patients
some patients may be weaned off PN at adolescence. Even are recurrent catheter related sepsis, prematurity and low
treated patients have a short stature and often a mental retar- birth weight, lack of enteral feeding, disruption of entero-
dation [130]. Other severe persistent diarrhea causing chronic hepatic biliary acid cycle (proximal stoma, ileal resection),
IF, with or without extra-digestive manifestations, have been intestinal stasis and SIBO (obstruction, dysmotility, lack of
described with genetic molecular biology based diagnosis ileo-caecal valve, over-tube feeding…). Table 2 reports the
[132, 133]. IF and PN related factors causing liver injury.
It should be stressed that the most important factors lead-
ing to IFALD are those related to individual patient charac-
Deletion of the Percc1 Gene teristics and, importantly, the episodes of catheter related
blood stream infections (CRBSIs) or SIBO [134–136] An
Eight patients from seven families (2 consanguineous) of important role in this process is played by liver inflammation
common ethno-geographic origin with IDI were recently caused by extra-hepatic infections in which microbial prod-
reported [133]. They presented an early onset severe diarrhea ucts brought to the liver through the blood stream, either
(7–21 days) with mild villous atrophy and variable PN directly or through production of cytokines, lead to altera-
dependency. Deletions of a sequence termed intestine-critical tions of bile flow. The inflammation associated with these
region (ICR) on chromosome 16 were identified. Transgenic changes may cause rapid fibrosis and eventually biliary cir-
mouse reporter assays showed that the ICR contains a regu- rhosis with end-stage liver disease [136–140].
latory sequence that activates transcription during develop- IFALD develops frequently at very early ages, especially
ment of the gastrointestinal system. Targeted deletion of the in premature infants in whom liver immaturity, frequent sep-
ICR in mice caused symptoms recapitulating the human consis and necrotizing enterocolitis (NEC) facilitate liver inflam-
dition. Transcriptome analysis uncovered an unannotated mation and severe damages. At this young age PN is most
open reading frame (Percc1) flanking the regulatory sequence often administered continuously over 24 h and CRBSIs is
whose expression was lost in the developing gut of ICR common. High risk situations for developing liver disease
knockout animals. Targeted deletion of the Percc1 gene in are summarized in Table 3. The combination of those factors
mice causes phenotypes similar to those observed upon ICR makes the onset of cholestatic liver disease likely. The cur-
deletion in mice and patients, whereas an ICR-driven Percc1 rent use of taurolidine lock procedure decreased dramati-
transgene was sufficient to rescue the phenotypes found in cally the rate of CRBSIs [141].
Table 2 Factors causing liver disease medium chain triglycerides (MCTs), the quantity of
Patient and intestinal failure related factors α-tocopherol and phytosterols [146]. The probable detrimen-
• Prematurity and low birth weight tal effect (pro-inflammatory) of ω-6 FAs on liver function is
• Lack of enteral feeding provided by studies that showed fat emulsions based on pure
– Total parenteral nutrition
fish oil (containing ω-3 FAs) being successful as rescue ther-
• Dysruption of entero-hepatic biliary acid cycle
– Proximal stoma, ileal resection
apy in pediatric patients with SBS affected by severe liver
• Intestinal stasis and bacterial overgrowth disease. The infusion of exclusively ω-3 FAs ultimately
– Obstruction, dysmotility, lack of ileo-caecal valve, changed the management of these patients since it allowed
over-tube feeding the reduction of intake of pro-inflammatory ω-6 and phytos-
Parenteral nutrition related factors terols while increasing the amounts of alpha-tocopherol, a
• Duration of PN powerful antioxidant agent [146].
• Recurrent catheter related sepsis
The evidence gathered on the beneficial effects of fish-oil
• Unadapted protein energy delivery
– Excessive or unadapted amino acid intake in these patients has led to its use in clinical practice.
– Continuous versus cyclic infusion However, two different approaches have been developed in
– Excessive glucose intake North America as compared to Europe. In North America,
– Unappropriate use of lipid emulsion following the paper by Gura et al. or Cowles et al., a pure fish
Phytosterols oil based lipid emulsion (Omegaven®) has been promoted
Lipoperoxidation and has been, until recently was the unique emulsion to be
Excess of omega-6 fatty acids
available on the market [147–149]. In Europe it has become
Essential fatty acid deficiency
• Potential toxic components of PN early possible to use a composite lipid emulsion containing a
Iron mixture of soybean oil (30%), coconut oil (30%), olive oil
Aluminium (25%) and fish oil (15%) (SMOF-lipid®). Both ILEs contain
Chromium 200 mg/L of alpha-tocopherol. Clayton compared the level
Manganese of phytosterols in plasma of healthy subjects, patients with
• Deficiencies mild hepatic dysfunction and those with severe dysfunction
Taurine
who received soybean oil emulsion - rich in sterols, and
Chlorine
found a link between liver damage and phytosterols plasma
levels [150]. Phytosterols contained in soybean oil have been
Table 3 High risk situations for developing liver disease found to be associated with liver disease progression and
• Premature and young infants their exclusion from ILE may also be beneficial in children
• NEC or gastroschisis ± atresia on PN [151].
• Protracted bowel rest/intestinal stasis
Regarding the presence of tocopherol in lipid emulsions,
• Bacterial overgrowth/gram negative sepsis
• Recurrent catheter-related sepsis one should emphasize that there are different preparations of
• Unadapted and/or continuous PN tocopherol: alpha-tocopherol is the form with far greater
The combination of these factors makes cholestatic liver disease likely antioxidant activity [152]. While soybean oil emulsions con-
tain a high amount of gamma-tocopherol (which has 25% of
the antioxidant power as compared to alpha-tocopherol), lip-
Intravenous Lipid Emulsions and Liver Disease ids based on fish oil are rich of the most powerful antioxidant
vitamin E, alpha-tocopherol [153]. To ensure a proper anti-
Frequently cited observational studies suggested a link oxidant power in lipid preparations it is advisable to add
between intravenous lipid emulsions (ILE) and liver disease 0.5 mg of alpha-tocopherol per gram of PUFAs.
[142, 143]. It has been reported that the improvement of cho- Some concerns have been raised on providing fish oil as
lestasis depends also on maintaining an appropriate protein/ the sole source of lipids over a long period of time. Pure fish
energy ratio in PN, achieving cyclic rather than continuous oil provides less essential ω-6 fatty acids than that currently
PN infusion, using medium-chain triglycerides (MCT) based recommended in infants and young children. Furthermore,
lLE and adding α-tocopherol in ILE [144]. Omegaven® (pure fish oil) can only be given at lower infu-
IFALD is a multifactorial disease in which the use of soy- sion rates compared to SMOF-lipid®). Omegaven® may not
bean oil-based ILE in PN may represent the major culprit be able to provide enough calories to sustain growth. Thus,
[145]. Several factors should be taken into consideration the combination of several types of oil by mixing soybean oil
when choosing an ILE for parenteral use: the content in (rich in ω-6 FAs), coconut oil (rich in MCTs), olive oil (rich
essential fatty acids (EFAs), the ratio of ω-6/ω-3, the in MUFAs) and fish oil (rich in ω-3 FAs) appears to promote
polyunsaturated fatty acid (PUFAs) content, the amount of better growth while limiting hepatic toxicity [145]. A ran-
domized, double-blind, controlled trial on 60 preterm babies 2 years, concluded that the Long-term use of the composite
stratified by body weight has analyzed a set of parameters fish oil based ILE was well tolerated in home PN-dependent
(clinical data, laboratory data, fatty acids in plasma and red children. The RBC-FA profile alterations were consistent
blood cells, plasma levels of alpha-tocopherol and- with the ω-3 PUFA-enriched composition of this emulsion
phospholipids) after infusion of PN with SMOF-lipid® or without evidence of essential FA deficiency [158].
soybean oil based emulsion [154]. The SMOF-lipid® emul-
sion increased the content of eicosapentaenoic EPA and doc-
osahexaenoic (DHA) acids and reduced the ω-6 / ω-3 ratio, Long Term Management of Intestinal Failure
improving also liver function tests).
Another study evaluated the long-term effects of the lipid Home Parenteral Nutrition
mixture SMOF-lipid® versus a soybean oil based preparation
in pediatric patients on home PN [155]. This randomized, Long-term PN administration is best achieved at home.
double blind study involved 28 children who received more Home PN, first used in the early 1980s, allows for full nutri-
than 4 infusions of PN per week for 4 consecutive weeks. tional support of children and adults with temporary or per-
The infusion was administered in 12–14 h overnight. At the manent IF at home [8, 94, 159, 160]. Survival of children
end of the study no differences between biochemical and receiving prolonged PN depends mainly on the underlying
nutritional outcomes were recorded, but there was a clear diagnosis and has increased dramatically during the last
association between the use of SMOF-lipid® and a signifi- three decades; nevertheless complications such as CRBSIs,
cant decrease of bilirubin levels, that conversely increased in IFALD and loss of venous access can seriously challenge the
the soybean oil based group. clinical stability of patients with IF [8, 94, 159–165].
A confirmation of these findings comes from the study of The expertise required to prescribe PN both at home and
Muhammed et al. who examined the effect of the switch in the hospital usually comes from a dedicated hospital-
from a soybean based lipid emulsion to SMOF-lipid® in 17 based nutritional team who has a thorough knowledge of
children with cholestasis [156]. The subjects were assigned energy expenditure, nutrients and trace-elements require-
to a treatment group receiving SMOF-lipid® and a group ments by age, appropriate central catheter handling, and
receiving soy based lipids. Over a period of 6 months the use awareness of the risk and complications of long-term
of SMOF-lipid® was associated with a marked statistically PN. Home PN must be tailored to the single patient and its
significant reduction in the levels of bilirubin when com- family, always maintaining the goal of counteracting the del-
pared with the soy based lipid group [156]. eterious aspects of intestinal failure. Official guidelines and
Finally, recent studies have emphasized the “superiority” position statements on central catheter handling and PN pre-
of fish-oil derived lipid emulsions as a major advance for the scription have been published [135].
management of patients on long-term PN. Preparations with One of the largest cohort from a single center has been
pure fish oil are effective in decreasing cholestasis but their recently reported [8]. It involves 251 children referred to the
use as the sole source of lipids may not meet essential fatty Paris-Necker Intestinal Rehabilitation Center and discharged
acids requirements especially in the long-term [145]. on HPN between January first 2000 and December 31st
Nevertheless, while some randomized controlled trials have 2013. In this survey, 217 children (86%) had a primary diges-
demonstrated the beneficial effect of SMOF-lipid® versus tive diseases (PDD). The mean age at HPN onset was
soy-based lipid emulsion, no studies have compared SMOF- 0.7 ± 0.3 year with a mean duration of 1.9 ± 0.4 years. The
lipid® to Omegaven® in these patients The last ESPGHAN/ major indication for HPN was SBS (59%) secondary to mid-
ESPEN guidelines make the following recommandations gut volvulus (16.7%), necrotizing enterocolitis (12.3%), gas-
[157]: As part of measures to reverse IFALD in paediatric troschisis (12%), extensive Hirschsprung Disease (10%) and
patients, a discontinuation of Soy based ILE, a reduction of intestinal atresia (6.4%). Other PDD were congenital enter-
other ILE dosage and/or the use of composite ILE with FO, opathies (10%), CIPOS, (9.1%) and Inflammatory Bowel
should be considered along with the treatment and manage- Diseases (IBD, 5.1%). At the end of the study period, 56% of
ment of other risk factors (LoE 2þ, RG B, strong recommen- children were weaned off HPN, 8% had intestinal transplan-
dation for). tation and 9.6% of children died - most of them had immune
R 4.19 The use of pure FO ILE is not recommended for deficiency. The major complications of HPN were catheter-
general use in paediatric patients but may be used for short- related blood stream infections (CRBSI, 1.7 per 1000 days of
term rescue treatment in patients with progression to severe catheter) and IFALD, 51 children, (20% of the cohort).
IFALD, based on case reports. (LoE 3e4, GPP, conditional Children with congenital enteropathies had the highest rates
recommendation for, strong consensus). of IFALD (44% of the sub-group). Children on HPN in this
A recent study of the long-term use of the composite ILE cohort have a shorter HPN duration to weaning, lower death
SMOF-lipid® at a dose of 1.5–2 g/kg/day for more than rate and longer interval to catheter replacement than other
studies. One of the most important advances for long term the rate of CRBSIs dropped from 1.04 CRSBIs per 1000 days
PN dependent patients has been the onset of antiseptic cath- HPN in 2014 to 0.61 in 2019 (p < 0.001) while in meantime,
eter locking [92, 166]. the percentage of children receiving TLP increased from
The European data on the long-term management of IF on 29.4% to 63.0% (p < 0.001). The prevalence of cholestasis
HPN need to be compared with other continent, especially (conjugated bilirubin ≥20 μmol/l) was low and stable
North America. Several papers from the US, report “intesti- between 4.1 and 5.9% of children during the study period.
nal rehabilitation centers” including early management of
intestinal failure (IF), especially short bowel syndrome in
both neonatalogy and surgical wards, with the aim of the ear- I ntestinal Rehabilitation Centers
liest PN weaning [87, 88, 167–170]. Some patients get severe and Multidisciplinary Team
complications and become candidates for ITx. Some others
fail to be weaned off PN and are discharged on home-PN Paediatric IF is a multifaceted condition requiring the com-
when suitable. The organization and follow-up of home PN petent contributions of several medical and allied health pro-
is supposed to be shared between paediatric gastroenterology- fessionals both for inpatient and outpatient care. Therefore,
nutrition teams and home care-giver companies according to the formation of a multidisciplinary team is crucial to achieve
the local facilities. Unfortunately, there is almost no report in optimal results [165, 167–170].
the literature about the prevalence and results of paediatric The IF team should ideally include staff specialised in
home PN programs making a comparison with North- surgery, neonatalogy, gastroenterology and nutrition, a pae-
America management almost impossible. One of the reasons diatric dietician and nurses experienced in central venous
is linked to the organization and the management of IF. In catheters handling and parenteral nutrition infusion. Special
France, patients suffering from IF, especially those with consideration should be given to the link between the hospi-
SBS, are managed by specialized medico-surgical depart- tal team and the home care team. Fostering coordination of
ments, including paediatric surgeons and paediatric surgical, medical, and nutritional management is mandatory
gastroenterologists-nutritionists or neonatology units. The to provide high quality, integrated care of patients with IF,
decision of discharging the child on home PN and the fol- thus improving remarkably the survival of these patients [8].
low-up are fully dependent on paediatric gastroenterology The three most important issues in the management of chil-
and nutrition teams. The French network is organized region- dren with IF include:
ally. Patients are referred to the closest of the 7 reference
centres for HPN. The world largest cross-sectional study 1. A good and early link between primary care givers and
included all children enrolled in any of the 7 French HPN intestinal failure programs.
certified centres from January 1st, 2014 to December 31st, 2. The presence in the program of both intestinal rehabilita-
2019 [165]. The number of patients increased by 43.6% tion and intestinal transplantation expertise.
between 2014 and 2019. According to the year of follow up, 3. The participation in the network of the organisations pro-
the indications for HPN were short bowel syndrome (SBS) viding home PN bags.
(42.3–46.6%), congenital enteropathies (CE) (18.5–22.8%),
chronic intestinal pseudo-obstruction syndrome (CIPOS) Collaborative strategies must be developed in order to reduce
(13.0–16.3%), long segment Hirschsprung’s disease (LSHD) mortality and morbidity in patients with IF, especially for
(9.7–13.3%), Crohn’s disease (CD) (1.6–2.6%) and other those who are referred for permanent IF or intestinal trans-
non-primary digestive diseases (NPDD) such as immune plantation [144].
deficiency, cancer or metabolic disease (4.0–9.2%). The
median age at discharge on HPN decreased from 11.7 months
in 2014 to 8.3 months in 2019 (p < .001). By December 31st, Intestinal Transplantation
2019, 44.8% of children had left the HPN program after a
median duration ranging between 39.9 and 66.4 months. Although a large percentage of children with IF can survive
Among these patients, 192 (74.2%) were weaned off PN with long-term PN, a proportion of patients develop life-
(94.7% SBS), 41 (15.8%) were transferred to adult centers threatening complications such as severe septic episodes
for CIPOS (42%), SBS (31%) or CE (27%), 21 died (8.1%) - (CRBSIs and/or SIBO related), fluid and electrolytes imbal-
mostly in relation to cancer or immune deficiency - and 5 ance with renal disease, loss of venous access for PN and end
were transplanted (1.9%): 4 underwent combined liver- stage liver disease. In these patients, nutrition has failed both
intestine transplantation for LSHD (n = 2), SBS, CE and one in the enteral and the parenteral routes. These patients are
multivisceral Tx for CIPOS. The use of a composite fish-oil considered to have “nutritional failure” [9, 144, 171]. They
based ILE increased from 67.4% in 2014 to 88.3% in 2019 should be referred for intestinal transplantation (ITx).
(p < 0.001). With the use of taurolidine lock procedure (TLP) Successful ITx were first reported in the late 1980s and pro-
posed for the treatment of patients affected by irreversible referred to an IF multidisciplinary team for ITx work up for
intestinal failure [172, 173]. In 2001 the American Society of irreversible IFALD, eventually reversed their cholestasis
Transplantation defined irreversible liver disease, exhaustion with an appropriate nutritional management [144].
of central venous access sites, and recurrence of life- Therefore it was suggested that ITx should be used only
threatening situations (recurrent sepsis or dehydration) as as a life-saving procedure. Although experienced transplan-
indications to consider ITx for patients with IF [174]. Despite tation centers have suggested that the role of ITx should be
important surgical and medical advances in the transplant expanded to a pre-emptive/rehabilitative procedure applica-
techniques, reported long term patients’ and grafts’ survival ble to all patients with irreversible IF, the recent findings
rates remains around 50% at 5 years for children [175]. As an have shown that home PN is the treatment of choice for IF in
example, from a series of children with ultra-SBS referred to adults as well as in children. An early referral to IRC is
our institution some of them underwent ITx for nutritional essential to prevent or optimize the long-term management
failure while the others were maintained on HPN. With of IFALD. Central venous-catheter-related major complica-
5 years follow up, all children on HPN (100%) survived tions might be indications for a pre-emptive ITx in selected
while those who have died anyway from nutritional failure patients. As a matter of fact, “nutritional failure” should be
survived in only 60% of cases [26]. This suggests that ITx regarded mostly or even only as a clear indication to ITx [9].
has been a life saving procedure for 60%. In certain patients with other major organ failure in addi-
There is probably a different threshold for ITx on both tion to SBS-IF, both long-term home PN and ITx may pro-
sides of the Atlantic Ocean. The European approach is more long suffering without improving quality of life. In such
inclined to support long-term home PN, which is cost- cases a wide-ranging ethical discussion should be performed
effective and provides a better quality of life, rather than to to establish the best course of further treatment for the indi-
refer a child for ITx. Support for this view comes from Pironi vidual child. If home PN and ITx are not considered in the
et al. who have performed a 3-year prospective study includ- child’s best interests it is important to involve a symptom
ing both adults and children on long-term PN for IF [176]. care/palliative care team and if necessary make an end of life
They compared ‘non-candidates’ for ITx (no indications nor care plan [180].
contraindications), with ‘candidates’ who had an indication Isolated liver Tx has been performed for IFALD in
according to the USA Medicare and Medicaid Services defi- patients with SBS. Taha et al. reported a group of children
nitions, and a high risk of death or morbidity according to the with SBS and IFALD who have the potential for adaptation
American Society of Transplantation position paper [177, in the residual bowel underwent isolated LTx [181, 182]. The
178]. The results showed that only patients with nutritional prognosis remains poor after this procedure, 8 survivors out
failure due to IFALD or major catheter complications had an of 14 [181]. This procedure should be avoided by preventing
increased risk of death on home PN, thus supporting its use liver disease. If performed, it should be exercised with
as the primary treatment for IF. Those results were confirmed extreme caution. These children need careful assessment
by another 3 years prospective follow-up study on potential before isolated LTx and close follow-up with an experienced
paediatric candidates to ITx in Japan [179]. Bilirubin levels multidisciplinary team to monitor nutritional outcomes and
>100 μmol/l seem to negatively impact on post ITx survival. may need consideration for transplant or non-transplant sur-
It is an important observation that a quarter of patients gery in the long term (Fig. 5).
Fig. 5 Algorithm for managing intestinal failure from referral to possible intestinal transplantation
Conclusion tation programs at leading centers has improved the sur-

vival of children with IF while the morbidity associated
Intestinal failure requires specialized and individualized with both IF and PN has significantly decreased. These pro-
medical therapy that includes surgery, medical equipment, grams almost all include neonatalogists, pediatric surgeons,
nutritional products, and standard nursing care. Intestinal pediatric gastroenterologists, specialized nurses, and dieti-
rehabilitation programs provide such complex care with the tians; many also include a variety of other medical and
goal of achieving enteral autonomy and oral feeding with allied medical specialists, providing integrated interdisci-
or without intestinal transplantation. The treatment of per- plinary care.
manent IF has made remarkable strides in the past decades. Recent advances in the knowledge of factors implicated
The establishment of multi-disciplinary intestinal rehabili- in PN and IF complications and improvements in the medi-
cal and surgical management of SBS result in better out- 6. Konstantinos C, Fragkos AF. Citrulline as a marker of intestinal
function and absorption in clinical settings: a systematic review
comes for these patients. Isolated liver Tx for SBS patients
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Part IV
Consequences of Intestinal Failure
Consequences of Undernutrition
and Dehydration
Pete Turner, Simon Alison, and Jeremy M.D. Nightingale
Key Points that leads to altered body composition (decreased fat free
1. Undernutrition is common in all patient groups and mass) and body cell mass leading to diminished physical and
affects all body systems. mental function, and clinical outcome from disease’ [1].
2. Undernutrition adversely affects all disease processes Gastrointestinal disease gives rise to undernutrition by
resulting in longer hospital admissions with increased reduction of appetite, oral intake, digestion and/or absorp-
nursing dependency, higher morbidity and mortality. tion, and increased metabolic demands.
3. Severe malnutrition impairs thermoregulation so that The physical and mental consequences of starvation and
patients with a severe sepsis may not be identified. undernutrition have been known since ancient times. An
4. Albumin is generally not a marker of nutritional status. ancient Egyptian royal tomb of more than 2000 years BC
5. Patients who have been obese can have a high body mass bears the inscription:
index (BMI) yet be severely undernourished (sarcopenic I am mourning on my high throne for the vast misfortune,
obesity). because the Nile flood in my time has not come for seven years!
6. With no food (oral intake) but with water a healthy adult Light is the grain; there is lack of crops and of all kinds of food.
may be expected to live 2 months. This time is reduced in Each man has become a thief to his neighbours. They desire to
hasten and cannot walk. The child cries, the youth creeps along
the presence of sepsis/inflammation. as does the old man; their souls are bowed down, their legs are
7. With no water intake (oral, enteral or intravenous) an adult bent together and drag along the ground and their hands rest in
may be expected to survive for up to 2 weeks. This depends their bosoms. The counsel of the great ones in the court is but
upon activity, ambient temperature and fluid losses. emptiness. Torn open are the chests of provisions, but instead of
contents there is air. Everything is exhausted.
During the twentieth century, a number of studies of normal

and obese individuals undergoing prolonged starvation, [2,
Introduction 3] of populations under famine conditions, [4] and of patients
suffering from disease-related undernutrition, [5] have given
The European Society of Enteral and Parenteral Nutrition us a clearer picture of the relationship between weight loss
(European Society of Clinical Nutrition and Metabolism) or, more particularly, loss of body cell mass and deteriorating
(ESPEN) have stated that the terms undernutrition and mal- mental and physical function. The relationship between
nutrition can be considered synonymous and can be defined structure and function is not always linear [6] with some
as ‘a state resulting from lack of intake or uptake of nutrition functions beginning to deteriorate early in the process of
starvation, whereas others are relatively unimpaired until
later. In some cases there may be a threshold above, which
P. Turner (*)
function is largely maintained but below which it falls rap-
Department of Nutrition and Diet Therapy, South Eastern Health
and Social Care Trust, Belfast, UK idly [7]. Much depends upon the initial nutritional state of
e-mail: [email protected] the subject and also on the rate at which tissue is lost [8].
S. Alison Total starvation may have different effects from partial star-
Ex-Department of Diabetes, Endocrinology and Nutrition, Clinical vation, and there may also be a process of adaptation to
Nutrition and Investigation Unit, Queen’s Medical Centre, chronically low intakes, as seen among the lean subsistence
Nottingham, UK
farmers of Asia. The relative proportions of energy and pro-
J. M.D. Nightingale tein deficiency, the development of single or multiple defi-
ciencies of minerals, trace elements and vitamins, and the

340 P. Turner et al.
presence of disease may all modify the consequences of par- 20% of their body weight prior to surgery for peptic ulcers,
tial starvation. they had a 33% mortality compared with 4% if less than 20%
This chapter mainly outlines the consequences of disease- body weight had been lost [9].
related undernutrition consequent upon intestinal failure, Children are even more vulnerable because of the
with supportive and relevant evidence from other studies of demands of growth and development and, during infancy,
starvation. Much data about the consequences of undernutri- because of their high metabolic rate in relation to body size
tion come from paediatric reports from developing countries and high surface to volume ratio. The survival of a totally
and from work on young people with anorexia nervosa. The starved neonate may be no more than a few days. Studies
chapter also summarises the consequences of dehydration among undernourished Asian children by Pelletier et al. sug-
which are known to most clinicians but for which there are gested that their odds of dying from disease and undernutri-
few publications to reference. tion increased by a compound rate of more than 7% for each
percentage point deterioration in weight for age [10]. There
was also an exponentially increasing probability of morbid-
Survival ity as weight fell below 80% of normal for age.
The protective effect of obesity is illustrated by reports of
Hunger strikes have occurred since Roman times, and the survival by fat adults undergoing periods of starvation of
suffragettes brought this method of protest to public atten- 130–382 days [3]. This protective effect is not only due to
tion in Britain in the early twentieth century. Mahatma greater fuel reserves, but also to the lower daily losses of
Gandhi fasted at least 14 times but never for more than nitrogen in relation to lean mass, implying a metabolic con-
21 days. The most striking example of total starvation in pre- trol mechanism. Whether obesity is similarly protective in
viously healthy young men without disease was provided by the presence of intercurrent illness is unclear.
the 30 Irish Republican Army (IRA) hunger strikers of The extraordinary studies carried out by the Jewish physi-
Northern Ireland [8]. In 60–70 days, they lost 38% of their cians in the Warsaw ghetto in 1942 gives us further insight
body weight and one-third of them had died, allowing us to [4]. Most of the inhabitants had been on 800 kcal a day or less
conclude that, in the absence of disease, previously normally for many months and at the point where they were studied had
nourished adults may survive weight loss of 35%, or approx- already lost between 20% and 50% of their pre-war weight
imately 60 days of total starvation (Fig. 1). Beyond this point and weighed between 30 and 40 kg. One woman, for exam-
mortality rises steeply. This time point is considerably ple, with a height of 1.52 m weighed 24 kg, giving a body
reduced if a patient has already lost weight or has underlying mass index (BMI) of 10.3 kg/m2. Many were suffering from
sepsis or malignancy. One of the hunger strikers, who was intercurrent infections and most died within 3 weeks of the
suffering from a gunshot wound, survived for only 45 days, studies, although there were clearly some variations in the
emphasizing the cumulative effect of illness and starvation. ability to survive starvation. A review suggests that the lower
Studley in 1936 showed that if patients had lost more than limit of BMI compatible with survival is approximately
10 kg/m2 in women and 12 kg/m2 in men [11]. These observa-
tions have important implications for clinical work. The
0 MEED guidelines suggest admitting anyone with a BMI of
5 Oral less than 13 kg/m2 [12]. It is not uncommon to be referred
intake
patients for nutritional support who have lost 20–35% of their
10
body weight and in whom not only function but also survival
15 Decision box
is at stake. It can also be argued that, if parenteral nutrition is
20 required for a total of 60 days or more because of continuing
% Weight
loss
gastrointestinal dysfunction, such treatment is life-saving in
25
the same sense that dialysis is life-saving in renal failure and
30 ventilation in respiratory failure. The difference between
35
these situations is not one of principle but of time-scale.
30% Mortality
40
45 Undernutrition in Intestinal Failure

0 10 20 30 40 50 60 70 80 90 100
Days
Undernutrition in intestinal failure (IF) can be considered
as disease related malnutrition that occurs not only due to
Fig. 1 Percentage weight loss and days after starting to starve. The
decision box indicates the time when an oral intake will lead to a rapid reduced intake/loss of appetite but through malabsorption,
recovery high GI losses, multiple surgical procedures, immobilisa-
Consequences of Undernutrition and Dehydration 341
tion and sepsis/inflammation all of which result in a loss of Consequences of Undernutrition

body mass. This is classified by ESPEN as ‘disease related
malnutrition with inflammation’ [1]. A further subcategory General
‘chronic disease related malnutrition with inflammation’ is
considered synonymous with cachexia and can include that A clear description of undernutrition/starvation comes from
caused by inflammatory bowel diseases [1]. In this a less data in Western Holland in 1945. Complaints were of back-
severe inflammatory response (CRP ≤40 mg/L) due to the ache, aching legs, tingling of fingers and toes, periods of diar-
disease itself over a prolonged period can lead to significant rhoea, nocturnal urinary frequency. Superficial haemorrhages,
muscle wasting. A detailed nutritional assessment taking on skin on the back of the hands and on the face, hunger
into account the degree and cause of inflammation is imper- oedema, cyanosis of the skin of the extremities and rarely
ative for successful management of malnutrition in IF. In gangrene of the toes. A low temperature down to 35 °C was
the presence of sepsis/inflammation nutritional status may recorded, the heart rate was usually slow at 40 beats per min,
not improve despite adequate energy being given. A study the systolic blood pressure was down to 80 mmHg. There was
of 1950 medical patients found that those with a CRP level often a red tender tip of tongue. The reflexes were normal, the
<100 mg/L did not respond well to nutrition support in urine testing showed no albumin, acetone or glucose. Anaemia
terms of improvements in 30 day mortality or functional was common (Hb 110 g/L) as was a leucopenia. Osteoporosis
measures, whereas those with moderate (CRP 10–100 mg/ and kyphoscoliosis of the upper spine was observed [16].
mL) or low inflammation (CRP <10 mg/L) did [13]. This Observations from hunger strikers state that they feel faint
phenomenon forms a key part of the SNAP (Sepsis, and dizzy. They learn to stand up very slowly and may
Nutrition, Anatomy, Plan) principle of treating IF (chapter become bed bound. Bradycardia and drop in blood pressure
“Acute Surgical Intestinal Failure. Sepsis and occur after even relatively short fasting. Orthostatic hypoten-
Enterocutaneous Fistula(s)”). sion is present by about day 20 and may be disabling.
Due to malabsorption and high GI losses, IF patients are Weakness and light headedness are common. Although thy-
at a high risk of multiple micronutrient deficiencies. These roxine concentrations are maintained in fasting, tri-
have been demonstrated in paediatric studies and are likely iodothyronine is converted rapidly to an inactive metabolite,
to occur in adults. A study of long term paediatric IF patients thus reducing effective thyroid function. This will lead to
having undergone transition from PN to oral nutrition dem- weakness and a sensation of feeling cold. Abdominal pain
onstrated a high incidence of vitamin, mineral and trace ele- has been described in around three quarters of hunger strik-
ment deficiencies, despite most (101 of the 138) children ers [17–19].
studied being on micronutrient supplements (Table 1) [14]. Undernourished patients in hospital require high-
Zinc and copper are excreted in bile and deficiencies can dependency nursing, having an increased hospital stay with
therefore easily occur in patients with high output fistulas an increased morbidity and mortality compared with patients
and stomas. Their levels should be interpreted with caution of normal weight having similar underlying clinical prob-
in acutely unwell patients; zinc is a negative acute phase lems [20–24]. The consequences of undernutrition are sum-
reactant being bound to albumin and copper a positive one marised in Table 2.
being bound to caeruloplasmin [15].
Biochemical
Table 1 Micronutrient deficiencies in children with IF [14]
In uncomplicated starvation, hepatic gluceonogenesis main-
Micronutrient Deficiency % p-value
Vitamin A 19.1 0.046
tains blood glucose for use by the brain, blood cells and renal
Vitamin B12 12.4 0.41 medulla. Muscle, some neural tissue, adrenal cortex and adi-
Vitamin D 30.1 0.56 pose tissue switch from using glucose to using fatty acids
Vitamin E 6.2 <0.001 and ketones, derived from lipolysis, for energy. Muscle sup-
Folate 0 1 plies alanine, glycine and lactate for hepatic gluceonogene-
Copper 7.7 0.14 sis, and glutamine as a source of energy to intestinal and
Iron 61 0.003
lymphoid tissue. The glycogen reserves are rapidly utilised
Selenium 4.3 0.26
(6 h–3 days). As there is no carbohydrate for energy insulin
Magnesium 10.9 0.71
Phosphorus 8.8 0.88 levels fall and glucagon levels rise. The increased plasma
Zinc 22.9 0.73 glucagon levels (like GLP-1) induce a naturesis and thus
Anaemia 43.2 <0.001 weight loss. Energy starts (day 3 onwards) to be derived
Iron deficiency anaemia 29 0.21 mainly from lipid via ketones. The sodium/potassium pump
fails. Whole body phosphate, potassium and magnesium fall.
Table 2 Consequences of undernutrition

System with reduced function Consequence
Psychological/neurological Apathy/depression/anxiety/psychosis
Depletion of water soluble vitamins Increased sleep time
e.g. thiamine
Reduced recent memory
Loss of appetite
Muscle Weakness, impaired rehabilitation
Skeletal Chest infections
Pressure sores
DVT/pulmonary emboli
Cardiac Bradycardia/low BP/orthostatic hypotension
Cardiac failure, Cardiac atrophy
Long QT interval, T wave abnormalities, sudden death
Gastrointestinal Parotid hypertrophy, reduced gastric acid and pancreatic enzymes
Mucosal atrophy with inflammatory infiltrate
Gastric dilatation and slow gastric emptying, colonic stony
Bacterial overgrowth/change in microbiota
Increased translocation
Reduced gut associated lymphoid tissue
Reduced colonic sodium and water absorption Diarrhoea
Sepsis/multi-organ failure
Liver Steatosis, abnormal nuclear receptor PPARalpha signaling, synthetic function reduced (e.g.
conjugated bile acids, complement proteins and albumin)
Endocrine (low sex, thyroid and Poor growth
growth hormones)
Delayed puberty
Amenorrhoea
Infertility
Osteopaenia/osteoporosis
Thermoregulation Hypothermia
Repair mechanisms Slow wound healing
Pressure sores
Immune Reduced lymphocyte count
Infections
Fluid and electrolytes Oedema
Metabolic Low creatinine, urea, glucose, phosphate and potassium
Faecal alpha 1 antitrypsin increased
Haematological Anaemia, neutropaenia, thrombocytopaenia
Bone Osteopaenia/osteoporosis
In the presence of sepsis, lipolysis is impaired and a further In his introduction to the Biology of Human Starvation,
increase in muscle protein catabolism occurs. Protein is ini- [2] Sir Jack Drummond wrote of the famine in Holland in
tially protected (making up only about 10% of the energy 1945:
source) but in the latter stages, when fat stores have been Two impressions dominated: firstly the immense importance of
exhausted there is catastrophic protein catabolism including the psychological aspects of inanition; secondly the compara-
from cardiac muscle and ultimately death [19]. tive simplicity of the nutritional and biochemical problem. One
of the curious and rather disconcerting psychological manifes-
tations of starvation, seen repeatedly in Western Europe, was the
unresponsive and uncooperative attitude of those to whom relief
Psychological and Neurological was brought. It disappeared without trace when calorie intakes
rose above 1500 to 1800 a day…. An outstanding impression
Apathy/Depression gained in Western Holland in 1945 was the importance and sig-
nificance of the psychological consequences of food shortage….
The mental changes associated with starvation, noted by the From the grumbling and grousing that are inevitably provoked
ancient Egyptians, were a striking feature of the studies car- when the energy intake is deficient to the extent of 15–20%, to
ried out by the Warsaw physicians [4]. They reported: ‘The the apathy and dissolution of higher human qualities that come
most striking psychiatric finding is the prevalence of depres- with severe starvation, there is a wide variety of psychological
reactions to hunger, many of which are almost of themselves
sion, even in young people. There is complete apathy, lack of diagnostic of the level of calorie intake.
interest, poor thinking, and even incoherence.’
In their study of normal young male volunteers undergoing significant reductions in muscle enzymes and a change in
semi-starvation for 24 weeks, Ancel Keys and his colleagues muscle histochemistry with type II fibre atrophy. Comparing
described not only the diminished physical powers which were the effect of undernutrition with the effects of surgery and
associated with a loss of up to 23% of the body weight during sepsis, Brough et al. [31] found abnormal muscle function
that time, but also a rise in a depression score of 30% [2, 25]. consequent upon sepsis, but the changes were easily distin-
This was slow to recover during the process of re-feeding. guishable from subjects taking an inadequate diet. They
Indeed it took up to 4 months to return to normal. Similar found no effect on muscle function following trauma, sur-
observations have been made in prisoner of war camps, during gery or steroid administration. They also showed that, fol-
the Russian famine of 1918–1921, among undernourished chil- lowing the initiation of parenteral nutritional support, there
dren in the Indian subcontinent and in Africa. was a rapid initial improvement in muscle function within
It is important to remember that patients suffering from days, which occurred before any change in anthropometric
disease-related undernutrition are often apathetic, depressed variables or plasma proteins. Hill found similar changes in
and awkward. These difficulties soon dissolve with appropri- undernourished patients with inflammatory bowel disease [5,
ate nutritional care. The fatigue, which follows illness, may 6]. Measuring whole body protein by neutron activation
also be prolonged by undernutrition. techniques, he showed that a 20% reduction in total body
protein, reflecting lean mass, was associated with little
Intellectual Performance/Sleep change in respiratory muscle strength, but beyond this there
Intellectual performance changes little though short-term was a steep deterioration.
memory is reduced and sleep-time increased [2, 11, 26]. Over the first 5 days of nutritional support, both grip
strength and peak expiratory flow rate rose from a mean of
Appetite 65–75% of normal [5, 6]. This was followed by a much more
Undernutrition causes a reduction in appetite. A vicious cir- gradual and sustained improvement over the ensuing weeks
cle is thereby created which needs to be broken if normal as body composition was restored. This again illustrates the
oral intake is to be resumed. After 1–2 weeks of overnight two-phase response to refeeding. The first is associated with
nasogastric tube feeding, the appetite may be restored so that a rapid improvement in cellular function and the second with
voluntary oral intake by day is increased [26]. This is some- the much more gradual process of the restoration of body
times very striking in some cases of inflammatory bowel dis- cell mass. Muscle function may also be seriously impaired
ease. Once a certain weight has been reached, the appetite with single or multiple electrolyte, mineral or micronutrient
appears to be self-perpetuating and nutritional support may deficiencies, conditions that are not uncommon in patients
be discontinued. Interestingly it has been demonstrated that with gastrointestinal disease. Hypokalaemia may be respon-
patients undoing upper gastrointestinal surgery such as sible for muscle weakness or even paralysis; selenium defi-
oesophagectomy may have decreased appetite similar to that ciency causes impairment of both myocardial and skeletal
seen following bariatric surgery, mediated by enhanced muscle function. Deficiencies of magnesium and of calcium
release of satiety hormones [27]. decrease peristalsis but increase skeletal neuromuscular
excitability and may cause fits.
keletal Muscle Function
S
Protein/energy malnutrition is characterized by muscle wast-
ing with particular loss of the Type II fast-twitch fibres, Respiratory
which are prevalent in the respiratory muscles, including the
diaphragm [28–33]. The poor function of skeletal muscle in Undernutrition impairs respiratory function, chiefly through
the chest increases the risk of developing chest infections its effect on respiratory muscles, impairing ventilation and
[34] including tuberculosis, and the resulting reduction in the ability to cough and clear secretions [38–44]. It also
mobility increases the risk of deep venous thrombosis, pul- reduces respiratory response to hypoxia [45, 46] and the
monary emboli and pressure sores [33–37]. ability to wean from ventilators [43]. In contrast, nutritional
In a study of ten patients with various gastrointestinal dis- support improves ventilatory function and has facilitated
orders, Lopez et al. [28] measured the function of the adduc- weaning from ventilators. Respiratory complications of sur-
tor pollicis muscle by electrical stimulation of the ulnar gery, trauma or acute illness are one of the major conse-
nerve and found that undernutrition resulted in increased quences of under-nutrition. The terminal event in progressive
muscle fatiguability and an altered pattern of muscle con- starvation is nearly always bronchopneumonia [16].
traction and relaxation, all of which were reversible by nutri- One corollary of weak respiratory muscles is the inability
tional supplementation. In a study of five morbidly obese to cope with the additional respiratory demands imposed by
female subjects, on a 400 kcal/day carbohydrate diet, Russell excessive caloric feeding, particularly of carbohydrate. Such
et al. [29, 30] showed similar changes in muscle function, patients may be rendered breathless by carbohydrate loads in
excess of 5 mg/kg/min or total energy intakes in excess of These changes may be seen during parenteral feeding
40 kcal/kg/day, owing to increased oxygen consumption and when there is a lack of oral/enteral intake, or in segments of
CO2 production [47, 48]. bowel that have been by-passed. The introduction of food, by
the oral or enteral route, reverses these changes and acceler-
ates adaptation of a retained ileum in patients with a short
ardiovascular and Sympathetic Nervous
C bowel. Particular substrates may be important. Soluble fibre
System and prebiotics such fructo-oligosaccharides, giving rise to
short-chain fatty acids, may enhance both small and large
The Warsaw studies of advanced starvation [4] showed that this bowel mucosal growth and function. Glutamine is an essen-
was associated with lower systolic and diastolic blood pres- tial fuel for the mucosal epithelium and may enhance the
sures at rest and in response to exercise. Bennett et al. showed protective effect of the gut-associated lymphatic tissue.
that starvation, with sodium supplementation, for 48 h in Pancreatic function has been studied in undernourished
healthy men was associated with a small drop in supine blood infants and in adults, and been shown to be impaired. Winter
pressure, but after 10 min standing, there was a fall in systolic and colleagues [62–64] studied a series of patients with a
blood pressure of 15 mmHg with no change in the non-starved mean BMI of 13.6 kg/m2 before treatment and 16.5 kg/m2
controls [49]. There is a reduction in heart rate, blood pressure after nutritional support. They found that before treatment,
and cardiac muscle mass; although this reduction in cardiac pancreatic protein synthesis and enzyme production was
muscle is considerably less than that of skeletal muscle, it could reduced, so that 70% of gastric and pancreatic secretion was
predispose to cardiac failure [50, 51]. A prolonged QT interval lost with consequent impairment of xylose and fat absorption.
may lead to ventricular arrhythmias [52]. The long QT interval All parameters were restored towards normal by refeeding.
is a function that takes the longest to recover on refeeding. They confirmed findings of impaired gastric acid secretion, as
Patients who have a postural fall in BP greater than 20 mmHg well as pancreatic amylase and trypsin secretion.
(or syncope), a bradycardia less than 40 bpm, and or a long QT Malnutrition-related enteropathy is well described though
internal are at risk of sudden death [12]. can be difficult to differentiate from environmental enteric
As sympathetic nervous system function is a major deter- dysfunction (EED) (“tropical sprue”). It is characterised by
minant of metabolic rate and as its function is reduced in villous atrophy, crypt hyperplasia, loss of tight junctions, and
undernourished patients, it is not surprising to find a mark- an influx of inflammatory cells into the intestinal mucosa
edly reduced resting metabolic expenditure in these patients. [65]. This is why care must be taken in interpreting small
This must be borne in mind when estimating the nutritional bowel biopsies (usually to determine if there is an enteric
requirements of depleted patients. myopathy or neuropathy) in the presence of severe
malnutrition.
Gastric emptying for liquid and solid is delayed in under-
Gastrointestinal nourished patients with anorexia nervosa [66, 67]. Gastric
dilatation, peptic ulcer, acid reflux and colonic atony leading
The effects of undernutrition upon the gastrointestinal tract to constipation have been reported.
are complex and depend upon its severity. The Warsaw stud- Malnourished patients with Crohn’s have a worse disease
ies [4] demonstrated, in patients with more than 30% weight progression than those who are normally nourished and
loss, an impairment of gastric acid secretion. Lack of luminal indeed feeding and increasing the weight of malnourished
nutrition during parenteral nutrition, in studies on normal patients with Crohn’s disease reduces the inflammation [68].
subjects or associated with undernutrition, may result in vil- The microbiota of malnourished children change to being
lous atrophy, impaired small bowel mucosal function and less diverse and there being an increased relative abundance
increased intestinal permeability [53–56]. Gut mucosal atro- of pathogenic genera within the phylum Proteobacteria
phy may be responsible for mucosal barrier dysfunction and (Enterobacter, Escherichia, Klebsiella, and Shigella), and a
bacterial translocation which may gives rise to an endotoxae- decreased relative abundance of genera containing beneficial
mia, which with immune impairment, in turn may contribute bacteria (Bifidobacterium, Butyrivibrio, Faecalibacterium,
to multi-organ failure [57]. The addition of antibiotics to Lactobacillus, and Roseburia) [69].
therapeutic regimens for uncomplicated severe acute malnu-
trition in children is associated with a significant improve-
ment in recovery and mortality rates [58]. The colon can be Immunological
affected, losing its ability to reabsorb water and electrolytes,
so diarrhoea may result [59, 60]. There may be altered intes- In undernutrition, many aspects of immune function, partic-
tinal flora with migration of bacteria proximally into the ularly of cell-mediated immunity, are impaired and increased
small bowel, thereby exacerbating malabsorption [61]. susceptibility to infection is well documented in adults, [4,
70–73] children [74, 75] and the elderly [76]. Conversely, viduals were put in a cooling suit, Fellows et al. [82] found
one of the consistent features of positive trials of nutritional normal vasoconstriction but no increase in thermogenesis in
support is a reduction in postoperative and other infections response to the challenge. Mansell et al. [83] showed, in
[74–80]. Much of the tissue involved in immune responses younger subjects, that the thermogenic response to cooling
lies in the gastrointestinal tract and the gut-associated lym- was restored when body composition was returned to normal
phatic tissue. The provision of luminal nutrients and special by nutritional support. They also showed [84] that the vaso-
substrates such as glutamine may have their beneficial effects constrictor response to cooling was impaired in normal sub-
partly through providing essential nutrients to this tissue. It is jects who fasted for 48 h. Both short-term starvation and
important, however, not to over-simplify the situation, since weight loss, therefore, impair thermoregulation but by differ-
the relationship between nutritional status and immune com- ent mechanisms.
petence is a complex one and may vary according to the In adults, with a temperature of 34–36 °C: they will feel
clinical condition and the nutritional deficiencies involved. cold and will move around more, but may become with-
As well as protein-energy undernutrition, mineral and micro- drawn or aggressive. At a temperature of 33–34 °C: they may
nutrient deficiencies may also impair immunity. Good et al. stagger and become confused and drowsy, but strangely the
[73] for example, found zinc to be an important factor for the patient may feel warm and remove clothes. At a temperature
maintenance of cell-mediated immunity. of 26–32 °C, coma may occur and at less than 26 °C death
Immune competence, as measured by delayed cutaneous may occur (sometimes after ventricular fibrillation) [12].
hypersensitivity (DCH), is affected by severe protein-energy Thus undernourished patients are prone to hypothermia
malnutrition. While it is true that immune competence as and the recognition of sepsis/fever may be difficult as their
measured by DCH is reduced in protein-energy malnutrition, temperature tends to be lower than normal.
several diseases [53] and drugs influence this measurement
making it a poor predictor of protein-energy malnutrition in
sick patients. The following factors non-specifically alter Wound Healing
DCH in the absence of protein-energy malnutrition:
The metabolic response to injury in which energy and sub-
1. Infections (viral, bacterial and granulomatous) strates are mobilized from within the body to meet the
2. Uraemia, cirrhosis, hepatitis, trauma, burns and demands of illness and injury must have a survival value to
haemorrhage have evolved at all. The paradox is that, when taken to
3. Steroids, immunosupressants, cimetidine, warfarin and extremes, it may threaten survival. One of the crucial fea-
perhaps aspirin tures of the response is the mobilization of nitrogen from
4. General anaesthesia and surgery. muscle to meet metabolic requirements. This feature was
blunted in traumatized rats that had previously been exposed
Hence in the critically sick patient many factors can alter to a low protein diet [85].
DCH and render it valueless in assessing the state of nutri- There is an impairment of wound healing [86–92].
tion. Meakins et al. [54] have shown that simply draining an Windsor et al. [86] showed, in man, that a low preoperative
abscess can reverse anergy. Immunity is therefore neither a food intake impaired wound healing. Haydock and Hill [87]
specific indicator of protein-energy malnutrition nor is it eas- also documented impaired wound healing in undernourished
ily studied [55]. surgical patients and further observed that this can occur
with quite modest degrees of undernutrition. Pressure sores
are also more likely to develop in undernourished patients
Thermoregulation and are slower to heal [88]. Nutritional support may contrib-
ute to more rapid healing. An adequate supply of minerals
The Warsaw physicians observed lower than normal body and micronutrients is necessary for wound healing, including
temperatures in their patients, as well as failure to develop a vitamins A, B, C, D, E and K [89]. Zinc is a cofactor for col-
fever in response to typhoid or tuberculosis [3]. Similar lagen formation, [89] and zinc deficiency has been associ-
changes may be seen among the undernourished and the ated with failed wound healing which is restored to normal
elderly in routine hospital practice. Bastow et al. [81] by zinc supplementation [90, 91].
observed low core temperatures in winter (<36 °C) among
elderly women admitted with fractured femur, whose anthro-
pometric indices were more than two standard deviations Endocrine and Bone
below the reference range. In contrast, the normally nour-
ished fractured femur patients had core temperatures in Anorexia nervosa with a BMI below 17 kg/m2 is character-
excess of 36 °C on admission. When undernourished indi- ized by amenorrhoea with subdued hypothalamic function
and secondary effects upon the pituitary and the ovaries or in 0.9% saline as the sodium load and constriction of renal
testes. Exactly the same changes are seen in patients who are arteries caused by hyperchloraemia increase the risk fluid
cachectic as a result of gastrointestinal disease. Low sex and overload and oedema [103, 104]. Bowel oedema may lead to
growth hormone coupled with increased cortisol and gluca- ileus and poor healing of anastomoses and fistulae [104,
gon levels reduce muscle mass, strength and energy, as well 105]. However since IF patients may have high GI losses of
as reducing bone density. We have observed a young patient fluid, sodium, chloride, potassium and magnesium, a careful
with Crohn’s disease to have a bone density three standard daily assessment of fluid and electrolyte requirements is
deviations below the mean for his age and a low serum tes- imperative to ensure the correct composition of maintenance
tosterone. These were both restored to normal within 2 years, fluids and those used to replace GI losses [106].
once his chronic state of undernutrition had been adequately Resistant oedema can be encountered in acutely unwell IF
treated. Protein/energy malnutrition may also affect bone patients and unusual causes such as beri beri may need to be
structure; osteoporosis is characteristically more prevalent in excluded. A slightly negative sodium and fluid balance
the undernourished. Malabsorption of fat-soluble vitamins should be the target with provision of adequate potassium
may result in vitamin D deficiency and osteomalacia. [107]. Whole body potassium depletion can lead difficultly
in excreting sodium if there is insufficient potassium to
exchange in the kidney, thus ensuring patients get adequate
Growth and Development amounts is imperative and at least maintenance amounts
should be given even if plasma levels are normal [106, 107].
Undernutrition in childhood leads to reduced growth veloc- Strict fluid balance recording is essential and is important to
ity which may be restored by nutritional intervention. take into account the effect of fluid balance, including GI
However, prolonged undernutrition permanently impairs losses, on body weight and its use for nutritional
achievement of genetic potential for height, which cannot be assessment.
recovered even with optimal nutrition [93, 94]. Puberty is
also delayed since the pituitary gonadal axis fails to function
normally and it is a common experience to find impaired Albumin
growth and development among adolescents with severe gas-
trointestinal disease and malabsorption. In the past a low serum albumin has been considered a
marker of malnutrition. Although oedema is often seen in
hospitalised malnourished patients it is a common miscon-
Fluid and Electrolytes ception that this is due to starvation or low protein intake
leading to hypoalbuminaemia [107]. Starvation does not
Starvation and subsequent refeeding have profound effects cause hypoalbuminaemia, [108, 109] a point illustrated by
on fluid and electrolyte balances. Intracellular concentra- patients with anorexia nervosa who may have a very low
tions of key ions such as sodium and potassium are main- BMI but neither low albumin nor oedema [110, 111].
tained by cell membrane pumps. Since cell membrane pumps The concentration of serum albumin represents the net
are activated by insulin and account for approximately a summation of many events—albumin synthesis, albumin
third of resting energy expenditure [95], there is likely to be degradation, albumin losses from the body, exchange
a significant reduction in their activity during starvation between intra- and extravascular albumin compartments, and
which is responsible for depletion of intracellular ions such the volume in which albumin is distributed. Albumin is
as potassium, magnesium and phosphate. 98% of body highly water-soluble and resides in the extracellular space.
potassium is intracellular [96] and starvation can lead to a The total body pool of albumin in a normal 70 kg man is
significant reduction in whole body potassium that is not about 300 g (3.5–5.3 g/kg). Approximately one-third of the
reflected in plasma levels which may remain normal [97]. total pool constitutes the intravascular compartment and
Oedema has been observed during refeeding [4, 98] and two-thirds the extravascular compartment [112]. The con-
may partially be due to reactivation of cell membrane pumps centration of albumin in blood is greater than that in lymph
leading to a loss of accumulated sodium and water from or other extracellular fluids, and the ratio of intravascular to
cells, with subsequent failure to excrete this load due to the extravascular albumin concentration varies from tissue to tis-
effects of insulin and potassium depletion on the kidney [99]. sue. Within 30 min of initiating albumin synthesis, the hepa-
Since sodium excretion more or less ceases in refeeding tocyte secretes albumin into the bloodstream [113]. Once
[100] it has been recommended that sodium provision be albumin is released into plasma, its half-life is 20 days.
restricted to <1 mmol/kg and fluid to around 20 mL/kg/day, During steady state conditions ~14 g of albumin (200 mg/kg)
[101] especially as malnourished patients who may have car- are produced and degraded daily. Thus, each day about 5%
diac atrophy and risk of cardiac failure [102]. Extreme cau- of the total albumin pool is degraded and replaced by newly
tion should be taken when providing electrolytes or medicines synthesized albumin. Equilibration of albumin in the intra-
vascular compartment is rapid and occurs within minutes Rapid drops in plasma levels can be seen in sick individuals
after albumin enters the bloodstream. Equilibration between due to the inflammatory response leading to increased vascu-
intra- and extravascular albumin occurs more slowly. Every lar permeability and loss of albumin to the extravascular
hour about 5% of the plasma albumin pool exchanges with compartment [108, 109]. In hospital excessive provision of
extravascular albumin so that the total plasma albumin mass high sodium and chloride IV fluids may contribute to this.
exchanges with extravascular albumin each day. Because the Lobo et al found that the rapid IV infusion of 2000 mL 0.9
rate of equilibration varies among tissues complete equili- saline led to a 20% drop in serum albumin that did not
bration may take 7–10 days. recover over the 6 h study period (indeed it took 2 weeks to
Protein-calorie malnutrition causes a decrease in the rate return to normal), with the authors concluding that this was
of albumin synthesis because adequate nutrient intake is not only due to dilution but to increased loss of albumin to
important for polysomal aggregation and maintenance of the extravascular compartment [123].
cellular RNA levels needed for protein synthesis. Within While a very poor nutritional marker, albumin is a good
24 h of fasting, the rate of albumin synthesis decreases mark- marker of disease severity, and moves inversely as the as the
edly [114]. However, a short-term reduction in albumin syn- acute phase reactants (e.g. CRP) rise [124]. In a recent
thesis has little impact on albumin levels because of a large Malaysian IF study, low BMI and serum albumin and corre-
pool size, compensatory decrease in the rate of degradation, lated with poor healing of enterocutaneous fistulae and
a transfer of extravascular albumin to the intravascular com- increased mortality [125]. It is also a good marker of saline
partment and an increase in colonic urea salvage [115]. excess.
Indeed, plasma albumin concentration may actually increase
during short-term fasting largely because of contraction of
intravascular water [116]. Prealbumin
Prolonged protein-calorie restriction induced experimen-
tally in human volunteers [2] or observed clinically in Prealbumin is a transport protein for thyroid hormones and
patients with anorexia nervosa [111] causes marked reduc- exists in the circulation as a retinol-binding–prealbumin
tions in body weight but little change in plasma albumin con- complex [126]. The turnover rate of this protein is rapid with
centration. A protein-deficient diet with adequate calories in a half-life of 2–3 days. It is synthesized by the liver and is
elderly persons causes a decrease in lean body mass and catabolized partly in the kidneys. Protein-energy malnutri-
muscle function without a change in plasma albumin con- tion reduces the levels of prealbumin and refeeding restores
centration [117]. levels [127]. However, prealbumin levels fall without
Hospitalized patients may have low levels of plasma albu- protein-energy malnutrition in infections [128, 129] and in
min for several reasons. Inflammatory disorders cause a response to cytokine [130] and hormone infusion [131].
decrease in albumin synthesis, [118] an increase in albumin Renal failure increases [132] while liver failure may cause
degradation, [119] and an increase in albumin transcapillary decreased levels. Although, prealbumin is responsive to
losses [120]. Gastrointestinal and some cardiac diseases nutritional changes it is influenced by several disease-related
increase albumin losses through the gut, while renal diseases factors making it unreliable as an index of nutritional status
may cause considerable albuminuria. Wounds, burns and in patients.
peritonitis cause major losses from the injured surface and in
certain circumstances an increase in albumin losses through
the gut, kidneys, or damaged tissues. Because the exchange Serum Cholesterol
between intra-and extravascular albumin is so large, even
small changes in the percentage of exchange can cause sig- Low levels are seen in undernourished patients. However,
nificant changes in plasma albumin levels. The normal rate very low levels are seen in patients with liver disease, renal
of albumin exchange between intra- and extravascular com- disease and malabsorption. In addition, low levels correlate
partments is more than ten times the rate of albumin synthe- with mortality [133, 134].
sis or degradation. During serious illness vascular
permeability increases dramatically. Albumin losses from
plasma to the extravascular space were increased twofold in Refeeding
patients with cancer cachexia and threefold in patients with
septic shock. Plasma albumin levels will not increase in Functional improvements in cell function occurs long before
stressed patients until the inflammatory stress remits and is any gain in tissue mass. Muscle function may improve rap-
not affected by nutritional intake. For example, albumin lev- idly (15% over the first 5 days) with refeeding, but the resto-
els fail to increase in patients with cancer after 21 days of ration of muscle mass, unlike that of adipose tissue, is very
intensive nutritional therapy [121] and in nursing home slow [2, 8]. Functional improvements should be seen as the
patients after enteral feeding through a gastrostomy [122]. initial goal of nutrition support, with restoration of body
composition a longer term aim that can be achieved once dren are especially susceptible to rapid overheating and
inflammatory issues have been treated (chapter “Refeeding dehydration.
Problems”).
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SP, Kinney JM, editors. Perioperative nutrition.
Refeeding Problems
Aminda De Silva and Jeremy M.D. Nightingale
Key Points 9. Nutritional support to the high risk patient should start at
1. Refeeding syndrome (RFS) describes the adverse clini- no more than 50% of estimated needs for the first 24–48 h.
cal and biochemical problems that may result from feed- 10. Monitor phosphate, potassium and magnesium regularly
ing severely malnourished patients via any route, be it (especially after the first feed).
oral, enteral or parenteral. 11. Hypothermia and low blood glucose are often an indica-
2. Clinicians need to be aware of it and assume most mal- tion of co-existing sepsis and must be treated.
nourished patients are at risk. 12. These patients should be cared for by healthcare profes-
3. Hypophosphataemia is the most commonly used marker sionals with skills, training and knowledge about nutri-
of refeeding syndrome and it commonly occurs when tional requirements and nutritional support.
artificial nutritional support is started (especially with
carhohydrate) and can rarely cause death.
Hypomagnesaemia, hypokalaemia and hypo (or hyper)
glycaemia may also occur. Definition
4. More enterally fed patients have refeeding hypophos-
phataemia than those given parenteral nutrition. There are wide variations in what is defined as refeeding syn-
5. Sodium and water retention is common as the cell mem- drome (RFS) [1]; hence in this chapter the phrase “refeeding
brane sodium/potassium pump reactivates and can lead problems” is mostly used. RFS is a potentially fatal condi-
to oedema and cardiac failure. tion commonly characterised by rapid changes in fluid and
6. Confusion can be due to thiamine deficiency (Wernicke’s electrolyte balance leading to problems of cardiac arrthym-
encephalopathy) which if untreated may lead to a per- ias, cardiac and respiratory failure. There are also a wide
manent loss of short term memory (Korsakoff variety of other manifestations that can occur, including hid-
psychosis) den sepsis, acute fatty liver, endocrine & haematological
7. United Kingdom NICE guidelines are are helpful but not abnormalities along with acute thiamine deficiency (which
a reliable predictor of high risk patients. Low magne- can lead to Wernike’s syndrome and possibly Korsakoff’s
sium or Insulin like growth factor-1 (IGF-1) may psychosis) and other neurological syndromes such as delir-
improve them. ium and centropontine myelinolysis.
8. When feeding malnourished patients carbohydrate must RFS is thus best described as the adverse clinical and bio-
be introduced slowly (non-protein energy usually 50% chemical problems that can result from feeding malnour-
carbohydrate and 50% lipid). Additional phophate, B ished patients via any route, be it oral, enteral or parenteral.
vitamins, potassium and magnesium may be given
before starting and when feeding commences. Little or
occasionally no sodium is given. History
The first records of the problems of refeeding come from

A. De Silva when towns/cities were surrounded and the inhabitants
Royal Berkshire NHS Foundation Trust, Reading, UK
starved into surrendering. In AD 70 after the Seige of
Jerusalem by the Romans, written about by Flavius Josephus:
“they all on the sudden overfilled those bodies that were
e-mail: [email protected] before empty, and so burst asunder, excepting such only as

354 A. De Silva and J. M.D. Nightingale
were skillful enough to restrain their appetites, and by day) and during this time they had to walk 22 miles per week.
degrees took in their food”, “death was observed in those and on this they lost more than 25% of their body weight. No
who overindulged but not in those who restrained their appe- deaths occurred on refeeding with 4 regimens (400, 800,
tite” [2], Then in AD 543 after the Siege of Naples by the 1200, 1600 kcal more than in semi-starvation).
Ostrogoths, Totila “exhibited a considerable humanity.” “He
knew that if an abundance of food were at once supplied, the
famished inhabitants would gorge themselves to death. He Evidence for RFS in Clinical Practice
posted sentinels at the gates and in the harbour and allowed
no one to leave the city. Then he dealt out small rations, grad- The lack of a uniform definition of RFS hampers all studies.
ually increasing the quantity every day until the people had The evidence of refeeding problems from oral, enteral and
recovered their strength” [3]. parenteral feeding is poor. Two patients (1 anorexia nervosa,
While many associate the problems of refeeding with the 1 alcohol excess) were described as having a low phosphate
Second World War, the scientific literature for this is sparse. after oral refeeding [8]. A low phosphate was observed in a
There are reports stating that “Untold thousands of the study of 25 post-operative patients [9]. With parenteral nutri-
liberated starved prisoners from the Nazi concentration
tion 3 patients are described with paraesthesia, weakness sei-
camps died immediately after liberation, after having been zures 4–5 days after starting and a low serum phosphate was
given some food by well-meaning soldiers. According to an observed [10]. The paper that brought attention to the prob-
oral testimony a woman died after eating just a few sugar lems of refeeding was entitled “Death resulting from over-
packets.” The three scientific papers that relate to the second zealous total parenteral nutrition” [11] in which 2 deaths
world war are from the Leningrad siege of 1940 [4], freed were described associated with hypophosphataemia; yet
Japanese prisoners of war [5] and from when the Netherlands both were being given large amounts of intravenous glucose
was liberated towards the end of the Second World War (500 and 700 g glucose in 24 h). Hypophosphatemic respira-
(1944–1945) [6]. The information from the Lenningrad siege tory failure has been described in patients given post-opera-
is surprisingly scarce; in the 2 years following the siege of tive total parenteral nutrition [12].
Leningrad there were a high number of hospital admissions The UK NCEPOD report of 2010 showed that 60%
for hypertension (BP > 140/90), oedema and cardiac failure. (455/877) of patients given parenteral nutrition were at risk
The observations in 1945 of 24 Japanese prisoners of war of refeeding problems with hypophosphataemia occurring in
who typically weighed 35 kg having lost 30% of their body 18%. Hypokalaemia, hypomagnesaemia and hyperglycae-
weight in the preceeding 6 months reported that an interven- mia were also common [13].
tion of a diet containing approximately 3500 kcal/day was A retrospective study by Zeki et al. showed that a phos-
made and it was observed that 5 of the 24 died. However they phate fall to less than 0.6 mmol/l occurred in 36/168 21% fed
all had a serum albumin of less than 20 g/L, indicating that nasogastrically and 23/153 8% fed parenterally within a
there were other medical issues in addition to simple malnu- week of starting feeding [14]. Rio et al. using more strict cri-
trition (e.g. infection or inflammation). It was observed that teria (K+ < 2.5, P < 0.32, Mg < 0.5 mmol/l, oedema/circula-
an attack of malaria made their oedema worse. The large tory fluid overload or disturbance to organ function) showed
informative publication from when the Netherlands was lib- only 3/243 patients met these criteria within 15 days of start-
erated towards the end of the Second World war (1944–1945) ing to feed though 6% had a phosphate less than 0.5 mmol/l
reported that deaths in severely malnourished people on day 3 [15].
occurred in 3 ways; Firstly suddenly shortly after admission.
Secondly after seeming to recover then a low blood pressure
and tachycardia occurred with death within 1 h. Thirdly a Pathophysiology and Biochemistry
slow death preceded by coma taking days. While there is of Refeeding
much haematological and biochemical detail regular phos-
phate/magnesium measurements were not made. The overall Biochemistry of Starvation
death rate was 10% and it was noted that “obstinate diar-
rhoea” had a particularly poor prognosis. Many of the sub- With reduced glucose levels resulting from starvation, insu-
jects had increased pigmentation though the cause was not lin secretion drops and glucagon levels increase, resulting in
clear. higher glycogenolysis to generate energy from carbohydrate
Towards the end of the second world war (19 November sources. However as starvation continues glycogen stores
1944 to 20 December 1945) Ancel Keys performed studies become depleted, typically within 6 h to 3 days, then the
upon 36 men (22–33 years) who were all conscientious body shifts to using fat and eventually muscle to produce
objectors at the University of Minnesota, USA [7]. They energy resulting in a high production of ketone bodies which
were put on a semi-starvation diet for 24 weeks (1560 kcal/ are in turn used for energy instead of glucose.
Refeeding Problems 355
Other changes include reducing basal metabolic rate and refeeding with glucose will result in rapid depletion of the
down-regulating energy consuming processes. This includes already low stores of thiamine [18].
down-regulating the activity of ATP pumps such as the Secondly the cell membrane sodium/potassium pump
sodium/potassium ATP-pump. Down-regulation of these starts actively pumping sodium out of the cell and taking
pumps results in changes of electrolyte handling causing potassium and magnesium into the cell thus furthering the
leakage of mainly-intracellular cations such as potassium, deficit in circulating electrolytes. In addition to this insulin
magnesium and phosphate into the circulation where they stimulates sodium reabsorption from the distal nephron [19].
are lost in urine. Down-regulation of cell membrane Na+/K+- Water and sodium efflux into circulation also results and
ATP pump also allows sodium and water to leak into cells. may result in fluid overload and heart failure [20]. This com-
Despite poor dietary intake of electrolytes, serum levels bination of a sudden fluid load into the circulation in to a
of these cations during starvation could remain normal dur- system where the heart (like all other muscles) has been
ing starvation (or could even be high if there is a degree of weakened and atrophied due to starvation, along with low
renal failure) as these electrolytes move from the intracellu- circulating electrolytes (causing a propensity to cardiac
lar to the extracellular space [16], so measuring electrolyte arrhythmias) can easily lead to pulmonary oedema or signs
levels as a one off investigation at this point gives littles or no of heart failure and potentially death (Fig. 2) [20].
useful information to the risk of refeeding syndrome
occurring.
Severe starvation may lead to hepatic steatosis through Clinical Manifestations of Refeeding
various mechanisms. Protein deficiency can result in
decreased apolipoprotein synthesis, leading to decreased Hypophosphataemia
very low density lipoprotein (VLDL) synthesis and inhibited This is often considered the hallmark feature of the refeeding
VLDL transport. Reduced VLDL transport plays a signifi- “syndrome” (Table 1) though there are many other reasons
cant role in lipid accumulation in the liver during starvation for hypophosphataemia than just refeeding syndrome
[17]. (Table 2). Within the cell phosphate is vital for many cellular
pathways including glycolysis and the decarboxcylic acid
cycle. Hypophosphataemia results in reduced ATP so many
Biochemical Changes of Refeeding metabolic pathways are slowed/stopped. The low phosphate
also reduces the levels of 2,3-diphosphoglycerate so causing
Two key events happen on feeding glucose to patients who the RBCs to be less able to give up oxygen (shifting the oxy-
have been starving (Fig. 1). gen dissociation curve to the right). Hypophosphataemia is
Insulin levels increase which drives glucose and phos- common in the critically ill but may not be associated with
phate into cells. This leads to an increased uptake of glucose, adverse outcomes [22]. The normal adult range of phosphate
phosphate and thiamine (needed for glycolysis and thus ATP is 0.8–1.5 mmol/l. About 3% of patients admitted to hospital
manufacture). As a result, serum levels of phosphate along will have a phosphate below 0.85 mmol/l. Blood levels below
with other cations such as potassium, magnesium, calcium 0.32 mmol/l are considered severe in the literature.
may fall, as will thiamine. Thiamine is a co-factor in many
metabolic processes including its essential role in cerebral Thiamine Deficiency
energy utilization, it will already be depleted in starvation so The body stores of thiamine (vitamin B1) are sufficient for
up to 7 days. It is a co-factor in aerobic glucose consumption.
In thiamine deficiency, a combined enzyme defect results in
Cell
Insulin aerobic metabolism impairment and isufficient ATP genera-
tion. Furthermore, pyruvate is converted into lactate, result-
Glucose Glycolysis ing in hyperlactaemia and lactic acidosis. As thiamine
TCA Cycle dependent metabolic pathways are present in almost all
PO4– human cells, deficiency can affect many organ systems. It
ATP synthesis
Thiamine
can also exacerbate the hypmagnesaemia, hypokalaemia and
Na+ hypophosphataemia associated with increased renal losses
due to oxidative stress that has damaged the renal tubules
Na/K
Pump [23]. Thiamine deficiency can lead to the development of
K+ (Mg2+) Wernicke’s encephalopathy which is a triad of encephalopa-
thy, ataxia and ocular dysfunction (nystagmus). Other fea-
tures include hypothermia, peripheral neuropathy and heart
Fig. 1 Diagragm to show key events in RFS failure [18]. Wernicke’s encephalopathy can progress to the
Starvation
Fluid retention Oedeme/heart failure
Energy from glycogen (glucose) (days), Thiamine deficiency
protein then lipid (ketones) (weeks) Abnormal LFTs
insulin fells
In Blood: Low 2, 3 Diphospho-glycerate

Low serum phosphate, megnesium
Whole body depletion of minerals and potassium
(including phosphate, potassium
and magnesium) and vitamins.
Insulin levels increase (esp with CHO)

Glucose / phosphate enter cells and
ATP is synthesised using thiamine.
Sodium / potassium pump fails. Distal renal tubule sodium absorption
Salt and water intolerance Sodium / potassium pump reactivates
Refeeding
Fig. 2 Diagram summarising events in RFS. Based upon [21]
Table 1 Effects of hypophosphatemia

Muscular Weakness (diaphragm), respiratory failure substantial percentage of patients suffer from confabulation.
Rhabdomyolysis Patients with Korsakoff syndrome often lack insight into
Cardiac Biventricular failure, low blood pressure their problem.
Arrhythmias, sudden death
Haematological Low and dysfunctional white blood cells, red blood
eturn of Activity to the Cell Membrane Sodium/
R
cells and platelets
Haemolysis Potassium Pump
Neurological Weakness, lower motor neurone type paralysis As the cell membrane sodium/potassium (Na+/K+) pump
(loss of reflexes) returns to activity the osmotically active sodium enters the
Cranial nerve palsies interstitial space and circulation so giving rise to oedema
Confusion, ataxia, tremors, fits, coma and occasionally cardiac failure. This effect is compounded
Hepatic Dysfunction (esp alcohol excess)
by insulin causing sodium retention in the kidney [19], dys-
regulation of anti-diuretic hormone and aldosterone secre-
Table 2 Causes of hypophosphataemia other than refeeding tion, and the addition of carbohydrate into the diet which
Sepsis leads to a rapid decrease in renal excretion of sodium and
Post op/trauma/burns water [19]. This sudden fluid flux into the circulation and
Recovery from acidosis (e.g. diabetic ketoacidosis) the inability to excrete it, particularly in the presence of a
Alcohol withdrawal heart that may well be functioning less well in the context
Insulin (±glucose) treatment
of poor nutrition, along with the possibility of low circulat-
Drugs—chemotherapy, diuretics, biphosphonates, phosphate binding
antacids ing elctrolytes giving a predisposition to cardiac arrhyth-
Renal dialysis/transplantation mia, can lead to oedema, left ventricular failure and
Hyperparathyroidism hypertension. Thus, the first clinical manifestions of refeed-
Respiratory alkalosis ing problems may be a raised pulse and respiratory rate. In
patients with low BMIs, one would often expect a sinus
irreversible Korsakoff’s syndrome which is an amnesic syn- bradycardia, so even a pulse of above 60 beats/min might
drome consisting of retrograde and antegrade amnesia (short indicate a relative tachycardia and should alert the clinician
term memory loss) but preservation of long-term memory. A to a potential problem.
Hypokalaemia Infection
Potassium is the main intracellular cation. Depletion in star- Hypothermia and low blood glucose are often an indication
vation and malnutrition is mainly driven by low intake and/or of sepsis and these must be urgently treated. Studies have
excessive losses (e.g. hyperemesis). Serum potassium levels documented significantly elevated rates of infection and leu-
may remain normal in starvation because of movement of kopenia among hospitalized patients with anorexia nervosa
potassium along chemical gradients to the extracellular space. [27]. In a case series of 14 patients, two patients developed
Insulin is important in stimulation of potassium influx into occult sepsis that proved fatal, in one case despite of ITU
cells through the cell membrane Na+/K+-ATP pump. With ini- treatment. Two patients in the same series had severe leuko-
tiation of nutrition the resulting increased secretion of insulin penia with WBC of less than 0.5 × 109/l [28]. While infection
precipitates potassium influx into cells causing a fall in serum and sepsis are not classical presentations of refeeding syn-
potassium levels. Hypokalaemia can cause muscle weakness drome, it is important to monitor for these during the initial
including the respiratory muscles, atrial and ventricular period of refeeding as patients with significant malnutrition
arrhythmias (QT prolongation), atrioventricular block, a U are at higher risk of developing severe infections. These
wave on the electocardiogram and can cause/prolong an ileus. patients often don’t develop the usual signs of sepsis (eg
pyrexia, neutrophilia or increased CRP). In fact, their tem-
Hypomagnesaimia peratures often fall, and blood sugars can be high or low. The
Magnesium is a predominantly intracellular cation. combination of low BMI, hypoglycaemia and hypothermia
Deficiency in malnutrition and starvation stem from poor is often termed the deadly triad and is a marker for severe
intake and redistribution. Upon refeeding, magnesium moves infection and should always trigger consideration of antibac-
into cells with resultant drop of serum levels. While clini- terial treatment [21].
cians usually treat low serum magnesium levels patients with
high stomal outputs are often seen with very low levels and
apparently no symptoms or signs. The literature suggests Who Is at Risk of Refeeding Problems
that hypomagnesaemia alone (in the absence of hypocalcae-
mia) may cause a tremor, poor memory and precipitate Not only gastroenterological patients who have become
arrhythmias in susceptible patients [24]. severely malnourished often with IF or pancreatic disease
are at risk of refeeding problems; but also patients with
oderate Abnormalities of Liver Function
M anorexia nervosa, classic kwashiorkor/marasmus, prolonged
Liver enzyme abnormalities are commonly found both in fasting (greater than 7–10 days including hunger strikers),
periods of starvation as well as during the refeeding phase. some critical care patients, elderly patients (particularly
Excess glucose administered in the early phase of refeeding, those who are depressed), patients with cancer and those
particularly after prolonged periods of starvation leads to who are post bariatric surgery [29, 30]. It is especially com-
lipogenesis, again as a result of insulin stimulation. mon to find patients who look obese (BMI within the normal
Deposition of fatty acids and triglycerides (hypertriglyceri- range) but who have lost much of their muscle mass (sarco-
daemia may occur) in the liver can lead to an acute fatty liver penic obesity) due to a poor intake of food and/or an inflam-
often being detected through raised liver transaminases. matory process (e.g. sepsis, surgery etc) and thus become
Moderate abnormalities of liver function (e.g. alanine trans- relatively immobile and so are at a high risk of hospital
aminase up to 10 times the upper limit of the normal range) acquired complications (e.g. sepsis, DVT etc).
should not delay feeding [25].
ther Metabolic/Clinical Abnormalities

O ow to Detect a Patient at Risk of Refeeding
H
Both hyperglycaemia or hypoglycaemia can occur. Glucose Problems
intake after a period starvation, can suppress gluconeogene-
sis through the release of insulin. Excessive administration The current United Kingdom (UK) guidelines for nutrition
of glucose can therefore lead to hyperglycaemia and its support [29] identify criteria as risk factors for developing
sequelae including osmotic diuresis, dehydration, metabolic refeeding syndrome (Table 3). These criteria are not always
acidosis and ketoacidosis. Conversely, hypoglycaemia can reliable in predicting RFS as an accurate history regarding
also occur, particularly in the presence of sepsis [26]. This weight and recent nutritional intake may not be available.
may relate to depleted glycogen stores, impaired gluconeo- Moreover, the sensitivity of NICE guidelines (i.e. the propor-
genesis and increased peripheral glucose utilization. tion of those who developed refeeding hypophosphataemia
Hypoglycaemia must be detected and corrected quickly as if who were correctly identified) was poor; scoring just 0.5 for
prolonged can lead to perminant cerebral damage. Symptoms enteral nutrition and 0.38 for parenteral nutrition but the
of bloating / constipation have been reported [25]. specificity was better 0.76 for nasogastric tube feeding and
Table 3 UK NICE risk factors for developing refeeding problems [29] increase/exaggerate insulin secretion from the pancreatic
One or more of the following islet β cells. It is for this same reason that hyperglycaemia is
• BMI <16 kg/m2 more common with parenteral than enteral feeding.
• Unintentional weight loss >15% within last 3–6 months Refeeding problems must be considered very seriously when
• Little or no nutritional intake for more than 10 days
starting enteral feeding.
• Low potassium, magnesium or phosphate prior to feeding
Two or more of the following
• BMI <18.5 kg/m2
• Unintentional weight loss >10% within last 3–6 months reatment of Patients at Risk of Refeeding
T
• Little or no nutritional intake for more than 5 days Problems
• A history of alcohol abuse or drugs including insulin,
chemotherapy, antacids or diuretics Circulatory volume (dehydration) should be restored and
fluid balance monitored. Hypothermia and sepsis must be
treated [34]. In the acute phase cardiac monitoring is advised.
0.73 for parental nutrition [14]. There are a variety of other It is also recommended for inpatients with cardiac manifes-
risk factors identified in other studies that have identified tations and/or ECG changes secondary to hypokalaemia,
those at risk of refeeding syndrome including, age, higher patients with a QTc >450 ns or where intravenous correction
nutritional intake during feeding and nutritional risk feeding of potassium is needed at a rate of more than 10 mmol/h is
score >3 [1] however there are no data on their sensitivity or deemed necessary [21].
specificity. A baseline low serum Mg2+ was a predictor in one There is varied opinion about giving vitamins/minerals
study [15]. Refeeding Index (a score generated from baseline (including phosphate) before starting to give feeding. It can
insulin-like growth factor and leptin) has been proposed as a be argued that without the necessary energy to switch the
useful biochemical marker for predicting those at risk of celluar homestatic mechanisms back on, thereby enabling
RFS [31]. A study in 2015 has shown that using highly sensi- them to move vitamins/minerals (including phosphate) from
tive baseline IGF-1 alone is an objective, sensitive and spe- the circulation to the intracellular compartment, there is a
cific biochemical marker in identifying patients who are at concern that any administered may simply be excreted via
high risk of developing refeeding hypophosphataemia in the kidneys. This argument is especially around phosphate
patients starting parenteral nutrition (a ≥30% drop in PO4 and pre treating with it. Most institutions would give supple-
during the first 36-h of PN administration) [32]. mentation prior to feeding if serum electrolyte levels are low
or low normal before feeding.
hy Is Refeeding Hypophosphataemia More

W Energy
Common with Oral/Enteral Feeding Than When the UK NICE guidelines were published there were no
with Parenteral Feeding? good quality trials to enable evidence based management
protocols to be developed so reliance was upon expert opin-
Zeki et al. showed that the occurance of refeeding hypopho- ion (Level D evidence considered a Good Practice Point)
taemia in adult patients fed enterally vs those fed parenter- [29]. It suggested that people who had eaten little or nothing
ally was more common in those fed enterally (21 vs 8%, p < for more than 5 days should have nutrition support intro-
0.05) [14]. The reason for the more significant fall in phos- duced at no more than 50% of requirements for the first 2
phate after enteral rather than intravenous feeding was not days; that the prescription for people at high risk of develop-
due to more phosphate being in the parenteral feed rather ing refeeding problems could be giving nutritional support at
than the enteral one (both had about 20–30 mmol). It does a maximum of 10 kcal/kg/day, increasing levels slowly to
not relate to a difference in the lipid or carhohydrate amount meet or exceed full needs by 4–7 days. It even controver-
in enteral and parenteral feeds (generally the lipid and carbo- sially went on to suggest using only 5 kcal/kg/day in extreme
hydrate energy were the same). The main reason is likely to cases (for example, BMI less than 14 kg/m2 or a negligible
relate enteral feeding stimulating a greater insulin secretion intake for more than 15 days). A survey in 2008 showed 39%
than parenteral feeding and so the mechanism that drives felt the guidance was appropriate and 36% felt it was too
refeeding hypophospahtaemia is amplified. This “incretin cautious [30].
effect” was first recognised in the 1960s and describes the Subsequent to this there have been two trials in intensive
descibes the greater insulin secretion after a patient is given care units to show that a hypocaloric diet given to patients
the same amount of glucoses orally as intravenously [33]. with refeeding hypophosphataemia in ITU do have a better
This response has subsequently been related to the release of survival than in those fed without restriction [35, 36]. Most
two upper gut peptide hornones gastroinsulinotropic peptide nutrition support teams in UK do give reduced amounts of
(GIP) and glucagon-like peptide 1 (GLP-1) which both act to energy and gradually increase the energy to requirements
over 4–7 days. The Parenteral and Enteral Nutrition Group anced multivitamin/trace element supplement once daily for
(PENG) which is a specialist group within the British 10 days is recommended by UK NICE guidelines [29]. If
Dietetic Association now recommends 10–20 kcal/kg feed- signs of Wernicke’s encephalopathy are present the B vita-
ing for the severely malnourished [37]. Some however, are mins need to be given intravenously.
bolder and start the parenteral feed to meet the requirements
of the BMI and after taking into account the protein energy, lectrolytes (Potassium and Magnesium)
E
give the lipid and carbohydrate energy as half each. Severely abnormal blood electrolytes (e.g. phosphate, potas-
Refeeding of adolescents with anorexia nervosa at 1200 sium or magnesium are corrected prior to feeding. A drop of
kcal/day versus 500 kcal/day resulted in improved weight serum potassium by 1 mmol/L is equivalent to a total deficit
gain but no other adverse effect, including on QTc interval of approximately 200–400 mmol. Mild asymptomatic hypo-
[38]. Within 48 h of feeding commencing, 28% of high calo- kalaemia is ideally be corrected orally with potassium chlo-
rie and 11% of low calorie developed hypophosphataemia ride used to provide up to 50 mmol/day. However, many
but in the absence of other electrolyte abnormality patients suffer from gastrointestinal side effects that limit
compliance [39]. Intravenous potassium can be used to treat
Phosphate Replacement significant hypokalaemia with potassium levels less than 3.0
Most authorities suggest that in patients with mild to moder- mmol/l. Intravenous infusion with potassium chloride con-
ate hypophosphataemia (phosphate above >0.32 mmol/dl) centration of 40 mmol/l are used when using peripheral veins
oral replacement should be initiated unless there are con- [39]. This can be administered at a rate of 10–20 mmol/h.
cerns about absorption from the gastrointestinal tract. Higher concentrations of intravenous potassium delivered
However in RFS, it could be argued that in the context of into a central vein can be used with close cardiac monitoring
multiple electrolyte disturbances, a lower threshold for start- after specialist advice. Some authorities accept up to 40
ing intravenous correction should be employed and most mmol/dl administered into a large central vein. The UK
advocate IV replacement for patients at high risk of RFS at NICE quideline recommends providing oral, enteral or intra-
PO4 levels of <0.6 mmol. venous supplements of potassium with the likely require-
Intravenous phosphate supplements could be in the form ments being 2–4 mmol/kg/day [29].
of monbasic potassium phosphate or the more-widely used About 80% of plasma magnesium is filtered through
phosphate infusion, Polyfusor. Electrolytes need to be glomeruli. 20% is reabsorbed by the proximal tubules and
closely monitored as the latter contains significant amounts about 80% is reabsorbed by Loop of Henle, a process influ-
of sodium and potassium. One litre of Polyfusor contains enced by the plasma concentration of magnesium.
100 mmol of PO43ˉ, 162 mmol of sodium and 19 mmol of Intravenous infusion of magnesium will result in a transient
potassium. Excessive doses should also be avoided as they increase in magnesium levels and consequently renal wast-
can result in hypocalcaemia and metastatic calcification. The ing of a substantial proportion of that magnesium. So, in
BNF defines maximal dose as 500 μml/kg. Maximal dose is more severe hypomagnesaemia where higher magnesium
50 mmol/24 h i.e. 500 ml of polyfuser [39]. We would advo- supplements are required, these should be administered over
cate smaller infusions of 10–20 mmol phosphate i.e. 100– longer hours to avoid sudden increases in magnesium levels
200 ml of polyfuser repeated if necessary to reduce the risk [39]. In mild hypomagnesaemia 4–8 mmol of magnesium
of metastatic calcification. The UK NICE guidelines suggest sulphate can be given over 1–2 h [39]. Oral formulas like
the likely requirement for potassium is 0.3–0.6 mmol/kg/ magnesium glycerophosphate, oxide or aspartate can be used
day. to prevent recurrence of the deficit. The UK NICE quideline
A study showed 36.8% of critically ill, mechanically ven- recommends providing oral, enteral or intravenous supple-
tilated patients developed hypophosphataemia and those fed ments of magnesium with the likely requirements being 0.2
at 50% target rate had improved 6 month outcomes [36]. mmol/kg/day intravenous, 0.4 mmol/kg/day orally [29].
There is no doubt that phosphate must be administered
concurrently with a low rate feeding. Fluid
Should problems with fluid overload occur an ‘ABC’
hiamine, Other Vitamins and Trace Elements
T approach to resuscitation should be taken and transfer to ICU
It is crucial that thiamine supplementation is started prior to should be considered. If absolutely necessary, diuretics may
and continued during nutrition support and glucose adminis- be required but may have the effect of lowering circulating
tration. Oral thiamine can be given at a dose of 200–300 mg electrolytes further. If this occurs, central access should be
daily. One to two tablets of vitamin B co strong can be given sought and administration of concentrated electrolytes in ICU
three times a day. A daily intravenous vitamin B preparation may be appropriate. The feed should be slowed further whilst
such as Pabrinex can be given intravenously (usually for 3–5 these issues are being managed. Sodium administration at
days) in addition to oral multivitamin supplements. A bal- first is very reduced. Patients at high risk of refeeding prob-
lems should receive about 20 ml fluid/kg and <1 mmol/kg 6. Burger GCE, Drummond JC, Sanstread HR. Malnutrition and
starvation in Estern Netherlands. September 1944-July 1945. The
sodium. Sodium excretion is limited in refeeding and excess
Hague General State Printing Office 1948. Part I and II.
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circulatory overload (heart failure and severe oedema) which starvation. Minneapolis: University of Minnesota Press; 1950.
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hypophosphatemia in patients receiving hyperalimentation.
be taken into consideration (200 kcal/l). Ideally electrolytes
should be added to the PN bag and oral preparations in water 11. Weinsier RL, Krumdieck CL. Death resulting from overzealous
should be used where possible for oral and enteral tube feed- total parenteral nutrition: the refeeding syndrome revisited. Am J
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ure patients may need additional sodium and fluid to replace
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gastrointestinal losses from stomas/ fistulas. Surg. 1982;67:371–2.
13. Stewart JAD, Mason DG, Smith N, Protopapa K, Mason M. A
mixed bag. An enquiry into the care of hospital patients receiving
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Conclusion into Patient Outcome and Death, 2010.
14. Zeki S, Culkin A, Gabe SM, Nightingale JM. Refeeding hypophos-
Refeeding problems are common however are less likely to phataemia is more common in enteral than parenteral feeding in
occur if patients are identified as at risk and if precautions are adult in patients. Clin Nutr. 2011;30:365–8.
15. Rio A, Whelan K, Goff L, Reidlinger DP, Smeeton N. Occurrence
taken (14 vs 46%) [13]. Electrolyte (especially hypophos-
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Intestinal Failure Associated Liver
Disease
Sue V. Beath and Alan L. Buchman

1. Intestinal failure-associated liver disease (IFALD) is a
stand-alone disease that may have multiple aetiologies, Intestinal Failure-Associated Liver Disease (IFALD), for-
but develops exclusively in patients with dysfunctional merly known as parenteral nutrition-associated liver disease
gastrointestinal tracts, namely short bowel syndrome, (PNALD) develops in a significant percentage of patients
intestinal dysmotility and various malabsorptive who cannot maintain nutritional autonomy and thereby
disorders. require the infusion of parenteral nutrients. It must be recog-
2. Paediatric patients often present with cholestatic liver nized that the assimilation of nutrients when delivered to the
function tests (LFTs). body intravenously differ, at least for some nutrients, when
3. In acute intestinal failure abnormal liver function is most they are consumed via the oral or enteral route [1] The
commonly due to sepsis, drug therapy or pre-existing bypassing of the enterohepatic circulation and associated
liver disease, rather than due to the parenteral nutrition. homeostatic mechanisms, combined with different presenta-
4. An excess of any of the macronutrient components of tions of nutrients across the sinusoids explains the tendency
parenteral nutrition (PN) can cause abnormal LFTs. In to hepatic steatosis in patients who are committed to extended
particular first-generation, soya bean-based lipid prepara- periods of PN [2, 3].
tions are associated abnormal liver function.
5. An excess of copper, manganese, or aluminium and defi-
ciencies of choline, taurine, carnitine or essential fatty he History of IFALD, Epidemiology
T
acids may all cause abnormal LFTs. and Outcome
6. Treatment involves treating sepsis, reviewing medication
and parenteral nutrition prescription, maximising oral/ First recognized in 1971 in an infant [4], for many years
enteral feeding, giving cyclical PN and changing bile IFALD was described as one cause for non-alcoholic steato-
composition (e.g. ursodeoxycholic acid (URSO)). hepatitis (NASH) [5]. Although NASH has many aetiologies,
7. Bacterial overgrowth should be evaluated and treated with IFALD is an unrelated disease with different pathophysiol-
antibiotics and small bowel dilation sub-acute obstruction ogy, histology, and outcomes [6]. Transient biochemical
should be actively managed by a multidisciplinary team abnormalities in hepatic aminotransferases and alkaline
(MDT) which includes gastrointestinal surgeons. phosphatase have been reported in over 90% of adults within
8. Severe IFALD-associated liver failure is an indication for 1–6 weeks of starting parenteral nutrition [7]. These reports,
small bowel transplantation. however, came from an era of overfeeding wherein excess
carbohydrate energy was often provided to patients (often
>50 kcal/kg/day) [8]. With longer term use (home parenteral
nutrition) Aspartate aminotransferase (AST) and alkaline
S. V. Beath (*) phosphatase (ALP) become progressively more elevated [9].
The Liver Unit (Including Small Bowel Transplantation), It should be recognized however, that biochemical indices of
Birmingham Women and Children’s Hospital,
liver injury provide little information with regards to hepatic
Birmingham, West Midlands, UK
e-mail: [email protected] function and specifically, serum aminotransferase concentra-
tions are often insensitive and nonspecific indicators of
A. L. Buchman
Department of Surgery, University of Illinois at Chicago, hepatic histopathology [10]. This is equally true of IFALD in
Chicago, IL, USA children [11, 12].

364 S. V. Beath and A. L. Buchman
The frequency of clinically-significant IFALD remains matched donors for young recipients typically weighing
substantial, but is much less when compared to the 1980s 10–20 kg.
[13]. In the Cavicchi study of adults, at least two of three The improved awareness of IFALD and willingness to
enzymes (ALT, AST or alkaline phosphatase) were elevated ameliorate risk factors such as over provision of nutrients
in 55% of patients at 2 years, 64% at 4 years, and 72% at 6 and a more active approach to supplemental enteral nutrition
years in a group of 90 (57 with histologic data) patients that has led to a reduction in severe IFALD in children and adults
had received home parenteral nutrition (HPN) [13]. However, the past three decades [24, 25].
modern cohorts differ from this historic group in which half
the patients developed clinically significant liver disease;
when defined by a serum total bilirubin concentration Definitions
exceeding 60 μmol/L (3.5 mg/dl) for at least one month, the
presence of ascites, hepatic encephalopathy, variceal haem- Intestinal failure is defined as a condition where an individ-
orrhage, a serum factor V concentration less than 50% or ual is unable to absorb sufficient nutrients and/or fluid to
portal fibrosis or cirrhosis on biopsy, the percentage of maintain nutritional autonomy. The European Society of
patients was 26% at 2 years, 39% at 4 years, 50% at 6 years Enteral and Parenteral Nutrition (European Society of
and 53% at 8 years. Clinical Nutrition and Metabolism) (ESPEN) has defined
In adults, the elevation of serum bilirubin is an ominous intestinal failure as “the reduction of gut function below the
sign, with a mean lifespan of only 10.8 months following this minimum necessary for the absorption of macronutrients
observation and death in all once the total serum bilirubin and/or water and electrolytes, such that intravenous supple-
concentration exceeded 61 + 20 μmol/L (3.6 + 1.2 mg/dl) for mentation is required to maintain health and/or growth” [26].
6–12 months [14]. IFALD is the complication in patients The International Small Bowel Transplant Association
with intestinal failure with the greatest risk of death [15], and (ISBTA), now known as the Intestinal Rehabilitation and
impending hepatic failure is the most common indication for Transplant Association (IRTA), a subdivision of The
isolated small bowel transplantation [16]. Chan et al. reported Transplantation Society, has defined IFALD as “a persistent
15% of their 42 adult patients that received long-term PN at elevation of liver enzymes, alkaline phosphatase and
the Beth Israel Deaconess program in Boston developed γ-glutamyl transferase 1.5 times the upper limit reference
IFALD that progressed to end stage liver disease; all died range which persist for more than or equal to 6 months in
shortly thereafter [14]. Should the liver fail, a combined adults and more than or equal to 6 weeks in children” [27].
liver-small bowel transplant is necessary given that contin- This definition of IFALD includes pragmatic definitions of
ued malabsorption will result in continued hepatic insult. severity—clinically described as mild/early IFALD; moder-
Timely isolated intestinal transplant carried out before end ate IFALD; advanced/end stage IFALD. And acknowledges
stage liver disease has developed has lead to the reversal of that IFALD is a disease with a spectrum of responses by the
IFALD [17–19]. liver to a variety of biological provocations including: abnor-
Children, especially pre-term infants are particularly sus- mal route of nutrient administration causing greater glucose
ceptible to IFALD [20]. A study which recruited pre-term uptake (PN versus EN) [3]; excess nutrient provision [13,
babies born between 28 weeks gestation and 37 weeks week 28]; bacterial overgrowth; systemic sepsis, especially origi-
found that lower gestational age (<34 weeks) was associated nating from the bowel [29, 30].
with higher serum bilirubin and that episodes of sepsis were
on average responsible for 30% increase in serum bilirubin
[21]. Physiologically babies are less robust because the Histopathology
immaturity of liver canalicular membranes reduced glutathi-
one reserves and dependency on exogenous taurine, choline Steatocholestasis (combination of steatosis and cholestasis)
[2, 20, 22]. Fifty percent of children become jaundiced (bili- is the hallmark of IFALD, and a histologic finding that dif-
rubin in excess of 70 μmol/L) at some point during the ferentiates it from non-alcoholic fatty liver disease
administration of PN [23]. In addition to immature homeo- (NAFLD), which includes non-alcoholic steatohepatitis
static mechanisms, infants and children are exposed to rela- (NASH) [6], although steatosis tends to predominate in
tively higher toxic impact of intravenous nutrition intakes most adults. Steatosis generally develops initially as macro-
because of the greater calories requirement per kg to account steatosis in zone 1 (periportal) (Fig. 1). Microvesicular ste-
for growth requirement. As in adults the development of per- atosis is seen in the majority of adults, and in some patients
sistent jaundice was associated with mortality, and in the a combination of both macro- and microsteatosis is observed
early phase of intestinal transplantation in the 1990s approx- [13] (Fig. 2). Steatohepatitis is uncommon and is rare in the
imately twice as many children as adults were transplanted absence of cholestasis [13, 31]. Therefore, although IFALD
for end stage IFALD, despite the difficulties in finding size is a unique liver disease unto itself, in children it is often
Intestinal Failure Associated Liver Disease 365
Fig. 1 Macrosteatosis with steatosis (steatocholestasis) in zone 1 Fig. 3 Ductopenia (the absence of bile ducts in >50% of portal tracts)
(periportal) found in a 4 months old baby who has been on parenteral nutrition since
being born prematurely. Slide H&E × 200. Arrow head = artery, arrow
= vein branch, but no accompanying bile duct. Kindly supplied Dr.
Rachel M. Brown Consultant Histopathologist Queen Elizabeth
Hospital Birmingham, UK
Fig. 2 Macro-and microsteatosis
noted to resemble numerous other diseases such as extra

hepatic biliary atresia, α1anti-trypsin deficiency, or cystic Fig. 4 Fibrosis begins with portal expansion and may progress to cir-
fibrosis, and thus careful clinical pathological correlation is rhosis, often in a characteristic “jig-saw” pattern)
required. It is to be noted cholestasis may be evident bio-
chemically (1.5× the normal upper value for at least 2 of 3 In young children, cholestasis dominates the histopathol-
livers tests including alkaline phosphatase, conjugated bili- ogy, with steatosis being relatively inconspicuous [32, 33]. A
rubin and γ-glutamyl transferase as defined by Cavicchi peri-cellular pattern of fibrosis is often seen in early cases of
et al. or the ISBTA [13, 27]. Other histologic findings may IFALD in children along with Mallory-Denk bodies which
include features of biliary obstruction with portal inflamma- are often seen with toxic insults. The combination of peri-
tion, edema and ductular proliferation, although ductopenia venular and portal fibrosis is especially characteristic of
(the absence of bile ducts in >50% of portal tracts) may also IFALD [31]. Although cirrhosis is not common in IFALD,
occur uncommonly [6] (Fig. 3), this is important as it illus- when it occurs there is a risk of hepatocellular carcinoma
trates how IFALD can mimic other diseases histologically. development [34]. Ischaemic hepatitis has also been reported
Fibrosis begins with portal expansion and may progress to in an acute case of intestinal failure caused by mid-gut vol-
cirrhosis, often in a characteristic “jig-saw” pattern) vulus and septic shock—this child developed rapidly pro-
although hepatic failure may occur prior to development of gressive liver disease but did well after combined liver and
cirrhosis (Fig. 4). bowel transplant [35].
Pathophysiology of IFALD in Adults Table 1 Factors associated with the development of IFALD
Malnutrition Excessive dextrose calories
Adult patients with the least functional residual intestine Essential fatty acid Excessive omega-6 fatty acids
and thereby the most significant nutrient malabsorption and deficiency
Glutamine deficiency Toxic effects of protein hydrolysates
most dependent on PN are at the greatest risk for develop-
Choline deficiency Carnitine deficiency
ment of IFALD [36]. Normally, upon ingestion of food, Taurine deficiency Differential metabolism of intravenously-
nutrient digestion begins in the mouth and continue into the infused nutrients
stomach and small bowel, with absorption in those organs Hyperglycemia Increased portal insulin: glucagon ratio
with transport to the liver via the portal vein. When nutrients Bacterial overgrowth Bacterial endotoxin
are intravenously infused, they are infused directly into the Bile salt deficiency Toxic bile salts
Lithocholic acid toxicity Aluminum and heavy metal toxicity
vena cava at the cardiocaval junction. After passing through
the heart, the nutrient-enriched blood eventually makes its
way to the liver via the hepatic artery. As such, first pass with the development of hepatic steatosis. The undernutri-
metabolism is effectively bypassed. In 1972 Stegink and tion presumably would be corrected with PN although a
Den Besten showed that orally-administered methionine minimum of 2–4% of total energy must be supplied as lin-
was metabolized via the hepatic transulfuration pathway to oleic fatty acid via lipid emulsion to prevent development of
cystine [1]. Choline is a product of the same hepatic path- EFAD. Like choline, carnitine is also a product of the hepatic
way, which is incompletely functional when presented with transsulfuration pathway and blood concentrations are
intravenously-infused substrate, resulting in deficient cho- decreased in patients that receive PN, although not to the
line biosynthesis [37–39]. As a result of impaired methio- level generally seen in congenital carnitine deficiency [41,
nine metabolism, plasma methionine concentrations ranges 57, 58]; Carnitine supplementation however has not been
from high normal or elevated in patients that receive PN [37, useful in the treatment of IFALD [59].
40, 41]. In such circumstances, choline deficiency develops Nutrient toxicity has also been implicated in the develop-
in patients fed intravenously because there is minimal cho- ment of IFALD. These include dextrose overfeeding (>50
line supplied in PN (chiefly via lipids) and hepatic biosyn- kcal/kg/day), which leads to an increase in the portal insulin:
thesis is impaired. Plasma free choline concentration is glucagon ratio [60]. Mitochondrial carnitine acyltransferase
decreased below normal in 85–90% of PN patients, and is then inhibited and thereby fatty acid oxidation impaired
negatively correlates with serum hepatic aminotransferase since it is the rate-limiting step [61]. Hepatic acetyl-
concentrations and the degree of hepatic steatosis [42, 43]. coenzyme A is increased and acetyl-coenzyme A carboxyl-
Steatosis develops due to decreased very low-density lipo- ase is induced, which stimulates hepatic fatty acid synthesis
protein (VLDL) synthesis and a subsequent reduction in [62]. Case reports indicate lipid overload (>2.5–3.0 g/kg/day
transport of triglycerides from hepatocytes; choline is also causes severe cholestasis and even death [63, 64]. It has
required for VLDL biosynthesis. Small, but placebo-con- been suggested that phyotosterols (plant sterols) present in
trolled studies have shown IFALD can be improved or ame- soyabean based lipid infusions may decrease bile secretion
liorated with choline supplementation in adults [42, 44]. and contribute to cholesatasis [65]. What remains unclear is
Animal data have suggested choline also improves bile flow whether the increase in serum phytosterols is a result of
[45], which is decreased during PN infusion [46–48], and impaired hepatic function or a cause of impaired hepatic
thereby reduce cholestasis as noted by a fall in the serum function. There is limited data for the treatment of IFALD in
alkaline phosphatase [44]. Choline deficiency may be nec- adults short of intravenous lipid reduction (to a maximum of
essary for the development of IFALD, but not sufficient. A 1 g/kg/day) [13], and even here there is no prospectively-
second “hit” such as lipid peroxidation [49, 50], or the pres- controlled data to support this practice. Two single retrospec-
ence of endotoxin may be required [51]. tive case reports suggest some potential value of the use of a
There are however a myriad of other proposed etiologies fish oil-based lipid emulsion in adults with IFALD [66, 67].
for IFALD in adults (Table 1), some of have not been sub- Manganese toxicity has been described in association
stantiated by investigational studies (carnitine deficiency), with hepatic abnormalities during PN in case reports [68–70]
but others clearly contribute (carbohydrate overfeeding, although it is not clear whether these heavy metals, which
essential fatty acid deficiency, generalized malnutrition, lipid are eliminated in bile, accumulate in the liver because of cho-
overload), Others proposed etiologies have little human or lestasis, or whether they directly contribute to the exacerba-
animal data currently (glutamine, taurine and bile salt defi- tion of IFALD. There is concern that the amount of
ciencies, bacterial overgrowth and endotoxin, aluminum and manganese in PN is excessive [71], although there is no data
bile salt toxicities). currently that the dose of copper typically provided causes
Both severe protein undernutrition [52], and essential liver disease outside of the presence of IFALD or other liver
fatty acid deficiency (EFAD) [53–56] have been associated disease.
Pathophysiology of IFALD in Children min E, taurine and choline) and amplification by endoge-
nous factors such as abdominal sepsis especially NEC and
As in adults, the abnormal route of administration whereby VAP-1 released by inflammed bowel [29, 30], and the role
nutrients reach the hepatic sinusoial bed via the hepatic of bacterial overgrowth have resulted in IFALD being
artery rather than the portal vein must adversly affect the regarded as a multi-stage condition requiring multiple trig-
liver—but observations have focused more on the effect on gers [75–77]. See Fig. 5 processes leading to steatosis and
the canalicular membrane and the liver’s capacity to take up fibrosis.
glucose from PN solutions in the absence of enteral feeds [2, There is increasing acknowledgement of role of bacterial
3]. The role of choline in restoring bile flow and reducing overgrowth especially in dilated and/or, obstructed bowel.
steatosis has not been proven in children, although choline Hukkinen et al. [78] reported a relationship between degree
concentrations in blood are low [38]. However, taurine may of dilatation of bowel and blood stream infections. The small
be important in reducing serum bilirubin: in a study of 236 bowel diammeter (sbd) was standardised to vertebral height
premature infants with NEC—those who were supplemented (vh) and a ratio of sbd to vh was derived: ratio of >2.71 pre-
with taurine had a significant reduction of peak bilirubin (70 dicted PN dependency. Dilatation of the bowel also corre-
μmol/L versus 140 μmol/L) [72]. Vitamin E has been shown lated with: increased faecal calprotectin; serum bilirubin;
to protect against liver injury when given pre-operatively to and gamma glutamyl transferase (GGT); pre-albumin and
adults undergoing partial hepatectomy for tumour surgery inversely correlated with citrulline [78]. Patients with dilated
[73], and the positive effects on liver biochemistry of the bowel were also more likely to demonstrate abnormal liver
multisource lipid emulsion SMOFlipid (SMOFlipid™ histology (i.e. increased portal inflammation and
Fresenius-Kabi, Uppsala, Sweden) reported by Goulet et al. cholestastis).
[74] may in fact be a function of vitamin E which was found The importance of the intestinal microbiome in a wide
to be significantly increased in the SMOFlipid 20% when range of diseases is well described and has led to the notion
compared to Intralipid 20%, although definitive studies in that a “fibrogenic microbiome” exists [76, 77]. Rifaximin
IFALD are lacking. was found in rodent study to significantly reduce portal
The role of fish oils which contain relatively greater ratio pressure, fibrosis, and angiogenesis and a follow up study in
of omega 3 lipids to omega 6 lipid (either multisource oils or TLR4 mutant mice confirmed that the effect of rifaximin
Omegaven, Frenius-Kabi, Bad Homburg, Germany) in long was dependent on lipolysachharide acting via the TLR4
term PN has been debated vigorously for two decades and pathway [77]. In a study of 21 children with intestinal fail-
opinion remains divided as to whether the the omega 3 lipids ure the loss of bacterial diversity in the colon and an over-
have a protective effect on sinusoidal/cholangiocyte function abundence of Lactobacilli, Proteobacteria, and
or whether a reduction in the pro-inflammatory omega 6 lip- Actinobacteria correlated with steatosis and fibrosis, which
ids is the key. An important caveat to the claims around the was noted to be a stronger association with steatosis than
value of the mulitsource lipid SMOF (Fresenius-Kabi, Bad duration of PN or bowel length [75]. These studies point to
Homburg, Germany; contains soya oil; medium chain fatty the loss of barrier function as being the key link between
acids; olive oil and fish oil) is that although many studies abnormal bowel; bacterial overgrowth, the “fibrogenic
have demonstrated a an improvement in serum bilirubin con- microbiome” and the development of IFALD in children
centration, improvement has not generally been seen in alka- [79] and adults [80]. There are only few human studies pub-
line phosphatase and improvement is variable for hepatic lished as yet but this is an expanding field and the excellent
aminotransferases [11]. More importantly, the long term out- review of the literature by Cahova et al. [81] is a good source
comes are unknown and there are publications calling atten- of further information.
tion to the development of fibrosis and cirrhosis despite the It is appreciated that the Gut-Liver axis is fundamental to
use of this lipid emulsion in children who have normal or health with many examples of the impact of disease in the
close to normal hepatic aminotransferases [11–13]. This lack bowel leading to liver dysfunction (e.g. inflammatory bowel
of concordance between hepatic aminotransferases tests and disease and autoimmune hepatitis) and the most obvious
liver histology is of concern and shows that improved means example in intestinal failure is the adverse impact of necro-
of monitoring and detecting IFALD are needed (see later tising enterocolitis on the liver [20]. Disruption to the entero-
section). hepatic circulation is inevitable in short bowel syndrome
Perhaps because of the obvious immaturity of organ especially if the distal ileum is affected as this is the region
function (liver and intestine) of infants and children, the of the bowel which contains cell surface active transporter
concept of toxic stress (excess calories/hypertonic glucose/ channels for the re-absorption of bile acids. Furthermore
phytosterols/w6 fats) as an important driver of IFALD has reduced bowel mass leads to less ileal fibroblast growth fac-
gained particular traction in the paediatric literature [33]. tor-19 (FGF-19) [81, 82] and, since FGF-19 activates the
This, combined with deficiency of protective factors (vita- nuclear transcription factor frasenoid X (FXR) in hepato-
Processes leading to steatosis & fibrosis
2. PRO-INFLAMMATORY LIPID
1. OVER PROVISION OF PN CALORIES
emulsions especially soya oil with
and lack of cytoprotection i.e.
relatively high proportion of w6
• Choline44
fatty acids98
• Taurine72
• Vitamin E33
Recruitment of Production of
neutrophils and other proinflammatory
inflammatory cells cytokines, chemokines
ROS
3. IMPAIRED
TRANSULFURATION Hepatocyte Activation of
liver Kupffer
reduced anti-oxidant cells
LPS
reserve, ER stress triggers Kupffer cell
cell death and Stellate cell
activation and fibrosis81 Stellate
cell
LPS
LPS
Fatty liver
Steatohepatitis
5. PROMOTION OF STELLATE CELL
ACTIVATION
4. ABNORMAL TERMINAL ILEUM Recurrent catheter sepsis; intestinal
impaired re-absorption of bile ischaemia; bacterial overgrowth; choline
salts and less FGF-19 results in deficiency increasing sensitization to
increased lipogenesis and bile salt endotoxin; amplification of chemokines
synthesis82 including VAP-1 by proteobacteria =
activated gut lymphocytes home in on liver30
Fig. 5 Processes leading to steatosis and fibrosis in IFALD
cytes, a lack of FXR ensues. The lack of FXR in short bowel overlooked. However, regular abdominal ultrasound every
syndrome permits excess lipogenesis and bile salt synthesis 6–12 months may be valuable [87]: changes in hepatic
[83, 84] and this leads on to the observed development of parenchyma reflectivity and the size of spleen may give early
steatosis and fibrosis reported in IFALD [85]. See Fig. 6 warning of steatosis and fibrosis. Biliary sludge and obstruc-
liver-gut axis in IFALD. However, recent investigation sug- tion to the biliary tree may also be detected prior to frank
gests the residual bowel ina model of short bowel syndrome jaundice. See Fig. 7—impacted gall stones in a young adult
in fetal pigs is unable to respond to FXR activation, casting with gastroschisis who required PN for first 12 months of
doubt for FXR as a treatment for IFALD [86]. life.
In addition to spleen size on ultrasonography, hypersplen-
ism may be tracked by regular measurements of the platelet
Detecting IFALD count [88], but it is often unclear whether thrombocytopae-
nia it is acting as a surrogate marker for portal hypertension
The monitoring of patients on PN is routine and rightly or inflammation, or both.
includes measures of anthropometry and biochemical stabil- Specific tests for IFALD are not available—detection
ity. Normal liver function and transaminases do not necessar- depends on the exclusion of primary liver pathologies (e.g.
ily correlate with a healthy liver as is clear from reports of heterozygote or homozygous alpha 1 antitrypsin deficiency;
hepatic fibrosis and cirrhosis in adults and children with nor- thyroid disease; viral hepatitis; autoimmune disease) and a
mal LFTs [10–12]. In addition, the haemodynamics of the baseline abdominal ultrasound, CT or MR, which are espe-
splanchnic circulatory system are different in intestinal fail- cially useful for the detection of steatosis, which may be dif-
ure: typically lower portal blood flow ensues, and this may fuse. Liver biopsy is not usually necessary in mild IFALD,
result in lesser varices and trivial ascites except in advanced except when staging of liver disease is helpful or where there
cases. This means that fibrosis and cirrhosis can be easily is persisting diagnostic uncertainty. Other less invasive tests
Fig. 6 Liver–Gut axis in IFALD
on 57 children who receive PN ≥3 months and found raised

AST and bilirubin levels were found in 51%, splenomegaly in
26%, and oesophageal varices in 3.5%. All the children had at
least one liver biopsy and histological fibrosis was present in
61% (Metavir stage F1; 27%, F2; 26%, F3-4; 9%), cholesta-
sis and steatosis was noted in a quarter. This group found that
transient elastography was superior to APRI in predicting
fibrosis Metavir F2 0.73 (95% CI 0.59–0.88). However, in
adults, elastography appears to correlate better with cholesta-
sis then it does with fibrosis [90].
Other non-invasive tests include: serum markers of col-
lagen synthesis (cytokeratin 18 fragment levels, hyaluronic
acid, matrix metalloproteinase [75]; and [13 C] methio-
nine breath test [91]). Duro et al. found that intravenous.
administration of the stable isotope [C]-Met was straight
forward and, in five patients who were studied serially, the
[C]-Met breath sampling reflected changing paediatric end
stage liver disease (PELD) scores [91]. These tests are
Fig. 7 Illustration of biliary disease in a child with short bowel syn- very interesting and may provide a more dynamic measure
drome—MRCP arrows show areas of filling defect caused by bilary of liver dysfunction in IFALD than other measures, but the
sludge and impacted gall stone
number of patients studied is small and not yet validated
with long term outcomes. See Fig. 8 algorithm to evaluate
such as the AST to platelet ratio (APRI) score have been used
abnormal liver function in children and adults with intesti-
to predict cholestasis in children but doe not correlate with
nal failure.
fibrosis. Hukkinen et al. in a retrospective study [89] reported
PN required for intestinal failure

- standard monitoring as per ASPEN; ESPEN guidelines
- Biochemistry to include GGT; ALP; AST; ALT and bilirubin
Carry out
- Trace elements; micronutrients; haematological indices
abdominal USS
in 6-12month
depending on
Evidence of IFALD ? age and co-
ALP and -GT persistently 1.5 times the upper limit reference range morbidities
for more than 6 months in adults and more than 6 weeks in children
YES
NO
Arrange abdominal USS to exclude biliary obstruction;

screen for drug exposure & primary hepatobiliary
disease e.g. alpha 1 antitrypsin deficiency; thyroid
disease; viral hepatitis; autoimmune disease
NO - primary hepatobiliary YES – primary hepatobiliary

disease detected disease detected
Withdraw drug
IFALD probable and/or treat
hepatobiliary
disease
Review known risk factors

associated with IFALD
• sepsis
• lack of EN Assign severity and stage
• bowel dilatation i) mild type 1 not jaundiced
• bowel obstruction ii) moderate type 2 bilirubin 50-100 mol/L
• bacterial overgrowth iii) advanced type 3 bilrubin >100 mol/L
• overprovision of PN calories Consider other tests to stage and monitor
progression of IFALD
• Transient elastography of liver
• Serum markers of collagen synthesis
Treat sepsis and any other • 13C methionine test
exacerbating factors • Imaging with CT; MRI; MRS
Consider treatment with • Liver biopsy
• Ursodeoxycholic acid Repeat LFTs monthly and abdominal USS in 6
• Rifaximin months – if deteriorating consider referral for
• Lipid minimisation intestinal transplantation
Fig. 8 Algorithm for detecting IFALD
Managing IFALD in Children and Adults newer lipids to prevent peri-oxidation, but may have a cytopro-
tective role equal to the use of fish oils [33, 73, 74].
The management of IFALD in children and adults has common Lipid management strategies is a term which covers a
principles which include scrupulous attention to the PN pre- huge range of approaches to mitigate the the pro-inflammtory
scription which should avoid excess calories in the form of car- nature of soyabean oil and its role in IFALD. The term
bohydrates [8] and minimisation of lipids [13, 92–94]. There is includes: reduction or removal altogether of soya oil lipid
long history of the use of substrates with cytoprotective proper- infusions (usually for limited periods only in order to avoid
ties e.g. choline [42, 44] and taurine [72] and and more recently development of essential fatty acid deficiency); the use of
the role of vitamin E which is added in high concentrations in mixed source lipid emulsions containing another of lipids
added to Soya oil lipid such olive oil (Clinolipid®, Baxter has also been reported in children with short bowel syn-
Healthcare Corporation, Deerfield, IL) or medium chain tri- drome and increased bowel frequency [102].
glyceride (Lipofundin® MCT/LCT; B Braun, Mesungen, Ursodeoxycholic acid may be helpful in preventing biliary
Germany), and multisource lipid emulsions containing soya- sludge gall stones especially in babies with low enteral intake. In
bean oil; medium chain triglyeride (from coconut oil); olive a prospective, double-blind, placebo-controlled study of ursode-
oil and fish oil (SMOFlipid™ Fresenius-Kabi, Uppsala, oxycholic acid in preterm infants, fecal fat excretion decreased
Sweden). Omegaven (Frenius-Kabi, Bad Homburg, Germany) and achievement of full enteral feeding was slightly earlier in the
is also used especially in the United states of America—this UDCA group, but these differences did not quite reach signifi-
last lipid consists entirely of fish oil as a 10% emulsion. There cance, although the gamma-glutamyl transferase activity was
are some significant claims for SMOF and Omegaven but significantly lower in the UDCA treated group for the duration of
although cholestasis improves, there are reports that these the study [103]. A smaller study in very low birth weight babies
lipid sources do not arrest the development of fibrosis [11, 12, showed some benefits of ursodeoxycholic acid: the group given
95–97]. Whilst most agree that lipids can contribute to the ursodeoxycholic acid had a shorter period of jaundice than the
pro-infammatory signal coming from the bowel or septic control group [104]. However, there is no prospective data to
states, there is no clear agreement about which type of lipid, support the role of ursodeoxycholic acid in adults.
if any, is best for prevent hepatic deterioration in patients on Multidisciplinary nutrition support teams faciliate monitor-
long term PN [97]. A pragmatic approach is to substitute at ing (as per algorithm in Fig. 8) and staff training [105] in the
least half the soya bean oil with any other [33, 98]. care of feeding catheters, and are well established approaches
Enteral feeding in short bowel syndrome should be pro- for minimising liver disease in intestinal failure [106].
moted and started as soon as possible as it may improve func- Dedicated multidisciplinary expert teams not only improve
tion of the residual bowel and is associated with beneficial staff training but the increasing prevalance of such teams is
effects on gut permeability [99]. A study of patients in critical thought to be behind the overall improvements in long term
care randomly allocated to recive either EN or TPN found outcomes of intestinal failure and the reduction in IFALD
that permeability was increased in both groups initially com- [25]. These teams allow timely management of dilated/
pared to controls, but only in the EN group did the recovery obstructed/bowel with tapering surgery [78, 107]. Dedicated
of lactulose relative to rhannose start to fall, suggesting that vascular access teams have been shown to have good long
mucosal integrity is better maintained by the institution of EN term results for vessel patency [108] and are especially impor-
[100] although the clinical ramifications of this observation tant for children and adults who may need PN for years.
are unknown. The hypothesis that excluding EN and relying The relationship between induction of inflamatory states
on TPN can adversely affect response to endotoxin was tested by sepsis especially the role of endotoxin and other products
in small group of human volunteers who were given either of gram negative bacteria is well known and thus attempts to
TPN or EN and then challenged with endotoxin—the TPN minimise infection from the bowel and/or catheter related
group had an exaggerated physiological response with twice blood stream infections (CRBSI) are now part of the man-
as much tumor necrosis factor detected and significantly agement of IFALD. Octenisan skin washes have been shown
increased serum lactate and C-reactive protein [101]. to reduce CRBSI [109] and a study of 200 adult patients the
It is not certain what component of EN, if any specific use of taurolidine line locks was associated with a five-fold
component(s), is beneficial in improving the mucosal integ- reduction in the incidence of CRBSI [110].
rity of stressed GI tracts: it could be the role of nutrients in
the bowel acting locally on the mucosa, or EN may be
influencing the microbiome. The lack of EN is associated Intestinal Transplantation for IFALD
with a loss of diversity of bacterial species combied with
overabundance of Lactobacilli, Proteobacteria, and Patients who demonstrate signs of worsening liver disease
Actinobacteria is linked with reduced mucin production by despite the measures above should be considered for iso-
Goblet cells; reduced Paneth cell activity; reduced expres- lated intestinal transplantation before irreresible liver dis-
sion of proteins associated with tight junctions and reduced ease supervenes. But the timing of referral can be difficult
IgA - all of which contribute to reduced intestinal epithelia as depending on liver function tests alone can provide false
barrier function [81]. The microbiome in children with re-assurance. Regular liaison with an intestinal transplant
IFALD and short bowel has been reported to show less centre and professional collaborations are key to identify-
diversity than in healthy children although it is not clear ing that point where a patient could benefit from an isolated
whether this directly leads to liver disease or whether it is small bowel transplant [27, 98]. This topic has been
and epiphenomenon of the short bowel syndrome causing reviewed recently [99] and based on reports that sustained
an abnormal microbiome [75]. Overabundance of but mild hyperbilirubinaemia can be reversed once enteral
Lactobacilli and decreased abundance of Ruminococcus feeding is re-established after successful small bowel trans-
plant [19], the following criteria based on degree of hepatic 14. Chan S, McCowen KC, Bistrian BC, et al. Incidence, prog-
fibrosis and markers of portal hypertension/hypersplenism nosis, and etiology of end-stage liver disease in patients
receiving home total parenteral nutrition. Surgery. 1999;126:
are proposed: (1) Total plasma bilirubin <100–120 mmol/L. 28–34.
(2) Minimal hepatosplenomegaly. (3) Platelet count 15. Pironi L, Goulet O, Buchman AL, et al. Outcome on home paren-
>150,000 × 109/L. (4) Stage 1 or 2 fibrosis on biopsy. Once teral nutrition for benign intestinal failure: a review of the litera-
patients are listed for isolated intestine transplant, it is ture and benchmarking with the European prospective survey of
ESPEN. Clin Nutr. 2012;31:831–45.
important they are re-evaluated if they wait longer than a 16. Buchman AL. Short bowel syndrome. In: Feldman M, Friedman
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sode given the likelihood of progression of disease. 9th ed. Philadelphia: Saunders; 2010. p. 1779–95.
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not be necessary if isolated intestinal transplantation is per- plantation. Hepatology. 2006;43:9–19.
formed at an appropriate time. 18. Fiel MI, Wu HS, Iyer K, et al. Rapid reversal of parenteral
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19. Fishbein TM, Kaufman SS, Florman SS, et al. Isolated intesti-
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Acid-Base Disturbances
Barry J. M. Jones
Key Points 8. Acetate (which is metabolisable) may replace chloride in

1. Acid-base disturbances (ABD) should be expected from parenteral nutrition (PN) infusions to reduce acidosis.
the changes to anatomy and physiology in Intestinal Rehydration solutions not based on sodium chloride
Failure, even when the gastrointestinal tract is intact. should be considered in intestinal failure patients at risk of
They may be exacerbated by intravenous nutrition or acidosis. Additionally stopping a patients proton pump
saline, oral rehydration solutions, acid suppressing treat- inhibitor (PPI)H2 antagonist may also reduce acidosis.
ments, urinary diversion, thiamine and phosphate defi- 9. Patients with a short bowel and a functioning colon in
ciencies, refeeding syndrome, L- or D-lactic acidosis continuity may develop a high anion gap acidosis due to
and renal or respiratory disease. D-lactate (worse if thiamine deficiency and/or liver dis-
2. Serum bicarbonate and chloride should be regularly ease); this may cause profound cerebellar signs, behav-
measured in intestinal failure (IF) patients and the serum ioural changes and coma.
anion gap calculated as recommended by international 10. Patients with a jejunostomy may develop chronic renal
guidelines. Blood gas measurements are occasionally failure from dehydration. If dialysed they should not
needed to give further information. have fluid removed (no weight loss), with additional
3. Metabolic high anion gap acidosis occurs with renal fail- fluid being given at the time (weight gain).
ure, ketosis, L-lactic acidosis, thiamine deficiency and 11. Muscle cramps during PN infusion are an enigma but
D-lactic acidosis. Coexistent impaired renal function is possibly relate to acute acid-base changes or electrolyte
the most important contributory factor, tolerance of fluxes across cell membranes. Slower infusion rates
which is further impaired by respiratory disease. appear to relieve symptoms.
4. Metabolic hyperchloraemic acidosis with a normal
anion gap is common and due to bowel bicarbonate loss,
sodium chloride infusions (or oral rehydration solutions)
and acid suppression therapy (also urinary diversion and Introduction
phosphate deficiency).
5. Metabolic alkalosis reflects loss of acid through vomit- Survival of our species depends upon maintenance of the
ing, and/or potassium and magnesium deficiencies “milieu interieur” within boundaries permitting normal
(often consequent upon diuretics, hypovolaemia and metabolism. Mammals including humans have evolved to be
hyperaldosteronism) and is associated with cardiac, able to cope with the production within their bodies of highly
intestinal, muscular and neurological symptoms. acidic and alkaline fluids without detriment to local struc-
6. Respiratory acidosis results from excessive glucose tures or the wider metabolic balance of the body—an extraor-
infusion, particularly if respiratory disease is present. dinary and finely balanced feat of evolution. It takes very
7. Chronic acidosis leads to bone mineral loss resulting in little to disturb this equilibrium yet the body is able to com-
osteoporosis. pensate for most of such disturbances—provided that those
compensatory mechanisms are intact and the demands upon
them are not excessive. The function of the gastrointestinal
system depends upon the interactions between its anatomy
B. J. M. Jones (*)
Department of Gastroenterology and Nutrition, Russells Hall
and physiology. The gastrointestinal tract has been likened to
Hospital, Dudley Group of NHS Hospitals NHS Foundation Trust, “a sleeping bear” with regard to acid-base homeostasis [1]. It
Dudley, West Midlands, UK should not be surprising that disturbed anatomy leads to dis-

378 B. J. M. Jones
ordered physiology. In the context of intestinal failure, the liary, pancreatic and ileocolonic function. Acid base equilib-
gut should be considered a critical part of the acid-base rium is maintained and finely controlled within the body
metabolic system [1]. Hitherto, the contributions of acid- principally by buffering systems. These include the ubiqui-
base disturbances (ABD) to the complications associated tous carbonic anhydrase and plasma proteins such as albu-
with intestinal failure have not received the attention they min. Any net excess of acid (H+) or alkali (HCO3−) from
deserve compared to other major organ failures. cellular metabolism must then be dealt with by the homeo-
The purpose of this chapter is to aid understanding, detec- static functions of the kidneys, lungs and liver.
tion, treatment and avoidance of ABD in intestinal failure The production of 2 l of gastric fluid containing hydro-
(IF), especially in patients with a short bowel (SB). ABD can chloric acid (HCl) in the stomach to a pH of 1–3 [1] means
cause profound short and long term consequences in these that a corresponding amount of alkali is left behind during
most complex patients. the synthesis of gastric acid. There is potential for major
The major contributors to acid base equilibrium are the acid-base disequilibrium if acid secretion is interrupted or
kidneys, lungs and buffering systems within the extracellular absent in IF/SB and if corresponding bicarbonate production
fluids including blood and the intracellular compartment. elsewhere in the gut is lost through diarrhoea or a stoma.
The metabolic and excretory roles of the liver should not be The buffering effect of diet, the dilution effect of oral fluid
forgotten with regard to metabolism of ketones, lactate, intake and alkaline saliva reduce the acidity of gastric con-
amino acids and other potentially acid substances with tents which then come into contact with alkaline secretions
onward transport via blood or bile. The roles of the kidneys from the duodenal ampulla. This leads to a rise in luminal pH
and lungs in the overall control of acid-base balance (ABB) to 6 [2] in the proximal jejunum and an average pH over the
are well known but the role of the gut is not. Unlike the kid- small bowel of 7 [3]. Small bowel intraluminal bicarbonate
neys and lungs, the gut has no role in normal acid-base rapidly disappears [4] partly due to an active transport sys-
homeostasis and under normal conditions, the fluxes of acid tem but also with a rise in pCO2 [5]. This reflects carbonic
and alkali within the gut do not lead to metabolic stresses on anhydrase activity in the mucosa with fluxes of hydrogen
the buffering systems or the final arbiters of acid–base bal- ions across the mucosa [5]. The overall impact of acid and
ance—the kidneys and lungs. However, in patients with a SB alkaline fluxes across the length of the gut are probably neu-
and other causes of IF, this is not so as ABB can become tral under normal circumstances but not so when IF is
severely imbalanced. The patient then becomes precariously present.
dependent on renal and respiratory function which are often The production of bicarbonate by the pancreas, hepato-
insufficient to maintain homeostasis leading to ABD. Other biliary system and salivary glands is also a potential meta-
causes of disturbed ABB include urinary diversion to the gut, bolic strain leaving behind net acid. The volume of these
abnormal intraluminal fermentation and specific nutritional fluids is approximately 2.5 l/day [1] but the pH of 7.6–8.6 is
deficiencies. Parenteral nutrition and hydration with saline not equivalent to that of gastric acid pH. Thus there must be
are major contributors to acid load. Treatment with acid sup- a net residuum of acid in the gut at the level of the duodenal
pressing agents may also prove critical in leading to meta- ampulla and proximal jejunum with a corresponding level of
bolic acidosis. The common scenario of inadequate fluid alkali (bicarbonate) in the extra—alimentary compartments
balance places IF patients at great risk of ABD—either meta- of blood/extracellular fluids. Under normal conditions, this
bolic acidosis or alkalosis. extraluminal excess is dealt with in the distal duodenum and
To adequately consider acid-base disturbances in the jejunum by buffer systems including carbonic anhydrase and
human suffering from intestinal failure, and in particular plasma proteins, notably albumin. Intraluminal pH falls
patients with a SB, we must first observe the main influences again to 5.7 in the caecum but rises towards 6–7 in the rec-
on acid-base balance under normal physiological tum. Any intraluminal excess of acid is normally removed by
conditions. ileal and colonic exchange of intraluminal chloride for bicar-
bonate [1, 4, 5]. Further influences on acid-base balance
occur in the colon from the formation and absorption of ace-
Normal Acid-Base Balance tate and other short chain fatty acids (SCFA) which are
metabolised with consumption of hydrogen ions to bicarbon-
Large amounts of H+ and HCO3− traverse the gut epithelia ate, thus reducing the impact of ileocolonic secretion of
daily and facilitate digestion and absorption of nutrients and bicarbonate [6].
water. When normal, only 40 mmol HCO3− are lost in the Assuming normal buffering capacity, any net imbalances
stool which does not stress acid-base homeostasis [1]. To the of H+ or HCO3− are easily dealt with in the bowel mucosa or
daily production of intrinsic acid production by cellular vascular compartments and any residual excesses of H+ or
metabolism and digestion of diet, must be added the impact HCO3− are dealt with by normal respiratory and renal func-
of fluxes of acid and alkali associated with gastric, hepatobi- tion along with the usual products of cellular metabolism.
Acid-Base Disturbances 379
Normality also assumes normal body stores of potassium, ment [1]. Normally stable long term HPN patients can
magnesium, sodium and water and normal urinary drainage develop ABD with acute changes in hydration as a result of
via bladder, none of which may apply in IF/SB. hot weather, intercurrent infections or increases in stomal
Armed with an understanding of normal acid base bal- losses, and hydration may be precarious even with full sup-
ance and gut physiology, it should be possible to predict portive measures [11].
ABD when IF/SB is present [1] but each individual differs To these disturbances can be added other causes such as
with regard to the quantitative impact of losses of bowel and D-lactic acidosis, sepsis related L-acidosis, hepatic causes
qualitative function of the remaining bowel, as well as day to (thiamine efficiency), phosphate deficiency and the meta-
day fluid balance, oral dietary and fluid intake and renal bolic impact of refeeding syndrome, potassium and magne-
function. The impact of dehydration on renal function and sium deficiencies.
aldosterone secretion on both renal and gut function must The scene is therefore set for extreme disturbances of the
also be factored in as well as potassium and magnesium metabolic norms enjoyed by healthy individuals. These
deficiencies. problems will be discussed further below.
Physiology of Acid-Base Balance in IF/SB patients Detection of ABD
The metabolic stresses of dehydration, lactic acidosis, keto- Although simple in principal, ABD often goes unnoticed or
acidosis, renal impairment and infusion of acid PN regimes undetected in IF. There are several reasons for this.
or “normal saline” are a challenge to the otherwise normal
patient. In IF, these challenges are amplified by the meta- 1. The possibility of acid-base disturbance is not considered
bolic stresses associated with reduced bowel length and as part of normal monitoring.
function. 2. Arterial blood gas analysis is not routine in chronic IF
These metabolic stresses caused by IF/SB are predict- patients and regarded as painful by many patients.
able and have considerable consequences. Even when nor- Blood pH may be normal but not reflective of underly-
mal compensatory mechanisms are intact, ABD may occur ing ABD if compensatory mechanisms are functioning
in IF/SB [7]. ABD does not only occur in patients with a adequately. Thus metabolic acidosis may be masked by
SB, but in other causes of IF in which the gut remains struc- respiratory compensation but careful inspection of all
turally intact but functionally incompetent, as in dysmotil- of the blood gas parameters including pCO2 and bicar-
ity syndromes in which vomiting may predominate [7]. In bonate should elicit the true picture. This is especially
addition, urinary diversion to colon or ileum, and loss of important in high anion gap acidosis due to L- or
gastric acid production (acid suppressing drugs, achlorhy- D-lactic acidosis.
dria, gastric or vagal surgery, radiation or vomiting) may 3. Many units do not monitor venous bicarbonate and chlo-
influence ABB. ride levels as part of a routine electrolyte profile. The rea-
To the above causes must be added the impact of the sons for this failure may lie in economic pressures to
nutritional support required for treatment of IF/SB, whether reduce laboratory costs incurred with assays with low
it be enteral or parenteral [8]. Parenteral nutrition (PN) [9] overall utility due to low rates of abnormality detection.
and some enteral nutrition (EN) solutions are acid. Elemental In IF, this can lead to chronic failure to detect metabolic
or semi-elemental diets are usually acid and are the types of acidosis and alkalosis with serious consequences for the
EN often used in borderline intestinal failure. So called “nor- individual patient in terms of bone disease, intestinal
mal saline” is itself an acid promoting infusion [10] and function or cardiac abnormalities. Until recently, neither
saline is often the mainstay of replacing intestinal losses in textbooks nor national and international guidelines
“net secretors” [11]. The influence of oral rehydration solu- included recommendations to monitor ABD using bicar-
tions should also be considered [12, 13]. All IF/SB patients bonate and chloride estimations [6] so IF/HPN units did
are as much at risk of the causes of ABD as normal patients not monitor these parameters. ESPEN and ASPEN have
plus those causes related to the disturbed physiology associ- now issued such guidance (see below).
ated with IF/SB. 4. Calculation of the serum and urinary anion gaps (SAG
Net alimentary losses of acid or bicarbonate pose meta- and UAG) is not routine.
bolic stresses leading to metabolic acidosis or alkalosis 5. An increased anion gap should lead to measurement of
unless compensatory mechanisms are intact and sufficient to L- and D-lactate. D-lactic acidosis should be suspected in
cope [1]. the presence of an increased anion gap and normal
Negative water balance may cause either metabolic acido- L-lactate in any patient with colon in continuity with
sis or alkalosis or a mixture of both linked by renal impair- residual small bowel [14].
380 B. J. M. Jones
6. Compensatory or mixed metabolic acidosis and alkalosis 8. The acid pH of PN solutions should be made clear on the
may mask underlying ABD [15]. labelling of PN bags [9].
7. Serum potassium levels are often not indicative of total
body potassium and may be normal even in the presence
of total body K+ deficiency. Raised bicarbonate levels Anion Gap and Types of Metabolic Acidosis
with a normal potassium may indicate metabolic alkalo-
sis due to potassium deficiency. K+ deficiency often Metabolic acidosis can be subdivided according to the pres-
accompanies magnesium deficiency so the presence of ence or absence of a serum anion gap (SAG) [17, 18], also
metabolic alkalosis as indicated by a high bicarbonate now known as Strong Ion Difference or SID. Calculation of
will highlight the need for potassium supplementation as serum anion gap differs from centre to centre with differing
well as magnesium [16]. normal ranges. Two methods are commonly used;
 Na + + K +  − Cl− + HCO3−  = Serum anion gap > 20 mmol / l = positive abnormal anion gap
Na + − Cl− + HCO3−  = Serum anion gap > 15 mmol / l = positive abnormal anion gap
Calculation of Urinary anion gap (UAG) excludes bicarbon-

ate [19];
 Na + + K +  − Cl− = UAG > 5 mmol / l = positive gap, < 5 mmol / l = negative UAG
ormal Serum Anion Gap (Non gap) Acidosis:

N decreased ammonium excretion due to renal tubular acidosis
Table 1 [19]. A negative UAG with normal SAG indicates increased
Hyperchloraemic acidosis is associated with a normal anion ammonium excretion due to extra renal causes such as gut
gap as bicarbonate levels fall reciprocally as chloride rises. bicarbonate losses together with potassium [19]. Interestingly,
Causes fall into 3 main groups which can be distinguished by renal ammonium excretion is derived from tubular metabo-
use of the UAG [18]: lism of glutamine [20], an amino acid which is often depleted
Loss of base (bicarbonate) via the gut: negative UAG of in malnutrition and which is not routinely added to PN solu-
−27 ± 10 mmol/l tions in chronic IF.
Loss of base via kidneys/reduction in ammonium excre- To make matters more complicated, combined metabolic
tion as in Renal tubular acidosis: positive UAG of >5 mmol/l acidosis and metabolic alkalosis can occur simultaneously
Infusion of acid solutions such as parenteral nutrition or [15]. For example, excessive bicarbonate losses from a jeju-
acidosis inducing solutions such as sodium chloride: positive nostomy lead to metabolic acidosis but the combination of
UAG. gut potassium losses and hyperaldosteronism due to the vas-
cular contraction lead to metabolic alkalosis. The interpreta-
igh Serum Anion Gap Acidosis: Table 2
H tion of such complex metabolic situations [15] is beyond the
A high SAG is caused by accumulation of unmeasured scope of this chapter but use of the “delta gap” [21] can help
anions [17, 18]. explain the presence of mixed ABD.
L-lactic or D-lactic acidosis patients have a high SAG due One of the principle mechanisms for controlling acid-
to accumulation of lactate as do ketoacidotic and renal fail- base equilibrium is the buffering system of blood and extra
ure patients. cellular fluid. The major extracellular buffer is serum albu-
Renal control of acid excretion depends on excretion of min. In low albumin states, during the early phase of treat-
hydrions via ammonium ions (NH4+) and phosphates together ment of IF, or during intercurrent illness, interpretation of
with bicarbonate reclaim. Renal tubular acidosis should be SAG requires adjustment for the low albumin which may
suspected if a normal serum anion gap acidosis is detected mask high SAG [22]. Such patients are also more likely to be
with hyperchloraemia, low serum bicarbonate and hypoka- susceptible to acidosis induced by endogenous or extraneous
laemia. An increased UAG with normal SAG indicates sources of acid or bicarbonate loss.
Table 1 Non anion gap acidosis; hyperchloraemic metabolic acidosis

Cause Mechanism Comments
Diarrhoea Loss of bicarbonate and Na+ Worse with gastroenteritis
Stomal losses Loss of bicarbonate Net secretors most at risk
Urinary diversion Ileocolonic exchange of chloride for bicarbonate More likely with colonic diversion and continent
pouch than ileal conduit
Oral rehydration solutions High chloride content. Lack of bicarbonate or Bicarbonate or citrate based ORS may prevent
citrate. acidosis
Normal saline and sodium chloride Causes greater changes in ECF chloride than Na+. Most common iatrogenic cause of Metabolic
in PN solutions Cl− is not a buffer acidosis in critical care
PN/HPN Amino acids and acid pH for stability. NaCl Acetate preferable to HCl and NaCl
content
PPI/achlorhydria/gastric resection/ Loss of H+ secretion into gut PPI used to suppress fluid losses in SB
vagotomy
Phosphate deficiency Reduced H+ elimination from tubules with Phosphate is a major factor in renal H+ excretion
chloride retention
Refeeding syndrome Hypophosphataemia May occur after intercurrent illness
Table 2 High anion gap metabolic acidosis failure can lead to rapid deterioration with acute acidosis or
Cause Mechanism Comment even alkalosis. IF patients are at particular risk of being
Renal Retention of acidic Respiratory compensation unable to respond to metabolic stresses caused by acute ill-
impairment/ ions, sulphate, may be inadequate. ness such as gastroenteritis [7] as the compensatory pro-
failure chloride
cesses are already under duress before the addition of further
L-lactic Sepsis Worse in liver disease,
acidosis thiamine deficiency stress.
Ketosis Diabetic or starvation Associated with renal
acidosis due to dehydration
D-lactic Colonic Colon continuity required but Metabolic Acidosis in IF
acidosis fermentation. Poor possible in dysmotility
metabolic capacity syndromes due to small
for D-lactate bowel bacterial overgrowth Historically, metabolic acidosis was a well recognised cause
Vitamin B1 L-lactate Worse if hepatic dysfunction of acidosis and confusion in the early days of PN [25].
deficiency accumulation Fructose and ethanol were both used as main energy sources
Drugs Ethanol, methanol, Rare in IF until superseded by glucose and lipid sources and interest in
salicylates
ABD seems to have waned. However, metabolic acidosis is
still a significant complication of PN in IF patients [7, 26–
Acid-Base Disturbances in Intestinal Failure 28]. In the experience of one UK HPN centre with appar-
ently stable Type 3 IF patients on HPN, normal anion gap
ABD, particularly metabolic acidosis, has long been recog- acidosis is more common than positive anion gap acidosis
nised as a complication of PN and saline infusion in hospital due to D-lactic acidosis [7]. In the acutely ill IF patient, per-
and critical care units [10]. The now obsolete practice of haps admitted with negative fluid balance due to excessive
hyperalimentation led not only to uraemia and dehydration intestinal losses, L-lactic acidosis should be considered as
but to metabolic and respiratory acidosis [23, 24]. There is the result of underlying sepsis, especially line related or
little to be found in the literature on ABD during long term intra-abdominal. Measurement of serum lactate and arterial
management of IF with HPN [7]. In the context of IF with or blood gases should be part of the investigation of such
without PN, respiratory alkalosis is the only ABD not to be patients who may have both hyperchloraemic acidosis and
represented, except as part of the acute compensatory high anion gap acidosis. In IF patients with underlying renal
response to metabolic acidosis or sepsis. Metabolic acidosis impairment or diabetes mellitus, lactic acidosis or ketoacido-
and alkalosis, and respiratory alkalosis occur frequently sis with a high anion gap may be compounded by hyper-
enough for every clinician involved in managing IF/HPN to chloraemic acidosis due to excessive bicarbonate losses and/
be fully aware of how to avoid, detect and treat such prob- or replacement therapy with normal saline. Arterial blood
lems [7]. No one patient with IF is the same as another in gases AND serum chloride and bicarbonate should be mea-
view of the wide variation in underlying causation, compli- sured and resuscitation with solutions other than sodium
cations and anatomical impact of loss of intestinal length or chloride considered, including sodium bicarbonate [29]. In
function, together with concomitant renal or respiratory those with a SB but some colon in continuity, D-lactic acido-
impairment. Intercurrent illness leading to sudden loss of cir- sis should be considered if confusion, cerebellar signs and a
culating volume, dehydration, sepsis, respiratory or renal high serum SAG are detected [14]. The high SAG is associ-
382 B. J. M. Jones
ated with low plasma pH although compensatory respiratory Enteral Feeds

alkalosis may mask the low pH. A low bicarbonate and pCO2 There is no data on the occurrence of ABD in patients with
but normal chloride would be characteristic. borderline SB who can be managed using oral supplements
The commonest cause of metabolic acidosis in IF is or enteral feeds. However, it should be noted that some
hyperchloraemic acidosis with low bicarbonate and nor- enteral feeds are themselves acidic, particularly peptide
mal SAG [7] and elevated potassium [1]. Bicarbonate based feeds. Since the degree of intestinal failure and the
losses from the gut, failure of gastric acid secretion, intensity of treatment are only moderate in the absence of
sodium chloride infusion or PN are the most likely causes. parenteral nutrition, serious episodes of ABD are unlikely
High serum potassium levels accompany acidosis due to but sub clinical ABD may be present nevertheless.
displacement of K+ from cells and impaired renal function However, when oral measures fail to maintain fluid and
[1]. However, concomitant renal impairment due to exces- sodium balance, intravenous 0.9% saline 1–2 L/day is often
sive losses of fluid from the gut (high stoma/diarrhoea) used [11], perhaps supplemented with magnesium [11] or
may lead to a combination of hyperchloraemic acidosis potassium. Such patients are at risk of saline induced
and high SAG acidosis due to retention of anions usually acidosis.
excreted via the kidneys (L-lactate, sulphate, phosphate,
ketones) [8, 30]. etabolic Acidosis Caused by Infusion Fluids
M
Since both negative fluid balance and sepsis are common Parenteral nutrition solutions must be titrated to a pH at
in patients with a SB and replacement fluids most usually which the constituents can remain stable under conditions of
include “normal saline”, the above scenario is common. storage and usage. This is typically 5–5.5 but pH as low as
4.36 has been used [9]. Thus the interaction between amino
acids and glucose (the Maillard reaction) and the stability of
Oral Treatments in IF calcium salts and lipids depends on an acid pH achieved by
use of hydrochloric acid (non metabolisable) or acetate
Patients with <1200 ml stomal losses/day can usually main- (metabolisable), both of which are added to PN bags during
tain sodium balance by adding salt (sodium chloride - NaCl) their preparation [9, 27]. Evidence suggests that titratable
to their food at the table [11]. With increased stomal losses of acidity due to non-metabolisable acid (hydrochloric acid)
1200–2000 ml, salt capsules (NaCl) or glucose—saline solu- rather than metabolisable acid (acetate) is the principal cause
tions may permit sodium balance to be maintained except of acidosis associated with PN infusions [9, 36]. When IF
when ambient temperatures are high. Many require an oral patients already have a tendency to metabolic acidosis due to
rehydration solution (ORS) of which the commonest in use bicarbonate losses, infusion of hydrions with chloride may
is based on the World Health Organisation (WHO) cholera precipitate acute or chronic acidosis, particularly if renal
solution without the potassium chloride. This contains NaCl impairment is present. Metabolism of acetate involves con-
60 mmol/L NaHCO3 (or citrate) 30 mmol/L and glucose 110 sumption of hydrions hence the improvement seen in acido-
mmol/L. This reflects the high concentration of sodium lost sis when this acid is used to acidify PN solutions [28].
from jejunostomies. Sodium losses from short jejunostomies PN solutions are also formulated with sodium chloride in
average 88 mmol/l but rise with longer residual jejunum and sufficient quantities to prevent dehydration and sodium
terminal ileal stoma sodium losses rise to 140 mmol/L [11]. depletion in those unable to maintain hydration due to a
Colostomy losses can be closer to plasma levels but the lower SB. Once infused, sodium chloride also induces metabolic
volumes lost mean that this is less of a problem. In the human acidosis although it is not itself acidic, nor does it contribute
jejunum, sodium balance breaks even at 90 mmol/L [31, 32] to the acid pH of PN solutions [10].
but solutions containing much higher concentrations of NaCl Lessons from critical care and surgery provide a back-
(136 mmol/L) have been used [33]. Use of high sodium chlo- ground for changes in the management of IF patients requir-
ride concentrations in ORS may therefore exacerbate meta- ing fluid resuscitation. Normal saline solutions have been
bolic acidosis [8, 12, 13] especially if a solution without implicated in metabolic acidosis during treatment of criti-
bicarbonate or citrate is used (NaCl 120 mmol, glucose 44 cally ill patients with a variety of diagnoses [29, 37] and by
mmol/L) [34]. inference, also contribute to the acidosis seen in IF patients
The potential for acidosis or alkalosis to occur in patients on PN or during resuscitation when hypovolaemic. More
receiving ORS [12, 13] may be exacerbated by the high chlo- importantly, saline has been shown to increase mortality in
ride, low bicarbonate content (acidosis) or absent potassium critical care whereas use of balanced salt solutions improved
(alkalosis). Oral sodium bicarbonate or citrate based solu- both metabolic acidosis [38] and mortality [39]. Chloride
tions can be used to treat hyperchloraemic metabolic acido- based crystalloids may not be the most appropriate solutions
sis [35]. Again, this emphasises that monitoring for ABD for rehydration, especially when other causes of metabolic
should be conducted in such IF patients.
acidosis such as stomal bicarbonate loss or renal impairment such as arginine, lysine and histidine, metabolism of which
are present [29, 40]. may contribute to ABD. Sulphates are excreted by the renal
Since NaCl solutions are neutral, it is important to tubules in exchange for chloride and oxidation of cationic
understand why NaCl causes or exacerbates acidosis. The amino acids generates hydrions thus contributing to hyper-
concentration of Na Cl in solution is not the reason—any chloraemic acidosis [8].
concentration may precipitate acidosis because it is the
imbalance between ECF concentrations of Cl− and Na+
which provokes acidosis. Unlike bicarbonate, chloride does oss of Gastric Acid Production: Effect
L
not act as a buffer. The equimolar concentrations of Na+ on Acidosis
and Cl− in infusion solutions lead to further imbalances
between Na+ and Cl− in the blood and ECF as a whole. Thus The integrated acid-base functions of the gut depend on
so called normal saline 0.9% contains 154 mmol/l of Na+ production of acid and bicarbonate as already discussed. If
and Cl−. Blood and ECF contain Na+ at 140 mmol/and Cl− acid is not produced, bicarbonate is not generated in the
at 100–110 mmol/l. Although the concentration of Na+ and gastric mucosa to balance the acid produced during secre-
Cl− both exceed the ECF concentrations and therefore tion of bicarbonate from liver and pancreas. If bicarbonate
increase the concentrations of Na+ and Cl− they do so to losses occur due to SB from a high stoma, acidosis may
different degrees. Chloride pairs with H+ to form hydro- occur even if gastric acid production is normal but if gastric
chloric acid, and sodium pairs with OH− and HCO3− to acid production fails for any reason, acidosis is promoted
form base but less so as the increment in sodium is less than further. In the presence of achlorhydria (due to gastritis or
for chloride. pernicious anaemia), gastric surgery (complete or partial
When sodium chloride is present in more dilute solutions gastrectomy, vagotomy) or drug inhibition of gastric secre-
as in PN, it is again the influence of the imbalance between tions (H2 receptor antagonists, PPI or somatostatin ana-
ECF Na+ and Cl− which determines the final balance between logues), acidosis is likely to occur if bicarbonate losses are
Na+ and Cl− which still contributes towards acidosis but less high. If renal compensation fails, acidosis is inevitable.
so than with normal saline. It follows that the greater the Omeprazole has been used clinically to correct metabolic
concentration of saline added to PN solutions, the greater alkalosis [42]. There is anecdotal evidence that PPI induce
effect on acidosis. In those who need large quantities of metabolic acidosis in SB/IF and that withdrawal of the drug
sodium to replace gut losses which usually include bicarbon- leads to correction of metabolic acidosis [7]. Since PPIs are
ate, use of chloride exacerbates the tendency to acidosis. used to reduce stomal fluid losses in IF [11, 43], and since
Hence the use of sodium acetate to replace not only HCl but those losses themselves predispose to acidosis, any patient
sodium chloride in PN solutions [28]. This permits a on a PPI should have appropriate monitoring to detect onset
reduction in chloride infusion and each acetate molecule of acidosis.
consumes one H+ during its metabolism in vivo [26]. Use of
acetate therefore achieves 2 aims—the reduction in chloride
infusion and a reduction in the non-metabolisable acid load Urinary Diversion to Colon or Ileum
of the PN solution required for stability purposes as described
earlier. The burden on buffering capacity and renal or respi- Urinary diversion to the ileum or colon can both lead to met-
ratory compensation on infusion of PN can therefore be off- abolic acidosis which is more common in those with uretero-
set by use of acetate. It has been suggested that when renal colonic diversions (50% or more) than with uretero-ileal
impairment is present chloride based PN solutions should be (2–20%) [44]. The tendency to acidosis does not prevent the
avoided [28]. occurrence of alkalosis from other causes [7]. Deficiencies
This strategy has been shown to improve measures of of potassium and magnesium leading to alkalosis may also
acid-base balance in a retrospective study [28] and a pro- occur. The impact on bone metabolism has also been high-
spective randomised controlled study [9]. lighted, partly as a result of the sub clinical acidosis which
The use of acetate does not come without some adverse routinely accompanies urinary diversion [44]. This appears
consequences. Acetate has been shown to inhibit osteoblast to decline over time [45].
activity [41] thus offsetting some of the benefits of avoiding The colonic exchange of chloride for bicarbonate and
acidosis although acidosis itself also inhibits osteoblasts and slower transit explain the occurrence of acidosis with urinary
enhances osteoclast activity. diversion to the colon. Clinical presentation may be influ-
The amino acid content of PN solutions may also contrib- enced by hyperammonaemic encephalopathy [46, 47]. If aci-
ute to acidosis as a result of sulphur containing amino acids dosis occurs with an ileal conduit, stenosis or obstruction of
such as methionine and cysteine, and cationic amino acids the conduit should be considered [48].
384 B. J. M. Jones
Thiamine Deficiency ileal bypass for obesity. It is possible that dysmotility syn-
dromes may also be complicated by D-lactic acidosis from
Acidosis caused by thiamine deficiency is a well recognised small bowel bacterial overgrowth [51, 52]. It may be acute,
feature of alcoholics presenting with withdrawal symptoms subacute or recurrent. It is characterised by confusion, ataxia,
and Wernicke–Korsakoff syndrome. High anion gap acidosis slurred speech, ophthalmoplegia, nystagmus and behavioural
requiring thiamine treatment has also been described during disturbances such as aggression. In severe cases, stupor may
parenteral nutrition [49]. Thiamine is essential to the correct progress to coma. The exact pathophysiology is unclear.
functioning of the Krebs cycle and metabolism of lactic acid Messing [6] states that only a few mmols of D-lactate are
to pyruvate and alpha keto butyrate which then enter the required to cause cerebellar signs and pseudo-ebriety or
Krebs cycle. L-lactic acid accumulates in the absence of this drunkenness. However, D-lactate levels do not correlate with
vitamin cofactor, particularly in septic and critically ill symptoms and administration of D-lactate to the levels seen
patients [50]. Malnourished patients including those with IF in D-lactic acidosis or above does not cause symptoms [53,
are at risk of this complication if thiamine is not included in 54]. To further confuse the picture, the syndrome can occur
their nutritional regime. The practice of feeding patients with in the absence of acidosis [6] and could be due to other prod-
incomplete “off the shelf” nutritional regimes, particularly ucts of colonic metabolism such as mercaptans, aldehydes,
PN can precipitate acute metabolic acidosis and should be amines and alcohols acting as false neurotransmitters [55]. It
discouraged. Indeed the metabolic consequences of provid- was thought that no enzyme capable of metabolizing
ing an incomplete regime containing no vitamins, trace ele- D-lactate existed in humans but it is now known that humans
ments, phosphate or potassium can be a catastrophic form of do have an enzyme capable of metabolising D-lactate to
refeeding syndrome. PN should never be administered in pyruvate (D-2-hydroxy acid dehydrogenase) in liver and kid-
such form and the use of PN solutions as an emergency out ney [56] and that most D-lactate is excreted via the kidneys.
of hours by inexperienced clinicians should be avoided. The enzyme is inhibited by low blood pH. Similarly, in the
Thiamine deficiency has also been shown to precipitate gut, a low pH favours greater D-lactate production.
L-lactic acidosis even in the absence of liver dysfunction in Diagnosis requires low pH, hypocapnia, an increased
ICU patients [50]. Many IF patients have liver disease conse- serum anion gap with low bicarbonate, elevated D-lactate
quent upon the long-term use of PN and a SB. Although less and normal L-lactate [56].
frequent now, especially in children with the introduction of Symptoms appear after ingestion of carbohydrate loads
newer lipid sources and prevention of line sepsis, liver dis- including those in enteral tube feeds, particularly monosac-
ease is not uncommon in IF so avoidance of L-lactic acidosis charides or disaccharides including sucrose and lactose.
is important. Thiamine deficiency may also precipitate Pickles, yoghourt, sour milk, tomatoes, apples, beer and
D-lactic acidosis as discussed below [50]. wine should be avoided as they contain D-lactate. Colonic
bacteria are required to metabolise these sugars to produce
the syndrome [54].
Hypophosphataemia B1 deficiency may also provoke D-lactic acidosis [51] as
may broad spectrum antibiotics [57]. Changes to colonic
Failure to provide adequate phosphate in PN solutions to the flora with a reduction in gram-negative anaerobes and an
malnourished (for example–anorexia nervosa) or acutely increase in gram-positive anaerobes, especially Lactobacillus,
sick IF patient can precipitate metabolic acidosis, acute psy- Eubacterium and Bifidobacterium [58] lead to an increase in
chiatric disturbances and muscle dysfunction [8]. Phosphate D-lactate [59].
is required as part of the renal elimination of hydrogen ions
together with the bicarbonate and ammonia systems. Renal reatment Options in D-lactic Acidosis
T
tubular excretion of H+ is impaired in phosphate deficiency Initial: Rehydrate and give IV bicarbonate with nil by mouth
and therefore predisposes to acidosis. At tissue level, phos- for 24 h. Haemodialysis has been used in serious cases.
phate deficiency impairs oxygen release and leads to lactic Prevention of future attacks: include nil by mouth with
acid accumulation [8]. These problems are most commonly introduction of enteral diet under supervision avoiding mono
found in the refeeding syndrome and when incomplete PN and oligo saccharides and rapidly digestible glucose poly-
solutions are used “off the shelf”. mers in favour of slow digesting complex starches [56, 60].
Since medium chain triglycerides may also provoke D-lactic
acidosis they should be omitted from the oral intake [61].
D-lactic Acidosis Antibiotics such as metronidazole, neomycin or vanco-
mycin may improve symptoms presumably by suppress-
This is a rare but serious complication of SB with colon in ing colonic flora but rifaxamin has proved most effective
line, occurring in <5% [6] but more commonly in jejuno– [14, 56].
Recently, faecal transplant has been used to treat D-Lactic • Vomiting of small bowel contents leading to losses of
acidosis successfully [62, 63]. potassium and sodium with secondary hyperaldosteron-
Probiotics containing B Breve (Yakult®) or L Casei ism and further potassium losses from the kidneys and
(Shirota®) producing L-lactate not D-lactate may help reset gut. Spironolactone may have a role as an aldosterone
the microbiome after a course of antibiotics but care should antagonist in severe cases [65].
be taken when choosing a probiotic containing lactobacillus • Activation of the renin—angiotensin—aldosterone sys-
as some may precipitate D-lactic acidosis [64]. tem by reduction in plasma volume/dehydration leading
The role of oral rehydration solutions containing bicar- to loss of potassium from kidneys and gut—so called con-
bonate to prevent recurrence by raising intestinal pH or mod- striction alkalosis (see below).
erating the systemic acidosis is unclear. • Hypokalaemia leads to alkalosis as hydrogen ions enter
cells to replace lost potassium, leaving bicarbonate in the
ECF. Any cause of hypokalaemia may lead to alkalosis
Metabolic Alkalosis: Table 3 including use of loop and thiazide diuretics leading to
tubular losses of potassium and magnesium. These diuret-
This is typically associated with potassium deficiency and ics also promote alkalosis through renal chloride excre-
hypochloraemia, often compounded by magnesium defi- tion [65]
ciency, especially if intestinal losses are great as in net secre- • Loss of sodium chloride in sweat as in cystic fibrotics or
tors. Hyperaldosteronism, as in chronically underfilled hot climates leading to contraction alkalosis.
patients, leads to increased renal potassium wastage and also • Magnesium losses occur in stomal effluent in SB inde-
causes increased colonic potassium excretion [65]. Without pendent of the length of residual small bowel, together
replenishment of magnesium, potassium levels will remain with potassium losses. Aldosterone increases both potas-
low with consequent muscle weakness, cardiac arrhythmias sium and magnesium losses from the kidneys. Since mag-
and ileus, the latter compounding potassium and acid losses nesium deficiency inhibits Na+/K+/ATPase leading to K+
through vomiting. Metabolic alkalosis should be regarded as loss from cells and excretion via the kidneys, potassium
a surrogate for total body deficiency of potassium, hence the deficiency is resistant to repletion until magnesium stores
importance of monitoring bicarbonate levels as well as potas- have been repleted [16] but this can only be achieved if
sium. Mortality associated with severe alkalosis is high [65]. underfilling due to dehydration and sodium depletion are
The main causes of metabolic alkalosis are: corrected first, thereby removing the influence of aldoste-
rone. Magnesium deficiency quickly leads to a 25%
• Vomiting or drainage of gastric contents (by NGT or reduction in total body stores of potassium [67]. Potassium
drainage PEG) leading to loss of HCL. This scenario may deficiency cannot be remedied without repletion of mag-
occur in patients on palliative PN for small bowel nesium stores [16] which are best assessed using 24 h uri-
obstruction due to cancer if palliative gastric drainage is nary excretion studies. Care should be taken to monitor
utilised. IF due to dysmotility of the gut leads to recurrent magnesium levels during octreotide therapy. Magnesium
vomiting of either gastric or small bowel contents or both. repletion may require oral 1 alpha-hydroxycholecalciferol
If gastroparesis predominates, metabolic alkalosis may treatment [68].
occur due to loss of gastric acid and increased aldosterone • Inadequate replacement of potassium, often due to mis-
activity leading to a low serum potassium. Cimetidine has leading serum K+ levels, is exacerbated by infusion of
been used successfully to treat severe metabolic alkalosis glucose (as in refeeding syndrome) and more so if insulin
in gastric hypersecretion in patients with a SB [66]. is given too. As cells return to an anabolic phase, K+
Omeprazole may be protective [42]. requirements increase so adequate replacement is essen-
tial if metabolic alkalosis is to be avoided.
Table 3 Metabolic alkalosis • Contraction alkalosis or chloride depletion alkalosis?
Cause Mechanism Comment • This term reflects the contraction of the vascular com-
Loss of K+ Diarrhoea, vomiting, stomal May be resistant if partment caused by fluid losses insufficient to reduce
losses, diuretics low magnesium too glomerular filtration but adequate to stimulate the renin—
Loss of Mg++ Stomal losses; Vit D May require vitamin angiotensin—aldosterone secretion system. Renal tubular
deficiency D to replete stores exchange of potassium for sodium leads to potassium
ORS solutions Potassium free ORS Taste and compliance
a problem
deficiency and alkalosis. Aldosterone also has a role in
Contraction Hyper aldosteronism. renal Now called chloride sodium and potassium exchange in the small bowel and
alkalosis and intestinal chloride loss depletion alkalosis colon, promoting alkalosis. Chronically fluid depleted
Refeeding Hypokalaemia May be masked by patients can thereby develop metabolic alkalosis. This can
syndrome acidosis even be enough to overwhelm the tendency to metabolic
386 B. J. M. Jones
acidosis associated with ureteric diversion in our experi- Octreotide and other somatostatin analogues may in the-
ence [7]. ory affect ABB by influencing gastric or pancreatic secre-
However, more recent publications have challenged the con- tions and there a few reports of metabolic acidosis in patients
cept of contraction alkalosis [65, 69] emphasising the role on octreotide [73] with pancreatic fistula but no evidence that
of chloride repletion in hypochloraemic alkalosis but this octreotide is either causal or therapeutic.
is beyond the scope of this article. Cholestyramine used to treat bile acid related diarrhoea in
patients with resected ileum has also caused metabolic
hyperchloraemic acidosis [74].
Respiratory Acidosis
Consequences of ABD
It has long been recognised that infusions of glucose lead
to an increase in CO2 production with concomitant These may be life threatening or lead to chronic morbidity.
increases in respiratory excretion. If respiratory function
is normal, this does not present a problem and CO2 is
exhaled sufficiently. When respiratory reserve is impaired Metabolic Acidosis
due to pulmonary infection, trauma or underlying disease,
CO2 can accumulate to cause respiratory acidosis [23, 24, Short term metabolic acidosis due to lactic acidosis is better
70]. If other causes of metabolic acidosis are present, understood than hyperchloraemic non gap acidosis or chronic
infusion of glucose may impose a rise in total body CO2 metabolic acidosis. Metabolic acidosis impacts upon cardiac
which contributes to an overall fall in pH due to a combi- function with hyperventilation, arrhythmias, vasodilatation,
nation of metabolic acidosis and respiratory acidosis, and hypotension and may also increase inflammation and
leaving the kidneys as the sole means of readjusting impair immune responses [75]. Hyperkalaemia is common
pH. Since the use of glucose is essential in PN solutions, and potentially fatal [1]. Some studies have shown that high
it follows that avoidance of metabolic causes of acidosis anion gap acidosis adversely affects mortality whereas non
are essential if compensatory mechanisms are not to be gap acidosis does not [10]. Other studies have shown
overwhelmed, particularly because many causes of meta- increased mortality with non-gap hyperchloraemic acidosis
bolic acidosis impact upon renal function (loss of intesti- [10, 37, 38]. Many studies have shown increased mortality
nal fluid, vomiting, sepsis). with the use of normal saline as a resuscitative fluid com-
pared to solutions with lower chloride content [10, 37, 38]
and others have shown improved acid-base parameters with
Respiratory Alkalosis alternatives to 0.9% saline solutions [29].
It should be clear that prevention of metabolic acidosis is
This is never chronic in IF but can occur acutely as part of of paramount importance and that modification of PN, intra-
the response to sepsis or haemorrhage. Hyperventilation venous and oral rehydration solutions offers the best oppor-
together with confusion and a low pCO2 should alert the tunity to do so. The treatment of acute severe acidosis is
clinician to the possibility of line sepsis or intraabdominal beyond the remit of this chapter.
causes.
cidosis and Metabolic Bone Disease
A
In the context of chronic IF on HPN, the long term effect of
Drug Therapy During IF acidosis on bone metabolism cannot be ignored. The impact
of chronic metabolic acidosis on bone metabolism and the
Potassium sparing diuretics have been implicated in precipi- benefits to muscles, bones and growth with treatment of
tating metabolic hyperchloraemic acidosis during PN [71] acidosis have long been recognised in renal failure [76–78].
by opposing renal aldosterone response and impairing tubu- Acidosis increases bone resorption by increasing osteoclast
lar function. Intracellular transfer of potassium leads to loss and decreasing osteoblast activity [79, 80]. Acidosis also
of intracellular hydrions to the ECF [71]. The carbonic anhy- impairs renal vitamin D activation. Mobilisation of bone
drase inhibitor, acetazolamide, has been used to treat alkalo- calcium leads to nephrocalcinosis and nephrolithiasis.
sis and may cause acidosis by inducing renal bicarbonate Although acidosis has not featured strongly in texts or
secretion [72]. guidelines until recently, the importance of treating acidosis
The role of acid suppressing agents has already been dis- to prevent metabolic bone disease in IF during HPN has been
cussed above. highlighted [13, 41].
Metabolic acidosis is considered to be an important con- acute delusional psychosis. Both cases had hypochloraemia,
tributor to metabolic bone disease in chronic renal failure. hypokalaemia, hypomagnesaemia and elevated creatinine
Improvements in bone metabolism follow treatment of aci- suggesting contraction alkalosis and hyperaldosteronism.
dosis [81]. Impaired bone metabolism has also been docu- Neither were taking a PPI. Both had high stomas but one had
mented in D-lactic acidosis [82], treatment of which urinary diversion to an ileal conduit.
improves bone metabolism. Subclinical acidosis is most There were 6 cases of subclinical metabolic acidosis,
likely to contribute to long term bone disease, hence the none of which had a raised anion gap or detectable D-lactate.
importance of monitoring acid-base balance and preventing All were detected on implementation of routine monitoring
acidosis by incorporating acetate in PN formulations. Pironi of serum bicarbonate and chloride for ABD. The PN formu-
[41] advises 160 mmol/day of acetate to avoid acidosis and lations were altered to include sodium acetate instead of
maintain bicarbonate within normal range. sodium chloride and the incidence of metabolic acidosis
declined. There was no colon in continuity in 6/9 acidotic
patients. One case had a dysmotility syndrome due to sclero-
Metabolic Alkalosis derma with the entire gastrointestinal tract intact.
Clinical features are those of hypokalaemia, low magnesium

and the decrease in ionised calcium caused by alkalosis efeeding Syndrome Scenarios Leading
R
itself. With increasing pH, ionised calcium increasingly to ABD
binds to albumen leading to further falls in ionised calcium
and tetany. Convulsions, muscular irritability and cramps or Instigating nutritional support in the malnourished or meta-
tetany, paraesthesia, psychosis and coma may occur. Cardiac bolically challenged patient without attention to providing
arrhythmias, gastroparesis or paralytic Ileus reflect hypoka- adequate amounts of all essential nutrients can lead to a
laemia. Mortality is high in severe cases [65]. refeeding syndrome. Typically, provision of energy sources
Alkalosis may also affect bone metabolism when associ- creates demands for other basic nutrients and exposes defi-
ated with low magnesium stores which reduce parathormone ciency states if those nutrients are in short supply. This
secretion and renal activation of vitamin D [83]. applies particularly to potassium, phosphate, thiamine, zinc
and selenium. Acidosis may result if insufficient thiamine or
phosphate are provided [8, 49–52] as in a case on HPN [84].
Incidence of ABD Stable HPN patients could be exposed to this risk after inter-
current illness such as line sepsis or surgery when the cata-
Little has been published on ABD in IF on HPN. This bolic phase gives way to the anabolic recovery phase.
author’s group described their experience in a small UK Vitamin B1 thiamine deficiency is well recognised, particu-
referral centre for Type 3 IF and HPN [7]. Of 39 patients, larly in alcoholics with the onset of Wernicke–Korsakov syn-
there were 11 episodes of ABD in 10 patients (25%). In 5/11 drome. The associated acidosis may contribute to the overall
episodes, the presentation was after many years on HPN with malaise of this condition but if acidosis is detected in such
severe ABD and renal impairment as a prominent feature. patients, B1 deficiency should be suspected and treated urgently.
The remaining 6 episodes were subclinical detected on rou- Phosphate deficiency is seen at its worst in anorexia ner-
tine screening and only 1 of these had renal impairment. vosa. The contribution of acidosis is unclear but impaired
Symptomatic hyperchloraemic acidosis (e.g. lethargy, oxygen release at tissue level due to 2,3-diphosphoglycerate
rapid breathing, confusion) was present in 3/5 severe presen- deficiency and ATP in red blood cells probably explains the
tations. Jejunostomy was present in 2 and jejunocolonic anas- symptoms of confusion, seizures, muscle weakness, paraes-
tomosis in one. All had impaired renal function, 2 were on a thesia, hyperventilation and coma [8].
PPI and all were taking modified WHO oral rehydration solu-
tions without potassium. Withdrawal of PPI in one case led to
improvement in the acidosis. None had D-lactic acidosis. Cramps During PN Infusions
Interestingly, 2 had a raised anion gap but both had elevated
serum creatinine. Smoking related chronic obstructive air- Muscle cramps occurring during HPN infusions represent
ways disease was present in one case with Crohn’s disease. the commonest side effect of HPN according to a multicentre
There were 2 severe symptomatic metabolic alkaloses, report [85] from the UK. These cramps should be distin-
one of which had also suffered from severe metabolic acido- guished from the tetanic cramps associated with calcium or
sis which resolved on withdrawal of PPI and supplementary magnesium deficiencies which occur independent of PN
IV saline infusions at home. On this occasion, she suffered infusions. The cause of PN related muscle cramps is unclear
388 B. J. M. Jones
but some theoretical possibilities can be entertained on the metabolism and fluid homeostasis, blood glucose concentra-
basis that PN solutions are acid (pH 4.4) and contain sodium tions and acid-base balance is important. They state categori-
at lower concentrations than in blood and extracellular fluid. cally that laboratory testing should include measures of
One particular observation stands out to direct investiga- acid-base balance.
tion into this problem. It is generally agreed that reduction in
flow rates of PN infusions either reduces the intensity and
duration of cramps but may help avoid them altogether [86]. ESPEN Guidelines 2016
This would suggest that it is the rate of infusion of fluid and
some constituent or property of that PN which causes the Recommendation 19 [13] recommends regular monitoring
cramps. There is no clear evidence that quinine reduces the of acid-base status in patients on long term HPN (serum
cramps although this treatment is often deployed. chloride and bicarbonate) because both metabolic acidosis
The suggestion that some cases may prove to be due to and alkalosis can occur. The guidance also states that chlo-
sodium deficiency does not explain why symptoms occur dur- ride and bicarbonate levels should be monitored frequently
ing infusion of sodium. Similarly, one would expect cramps until stable.
due to underlying calcium, magnesium or phosphate deficien-
cies to be corrected during infusion of PN solutions. Some
other cause must explain these cramps. On the other hand, Renal Impairment in IF
infusion of 3 l PN solution over 12 h may cause dilution of
serum sodium or other electrolytes sufficient to trigger cramps. Renal impairment in patients with intestinal failure is most
However, increasing the sodium content of HPN solutions commonly due to chronic dehydration in patients with a jeju-
does not improve the cramps in this author’s experience. nostomy and due to oxalosis in patients with a jejunum in
Transport of ions across muscle cell membranes during continuity with a functioning colon (chapter “Nephrolithiasis
glucose and amino acid infusions could create temporary and Nephrocalcinosis”). In addition parenteral chloride may
ionic transmembrane gradients as in the refeeding syndrome cause renal vasoconstriction so further impairing renal func-
but no evidence exists to support this theory. tion [88].
The infusion of large volumes of PN solutions with an acid Acute renal impairment due to hypovolaemia can often be
pH may alter acid—base balance sufficiently for polarisation treated with intravenous fluids but if a patient is allowed to
of muscle membranes to be affected adversely, thus triggering be chronically dehydrated (often an insidious process) then
cramps. To this theory may be added the dilutional effect of permanent renal dysfunction will ensure. Persisting dehydra-
infusing solutions with sodium concentrations well below tion is a reason for starting or increasing parenteral support.
those of serum and extracellular fluid bathing nerve mem- Patients with acute kidney injury secondary to a high out-
branes. A sudden drop in sodium concentration coupled with a put from a small bowel stoma may need dialysis (if acidotic
transient but rapid fall in pH of extracellular fluids could pre- or hyperkalaemic), however during dialysis fluid must not be
cipitate cramps. However, this theory requires further investi- removed, in fact they must continue to be rehydrated and ide-
gation. Meanwhile, reduction in flow rate of PN solutions is the ally gain 1–4 kg in weight depending upon how dehydrated
most effective treatment, albeit at the expense of time online. they are at the commencement of dialysis. If an already
Patients are willing to accept this trade off if they can avoid the dehydrated patient is dialysed and fluid removed their kidney
extremely painful cramps associated with their PN in my expe- injury may become irreversible.
rience. This is a subject requiring further investigation. If a patient is prone to acute kidney injury due to dehydra-
tion then it is important to avoid or closely monitor them if
they take a potassium containing rehydration solution (e.g.
Guidelines and ABD dioralyte®). While omeprazole and loperamide are relatively
safe in patients with renal impairment the dose of codeine
Until recent iterations of ASPEN and ESPEN guidelines, phosphate which has active renally excreted metabolites,
acid-base disturbances were not highlighted. However, the must be reduced.
latest ASPEN recommendations and ESPEN guidelines now
include clear advice on detection of ABD.
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Gallstones in Intestinal Failure
Jeremy M.D. Nightingale and Mattias Soop
Key Points 8. Cholecystectomy is recommended if there are gallstones

1. Gallstones are more common in patients with intestinal present and surgery is being performed for another reason.
failure (IF) 38% at 20 years of parenteral nutrition at 9. Prophylactic cholecystectomy and/or sphincterotomy are
home. They are also common in patients with a short not recommended if there are no gallstones.
bowel (21% over 10 years).
2. Most (76%) patients receiving home parenteral nutrition
(PN) with gallstones develop complications.
3. Gallstone formation may relate to a high-calorie and/or Introduction
lipid parenteral nutrition, a lack of oral intake, an ileal
resection or disease, and certain medications (anticholin- Gallstones (stones in the gallbladder or biliary ducts or both)
ergics, opioids or octreotide). are a major public health issue and are present in 10–15% of
4. Supersaturation of bile, nucleation, crystallization and adults in the Western world and are overall more common in
reduced gall bladder contractility are the key factors that women [1]. Of those with gallstones (mainly cholesterol ones)
contribute to gallstone formation. In IF patients biliary about 25% will develop symptoms, in particular women [2].
stasis is most relevant and leads to gall bladder sludge and Gallstones are of three main types: cholesterol stones, compris-
the formation of gallstones containing calcium ing about 75% of stones; pigment stones; and mixed. While
bilirubinate. pigment stones may predominate in patients with intestinal
5. Medical therapy is rarely used to prevent or dissolve gall- failure (IF), all types of stones can occur [3]. Gallstones may
stones in IF patients due to unpredictable absorption of cause severe and life-endangering complications from chole-
medication and a lack of proven benefit. cystitis (typically large stones >10 mm), biliary colic, obstruc-
6. Gallstones might be prevented changing the bile compo- tive jaundice (often multiple stones), pancreatitis (small stones),
sition directly (e.g. ursodeoxycholic acid) or indirectly by bowel obstruction (a large stone which passes from the gall-
increasing gut transit (e.g. cisapride) or changing the bladder through a choledocho-duodenal fistula into the small
bowel flora (e.g. metronidazole). bowel, where it may cause obstruction in the duodenum or ter-
7. Prevention could also be by maintaining regular gall minal ileum) and rarely gallbladder cancer or a cholangiocarci-
bladder contraction with oral diet, cholecystokinin noma. Generally, gallstones greater than 1–1.5 cm and of a
injections, rapid amino acid infusions, non-steroidal high number are most likely to cause symptoms.
anti-
inflammatory drugs (NSAID’s) and avoiding
octreotide. (a) Cholesterol gallstones are composed of cholesterol,
mucin, bile pigments, calcium salts and other com-
pounds. The pathogenetic factors for cholesterol gall-
stones include a genetic background, female, older age,
sedentary life style, high fat diet, lack of fibre, pregnancy
St Mark’s Hospital, Harrow, Middlesex, UK (high number of childbirths), hormone replacement ther-
e-mail: [email protected] apy. Insulin resistance, as occurs with obesity, metabolic
M. Soop syndrome and type 2 diabetes is a common aetiological
Head of Section of IBD and Intestinal Failure Surgery, Karolinska component. A further contribution may be from factors
University Hospital and Karolinska Institutet at Danderyd within the gallbladder: hepatic hypersecretion of choles-
Hospital, Stockholm, Sweden terol, supersaturation of bile (precipitation of cholesterol

392 J. M.D. Nightingale and M. Soop
Fig. 1 Pigment type

gallstone of 1 cm from a
patient with a short bowel
crystals), a sluggish gallbladder, mucin and inflamma- occur with equal frequency in men and women [8, 10]. These
tory changes in the gallbladder. Factors outside the gallstones often appear calcified on a plain abdominal radio-
bladder include slowing intestinal motility, increased graph [7]. Gallstones are more common in patients with ile-
intestinal absorption of cholesterol, and altered gut itis than in those with ileo-colitis or colitis [11] and the
microbiota [4, 5]. likelihood may increase with the length of bowel resected
In patients with IF (having PN or with a short bowel) [10], the duration of disease, previous surgery and the age of
however, the predominant type of gallstones found are the patient [8, 12].
pigment stones. Cholesterol may also play a part in gall- Patients with loss of functioning distal ileum due to dis-
stone formation in this group. ease or surgical excision have a disruption to the normal
(b) Pigment gallstones (Fig. 1) are composed of calcium enterohepatic circulation of bile salts. It was estimated that
bilirubinate and are classically associated with haemo- the frequency of gallstones in patients with an ileal resection
lytic anaemia but do occur in other circumstances. In greater than 50 cm in length was 33%, compared to 17% in
North India, where obesity is common, gallstones are those who had undergone a lesser resection [10]. However,
primarily (>80%) cholesterol stones whereas in south some studies suggest that the likelihood of gallstone forma-
India where most are vegetarian (less spices and fat) and tion is not related to the site of disease or resection but to the
non-obese, most (>60%) are pigment stones [1]. Liver duration of disease and previous surgery [12].
disease (non-alcoholic fatty liver disease and cirrhosis) Patients with ulcerative colitis (without operation) have
are also associated with pigment gallstones. Patients on average a 7–14% prevalence of gallstones, marginally
with cirrhosis have an incidence of 2–5% per year (most more than controls [9, 12, 13]. The risk of stones is higher
common if an alcoholic aetiology, a more severe cirrho- after a panproctocolectomy and ileostomy formation [6, 14].
sis and a longer duration of cirrhosis), which is four A large series of patients (180) who had an ileostomy follow-
times that of the general population [5]. ing a panproctocolectomy showed gallstones in 24–25%,
(three times the incidence that might have been expected in a
population of this age and sex distribution), it was higher if
more than 10 cm terminal ileum had been removed [15].
pidemiology of Gallstones in Intestinal
E
Failure
Short Bowel
Gallstones are prevalent in patients with acute or chronic
intestinal failure, and in chronic illnesses such as Crohn’s Work at St Mark’s Hospital showed that 17/27 (63%) men
disease, after intestinal resections and with the long-term use and 15/47 (32%) women with less than 200 cm small bowel
of parenteral nutrition (PN). Increased rates of cholelithiasis remaining had either had a cholecystectomy or were found to
and cholecystitis have been shown also following trauma, have gall stones on an ultrasound examination. This study
burns, truncal vagotomy and pregnancy. included subjects who were nutritionally autonomous and
subjects who required parenteral nutrition (PN). There was
no difference between those with a colon in continuity (15
Inflammatory Bowel Disease (44%)) and those with a jejunostomy (17 (43%)) [16].
Another study showed that 72 of 345 patients (21%) who had
There is an increased prevalence of gallstones (25%) a total small bowel length less than 104 cm (19% had a jeju-
(detected by cholecystography and ultrasonography) in nostomy) developed gallstones over a 10 year period. PN
patients with Crohn’s ileitis or ileo-colitis [6–9] and these dependence (34% of patients) and a very short length of
Gallstones in Intestinal Failure 393
remaining jejunum were independent risk factors. 39% iliary Sludge in PN and Crohn’s Disease
B
developed symptoms (23/28 (82%) acute cholecystitis/chol- Biliary sludge formation is an important stage in gallstone
angitis and 5/28 (18%) acute pancreatitis) [15]. development and is associated with PN. Messing et al.
reported a progressive increase in the incidence of biliary
sludge from 6% after 3 weeks of PN to 50% between 4 and 6
Parenteral Nutrition weeks, and reaching 100% in patients receiving intravenous
nutritional therapy for more than 6 weeks [21]. Sludge
Anecdotal reports in the 1970s suggested that PN might be appears to precede gallstone formation; gallstones were then
associated with an increased incidence of both acalculous noted in six of 14 patients who developed sludge, while none
cholecystitis and cholelithiasis [17]. There were also descrip- of the patients without sludge developed gallstones.
tions of massively dilated gallbladders in patients receiving Interestingly, five of seven patients who earlier had sludge or
PN [18]. Later studies confirmed the association between PN gallstones were found to be free of both after a short period
and gallstone formation. In one study of patients receiving of oral refeeding [21].
PN for a minimum of 3 months, 23% developed gallbladder There are considerably less data available on the preva-
disease after commencement of PN [19]. There was a 40% lence of sludge in Crohn’s disease itself without the concom-
incidence of gallbladder disease in this group receiving PN, itant use of PN but reduced gallbladder contractility, which
which is significantly greater than that in Crohn’s disease or predisposes to biliary sludge, has been demonstrated espe-
ileal resection patients not receiving PN. The same research- cially in those who have undergone ileal resection [28].
ers also found that the risk of development of gallstones Biliary sludge also commonly develops rapidly in patients
whilst on PN was greater in patients of less than 30 years old on an intensive care unit. Some of these patients had a previ-
and in patients whose ileal resection had been performed less ously recognized risk factor such as abdominal surgery or
than 15 years previously. Research on a population of chil- PN but neurosurgical procedures were also associated with
dren on PN showed that 43% of children on long-term PN sludge formation [29].
(mean duration 20 months) developed gallstones [20].
Subsequent studies also showed that long-term parenteral
nutrition in both adults and children is commonly associated Pathogenesis of Gallstone Disease
with gallstones (40%) [19–25], which in patients with a short
bowel are often symptomatic [24]. Acalculous cholecystitis Supersaturation of bile, nucleation and crystallisation, and
may occur but is less common [17, 23]. Gallstones were reduced gall bladder contractility are the traditional factors
more common in men than women in one study [22]. that produce “lithogenic bile”. In patients with IF the stones,
Patients receiving PN frequently develop sludge and may while containing some cholesterol, are mainly of pigment
go on to develop gallstones [21]. Dray et al. prospectively type composed of calcium bilirubinate. The stones develop
followed adult patients with a gallbladder in situ receiving within biliary sludge, which has formed due to gallbladder
HPN and 45/119 (38%) developed gallstones and/or biliary stasis often due to a period of no or reduced oral intake.
sludge (14 sludge alone), the probability of developing them Biliary sludge contains calcium bilirubinate or unconjugated
was 21% at 1 year and 39% at 2 years. Eight of the 45 devel- bilirubin, cholesterol monohydrate crystals and increased
oped biliary complications. It was estimated that the inci- amounts of mucin glycoproteins [30]. Biliary sludge may
dence of biliary complications was 5% at 1 year and 10% at disappear spontaneously but frequently evolves into gall-
2 years. No or negligible oral intake was associated with the stones [31]. Sludge may persist or recur in 50% of cases and
development of gallstones. There was no difference in inci- gallstones may form in up to 14% of affected subjects over 3
dence between the sexes in this study [26]. years [25]. Calcium bilirubinate crystals, within biliary
Appleton showed that 17/63 (27%) of patients with no pre- sludge, are more commonly found in men than women [32].
vious gallstones developed them over a median of 11 years of
HPN. The cumulative incidence was 21% at 10 years, 38% at
20 years and 47% at 30 years. No less than thirteen of the 17 Supersaturation of Bile
(76%) had symptoms (4 biliary colic, 4 acute pancreatitis, 2
common bile duct (CBD) stones, 1 cholangitis, 1 empyema/ While pigment stones are most common, cholesterol super-
abscess) and 10 of these required surgical or endoscopic saturation is well researched and may occur and contribute to
interventions. Increased energy content and the provision of the genesis of gallstones [3]. Cholesterol is secreted into the
lipid were predictors for cholelithiasis [27]. The authors con- bile canalicular lumina and subsequently taken up by biliary
cluded that complications from gallstones were so common lipid vesicles with a cholesterol: phospholipid ratio of 0.34:
that en-passent cholecystectomy is warranted when gallstones 0.38, but the ratio is higher in lithogenic bile [33, 34].
are present; in other words, during abdominal surgery for Cholesterol, lecithin (the most abundant biliary phospho-
other reasons, the gallbladder should be removed if safe [27]. lipid) and bile salts aggregate to produce mixed micelles and
vesicles in bile, in which the hydrophilic portions of these in the mucus layer adherent to the epithelium in gallbladders
lipids are located peripherally with the hydrophobic portions with reduced contractility.
orientated centrally in a hydrophobic domain, thus permit- It would appear that all three requirements—cholesterol/
ting lipid solubility in an aqueous environment [35]. calcium bilirubinate supersaturation, increased nucleation
Cholesterol solubility in bile has been defined using a rate mediated by mucin hypersecretion, and reduced gallblad-
triangular coordinate map comprising cholesterol, bile salts der contractility—occurring simultaneously allow cholelithi-
and phospholipids [36, 37]. Bile supersaturated with choles- asis to occur (the “triple defect of gallstone formation”).
terol may be a result of increased cholesterol secretion or Pigment stones have been shown to be largely composed
decreased phospholipid or bile salt secretion. Cholesterol- of calcium bilirubinate and other calcium salts. Less is
rich vesicles play an important part in the formation of cho- known about the process of pigment stone formation than
lesterol crystals [38]. about cholesterol gallstones, but biliary stasis appears to play
a major role. Unconjugated bilirubin concentration is higher
in gallbladder bile in patients with pigment gallstones than in
Nucleation and Crystallization controls and it is likely that unconjugated bilirubin forms
gallstones by precipitation in a similar fashion to that of cho-
Bile contains both anti-nucleating and pronucleating factors, lesterol [47].
the balance of which is important in determining the likeli-
hood of gallstone formation. Apolipoprotein A-1 and A-2,
and a glycoprotein (120 kDa), all found in human bile, have Biliary Sludge
been identified as anti-nucleating factors [39]. Pro-nucleating
factors include both mucin glycoproteins [40] and non- Biliary sludge may be an important intermediate factor in
mucin glycoproteins [41]. Mucin is thought to play a signifi- the formation of gallstones [45]. Sludge was initially identi-
cant role in crystallization of cholesterol. The evidence for fied by ultrasonography as low amplitude echoes without
this comes from three main sources. First, mucin glycopro- acoustic shadowing which layered in the most dependent
teins have been found in the matrix of cholesterol gallstones portion of the gallbladder [48] (Fig. 2). Biliary sludge is an
[42]. Second, mucin hypersecretion precedes crystallization amorphous precipitant of mucin glycoproteins, bile pigment
of cholesterol in animal models [43] and probably humans granules (calcium bilirubinate), cholesterol crystals, small
[44]. Third, mucin has been shown to promote crystal nucle- stones, protein and lipids. An ever-present constituent of
ation in cholesterol supersaturated bile in vitro. Mucin may biliary sludge in humans is calcium bilirubinate or unconju-
act as a nidus for crystal aggregation by entrapping choles- gated bilirubin. Cholesterol monohydrate crystals and a
terol crystals or calcium bilirubin on non-glycosylated marked increase in the amount of mucin are found in biliary
hydrophobic domains of the peptide chain of the mucin gly- sludge [45]. They also noted that the cholesterol and phos-
coprotein molecule [45]. pholipid concentration in bile from sludge-forming patients
In addition to mucin, several other non-mucin pro- was no different to that of normal controls and gallstone
nucleating factors have been identified in vitro such as amino patients [45].
peptidase N, a low-density lipoprotein particle, and
haptoglobins.
Crystal growth in bile follows nucleation. Cholesterol
monohydrate crystals are composed of bilayers of choles-
terol bonded to a water layer. Rapid growth occurs as these
crystals pack side-by-side in their long axis, resulting in
plate-like monohydrate crystals. Cholesterol also precipi-
tates in other forms such as helical, tubular and filamentous
forms of non-hydrated cholesterol [46].
Gallbladder Contractility
As well as cholesterol supersaturation and mucin hyperse-

cretion, reduced gallbladder contractility appears crucially
important in cholelithiasis by allowing the cholesterol crys-
tals entrapped in mucin to grow to a sufficient size to allow Fig. 2 Ultrasound image of the gallbladder in longitudinal section
showing layering of sludge without acoustic shadowing (courtesy of
them to remain in the gallbladder. Early cholesterol crystals
Professor M. J. Lee, Radiology Department, Beaumont Hospital,
are likely to develop into macroscopic stones only if formed Dublin 9)
Several possible factors leading to biliary sludge for- athogenesis of Gallstones in Intestinal
P
mation are cited in the literature including biliary stasis Failure
(due to no or little oral intake), use of total parenteral
nutrition, mucin hypersecretion, bile infection and acute Gallstones in IF patients may occur due to ileal disease/
illness. A definite association between development of resection, fasting, PN, surgery, rapid weight loss or drug
biliary sludge and gallbladder stasis has been noted treatments (Fig. 3). Bacterial overgrowth may have a role.
especially in patients receiving total PN with no oral Surgery, weight loss and parenteral nutrition may all
intake [24]. involve prolonged fasting. The main drugs that are causative
The exact mechanism of sludge formation has not yet are anticholinergic agents, opioid analgesics or octreotide.
been elucidated but one theory is that decreased gallblad- Other factors may include poor cholecystokinin secretion
der contractility leads to bile becoming progressively and less physical activity.
more concentrated due to water absorption and the choles-
terol vesicular carriers becoming enriched in cholesterol
content and depleted of lecithin and other phospholipids. Ileal Disease/Resection
Crystals of cholesterol are thus formed, and calcium salts
(especially bilirubinate) precipitate secondary to stasis as While disruption of the enterohepatic circulation and conse-
well. Thus, sludge may form. Prolonged stasis and further quent loss of bile salts should lead to an increase in choles-
growth may lead to the development of gallstones [49]. terol saturation (relates to concentrations of cholesterol, bile
Biliary sludge may disappear spontaneously or have a salts and phospholipids); this was the case in some studies of
fluctuating course but it frequently evolves into gallstones patients with “ileal dysfunction or resection” [53, 54] but not
[50]. It would appear that sludge may persist or recur in at in others [53]. A reduced amount of deoxycholic acid and an
least 50% of cases and that gallstones may form in up to increased amount of ursodeoxycholic acid are found in the
14% of affected subjects over 3 years [51]. Biliary sludge bile of patients with ileal Crohn’s disease [54, 55]. Bilirubin
always represents a pathological process and cholecystitis concentrations are two- to threefold higher in patients with
is common [52]. ileal disease compared to those with no ileal disease [54, 55]
while phosphatidylcholine levels are not different [54]. The
majority of patients (children and adults) who undergo ileal
Intestinal Microbiota resection and require long-term PN develop pigment gall-
stones [56]. Of note, some researchers have found normal or
Bile acids are cholesterol-derived molecules that can be even low cholesterol saturation of bile after resection of
modified by the gut microbiota and can act as signaling ileum [55]. In patients with Crohn’s disease gallbladder con-
molecules to regulate metabolic and physiological pro- tractility is reduced after a fatty meal [31, 57], which may
cesses. The gut microbiota releases many enzymes that contribute to the formation of biliary stasis. The fasting gall-
can modify the bile acids such as bile salt hydrolases bladder volume is decreased and fasting plasma cholecysto-
(7α-dehydroxylase, and hydroxysteroid dehydrogenase). kinin levels are surprisingly increased in patients with
These enzymes can change the gut microbiota composi- Crohn’s disease of the large bowel and patients after an ileo-
tion, and thus alter the bile acids (more secondary bile cecal resection) [58].
acids) and so predispose to gallstone formation. A slower Much data suggests that ileal resection results in altera-
gut transit time also allows more secondary bile acids to be tion of bilirubin rather than cholesterol metabolism so result-
manufactured. ing in pigment gallstone formation (Table 1). Ileal resection
Fig. 3 Pathogenesis of Ileal disease/resection

gallstones in patients with
intestinal failure
Surgery
Calcium bilirubinate
Weight loss stasis sludge
gallstones
Parenteral nutrition
Drugs
Vagotomy
Table 1 Gallstones in Crohn’s disease: disturbance of cholesterol or large bowel may occur in Crohn’s disease and may influence
bilirubin metabolism? gallbladder contractility.
Researchers Year Subjects Main findings In contrast to the increased prevalence of gallstones in
Dowling RH, Bell 1972 Patients with Increased cholesterol women compared to men in the general population, female
GD, White J [53] Crohn’s saturation index sex does not seem to be a risk factor for gallstones in Crohn’s
disease
Dowling RH, 1971 Rhesus Cholesterol disease [10]. In fact, some data suggest a higher prevalence
Mack E, Small monkey’s supersaturation of gallstones in men receiving PN compared to women [22].
DM [59] ileal resection Lithogenic bile model Men with a short bowel with or without a retained colon have
Kelly TR, Klein 1972 Prairie dog’s Increased cholesterol/ a much higher prevalence of gallstones than women [16].
RL, Woodford JW ileal resection phospholipid ratio
A diagnosis of CD, intestinal surgery, prolonged NSAID
[60]
Pitt HA, Lewinski 1984 Prairie dog’s Pigment gallstones use, disease activity and duration and bowel stenosis have
MA, Muller EL, Ileal resection Increased bilirubin been associated with cholecystonephrolithiasis in IBD [66].
Porter-Fink V, Den concentration in bile
Besten L [61]
Brink MA, Slors 1999 Patients with Increased bilirubin levels
FM, Keulemans Crohn’s in bile, probably
Fasting and Parenteral Nutrition
YCA, et al. [62] disease or secondary to enhanced
ileal resection colonic uptake of Patients who have a reduced or absent oral intake (e.g. if hav-
bilirubin ing total PN) may experience long periods when food-
stimulated intestinal hormone secretion (e.g. cholecystokinin)
in the prairie dog led to the development of pigment gall- is not activated. Cholecystokinin secretion in response to a
stones in 44% of animals compared to none in the control meal is significantly decreased in short bowel patients [67].
group [61]. Calcium bilirubinate crystals were found in up to This may result in gallbladder stasis and the rapid formation
94% of animals who underwent ileal resection and in none of of biliary sludge [21, 50, 68]. As reviewed above, the inci-
the control groups. It was noted that calcium and total biliru- dence of biliary sludge rapidly increases from 6% at three
bin concentrations in bile were significantly greater in ileal- weeks of TPN to 50% between four and six weeks, and 100%
resected animals. after 6 weeks [21]. The sludge gradually disappears when
Data from patients with ileal resection receiving TPN oral refeeding is begun [21]. Gallstones will have started to
have shown that there is a predisposition to development of become apparent by 4 months [21]. Bile is not supersatu-
pigment gallstones. Analysis of stones from adults and chil- rated consequent on TPN [69], but bile flow is impaired [70]
dren who have had significant ileal resection necessitating and gallbladder emptying during both continuous and cyclic
long-term parenteral nutrition shows that pigment rather than infusions is reduced [71]. A medium/long chain triglyceride
cholesterol stones form in the majority of these patients [56]. mixture in a PN regimen may be more likely to cause biliary
Research in humans has shown that there is a three- to sludge than one of long chain triglycerides alone [67]. In
tenfold increase in bilirubin levels (unconjugated and conju- children on PN, cholelithiasis may be associated with a mas-
gated) in gallbladder bile in patients with ileal disease and/or sively dilated gallbladder [18].
resection for Crohn’s disease compared to patients with Bile flow is impaired when PN is given [70]. Current evi-
ulcerative colitis or Crohn’s colitis [62]. Biliary bilirubin dence suggests that bile is not supersaturated as a conse-
concentrations correlated positively with the anatomic length quence of PN [69], but that prolonged stasis may be the key
of resection and duration of ileal disease. This shows that pathogenetic mechanism for increased cholelithiasis. The
there is an increase in the enterohepatic cycling of bilirubin evidence for the dominant role of stasis in this scenario
secondary to enhanced uptake of bilirubin in the colon. This comes from several sources. Gallbladder contractility mea-
may explain the increased risk of pigment gallstone forma- sured by ultrasound is reduced in patients receiving paren-
tion in patients with terminal ileal Crohn’s disease and after teral feeding [71]. The cholesterol saturation index in bile in
an ileal resection. prairie dogs receiving PN is not increased but gallbladder
There are several proposed mechanisms for reduced gall- stasis is noted [72].
bladder contractility in Crohn’s patients. Reduction in intes- Improved radiological imaging has lent itself to the investi-
tinal release of cholecystokinin or other peptides due to gation of gallbladder disease. Radionuclide imaging of the gall-
proximal small bowel disease may be a factor [63]. The num- bladder revealed biliary tract abnormalities in 92% of patients
ber of argentaffin cells in colonic mucosa in patients with who received PN [73]. Ultrasonographic measurements of gall-
ulcerative colitis is reduced [64]. Reduction in levels of pep- bladder motility during use of PN showed that, while maximal
tide YY concentration in the colonic mucosa of patients with gallbladder volume was similar in PN patients and controls,
ulcerative colitis and Crohn’s disease has also been demon- gallbladder emptying was significantly reduced in parenterally
strated [65]. Thus, changes in peptide secretion by small and fed patients during both continuous and cyclic infusion [71].
The mechanism underlying impaired gallbladder contrac- Many factors appear to influence development of gall-
tility in patients receiving PN is unclear. In one animal model stones in patients with inflammatory bowel disease who
using cholesterol-fed ground squirrels, agents which by- undergo surgery, including gender, episodes of fasting, TPN
passed receptors and their subsequent interactions with cal- and the type of surgery involved. Particular operations such
cium channels in the sarcolemma can restore gallbladder as ileal resection, which interfere with the enterohepatic bile
contractility in gallstone disease [74]. This suggested that salt cycle, are more likely to lead to gallstone formation.
bile saturated with cholesterol causes excessive integration Major abdominal surgery itself (not involving the biliary sys-
of cholesterol into the sarcolemma, thus changing its func- tem) also appears to accelerate gallstone development in
tional characteristics. The primary smooth muscle defect in some patients. Indeed, in one retrospective study of gallstone
this animal model would appear to involve the sarcolemmal formation after major abdominal surgery, surgery and age
membrane, rather than the intracellular signal transduction were the only statistically significant independent predictors
pathways or contractile apparatus [73]. of gallstone development during follow-up [79].
The finding of biliary sludge and potential for gallstone The possible mechanisms responsible for gallstone for-
formation during PN has also been documented during fast- mation in patients who have undergone major abdominal
ing after surgery. Ultrasound studies have provided evidence surgery outside the biliary tract. Lee et al. found that sludge
of the relationship between prolonged periods of fasting and preceded gallstone formation in six of 14 sludge-forming
gallbladder sludge formation in patients who have under- patients receiving TPN [51]. Gallbladder stasis and bowel
gone gastrointestinal surgery [68]. rest were felt to be important factors in sludge development.
Patients on intensive care units (who undergo periods of fast-
I s gallbladder Stasis Alone Sufficient to Cause ing) are predisposed to sludge development.
Gallbladder Disease in Patients Receiving PN? Harrison et al. found that patients who underwent valve
In untreated coeliac disease, the gallbladder enlarges, con- replacement surgery for rheumatic heart disease had a gall-
tractility after a fatty meal is reduced and biliary sludge may stone prevalence of 39% compared to 12% in a matched con-
occur [75, 76]. Reduced gallbladder contractility in response trol population [80]. No difference in the degree of
to a fatty meal has been noted in coeliac disease. This defect haemolysis between the two groups was detected; undermin-
appears to correlate well with decreased cholecystokinin ing the suggestion that excess haemolysis might be the cause
secretion [77]. Furthermore, gallbladder emptying improves of increased cholelithiasis in the surgical group.
after successful treatment with a gluten-free diet [77]. This finding has important practical and financial impli-
However, no increase in the prevalence of cholelithiasis has cations, and identification of patients at risk for development
been found in patients with coeliac disease despite impaired of gallstones postoperatively might encourage the use of pro-
gallbladder contractility. Thus, factors other than gallbladder phylactic measures such as earlier enteral feeding or admin-
stasis may be important in the development of gallstones but istration of cholecystokinin.
the lack of enteric stimulation of bile flow and impaired gall-
bladder contractility secondary to the absence of significant
oral intake may be the primary factors in biliary sludge and Rapid Weight Loss
gallstone development during PN use.
Cholesterol gallstones are common (40%) in morbidly obese
Type of Feed patients and this figure increases with a diet causing rapid
In adults those receiving parenteral lipid were at greatest risk weight loss or after weight reducing surgery [81]. 38% of
of stones [27]. In children on PN there was a higher preva- patients undergoing gastric by-pass surgery developed gall-
lence of sludge on pure soya lipid. Predictors for sludge in stones and a further 12% developed gallbladder sludge [82]
these children were young age at PN, lack of enteral feed, and these formed during the time of maximal weight loss.
and a motility disorder with stoma [78]. Reduced gallbladder motility is likely to be the most impor-
tant factor but cholesterol saturation also increases [82]. A
significant increase in the gallbladder volume occurred in
Surgery obese patients taking a low-energy, low-fat diet after 10 days
[83], and could be secondary to minimal cholecystokinin
Major abdominal (not involving the biliary system) [79], car- secretion or to excess secretion of pancreatic polypeptide or
diac valve replacement surgery [80] and a period in an inten- somatostatin (gallbladder wall relaxants).
sive care therapy [29] all predispose to gallstone development The proposed factors involved in gallstone formation dur-
with an equal sex incidence. This is again likely to be due to ing weight loss include impaired gallbladder motility and
bowel rest causing biliary stasis, biliary sludge and the for- modifications in biliary nucleation. Twenty-one obese
mation of gallstones. patients were placed on a low-calorie, low-fat diet for weight
reduction purposes [83]. A significant increase in the gall- term, it may shorten gut transit time (mainly by accelerating
bladder volume after 10 days ingestion of this diet was noted, colonic transit) and so increase dependency on PN. These
and was attributed to poor gallbladder contractility second- sequelae which may be due to a change in bile acid composi-
ary to minimal stimulation of cholecystokinin secretion or to tion (more diarrheogenic secondary bile acids) develop early
excess secretion of gallbladder wall relaxants such as pan- and persist for at least 4 years [94]. Furthermore, some data
creatic polypeptide or somatostatin [84, 85]. suggest that patients who have a short bowel and a cholecys-
tectomy may be more prone to liver fibrosis/cirrhosis [95].
Drug Treatments
Medical Prevention and Dissolution Therapies
The use of narcotics [86] and anti-cholinergics [87] both of
which reduce gallbladder contractility, in patients receiving There are many therapies that may prevent cholesterol gall-
PN has led to an increase in gallbladder disease. Narcotics, stones (Table 2). It is more difficult for pigment stones. The
by reducing bile flow through the sphincter of Oddi, encour- studies/reports suggest that cholesterol gallstones can be pre-
age gallbladder stasis, and anti-cholinergics have been shown vented by giving statins, ezetimibe, w3 polyunsaturated fatty
to antagonize the protective effect of sphincterotomy on gall- acids, liraglutide and many herbal, complementary or alter-
stone formation—both lending strong support to the idea of native medicines [1]. Dietary factors that may prevent the
gallbladder stasis playing the most important role in gall- development of cholesterol gallstones include a vegetarian
stone formation. Loperamide inhibits gallbladder contrac- diet, polyunsaturated or monounsaturated fat, fiber, and caf-
tion in healthy subjects at daily doses of 16 mg [88] and feine. In the past direct contact dissolution of cholesterol
inhibits pancreatic and biliary secretions in patients with a stones was done by infusing methyltertbutylether via a can-
short bowel at 6 mg daily [89]. nula into the biliary tree. Experimentally calcium bilirubi-
Octreotide, a long-acting somatostatin analogue often nate stones can be dissolved in a mixture of glycerol
used in the treatment of a high output jejunostomy, increases octanoate and EDTA [96], but no practical method of dis-
the risk of cholelithiasis [87]. It reduces post-prandial gall- solving them have been used in human clinical trials.
bladder contractility [90] secondary (more lithogenic) bile The role of medical treatments for gallstones has dimin-
acids are formed by intestinal bacteria [91] and it inhibits ished, but may on occasions, be considered an alternative to
cholecystokinin secretion. cholecystectomy in those patients who are not suitable for
surgery. The main medical treatment for gallstones, used
alone or in combination with extracorporeal shockwave lith-
Cholecystectomy and Sphincterotomy otripsy, is an oral bile salt (originally chenodeoxycholic acid
then subsequently ursodeoxycholic acid).
As several risk factors have been identified for cholelithiasis
in patients with a short bowel, namely ileal resection (espe-
cially if fewer than 120 cm of intestinal remnant is left), Changing Bile Composition
resection of the ileo-colonic junction, long-term PN and the
presence of Crohn’s disease itself, a role for prophylactic Ursodeoxycholic Acid
cholecystectomy in patients with a short bowel has been sug- Ursodeoxycholic acid (UDCA) and chenodeoxycholic acid
gested [92]. In patients with a short bowel, cholelithiasis is may, in addition to being used to help cholestatic IFALD,
usually symptomatic, often complicated by inflammation or have roles in both prevention and dissolution of gallstones in
bile duct stones, and is associated with a significant morbid- patients with intestinal failure. Chenodeoxycholic acid was
ity and mortality postoperatively.
The cumulative incidence for cholecystectomy in patients Table 2 Prevention of gallstones and biliary sludge
with Crohn’s disease after an ileal resection was 0.5% at 1 Cholecystectomy and/or sphincterotomy
year, 2.4% at 5 years, 4.6% at 10 years, and 10.3% after 20 Change bile composition
years with a higher rate in women, and higher than in the • Directly Ursodeoxycholic acid
general population [93]. Prophylactic cholecystectomy • Indirectly
should be considered when an abdominal procedure is being – Change intestinal microflora Antibiotics (Metronidazole)
– Increase gut transit Prokinetics (Cisapride)
done in patients with IF and gallstones [27]. The rationale for
Prevent biliary stasis (promote gallbladder emptying)
performing such an en-passent cholecystectomy is the mark- • Enteral feed
edly increased incidence of complications to gallstones in IF • Cholecystokinin
(76% in one study) [27]. Cholecystectomy is not without • Rapid amino acid infusions
problems; however, as a postoperative bile leak may interfere • NSAID’s
with the healing of any new intestinal anastomosis. Longer- • Avoid octreotide
used first but due to a dose-dependent increase in amino- be a good preventative option in patients having PN with no
transferases, an increase in serum low-density lipoprotein or little oral intake. In prairie dogs, daily injections of chole-
cholesterol and the development of bile salt-induced diar- cystokinin [30], or sphincterotomy [31], prevented gallstone
rhoea, it was superseded by ursodeoxycholic acid (urso formation. Data from human studies suggest that use of cho-
stands for bear from which it is derived) and has been suc- lecystokinin in patients receiving TPN stimulates gallbladder
cessfully used for patients to dissolve gallstones. emptying and prevents stasis and subsequent sludge forma-
UDCA decreases biliary cholesterol saturation by tion [32, 72]. The prophylactic use of cholecystokinin in adult
40–60% (i.e. makes cholesterol more soluble and less able to patients receiving total (no oral intake) PN, especially those
crystalize), by inhibition of cholesterol absorption in the with an ileal resection in whom the incidence of gallstone
intestine, reducing cholesterol secretion into bile and reduc- formation is increased may be beneficial. In children of whom
ing the concentration of several crystallization-promoting 10% develop mostly asymptomatic gallstones while having
factors (for example, amino-peptidase N, haptoglobin and total PN, cholecystokinin-octapeptide prophylaxis did not
some immunoglobulins) [97–99]. In addition UDCA prevent the PN-associated gallstones forming. In addition,
decreases the toxicity of bile acids which can damage cell URDA did not dissolve gallstones, once identified [103].
membranes and cause cholestasis [100]. The use of rapid infusion of amino acids [104–106] for
UDCA is most effective in patients with good gallbladder example 125 mL of an aminoacid mixture (Synthamin 14
function (and a patent cystic duct) who have few small non- without electrolytes) over 5 min (2.1 g/min) produced a 64%
radio-opaque cholesterol stones (<10–20 cm in size). UDCA reduction in gallbladder volume within 30 min [105]. A rapid
has been used successfully to reduce the number of episodes infusion prevents the formation of biliary sludge [106].
of pancreatitis due to microscopic gallstones or biliary sludge
[100]. The bile salt therapy may be required for more than 6 spirin and Non-steroidal Anti-inflammatory
A
months. The problem of UDCA is that there is a high recur- Drugs
rence rate of gallstones of 30–50% at 5 years and 50–70% at Studies involving the cholesterol-fed prairie dog showed that
12 years, after successful treatment [101]. use of high-dose aspirin prevented gallstone recurrence after
UDCA has not been studied in IF patients in whom there successful dissolution therapy. A decrease in mucin glyco-
may be major problems with absorption. protein involved in nucleation was found and, as aspirin is an
inhibitor of prostaglandin formation, it was suggested that
I ncrease Gut Transit or Change Intestinal secretion of mucin might be prostaglandin-mediated [107].
Microflora However, research in the same model showed that, at thera-
Slow intestinal transit results in more primary bile acids peutic doses, non-steroidal anti-inflammatory drugs
being converted by bacteria to the more lithogenic secondary (NSAIDs) had minimal effect on the production of mucin by
bile acids. Cisapride increases gastrointestinal transit rate the gallbladder [108].
(reversing any changes of octreotide treatment) and changes NSAIDs may prevent gallstone formation by a prokinetic
bile composition [91]. Thus it or another prokinetic drug effect on the gallbladder. In a human study, subjects with
could be useful in preventing gallstones in patients with gallstone disease given therapeutic doses of indomethacin
intestinal failure due to small bowel dysfunction. had increased post-prandial gallbladder emptying [109].
Metronidazole, by suppressing anaerobic intestinal organ- This effect was not seen in healthy control subjects. The con-
isms, reduced the rise in liver enzymes associated with par- centration of various eicosanoids in the gallbladder wall
enteral nutrition in Crohn’s disease [102]. This may be changes with bile cholesterol supersaturation and chronic
another simple way of reducing the chance of developing inflammation and it may be that inhibitors of prostaglandin
gallstones. formation such as NSAIDs promote the production of
prokinetic leukotrienes or prostaglandins in diseased but not
in healthy gallbladders.
revent Biliary Stasis (Promote Gallbladder
P
Emptying)
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Nephrolithiasis and Nephrocalcinosis
Charles R. V. Tomson and Matthew Bultitude

• Urate stones are common in patients with an ileostomy
and are prevented/treated by making the urine alkaline. Kidney stone formation, nephrocalcinosis, and resultant
• Calcium oxalate stones are common after an ileal resec- chronic kidney disease are well-recognised complications of
tion/disease providing the colon is functional and in conti- several forms of gut disease (Fig. 1). However, these are rela-
nuity. They can cause renal colic and/or end stage renal tively rare, and late, complications of gut disease, so most
disease (ESRD) by causing nephrolithiasis and/or nephro- physicians providing care for patients with gut disease lack
calcinosis which are both associated with inflammation. experience in managing these complications. Conversely,
• Calcium oxalate stones are prevented with a high fluid gut disease contributes only a small fraction of the caseload
intake, low oxalate diet, calcium supplements (to bind managed by most nephrologists or urologists. There are no
oxalate in the gut), preventing hypomagnesaemia, acido- randomized controlled trials informing the management of
sis (associated with low citrate) and pyridoxine defi- these complications. Absence of evidence for the benefit of
ciency. Cholestyramine and a reduced fat intake may be treatment is not the same of evidence of absence of benefit,
beneficial.
• Renal colic is common. Patients should have urine dip-
stick ± culture, serum creatinine, calcium and urate. A
computerized tomography (CT) scan of the kidneys, ure-
ters and bladder (CT KUB) is the recommended investi-
gation due to high sensitivity and specificity.
• Septic obstructed kidney is a medical emergency and
should prompt immediate drainage with ureteric stent or
nephrostomy tube.
• For renal stones, treatment options are surveillance,
shockwave lithotripsy, flexible ureteroscopy or percutane-
ous nephrolithotomy. Choice will depend on patient
choice, surgical expertise, size and location of the stone.
Fig. 1 Plain abdominal radiograph of a patient who had undergone

C. R. V. Tomson (*) extensive small bowel resection in 1985 as a result of spontaneous mes-
Department of Renal Medicine, Freeman Hospital, Newcastle upon enteric thrombosis complicating the lupus anticoagulant syndrome.
Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Stone formation was first reported in 1988, since when the patient had
e-mail: [email protected] passed hundreds of calcium oxalate stones. Three months prior to this
M. Bultitude radiograph being taken he was admitted with acute renal failure, septi-
Department of Urology, Guy’s and St. Thomas’ NHS Foundation caemia and pyonephrosis as a result of obstruction by stones. Urinary
Trust, London, UK oxalate was >1.0 mmol/day, but fell to 0.3 mmol/day on a synthetic
e-mail: [email protected] oxalate-free diet

404 C. R. V. Tomson and M. Bultitude
however: patients developing these complications therefore patients with Crohn’s disease and 3.0% of patients with
require specialized management. Such treatment, albeit Ulcerative Colitis, over a median disease duration of 12.8
based on limited evidence, can undoubtedly be successful in and 11.2 years respectively. In multivariate analysis, male
changing the course of disease and preventing life-changing gender, higher disease activity, intestinal surgery, use of non-
complications. steroidal anti-inflammatory drugs and reduced physical
activity were independent predictors of kidney stone disease.
Similar risk factors were reported for gallstones; patients
History and Epidemiology with gallstones had a relative risk of 4.87 (95% CI 2.8–8.0)
for kidney stones [31].
The first reports suggesting an increased risk of kidney No large-scale study of the epidemiology of kidney stones
stones amongst patients with inflammatory bowel disease has identified the proportion of episodes that are attributable
were published in the 1960s [1–10]. Both uric acid and cal- to intestinal disease. This proportion is probably very small,
cium oxalate stones appeared to be more prevalent than given the high and increasing frequency of kidney stone dis-
expected. A landmark study in 1972 was the first to demon- ease in the general population [32, 33].
strate hyperoxaluria in patients with ileal resection, bacterial Similarly, the proportion of incident end-stage kidney
overgrowth, sprue, and other conditions characterized by fat failure caused by complications of intestinal disease is also
malabsorption [11]. It has subsequently become clear that very small, although such cases do exist [19, 34]. The best
patients with ileostomies are at increased risk particularly of attempt to quantify the risk comes from a national registry
uric acid stones; patients with malabsorption and an intact study in South Korea, in which 38,812 patients with inflam-
colon are at particularly high risk of calcium oxalate stones. matory bowel disease were matched 3:1 with people from
The introduction of jejunoileal bypass for obesity was soon the general population. Over a mean follow-up period of 4.9
followed by recognition that this form of surgically induced years, end-stage kidney disease (ESKD) was detected in 79
intestinal disease was also associated with a significantly patients with inflammatory bowel disease (0.2%) compared
increased risk of stone disease [12–15]. to 0.1% of controls; this was driven by an increased risk of
Later reports have focused not only on kidney stone for- ESKD amongst patients with Crohn’s disease (adjusted haz-
mation but also on biopsy-proven oxalate nephropathy caus- ard ratio 6.33, 95% CI 2.75–14.56) with no increased risk in
ing progressive kidney failure amongst patients with Crohn’s Ulcerative colitis (adjusted hazard ratio 2.01, 95% CI 0.9–
disease and other causes of enteric hyperoxaluria [14, 4.51) [35].
16–20].
The precise frequency of these complications is difficult
to determine, as the risks of stone formation and oxalate Pathophysiology
nephropathy vary with the severity and type of the underly-
ing gut disease and with length of follow-up. Amongst The pathophysiology of kidney stone formation in general
patients with Crohn’s disease, urolithiasis is more common has been discussed in detail elsewhere [36, 37].
amongst patients who have undergone surgery compared to Calcium oxalate is highly insoluble, with a solubility of
those undergoing medical management. Most early reports around 7 mg/L at 37 °C in simple solution. However, urine is
were single-centre case reports or series, with no denomina- an extremely complex solution, containing inhibitors and
tor. Recent systematic literature reviews have summarized promoters of crystallization. For instance, citrate and pyro-
these reports [21–24], giving estimated life-time risks for phosphate form soluble complexes with calcium, thus
urolithiasis of 9–18% in patients with inflammatory bowel decreasing calcium availability; magnesium forms a soluble
disease: the risks are higher with increasing age, with Crohn’s complex with oxalate; and Tamm-Horsfall glycoprotein and
disease compared to ulcerative colitis [25], and with ileal other glycosaminoglycans inhibit one or several phases of
resection, particularly of the distal ileum [25]. Colonic pres- calcium oxalate stone formation. Even though normal urine
ervation is associated with an increased risk of stones [26]. is supersaturated with respect to calcium oxalate, calcium
Urolithiasis in children with inflammatory bowel disease is oxalate crystals do not normally form in free solution, but
rare, but does occur [27, 28]. Patients with ileal pouch after rather by deposition on existing surfaces, such as tubular
total colectomy remain at risk [29], although there are no casts, sodium urate or uric acid crystals, or cell debris [38].
controlled comparisons of stone frequency with pouch com- Uric acid is a weak acid, with a pK of 5.75. Undissociated
pared to ileostomy. Amongst patients with ulcerative colitis, uric acid is highly insoluble, with a solubility limit of 100
total colectomy is associated with markedly increased risk of mg/L, whereas urate salts are very much more soluble (e.g.
stone disease [6, 10, 30]. 1200 mg/L of urate at pH 6.5). Urine pH is therefore the
Possibly the best prospectively collected information main determinant of uric acid solubility; the most important
comes from the Swiss National Inflammatory Bowel Disease risk factors for uric acid stone formation are therefore high
Cohort Study. Kidney stones were reported in 4.6% of urine concentration and acid urine (Fig. 2). Total uric acid
Nephrolithiasis and Nephrocalcinosis 405
URINE pH concentration [43]. Thus, changes in urinary oxalate con-

4.5 5.0 5.35 centration are very much more important as a risk factor
600 for stone formation than changes in urinary calcium
concentration.
2. Oxalate is only absorbed from the gut in ionized form.
UNDISSOCIATED URIC ACID (mg/L)
500 5.5
Excess calcium in the gut lumen thus decreases oxalate
bio-availability by the formation of insoluble calcium
400 oxalate. Several studies have confirmed that, independent
5.75 of other factors, urinary oxalate excretion decreases with
300 increasing dietary calcium intake [43, 44], and, con-
versely, that dietary calcium restriction increases absorp-
6.0 tion of dietary oxalate, resulting in an increase in the
200
probability of stone formation [45]. Similarly, adminis-
tration of sodium cellulose phosphate (which decreases
100 gut absorption of calcium) results in an increase in uri-
6.5
nary oxalate excretion [46]. Increased intestinal absorp-
tion of calcium, as in vitamin D treatment and ‘absorptive
0 200 400 600 800 1000 1200 hypercalciuria’ may also increase stone risk not so much
because of the resulting increase in urinary calcium con-
TOTAL URIC ACID CONCENTRATION (mg/L) centration but because of the resulting hyperabsorption of
Fig. 2 Relationship between urine pH and solubility of uric acid.
oxalate.
Redrawn with permission [100]
excretion is often normal in patients with uric acid stones, Enteric Hyperoxaluria
although increased production of uric acid as a result of
increased purine catabolism can cause stone formation [39]. The major factor causing stone formation and kidney dam-
Patients with intestinal disease are at increased risk both age in gut disease is hyperoxaluria [47]. Enteric hyperoxal-
of calcium oxalate stones and oxalate nephropathy, and of uria has now been reported in a wide range of conditions that
uric acid kidney stones. Although the two conditions share alter oxalate bioavailability in the colon, including
some risk factors, most importantly reduced urine volume
and flow rate, calcium oxalate stones are largely caused by • Ileal resection [11, 48]
enteric hyperoxaluria, and uric acid stones by excessive urine • Jejuno-ileal bypass [18, 49, 50]
acidity due to alkali loss in ileostomy effluent. • Coeliac disease [51]
• High-dose oral phosphate supplementation [52]
• Intestinal lymphangiectasia [53]
I nfluence of Dietary Calcium Intake • Roux-en-Y gastric bypass [19, 54, 55]
on Oxalate Bioavailability • Orlistat therapy [56, 57]
• Chronic pancreatitis [58]
Epidemiological studies in men [40] and women [41] have
shown that a high dietary calcium intake reduces the risk of It has been known since the 1970s that enteric hyperoxaluria
developing renal stones. Other studies have also showed that is due to excessive absorption of dietary oxalate in the colon
variations in urinary calcium excretion are poorly, if at all [48, 59–65]. Two major mechanisms account for this. Firstly,
predictive of stone recurrence, whereas the risk of recurrence unabsorbed fatty acids form soaps with calcium in the gut
appears to increase exponentially as urinary oxalate excre- lumen. This reduces the amount of calcium in the gut lumen
tion increases [42]. The explanation for this paradoxical rela- that is available to bind to oxalate, thus increasing oxalate
tionship between calcium intake and stone risk is twofold. bioavailability. Secondly, unabsorbed bile acids increase
colonic permeability to oxalate [66]. High-dose chenode-
1. Studies in vitro and computerized iterative calculation of oxycholic acid for gallstone dissolution is associated with
activity products show that the risk of calcium oxalate increased absorption of radiolabelled oxalate [67].
crystallization in urine is little affected by variations in Absorption of oxalate after a test meal correlated so well
urine total calcium concentration (as a result of the for- with fat malabsorption that some investigators suggested that
mation of soluble complexes which decreases calcium it should be used as a diagnostic test for steatorrhoea [68, 69]
availability) but increases linearly with increasing oxalate although this test did not prove reliable [70].
Figure 3 summarises current understanding of the patho- largely by activating an innate inflammatory pathway, the
genesis of enteric hyperoxaluria, although the prominence nucleotide-binding domain leucine-rich repeat inflamma-
given to the possible contribution of vitamin B6 deficiency to some 3 (also called NALP3, NLRP3, or cyropyrin) [78–81].
hyperoxaluria is, as discussed below, speculative at best. In future, these findings might lead to new therapeutic
Since the 1970s, our understanding of the mechanisms of options to prevent the progressive kidney failure that can
oxalate transport in the colon has advanced considerably. It complicate enteric hyperoxaluria.
is now known that an active oxalate transporter, SLC26A6, is
responsible for oxalate secretion into the gut lumen [71, 72].
Oxalate absorption has long been thought to be passive and Mechanisms of Stone Formation
paracellular [73] although more recently it has been sug-
gested that SLC26A3 also mediates oxalate absorption [74]. Careful histopathological work has shown that the mecha-
Pro-inflammatory cytokines inhibit SLC26A6-mediated nism by which kidney stones form in patients with bypass
oxalate secretion, resulting in increased urinary oxalate surgery differs from that in ‘idiopathic’ kidney stone formers.
excretion: this is one mechanism by which obesity increases Inner medullary collecting duct crystals, comprising calcium
the risk of calcium oxalate stones [75]. A case report in a oxalate and hydroxyapatite, have been described in bypass
patient with subclinical coeliac disease and oxalate nephrop- patients but not in patients with idiopathic calcium oxalate
athy suggested reduced SLC26A6 expression as a contribu- stone disease [82]; whereas patients with ileostomies form
tor to hyperoxaluria [76]. SLC26A6 is also an inhibitor of interstitial hydroxyapatite deposits (known as Randall’s
the succinate transporter NaDC1, and reduced activity results plaques) and inner medullary collecting duct crystals made of
in reduced urinary citrate and an increase in serum succi- hydroxyapatite and uric acid salts [83]. In patients with gut
nate—which may cause renin-dependent hypertension [77]. resection, deposits in the inner medullary collecting duct uni-
formly contain hydroxyapatite, with a minority also contain-
ing calcium oxalate, with abundant Randall’s plaque [84].
Pathogenesis of Oxalate Nephropathy
It was previously thought that hyperoxaluria caused kidney Hypocitraturia

damage solely by causing obstructive nephropathy, resulting
from tubular or ureteric obstruction by calcium oxalate kid- Citrate is the most important inhibitor of calcium oxalate
ney stones. While this may well play a role, it is now clear crystallization in the urine; hypocitraturia is therefore a
that calcium oxalate crystals cause parenchymal damage major risk factor for kidney stone formation [85, 86].
Fig. 3 Pathogenesis of
enteric hyperoxaluria. From Vit B6 glyoxylate
Nazzal et al. [34], with Malabsorption
permission
FFA Calcium Soluble Oxalate
Bile acids Oxalate permeability
Inflammation
Dietary Plasma
Colonic lumen Oxalate
Oxalate
Urinary Oxalate
Nephrocalcinosis Nephrolithiasis
Inflammation
ESRD
Hypocitraturia is usually defined as urine citrate excretion Oxalobacter formigenes in the gut microbiome is associated
<1.67 mmol/24 h; average daily excretion in healthy indi- with higher urine oxalate excretion and an increased risk of
viduals is around 3.12 mmol/24 h [87]. Systemic acidosis is recurrent stone formation in patients without gut disease
an important cause of hypocitraturia, but the amount of [96]. In animal models, the organism promotes oxalate secre-
citrate filtered at the glomerulus is also a determinant. tion into the colonic lumen [97]. However, numerous other
Hypocitraturia is common in patients with malabsorption gut organisms, including some species symbiotically linked
and is due both to reduced filtered load and acidosis [88]. to Oxalobacter formigenes but without a direct role in oxa-
late breakdown, can affect oxalate metabolism in the gut
[98].
Low Urine pH
Highly acidic urine favours the formation of calcium oxalate Vitamin Malabsorption
and uric acid stones, and is common in patients with various
forms of gastrointestinal disease, including those with ileos- In health, most of the oxalate excreted in the urine comes
tomy [47, 50, 89]. from the liver, where oxalate is a metabolic end-product of
amino-acid metabolism. Pyridoxine is a co-factor for ala-
nine: glyoxylate aminotransferase, the enzyme that is defec-
Low Urine Volume tive in type 1 primary hyperoxaluria. Reduced enzyme
activity results in accumulation of glyoxalate and subsequent
Low urine volume results not only in increased concentra- overproduction of oxalate. High-dose pyridoxine can some-
tion of stone components but also causes reduced flow rate, times ameliorate hyperoxaluria in primary hyperoxaluria
which increases the risk that crystals will agglomerate and type 1, depending on genotype [99]. Pyridoxine deficiency
adhere to the urothelium. Low urine volume is a common caused by malabsorption could in theory contribute to hyper-
finding in many forms of gastrointestinal disease and results oxaluria in patients with intestinal disease [34], but this
from excessive fluid loss in the gut [47, 50, 90]. remains speculative: no study has demonstrated an associa-
tion between pyridoxine status and endogenous oxalate pro-
duction or urine oxalate excretion in patients with
Low Urine Magnesium malabsorption, nor are there even case reports showing that
pyridoxine supplementation reduces oxalate excretion in
Along with citrate, magnesium is an important inhibitor of patients with enteric hyperoxaluria.
calcium oxalate crystal formation. Hypomagnesuria in gas-
trointestinal disease is caused by malabsorption of magne-
sium [50, 91], which can be exacerbated by long-term use of ric Acid Kidney Stones Complicating
U
Proton Pump Inhibitors [92]. Ileostomy
The major risk factor for the formation of uric acid stones is
Effect of the Gut Microbiome urine acidity (Fig. 2) [39, 100]. Urine uric acid concentration
plays a lesser role. Although diet plays some part in deter-
Our previous understanding, in which oxalate absorption mining urine acidity (ingestion of animal-derived protein
was a passive process governed by oxalate intake and colonic being the major contributor to fixed acid excretion), the
‘permeability’ to oxalate, has now been superseded as major cause of highly acidic urine is excessive gastrointesti-
knowledge has grown. We now understand that the gut nal loss of bicarbonate—most commonly as the result of an
microbiome plays a crucial role in determining the amount ileostomy. This is combined with a chronic state of salt and
of oxalate absorbed from the gut. Several organisms metabo- water depletion causing reduced urine flow and increased
lise oxalate in the colon. In particular, the presence or urine concentration [4, 7, 90, 101]. These abnormalities are
absence of Oxalobacter formigenes, a normal anaerobic further exacerbated in patients with short gut.
colonic commensal, helps to determine overall oxalate bur- Although less directly relevant in a chapter on intestinal
den. This organism metabolises oxalate to carbon dioxide. failure, it is also noteworthy that obesity is strongly associ-
Antibiotics can reduce both oxalate-degrading capacity and ated with an increased risk of uric acid stones, due to an
colonic carriage of the organism [93]. In the general popula- ill-
understood defect in urine buffering capacity that
tion, exposure to antibiotics is associated with an increased occurs in the presence of obesity and insulin resistance
risk of kidney stone formation [94, 95]. Absence of [102–104].
Dietary Sources of Oxalate Table 1 High oxalate foods. Compiled from numerous sources,
including: case reports of acute oxalate nephropathy (see text). United
States Department of Agriculture Agriculture Handbook 8-11, 1984:
Restriction of dietary oxalate intake is clearly part of a logi- https://www.ars.usda.gov/northeast-a rea/beltsville-m d-b hnrc/
cal approach to treatment of enteric hyperoxaluria. It should beltsville-human-nutrition-research-center/nutrient-data-laboratory/
be obvious that advising patients to avoid a few very high docs/oxalic-acid-content-of-selected-vegetables/—the data from this
table are also available sorted by oxalate content at http://www.
oxalate foods (e.g. spinach, rhubarb, beetroot), that are infre-
petsnails.co.uk/documents/oxalates.html; a table previously published
quent components of most diets, is unlikely to have much by the Oxalosis and Hyperoxaluria foundation, www.ohf.org but no
effect on daily oxalate excretion: most dietary oxalate is longer available on their website; dietary advice from the University of
ingested in commonly-used foods with moderate or high Chicago, which provides detailed advice on food oxalate content,
including how to translate this into practice http://kidneystones.uchi-
oxalate content: wheat bran is a good example.
cago.edu/how-to-eat-a-low-oxalate-diet/; data compiled by the Harvard
Assessment of the oxalate content of food is complex, as TH Chan School of Public Health https://regepi.bwh.harvard.edu/
oxalate content can vary within individual foods from culti- health/Oxalate/files (this also provides advice on interpretation of the
var to cultivar and from season to season, as can the propor- data, a table of low-oxalate alternatives to high-oxalate foods and other
resources for dietitians); a website www.oxalate.org compiled by a
tion held as the calcium salt versus the soluble salts
patient from seven sources, not all of which remain available
(predominantly potassium oxalate)—the soluble salts have
Very high oxalate foods: to be avoided completely
much greater bioavailability. Boiling foods removes some
Star fruita (Averrhoa carambola)
soluble oxalate. Oxalate content also varies within foods— Irumban pilia (Averrhoa bilimbi)
for instance, in whole grains oxalate is concentrated in the Rhubarba
bran fraction, so refined flour contains less oxalate than unre- Peanutsa
fined flour, and bran products contain high amounts of oxa- Iced teaa
late. Preparation and cooking methods, and the calcium Chaga mushroomsa
content of the food, further add to variability in bioavailabil- Spinacha
Green ‘smoothies’ (depends on raw ingredients)a
ity of dietary oxalate [105]. This variability probably explains
Almonds
the wide variation in publicly available sources of advice on Amaranth seeds and leaves
dietary oxalate [106], and cannot easily be resolved (Table 1). Bamboo shoots
N.B. As discussed, both oxalate content and bioavailabil- Beetroot and beet leaves
ity are highly variable and can depend on the cultivar, the Black tea
method of cultivation, the season of harvest, and the precise Bran flakes
part of the plant used. Different sources give widely different Brown rice and brown rice flour
Buckwheat groats, flour, and leaf
values for oxalate content of the same foodstuff: this may
Bulghur wheat
relate to differences in assay method. Oxalate content may Cassava
also change during processing. Some soluble oxalate (e.g. Chard
sodium oxalate) can be removed by cooking in water, but this Chives
will clearly depend on cooking time and volume of water. Cocoa powder
Bioavailability depends on what the food is ingested with: a Corn grits
large dollop of cream on a bowl of raspberries may well sub- Cornmeal
Fava beans
stantially reduce the amount of oxalate absorbed, as would
Haricot beans (“Navy beans” in US parlance)
milk taken with breakfast cereals derived from wheat bran. Millet
Many sources provide data on oxalate content of named Miso soup
brands, e.g. of breakfast cereals commonly sold in North Okra
America: these are of limited utility elsewhere. Oxalate con- Parsley
tent is often measured in mg/100 g, but can also be expressed Poppyseed
per serving size: black pepper, for instance, has an oxalate Potatoes, baked with skin
Purslane
content of >3000 mg/100 g, but the amounts used in cooking
Rice bran
make this of very limited relevance. Sesame seeds
Soya flour and other soy products
Sorrel
Acute Oxalate Nephropathy Tahini
Wheat bran
Acute oxalate nephropathy is increasingly recognized as a High oxalate foods
Nuts
cause of acute kidney injury that can, if left untreated, prog-
Cashew nuts
ress to cause end-stage kidney failure. This syndrome is most
(continued)
Table 1 (continued) ence of intestinal disease greatly increases the risk at any
Hazelnuts given level of oxalate intake, as demonstrated in a number of
Peanut butter reports [121, 122]. These foods and food supplements should
Pecan nuts therefore be avoided in all patients at risk of enteric
Vegetables and legumes hyperoxaluria.
Beans—fava, red kidney, refried
Carrots (raw)
Celery (raw)
Collard greens ietetic Advice for Patients with Enteric
D
Okra Hyperoxaluria
Parsnip
Mustard greens Notwithstanding the variability in oxalate content and bio-
Potatoes—fried or chipped availability discussed above, and the fact that studies of oxa-
Swede (Rutabaga)
late bioavailability have largely been performed in normal
Sweet potatoes—baked
Tomato paste
subjects rather than in patients with enteric hyperoxaluria, it
Turnip remains reasonable to equip patients with advice on which
Yams foods to avoid entirely, which foods should be used with
Breads, pasta, rice care, and which foods are likely to be ‘safe’ with respect to
French toast the risk of stone formation and oxalate nephropathy. Such
Lasagna advice should be given by a dietitian: ideally all services pro-
Rice bran
viding care for patients with enteric hyperoxaluria should
Spaghetti
Fruit and juice
have a dietitian who is knowledgeable in this area. Table 1
Avocado contains an initial guide to the oxalate content of food. A
Dates comprehensive list, compiled by a patient from a variety of
Grapefruit sources, can be found at www.oxalate.org.
Kiwi fruit
Orange
Pineapple
Investigation
Raspberries
Breads, grains, and breakfast cereals
Bagels Biochemistry
Bran flakes
Cornmeal Patients with intestinal disease who develop symptomatic
Couscous renal colic, are found to have asymptomatic kidney stones on
French toast imaging, or who develop unexplained acute or chronic kid-
Millet
ney disease, should all be offered further investigation with a
a
Implicated in case reports of acute oxalate nephropathy view to treatment. Biochemical evaluation should include
the following
commonly recognized after excessive ingestion of a dietary
source of oxalate. Substances responsible include the • Full biochemical profile (including eGFR, calcium, mag-
following: nesium, bicarbonate, urate)
• Spot urine pH (ideally using a pH meter, as these are more
• Star fruit (Averrhoa carambola) [107–109]—ingestion accurate than urine dipsticks)
can also cause chronic oxalate nephropathy [110] • 24 h urine for volume, creatinine, sodium, calcium, mag-
• Irumban puli (Averrhoa bilimbi), used in a traditional nesium, citrate, and oxalate (all these analyses can be per-
remedy in Kerala [111] formed on a single 24 h urine collection: most laboratories
• Rhubarb [112] recommend acidification of the sample to prevent in vitro
• Peanuts [113] changes, including ‘in vitro oxalogenesis’ from oxalate
• Iced tea [114] precursors)
• Massive Ascorbic acid intake [115–117]
• Green smoothies [118, 119] The purpose of including 24 h urine creatinine is to allow
• Chaga mushrooms [120] assessment of the completeness of urine collection. This is
particularly useful when comparing repeated 24 h urine col-
If dietary oxalate is excessive enough, this can occur without lections over time: barring significant changes in muscle
intestinal disease, but it is reasonable to assume that the pres- mass, creatinine excretion remains constant over time within
an individual. So if a given patient returns a 24 h urine col- Differential Diagnosis

lection containing around 10 mmol of creatinine on several
measurements but then returns one containing only 5 mmol, The primary hyperoxalurias (type 1, type 2, and type 3) are
it is safe to conclude that the latest collection is incomplete; autosomal recessively inherited disorders of hepatic amino-
similarly, if the latest collection contains 15 mmol, it is rea- acid metabolism that result in hyperoxaluria. Phenotype is
sonable to conclude that the patient continued the collection variable in each type, but in general, type 1 has a more severe
for more than 24 h. phenotype (earlier onset, higher oxalate excretion) than type
Amongst patients who cannot reliably collect a 24 h urine 2, and type 3 is milder still; a subgroup of type 1 patients
collection (children, for instance), the use of analyate: creati- respond to high-dose pyridoxine [128]. Testing for known
nine ratios is a reasonable ‘second best’ for assessment of pathogenic mutations is now the best way to confirm a
urine chemistry. These ratios rely on the assumption that the diagnosis.
excretion of both analytes remains constant over 24 h; and
that an ‘average’ adult excretes around 10 mmol of creati-
nine per 24 h. An oxalate: creatinine ratio of 0.07 mmol/ Kidney Biopsy
mmol, for instance, would suggest a 24 h urine oxalate of
0.07 × 10 = 0.7 mmol—significantly higher than the upper Patients with suspected oxalate nephropathy may present
limit of normal of around 0.45 mmol/24 h. Creatinine and with slowly progressive chronic kidney disease (CKD) or
albumin excretion show little diurnal variation (hence the with an acute deterioration in kidney function, often on a
widespread use of albumin: creatinine ratios to quantitate background of stable or slowly progressive CKD. Urinalysis
albuminuria, for instance in diabetic kidney disease) but this is often negative for blood and protein. A high index of clini-
is less true of urine calcium, magnesium, citrate, or oxalate, cal suspicion is required, as patients with CKD who have
and 24 h creatinine excretion may be substantially less than negative urinalysis are often assumed to have non-specific
10mmol in many patients with intestinal disease—so these ‘hypertensive nephrosclerosis’—a pattern of kidney damage
ratios should be interpreted with caution [123]. for which there is no treatment other than optimization of
Because of differences in assay performance, the labora- cardiovascular risk factors. In a patient with intestinal dis-
tory reference range should be used to interpret results. ease likely to cause enteric hyperoxaluria, however, this
Normal adults 24 h oxalate excretion is typically <460 assumption would be dangerous. Urine microscopy in
μmol/24 h; patients with enteric hyperoxaluria may excrete patients with oxalate nephropathy can demonstrate calcium
up to 1500 μmol/L, depending on the severity of the intesti- oxalate crystals, but the sensitivity and specificity of this
nal disease. finding is unknown. Kidney biopsy is the definitive test, and
Measurement of plasma oxalate concentration (only per- carries a low risk when undertaken by an experienced opera-
formed in a few specialized laboratories) is not helpful in tor [129]; these risks can easily be justified by the possibility
most patients, as plasma oxalate remains close to normal that the results will alter management in a patient with intes-
(e.g. <5 μmol/L) in patients with normal glomerular filtra- tinal disease and unexplained chronic or acute kidney
tion rate even in the presence of enteric or primary hyper- disease. Kidney biopsy is also indicated when mesalazine-
oxaluria. However, as GFR declines below 45 ml/ induced nephropathy—another condition causing CKD with
min/1.73 m2, plasma oxalate rises, even in the absence of negative urinalysis and normal ultrasound appearances—is a
increased oxalate load, often to concentrations of around possible differential diagnosis [23, 130].
20–30 μmol/L. In parallel, 24 h oxalate excretion may fall
(as calcium oxalate crystals are deposited in the body), so
measurement of 24 h urine oxalate in a patient with Treatment
advanced kidney failure may give a misleadingly ‘normal’
result [124]. In this situation, measurement of plasma oxa- High Fluid Intake
late may be helpful. Kidney failure of any cause will result
in hyperoxalaemia; in patients receiving modern dialysis The most rational, and certainly the safest, treatment to
plasma oxalate concentrations are usually around 30 reduce the risk of stone formation in patients who have had
μmol/L [125, 126]. Concentrations significantly higher an ileal resection or have ileal disease is to increase water
than this—e.g. >50 μmol/L—should prompt further inves- intake, and thus to make the urine more dilute, reducing
tigation for primary or enteric hyperoxaluria. In less supersaturation with respect to calcium, oxalate and any
advanced chronic kidney disease, plasma oxalate concen- other potential constituents of urinary tract stones. Ideally,
tration rises as GFR falls; at a given GFR, plasma oxalate is water intake should also be increased at night, when
lower in patients with no disorder of oxalate metabolism, decreased urine flow and increased urine concentration may
higher in patients with enteric hyperoxaluria, and higher increase the risk of stone formation, although fluid intake
still in patients with primary hyperoxaluria [127]. should also be increased at meal-times to compensate for
transient hyperoxaluria due to absorption of dietary oxalate. Table 2 Available measures to decrease risk of calcium oxalate stone
However, it is remarkably difficult to persuade patients with formation in patients with a short small bowel in continuity with the
colon. N.B. none of these therapies have been proven to prevent stone
normal intestinal function to increase fluid intake to ensure a recurrence in trials: all recommendations are based on pathophysiologi-
daily urine volume of >3 l. Drug therapy with the vasopressin cal reasoning
antagonist Tolvaptan has been proposed [131, 132], but is 1. Maintain a high flow of dilute urine by maximizing fluid
extremely expensive. absorption
In patients with short bowel and a retained colon, who 2. Low oxalate diet
may be even more reluctant to increase fluid intake, efforts 3. Calcium supplements with meals; consider sevelamer,
should also be directed to minimizing gastrointestinal fluid lanthanum, aluminium as alternatives
4. Bile acid sequestrants, particularly if there are other indications
losses, with drugs that reduce motility and/or secretions. In
5. Citrate supplements (particularly if hypocitraturic)
patients with an ileostomy or jejunostomy who have prob- 6. Magnesium supplementation (but avoid diarrhoea)
lems of renal stones, a glucose–electrolyte solution should 7. Oral oxalate decarboxylase, if current trials prove successful
be encouraged (chapter “Management of a High Output 8. Biotherapy: oxalobacter formigenes
Stoma, Jejunotomy or Uncomplicated Enterocutaneous
Fistula”) or slow release sodium supplements (as chloride or output) they remain a logical part of the treatment strategy
bicarbonate). If receiving parenteral nutrition good hydration for patients with enteric hyperoxaluria.
must be achieved and consideration given to reducing the
acidity of the solution infused (if urate stones).
Restriction of Dietary Oxalate Intake
Treatment of Enteric Hyperoxaluria The early descriptions of enteric hyperoxaluria included

convincing proof that a low-oxalate diet could normalize
The aim of treatment should be to prevent episodes of symp- urine oxalate excretion, at least in the short term [59], but
tomatic kidney stone; to prevent obstructive nephropathy provision of a low oxalate diet for the purpose of this dem-
and resultant CKD from clinically silent obstructing kidney onstration required a synthetic diet. Provision of such a diet
stones; and to prevent acute and chronic oxalate nephropa- can prove that hyperoxaluria is enteric in origin (Fig. 4). The
thy. These risks vary from patient to patient, depending on extent to which dietary restriction of natural foods results in
the severity of the gut disease and on other variables includ- reduction of oxalate excretion has never been adequately
ing habitual diet and fluid intake. The extent to which tested. One short-term study in 9 patients with mild enteric
patients will agree to additional treatment (including the hyperoxaluria after bariatric surgery suggested that a low
drug treatments listed above, a high fluid intake, and signifi- oxalate (70–80 mg/day), moderate protein, normal calcium
cant dietary restrictions) will require shared decision-mak- diet had negligible effect on urinary oxalate but did reduce
ing based on the value placed on avoidance of long-term calcium oxalate supersaturation by increasing urine volume,
complications compared to the perceived burden of treat- citrate and pH [134]. It is logical to advise patients with
ment—which, in the case of patients with intestinal failure, enteric hyperoxaluria to restrict intake of very high and high
is likely to be in addition to an already significant burden oxalate foods, but long-term studies are required.
(Table 2).
Ideally, all patients at risk of complications of enteric
hyperoxaluria should achieve a high urine volume (e.g. xalate ‘Binders’ to Reduce Bio-availability
O
>2.5 L per 24 h), urine oxalate excretion <300 μmol/24 h, of Dietary Oxalate
urine citrate excretion >3.0 mmol/24 h. Hypercalciuria (e.g.
urine calcium >6.5 mmol/24 h) should be avoided, but is sel- Calcium Salts
dom seen in patients with enteric disease. Although it may seem counter-intuitive to administer cal-
cium salts to reduce the risk of formation of calcium oxalate
stones, this is the treatment strategy for which there is the
Bile Acid Sequestrants best evidence in enteric hyperoxaluria. There is extensive
evidence in the general population that a low calcium diet is
In the seminal paper describing enteric hyperoxaluria in associated with a higher risk of kidney stone disease [40, 41,
1972, Smith et al. reported that urinary oxalate excretion was 135, 136], and good experimental evidence that absorption
normalized by Cholestyramine [11], but subsequent reports of oxalate from the diet is inversely related to dietary cal-
have cast doubt on the utility of bile acid sequestrants [67, cium [137, 138]. Amongst patients with idiopathic hypercal-
133] and this may well vary with the severity of bile salt ciuria, a randomized controlled trial showed a higher risk of
malabsorption in the individual patient. Given that bile acid recurrent stone formation with a low calcium diet [139]. In
sequestrants can improve diarrhoea (and thus improve urine patients with enteric hyperoxaluria, short-term studies have
Urine oxalate excretion (micmol/24h)

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16/12/1996
16/06/1997
16/12/1997
16/06/1998
16/12/1998
16/06/1999
16/12/1999
16/06/2000
16/12/2000
16/06/2001
16/12/2001
16/06/2002
16/12/2002
16/06/2003
16/12/2003
16/06/2004
16/12/2004
16/06/2005
16/12/2005
16/06/2006
16/12/2006
16/06/2007
16/12/2007
16/06/2008
16/12/2008
16/06/2009
16/12/2009
16/06/2010
16/12/2010
date
estimated GFR
80
70
60
eGFR
50
40
30
20
10
0
16/06/1991
16/12/1991
16/06/1992
16/12/1992
16/06/1993
16/12/1993
16/06/1994
16/12/1994
16/06/1995
16/12/1995
16/06/1996
16/12/1996
16/06/1997
16/12/1997
16/06/1998
16/12/1998
16/06/1999
16/12/1999
16/06/2000
16/12/2000
16/06/2001
16/12/2001
16/06/2002
16/12/2002
16/06/2003
16/12/2003
16/06/2004
16/12/2004
16/06/2005
16/12/2005
16/06/2006
16/12/2006
16/06/2007
16/12/2007
16/06/2008
16/12/2008
16/06/2009
16/12/2009
16/06/2010
16/12/2010
Date
Synthetic zero-
oxalate diet
Fig. 4 Repeated measurements of urine oxalate in the patient whose radiograph is shown in Fig. 1, including measurements on a synthetic zero-
oxalate diet
demonstrated a reduction in oxalate excretion with calcium minium from dialysate water into the bloodstream is the
supplements given with meals [67, 140–143]. The optimal dominant mechanism); the relative risk and benefit of using
dose probably varies between patients depending on the aluminium salts to reduce oxalate absorption in patients with
severity of the fatty acid malabsorption and on the calcium enteric hyperoxaluria has never been studied.
and oxalate content of the diet.
Lanthanum Carbonate
Aluminium Salts Lanthanum carbonate is now widely used as phosphate
Limited data suggest that aluminium hydroxide, adminis- binder for patients with chronic kidney disease, and has
tered with food, will reduce oxalate bioavailability [142, in vitro affinity for oxalate that exceeds that of calcium and
144]. The use of aluminium salts to reduce phosphate absorp- aluminium [142]. Lanthanum reduces oxalate absorption in
tion from the gut in patients with chronic kidney disease is animal models [145], and although there are no published
now thought inadvisable because of the theoretical risk of reports of its use in human enteric hyperoxaluria, it would be
aluminium intoxication (even though direct transfer of alu- a logical drug to try if other treatments fail.
Sevelamer metabolizing luminal oxalate led to early studies in adults

Sevelamer, another drug licensed for treatment of hyper- [153] and infants [154] with primary hyperoxaluria in which
phosphataemia in chronic kidney disease, reduces urine oxa- Oxalobacter formigenes was administed as frozen paste or
late excretion (although less effectively than calcium enteric-coated capsules, resulting in time-limited reduction
carbonate) in patients with chronic kidney disease [146] but in urinary oxalate; however, faecal recovery of the organism
was found to have disappointing effects in one small study of dropped directly after cessation of administration of the bio-
patients with enteric hyperoxaluria [147]. therapy [153]. However, a small randomized controlled trial
failed to show benefit, although this negative result could
Magnesium partly have been due to inaccurate 24 h urine collections
Magnesium is an inhibitor of calcium oxalate crystalliza- [155]. Biotherapy with lactobacilli has also been studied,
tion, so maintaining a high urine magnesium is likely to with positive preliminary results in patients with enteric
reduce the risk of stone formation. Magnesium also binds hyperoxaluria [156] and after an oral load of oxalate [157]
oxalate in the gut, reducing its bioavailability. Many but negative results in stone-formers with mild hyperoxal-
patients with malabsorption are also hypomagnesaemic. uria and no gastrointestinal disease [158–160].
Proton pump inhibitors can cause magnesium malabsorp-
tion [92] and should be avoided if possible. Magnesium
supplements, given with meals to maximize the effect on Enzyme Therapy
oxalate bioavailability, should be given unless these prove
to exacerbate diarrhoea. An attractive alternative to biotherapy is to deliver oxalate-
degrading enzymes to the colon, where degradation of oxa-
late in the gut lumen will reduce the amount of oxalate
Citrate Supplementation available for absorption, and stimulate oxalate transport from
the systemic circulation to the gut lumen [161]. A proof of
Citrate supplementation has a proven role in reduction of principle study in human volunteers ingesting a high-oxalate,
stone recurrence rates amongst the general population of low-calcium diet demonstrated that oral capsules containing
stone formers [148, 149]. Urine citrate excretion can be oxalate decarboxylase (Reloxaliase: Allena Pharmaceuticals)
increased by dietary changes including drinking real lemon- caused a significant reduction in urine oxalate, but did not
ade [150] and increased intake of fruit and vegetables [87] fully correct the increase in oxalate excretion caused by the
but the effects of these dietary changes on oxalate excretion intervention diet [162]. At the time of writing, trials with this
would need careful study in patients with enteric hyperoxal- product are under way in patients with primary and enteric
uria. Potassium calcium citrate supplementation has been hyperoxaluria [163]. If it proves possible to prevent absorp-
shown to reduce the lithogenicity of urine in patients with tion of a dietary oxalate load by enzymatic digestion to CO2
enteric hyperoxaluria complicating bariatric surgery [151] with a tolerable tablet burden, this treatment could revolutio-
but there are no long-term data on stone recurrence rate. nise the treatment of enteric hyperoxaluria.
Nevertheless, pharmacological treatment of hypocitraturia
with citrate supplements is logical and usually well tolerated,
and is an important therapeutic option amongst patients with revention of Inflammation Caused by
P
enteric hyperoxaluria. Crystalline Calcium Oxalate
In an animal model, N-acetyl cysteine ameliorated experi-

Thiazide-Type Diuretics mental oxalate nephropathy caused by star fruit ingestion
[164]. The relevance of this finding for human oxalate
In the general population of stone-formers, treatment with nephropathy remains uncertain.
thiazide-type diuretics, which decrease urine calcium excre-
tion (and also probably preserve bone strength) has been
shown to be effective in reducing stone recurrence rate [152]. Reduction of Hepatic Synthesis of Oxalate
However, their utility in patients with enteric hyperoxaluria,
most of whom are hypocalciuric, is uncertain. Although increased hepatic production of oxalate is not
known to be a significant contributor to hyperoxaluria in
intestinal disease, reduction of hepatic oxalate production
Biotherapy would still be expected to ameliorate hyperoxaluria. Oxalate
is produced in the liver from glyoxylate by the action of lac-
The discovery (discussed above) that Oxalobacter formi- tate dehydrogenase isoenzyme 5 (LDH5). The antiepileptic
genes regulates oxalate bioavailability in the colon by drug Stiripentol (used in a rare form of epilepsy, Dravet syn-
Fig. 5 Dissolution of a large uric acid kidney stone with potassium citrate in a patient with an ileostomy following urine alkalinisation
drome) inhibits neuronal LDH5, and has recently been reatment of Uric Acid Stones Complicating
T
shown to inhibit hepatic LDH5 as well, reducing hepatic Ileostomy
oxalate production and alleviating experimental hyperoxal-
uria in experimental animals. Children with Dravet syn- Prevention of recurrent uric acid stones in patients with
drome treated with Stiripentol had lower oxalate excretion hypovolaemia and acid urine is highly rewarding. Regular
than children with cystinuria, and Stiripentol caused a sig- alkali supplementation sufficient to achieve a urine pH of 7
nificant reduction in oxalate excretion in one child with pri- or greater can result in complete dissolution of existing
mary hyperoxaluria [165]. stones (Fig. 5) and prevents recurrent stone formation [171,
172]. Currently available alkalinizing agents are sodium
bicarbonate (either in tablet form, or as baking powder,
reatment of Kidney Failure: Dialysis
T which can be dissolved in fruit juice to improve palatability)
and Kidney Transplantation and potassium citrate (either in liquid, effervescent or tablet
form: availability varies e.g. in the UK, tablets are not
If oxalate nephropathy caused by enteric hyperoxaluria con- licensed for use, are available on an individual patient basis
tinues for long enough, end-stage kidney disease can result, only and are prohibitively expensive). Some experts caution
necessitating renal replacement therapy with dialysis or kid- that sodium bicarbonate can increase calcium excretion, and
ney transplantation. As kidney function declines, oxalate load thus increase the risk of calcium stones: this concern is prob-
exceeds the capacity of the kidney to excrete oxalate, and ably misplaced, as sodium bicarbonate does not have the
plasma oxalate concentration rises, causing calcium oxalate same effect on urine calcium excretion as sodium chloride
supersaturation. When kidney failure complicates type 1 pri- [173]. Equipping patients with urine dipsticks and advice on
mary hyperoxaluria, kidney failure can result in a devastating how to titrate the dose of alkali to achieve a fasting urine pH
syndrome of systemic oxalosis, caused by deposition of cal- of >7 can be an effective treatment strategy, depending on
cium oxalate in tissues including the eyes, blood vessels, the activation and health literacy of the patient.
heart and cardiac conducting system, peripheral nerves, and
bones [126, 166]. Standard dialysis may be insufficient to
prevent or reverse this syndrome. Patients with severe enteric Surgical Aspects of Kidney Stones
hyperoxaluria are at risk of similar complications [167–169],
although only a small number of such cases have been Renal Colic
reported, probably because hyperoxaluria is usually less
marked in enteric disease compared to type 1 primary hyper- Renal colic is the term used to describe the pain experienced
oxaluria. Kidney transplantation can be complicated by early from obstruction of the ureter and should more correctly be
oxalate nephropathy caused by mobilization of calcium oxa- termed ureteric colic. It can be one of the worst pains ever
late deposits; for this reason, it is vital to ensure a high urine experienced and is caused by obstruction and spasm of the
flow, high urine citrate, and to continue dialysis (to control ureter. Pain classically starts suddenly and radiates to the flank,
hyperoxalaemia) until graft function is well established [170]. groin and testes or labia majora. It is an important teaching
point that although the pain is often assumed to be from stone als to have better analgesic efficacy than opioids and avoid
(or stone passage), any acute obstruction of the ureter will the side-effect profile of opiate medication [175]. There is no
cause the same symptoms so other causes are sloughed renal role for anti-spasmodic medication.
papilla or clot from a bleeding transitional cell carcinoma. All Management will depend on the clinical situation and will
patients should have a urine dipstick (±urine culture) as well depend on numerous factors including presence of a normal
as blood tests for renal function, calcium and urate [174]. contralateral kidney, renal function, evidence of infection/
Non-contrast CT KUB (Fig. 6) is the recommended imag- sepsis, size and location of the stone. Urgent surgical inter-
ing of choice for patients presenting with renal colic [175] vention is recommended in four situations: presence of an
due to its high sensitivity and specificity and has almost com- infected obstructed kidney, obstruction of a solitary kidney,
pletely replaced intravenous urogram (IVU) in most coun- bilateral obstruction or if there is uncontrolled pain [174]. An
tries. Low dose protocols can be implemented to limit the infected obstructed kidney is a surgical emergency as patients
radiation dose. Ultrasound is an alternative as an initial can become seriously unwell with sepsis and can be a cause
screening tool with the benefit of avoiding ionizing radiation of mortality. Patients should be treated with broad spectrum
although often patients will still require a CT in the situation intravenous antibiotics, fluid resuscitation and urgent decom-
of acute flank pain. It may be particularly useful in children pression of the kidney. This can be with either percutaneous
and young adults [176] when an alternative diagnosis is more nephrostomy or ureteric stent placement [177] and choice
likely e.g. young female patients. will depend on local preference and availability, stone char-
Patients usually require urgent pain relief. Non-steroidal acteristics and patient factors (obesity, coagulopathy, previ-
anti-inflammatory medication (NSAID) should be offered ous reconstruction etc.). Decompression should take place as
first line [175, 176] along with intravenous paracetamol soon as possible and treatment to the stone itself should not
[176]. Opiates should be used as second line treatment for be attempted due to the risk of worsening the sepsis.
refractory pain. NSAID’s have been shown in numerous tri- If the patient is well with normal renal function, no sepsis,
normal contralateral kidney and controlled pain then often
they can be managed conservatively and given chance to
pass the stone spontaneously. Medical expulsive therapy
(MET), mainly with alpha blockers, have been used to aid
stone passage. However a number of high quality random-
ized trials have questioned the benefit of MET in recent years
[178] although at the time of writing many guidelines con-
tinue to recommend the use of MET [175, 176] because of
the cheap cost and favourable safety profile. The most benefit
is likely for larger distal ureteric stones 5–10 mm in size
[175]. Stones that fail to pass should be offered surgical
treatment with either shockwave lithotripsy or ureteroscopy.
Stones that are unlikely to pass e.g. large upper ureteric
stones should be offered early intervention.
Stones in the Kidney
When stones form in the kidney they are often asymptomatic

and are a common incidental finding on other imaging as it is
estimated to be found in 8–10% of screened populations [179].
Thus it is important to realise that not all stones need treatment
and small asymptomatic stones may be suitable for observa-
tion [175]. However patients with metabolic causes, such as
those caused by intestinal disease, would be at higher risk of
complications (stone growth, infection, colic) and should be
carefully monitored if conservative treatment is chosen.
Stones in the kidney can cause a range of symptoms
Fig. 6 Two axial slices of a CT scan of a patient with renal colic dem- including discomfort, haematuria and infection. The pres-
onstrating hydronephrosis, mild perinephric stranding (top image) and
a mid-ureteric stone (lower image). Ultrasound alone would have
ence of symptoms, stone growth, local obstruction, patient
shown hydronephrosis but would not have seen the stone in that preference, social situation (e.g. a frequent traveler) would
location all be indications for intervention [176].
Fig. 7 A modern shockwave lithotripter
Stone Dissolution Therapy oral chemolysis can sometimes give spectacular results with
dissolution of even complete staghorn stones.
Realistically only uric acid stones can be dissolved by medi-
cal management. The stone type maybe known from previ-
ous stone analyses or can be judged from radio-lucency (pure Extracorporeal Shockwave Lithotripsy (ESWL)
uric acid stones are not seen on plain KUB X-ray); stone
density (Hounsfield Units of uric acid stones tend to be low) ESWL (Fig. 7) was introduced in the early 1980s and revolu-
or surmised by body habitus (obesity), raised serum urate tionised the treatment of urinary stones at the time [180].
levels and/ or history of gout. Prior to this relatively few other options were available and
If there is a high suspicion of a uric acid stone then and open surgery was often required even for relatively small
there is no immediate need for surgery (e.g. obstruction) then stones. The principal of the non-invasive treatment is that
attempt can be made to dissolve the stone by raising the pH shockwaves are generated and targeted using either ultra-
of the urine with either sodium bicarbonate or potassium sound or X-ray localization to the stone with the aim of frag-
citrate. Regular pH monitoring should be undertaken to menting into smaller pieces which pass spontaneously. The
ensure that adequate levels (pH > 7) are reliably reached first machines required general anaesthesia and hoisting into
[175]. Regular imaging, often with ultrasound, should take a water bath but modern machines typically require only oral
place to track dissolution. Whilst sometimes disappointing, analgesia or sedation with a thin water film as coupling
medium. The procedure is often performed by trained tech-

nicians/radiographers.
Unfortunately not all stones fragment with ESWL and
making sensible choices improves stone-free rates.
Consideration needs to be given to patient habitus as obesity
makes targeting the stone more difficult with longer skin-to-
stone distances and attenuation of the shockwaves. In addi-
tion large stone burdens significantly increases the risk of
complications with ureteric fragments causing a steinstrasse
(literally a stone-street of stone fragments in the ureter).
Anatomy is important because success rates for stones in the
lower pole of the kidney are lower as the fragments sit there
are don’t drain and lead to stone recurrence [175]. Thus
assessment can be made of the angle and depth of the lower
pole calyces [181]. Consensus guidelines suggest stones up
to 2 cm can be offered ESWL in the renal pelvis, mid or
upper pole and up to 1 cm in the lower pole [175]. Many
urologists are likely to take into consideration other factors
such as stone density and skin-to-stone distance. Certainly, if
the stone does not respond in 2–3 treatments then alternative
treatments should be offered. Complication rates are lower
for ESWL compared with more invasive treatments and
often patients will choose this as an initial treatment option.
Contraindications are bleeding diathesis, pregnancy,
untreated urinary infection, distal obstruction, significant
hypertension and proximity to abdominal aortic aneurysm
[181]. Complications include haematuria, perinephric hae-
matoma, renal colic. Previous concerns that it might cause
development of diabetes have not been substantiated in large
population based studies [182].
Fig. 8 An image intensifier image from the operating theatre with con-
trast opacifying the collecting system and a flexible ureteroscope
(passed from the urethra and through the bladder) deflected into the
Uretero-renoscopy lower pole
Ureteroscopy can either be with a semi-rigid instrument— lot of the morbidity associated with ureteroscopy with 80% of
commonly called rigid ureteroscopy (rURS) or with a flexi- people finding a reduction in quality of life [183].
ble fibre-optic instrument—flexible ureteroscopy (fURS)
(Fig. 8), also known as retrograde intrarenal surgery (RIRS).
rURS is typically used to access stones in the lower, mid or Percutaneous Nephrolithotomy (PCNL)
upper ureter, while fURS is also used to access the upper ure-
ter and the pelvi-calyceal system of the kidney. Advances in The other major advance in the treatment of stone disease
technology since the 1980s with smaller instruments and was PCNL with the first report in 1976 [184]. This became
wider availability of wires, baskets and the holmium laser has popularized in the 1980s around the world and is the main-
made ureteroscopy a popular choice for all ureteric stones and stay of treatment for larger renal stones (Fig. 9a, b).
renal stones up to 2 cm in size. Recent advances have seen the Historically the procedure was performed in the prone posi-
wider use of digital and disposable instruments. tion with ultrasound and fluoroscopy used to gain access to
Ureteroscopy requires general or spinal anaesthesia and is the kidney with a needle and guidewire. This tract was then
performed via the urethra. A guidewire is placed in the kidney dilated to 26–30 Fr to allow endoscopy, stone fragmentation
and then followed with the ureteroscope. If small, a stone can and retrieval. Even the largest of staghorn stones can often be
be removed with a nitinol basket but usually it will be frag- removed via a single tract.
mented using the Holmium laser into dust and tiny fragments. More recently the supine position has become more popu-
Often a ureteric stent is left afterwards to ensure drainage of lar and miniaturisation of instruments as small as 4.8Fr used
the kidney, allow oedema to settle and dilate the ureter to for the procedure. Commonly mini-PCNL (11–20 Fr) is used
facilitate passage of the stone debris. Ureteric stents lead to a for medium sized stones with larger tracts reserved for larger
a b
Fig. 9 (a) Complex staghorn stone of the left kidney. (b) Intraoperative Image intensifier image during PCNL showing the nephroscope (and
guidewire). The stone has been cleared and contrast outlines the pelvicalyceal system
stone burdens [184]. Guidelines would suggest that stones kidney, stone type (if known), hardness of the stone (can be
>2 cm are best treated with PCNL [175], however miniaturi- judged from previous surgery or by measuring the Hounsfield
sation has led to mini-PCNL taking on smaller stone burdens Units of the stone), patient preference and surgical experience.
and a clear overlap in stone size indication with fURS. Patients Careful patient counselling is required given the obvious differ-
are commonly left with a small bore nephrostomy afterwards ences between the treatments to ensure patient expectations are
with the benefit of avoiding an internal JJ stent. Ongoing tri- met whilst giving the best chance of stone clearance. For smaller
als are examining the best treatment modality for lower pole renal stones <1 cm often ESWL will be offered 1st line with
stones 1–2 cm in size. fURS as 2nd line treatment. For stones 1–2 cm, all 3 options are
One of the advantages of the supine position has been the reasonable, and choice will depend on stone and anatomical
advent of combining both fURS and PCNL simultaneously— characteristics as well as surgical opinion and patient choice.
endoscopic combined intra-renal surgery (ECIRS). This For stones >2 cm PCNL should be the 1st line treatment. Stone
potentially offers the best of both worlds with the ability to location and anatomy are important considerations e.g. a 15 mm
retrieve large stone burdens via the PCNL tract, whilst access stone in the lower pole of the kidney may be offered different
all the calyceal system with the fURS. Stones can potentially treatment options to a 15 mm stone in the upper pole.
be moved to the PCNL surgeon—so called ‘pass the parcel’. For patients with intestinal disease where recurrence risk
PCNL is the most invasive of the procedures described in is high then ensuring complete stone clearance is important
this chapter. Common risks include bleeding with risk of and thus more invasive treatments may be considered,
transfusion up to 7% [175] although this is commonly much although this must be traded off against the high risk of need-
lower. Other risks include fever, sepsis, injury to other organs ing repeat interventions in the future for recurrent stone for-
(bowel, liver, spleen, pleura). A risk of 1:1000 of needing mation. Ultimately careful review of these patients by a stone
nephrectomy is often quoted if bleeding is uncontrolled. It is specialist taking into account patient choice is important to
likely these risks are reduced with miniaturised techniques. make the correct decisions.
Choice of Treatment Follow-up
When deciding on the choice of treatment consideration has to Regardless of treatment choice, all patients with intestinal
be given to size and location of the stone(s), anatomy of the disease should have a thorough metabolic evaluation to mini-
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Bone and Joint Disease
Loris Pironi and Anna Simona Sasdelli
Key Points 7. DEXA is recommended at yearly intervals. Biochemical

1. A metabolic bone disease (MBD) characterized by osteo- measurements of serum concentrations and 24 h urinary
penia, osteoporosis or osteomalacia may affect 40–100% excretion of minerals (calcium, phosphate and magne-
of patients on home parenteral nutrition (HPN) for sium) are made every 4 months and the measurement of
chronic intestinal failure. Fifty percent will have osteope- serum parathormone (PTH) and 25-hydroxivitamin D
nia/osteomalacia when parenteral nutrition (PN) starts. every year. Vitamin K is assessed indirectly every
2. Osteopenia occurs in 13–57% and osteoporosis in 4 months with the international normalised ratio (INR).
18–44% of patients receiving long-term HPN. It is more 8. Treatment of osteopenia/osteoporosis includes life style
common in those who were young when starting PN and changes (stop smoking, little alcohol, more exercise and
in those with a low body mass index (BMI). Many (35%) some sunlight exposure). Adequate vit D, calcium and
have bone pain. magnesium intake is ensured and if necessary biphos-
3. The common reasons for bone mineral loss are general phate infusions are given (being aware of the rare com-
causes or underlying disease rather than intestinal failure plication of osteonecrosis of the jaw) or denosumab.
(IF)/HPN. These include: older age/female, reduced 9. As there is a loss of the diurnal parathormone rhythm
physical activity, low sunlight exposure, smoking/alco- with nocturnal PN, daytime PN may be considered.
hol, chronic inflammation and medication (e.g. cortico- 10. Chronic hypomagnesemia in patients with a short bowel
steroids, long-term anticoagulation). may result in symptomatic chondrocalcinosis.
4. Vitamin D deficiency is common in those not having
daily PN with Vit D supplementation.
5. PN composition can affect the calcium loss in the urine.
Excessive sodium should be avoided and the amino acid Introduction
content kept to less than 2 g/kg/day. At least 7.5 mmol
calcium and 30 mmol phosphorus daily promotes their The adult skeleton is composed by trabecular or cancellous
net retention. bone and by cortical bone. The trabecular bone appears as
6. A Dual-energy-X-ray absorptiometry (DEXA) measure- filaments that form the internal structure of the bones and
ment is made from the lumbar spine representing trabec- gives the bone its compressive strength. The cortical bone is
ular bone, and at the femoral neck representing cortical located around the circumference of bone and consists of
bone. The result of DEXA is expressed as a number of thick and densely packed layers of mineralized collagen. On
standard deviations from mean bone mineral density. an annual basis, about 4% of cortical bone and 28% of tra-
Two scores are given that relating to young adults becular bone undergo to remodeling (or bone turnover), that
(T-score) and that relating to age and sex-matched healthy is required to repair and reinforce bone to compensate for the
subjects (Z-score). A T-score between −1 and −2.5 SD is mechanical stress placed on the skeleton. Remodeling con-
osteopenia and lower than −2.5 SD is osteoporosis. sists of the balanced activity of skeletal destruction (or bone
resorption) by osteoclasts and skeletal reconstruction (or
bone formation) by osteoblasts. Skeletal remodeling is regu-
L. Pironi (*) · A. S. Sasdelli lated by numerous factors, including parathyroid hormone
Centre for Chronic Intestinal Failure, Department of Medical and (PTH), vitamin D, and serum calcium, magnesium, and
Surgical Science, University of Bologna, St. Orsola-Malpighi phosphorus concentrations [1–3].
Hospital, Bologna, Italy
e-mail: [email protected]; [email protected]

426 L. Pironi and A. S. Sasdelli
Fig. 1 Bone structure (a) a b

normal, (b) osteoporosis
Table 1 Frequency of metabolic bone disease in patients receiving

HPN according to dual-energy-X-ray absorptiometry (DEXA)
at starting HPN (lower BMD in younger patients) [7] have
assessment been reported. Only the study by Raman et al. [8], reported a
Patients significant negative association between BMD and duration
Author, year (n.) Osteopenia Osteoporosis of HPN.
Goodman WG, 6 100% Actually, the real incidence of MBD during HPN is
2000 unknown. Indeed, a MBD frequently affect patients with
Pironi L, 2002 165 43% 41% intestinal insufficiency, who never underwent HPN [9] and a
Raman M, 2006 25 37% (spine) 32% (spine)
MBD is frequently present before the beginning of the HPN
43% (femural hip) 21% (femural
hip) program [10]. Furthermore, as reported by longitudinal stud-
Raman M, 2007 69 18% (spine and 46% (spine) ies, long-term HPN is not necessarily associated with a wors-
femural hip) 13% (femural ening of bone health; in some cases an improvement on
hip) BMD may occur [7, 11–15].
Ellegard L, 78 44% 44%
2013
Nygaard L, 148 32% 57%
2017 Clinical Features
The main features of MBD in long term HPN may be asymp-

A metabolic bone disease (MBD) characterized by osteo- tomatic osteopenia, bone pain localized mainly at spine and
penia, osteoporosis (Fig. 1) or osteomalacia may affect the lower joints or bone fractures occurring with no or minimal
40–100% of patients on home parenteral nutrition (HPN) for trauma. The ESPEN prevalence study [4] showed that the
chronic intestinal failure (CIF) [1, 4, 5] (Table 1). lowest values of BMD were associated with bone pain in
Osteomalacia is characterized by defective mineralization 35% of patients (mainly at spine, knee, hip, ankle, feet and
and increased osteoid, which is the unmineralized bone hands) and with bone fractures in 10% (spine, rib and hip).
matrix. Osteopenia is a state of low bone mass due to a Moreover, the patients’ physical rehabilitation status may be
decrease in bone mineralization that precedes the state of negatively affected by MBD [16, 17].
osteoporosis, characterized by a loss of bone mass due to an
equal reduction in bone mineral and bone matrix [1–3].
The prevalence of MBD in patients with CIF was evalu- Histology
ated in a European multicentre survey [4] by dual-energy-X-
ray absorptiometry (DEXA) at lumbar spine and femoral The presence of either osteomalacia [13, 18–21] or osteopo-
neck. This cross-sectional study showed that 43% of patients rosis [13, 19, 20, 22, 23] have been reported by histomorpho-
had osteopenia and 41% had osteoporosis. Associations metric studies. A low bone formation rate [2, 13, 18–22], as
between bone mineral density (BMD) and age at diagnosis well as increased bone turnover [19, 23] or defective miner-
of intestinal failure (lower BMD in younger patients), with alization [18] were shown in most of the patients by the anal-
body mass index (higher BMD with higher BMI) [6] and age ysis of the dynamic histomorphometric indices.
Bone and Joint Disease 427
HPN-associated MBD seems to be characterized by low formation. The enzymatic conversion of 25-hydroxyvitamin
bone turnover. The only one follow up observation per- D to 1,25-dihydroxyvitamin D by the specific renal enzyme
formed by bone histology reported that most of the patients is also blocked by aluminium, thus directly inhibiting prolif-
had a hyperkinetic bone turnover at the first assessment, eration of osteoblasts [26]. Caseine hydrolysate solutions are
evolving to a low bone formation rate 6–12 months later no longer produced now-a-days, but other nutrient solutions,
[18]. Data consistent with the early results by bone histomor- such as phosphate salts, calcium gluconate, vitamins and
phometry were reported by an observation using a bone for- trace metals still may be contaminated with aluminium [26].
mation marker serum osteocalcin (OC) (a It may be possible to observe mild increase of serum alu-
hydroxyapatite-binding protein made by osteoblasts, odon- minium concentrations, without an association with positive
toblasts, and hypertrophic chondrocytes which constitutes aluminium staining in bone histology [22].
15% of the non-collagenous bone matrix) and a bone resorp- Also vitamin D deficiency or toxicity may be related to
tion marker urinary pyridinium cross links; together they MBD. Vitamin D increases intestinal absorption of calcium,
provide markers of bone turnover [24]. phosphorus and magnesium, and enhances renal tubular cal-
cium resorption. In bone, vitamin D induces osteoclast for-
mation and bone resorption that indirectly promote bone
Pathogenesis mineralization via maintenance of extracellular calcium and
phosphorus concentrations in a supersaturated state.
In patients on HPN, MBD is mainly due to general factors, Osteomalacia in adults and rickets in children are the conse-
like aging, postmenopausal status, alcohol and tobacco quences of vitamin D deficiency. Furthermore, the develop-
abuse, and to factors related to the patient’s underlying dis- ment of the giant osteoclast, as well as the regulation of the
ease (disease-associated MBD). However, accelerated bone immune system, and of several cell functions, are signifi-
loss has been reported during the HPN (HPN-associated cantly improved by vitamin D [29].
MBD), raising the question of a specific role of HPN-related Most of adult patients on HPN (77–100%), who were
factors [11, 12, 25]. receiving IV multivitamin supplementation including for
Disease-associated MBD has a multifactorial pathogene- each infusion day the recommended amount of 200 IU vita-
sis [1]. Some risk factors may be related to life-style changes, min D3 (cholecalciferol), have been reported to have either
such as reduced physical activity and low sunlight exposure. vitamin D insufficiency or deficiency, diagnosed by serum
Intestinal malabsorption of calcium, magnesium and vitamin concentration of 25-hydroxivitamin D <30 or <20 ng/mL,
D, calcium losses in the gut lumen, chronic inflammation respectively [30, 31] (Table 2). When reading these results,
and drugs, such as corticosteroids, immunosuppressive, loop however, it should be kept in mind the 25-hydroxivitamin D
diuretics, long-term anticoagulation with heparin or warfa- serum concentration behaviour as a negative inflammatory
rin, are other disease-related factors. Chronic inflammation index. Therefore, the serum concentrations of inflammatory
causes both increased bone resorption and decreased bone
formation due to cytokines such as Tumour Necrosis Factor Table 2 Vitamin D status in patients with intestinal failure or intestinal
(TNF), Interluekin-1 (IL-1), Interleukin-6 (IL-6) and to insufficiency, according to serum 25OH-vitamin D concentration
Prostaglandin E2. In patients with a short bowel, the meta- (lower limit)
bolic acidosis due to intestinal losses of bicarbonate or to Vit D Vit. D
d-lactic acidosis can activate the bone buffering systems may Author, year Patients n. insufficiency deficiency
Goodman 6, on HPN for CIF 100%
be directly affected by calcium and phosphorus resorption WG, 2000 (<50 nmol/L)
and can impair the metabolism of vitamin D. Compher C, 8, on HPN for CIF 100% (<20 ng/
There are several hypothesis about the HPN-related fac- 2007 mL)
tors. In the seventies, aluminium overload due to aluminium Corey B, 35, on HPN for 77% (<30 ng/
contamination of the amino acid solutions deriving from 2009 CIF mL)
Thomson T, 22, on HPN for 27% (20– 68% (<20 ng/
caseine hydrolysis was demonstrated to be associated with
2011 CIF 30 ng/mL) mL)
high serum concentration and urinary excretion of alumin- Kumar PR, 15, on HPN for 33% 0
ium, positive aluminium staining in bone, low serum concen- 2012 CIF (27.5– (≤27.5 nmol/L)
trations of PTH and of 1,25 dihydroxyvitamin D and 75 nmol/L)
hypercalciuria, and an histologic feature of osteomalacia Ellegard L, 106, on HPN for 67%
2013 CIF (<50 nmol/L)
[21, 26, 27]. The reversal of this feature was observed by
Nygaard L, 96, on HPN for 28% 14%
replacing casein hydrolysate with crystalline amino acid 2017 CIF (25– (<25 nmol/L)
solutions, containing negligible quantities of aluminium 50 nmol/L)
[28]. Aluminium impairs bone mineralization by deposition Nygaard L, 71, intestinal 31% 17%
at the mineralization zone of bone and by reduces the secre- 2017 insufficiency (no (25– (<25 nmol/L)
HPN) 50 nmol/L)
tion of PTH, whose physiologic activity is to stimulate bone
indices, such as C-reactive protein, should be considered calcium and low i.v. phosphate) [12]. According to some
when interpreting 25-hydroxivitamin D serum concentra- human studies [41] and an investigation on a nonhuman pri-
tions [32]. mate model, a reduction of renal calcium losses may occur
A higher risk of vitamin D deficiency was reported for during HPN adaptation [42].
those patients who did not receive daily administration of It has also been hypothesized that the balance of the
HPN [31]; moreover, during transition from HPN to enteral effect of PTH on bone between resorption and formation
nutrition an increased risk has been observed [33]. High might be altered in the direction of resorption by parenteral
doses of oral vitamin D failed to achieve appropriate nutrition [43]. According to Goodman et al. [20], the regu-
25-hydroxivitamin D serum levels in patients with short larity of PTH secretion together with moderate but persis-
bowel syndrome, either receiving HPN [34] or not [10]. tent elevations in serum PTH concentrations would be
According to a few studies from the same research group, increased by long-term HPN. Consequently, the PTH-
the hypothesis of vitamin D-poisoning has been advanced. It related peptide receptor expression might be lowered and
seemed that the PTH secretion may be impaired by the daily the response to physiological blood concentrations of PTH
intravenous infusion of 25-hydroxivitamin D amounts equal in target tissues might be diminished. Bone formation and
to the RDA for adult healthy people. Consequently, despite turnover and the renal calcium resorption would be both
normal serum 25 hydroxyvitamin D concentrations, PTH reduced.
physiologic effects like bone mineralization and HPN-associated MBD might also be related to deficiency
1,25- dihydroxyvitamin D synthesis might not occur. An or toxicity of micronutrients known to interfere with bone
increase of BMD together with the normalization of PTH metabolism [1, 19, 23]. In patients with SBS receiving HPN
and 1,25-dihydroxyvitamin D were observed after vitamin D a positive correlation between serum fluoride concentrations
withdrawal [25, 35]. These findings haven’t been confirmed and lumbar BMD, but no correlation with femoral neck
by any studies in the last decade. BMD, have been observed [44]. This data reflect the action
Patients on HPN show frequently high urinary calcium of this electrolyte on trabecular bone formation, increasing
excretion [13, 18, 19, 21–23]. The urinary excretion of elec- cancellous bone density, but having no effect on cortical
trolytes before (diurnal, 12 h) and during (nocturnal, 12 h) bone density. However, as some studies describe, the risk of
parenteral nutrition was measured by Boncompain-Gerard fluoride toxicity must also be considered: actually an
et al. [36] in 16 patients. Compared with diurnal urine, a sig- increased risk for bone fractures has been associated with
nificant increase in urine volume and excretion of urea, cre- high amounts of fluoride in drinking water. Other factors
atinine, sodium, magnesium, and phosphate but not involved in bone formation are osteocalcin, matrix Gla pro-
potassium was observed in nocturnal urine. Referring to tein (a small vitamin K-dependent protein, that is the most
24-h calciuria, 7 patients had normal values whereas 9 had powerful natural occurring known inhibitor of calcification
hypercalciuria. Although the calcium supply was identical, in humans), and protein S, which is also a vitamin
only the hypercalciuric patients had diurnal hypercalciuria, K-dependent protein. HPN patients supplemented with vita-
whereas both had excessive nocturnal calciuria. In patients min K seemed to have a trend toward a better hip BMD com-
with normocalciuria BMD was slightly, although not signifi- pared with patients without supplementation, as described by
cantly, higher, but in all patients, BMD had a significant cor- Aljarallah et al. [45]. There are no studies investigating the
relation with calciuria. A positive correlation between renal role of boron, silicon and copper deficiency in MBD as well
calcium loss and the amount of infused amino acids, glucose, as the potential toxicity from other micronutrients, like vita-
sodium and calcium with the parenteral nutrition solution min A, cadmium, strontium and vanadium, in patients on
has been shown by several cross-sectional studies [12]. HPN [46].
Contrarily, other studies reported a negative correlation Finally, according to a limited number of human studies
between urinary calcium and intravenous phosphate load, and a large number of animal investigations, low BMD dur-
appearing to enhance calcium reabsorption by the renal ing HPN administration is the result of a chronic inflamma-
tubules, independently of PTH actions [37–39]. Bone cal- tory condition characterized by increased circulating
cium reabsorption can be induced by metabolic acidosis, due concentrations of pro-inflammatory cytokines, such as TNF-
to titratable acids produced by the metabolism of neutral and αand IL-6, which stimulate osteoclast activity. Both the lack
sulphur-containing amino acid [1, 12]. Finally, according to of significant small intestinal mass (as in short bowel syn-
the study of Wood [40], cyclic infusion more than continuous drome) or the absence of small intestine stimulation (as in
infusions seem to be associated with a greater calciuria. dysmotility syndromes), as well as the components within
Hypercalciuria during HPN may be related to both increased the PN solution, like lipid emulsions rich in omega-6, may
glomerular filtration rate (i.v. fluids, amino acids, calcium lead to this chronic inflammation. Another suggestion is that
and sodium, metabolic acidosis) and decreased reabsorption the immune system interacts with the catheter as a foreign
by the renal tubules (excessive i.v. amino acids, glucose and body, leading to inflammation [47].
Table 3 Instrumental and biochemical parameters for the diagnosis Table 4 Prevention and treatment of metabolic bone disease in patients
and follow up of metabolic bone disease in patients on home parenteral on home parenteral nutrition for chronic intestinal failure due to benign
nutrition for chronic intestinal failure due to benign disease (frequency disease
of assessment)
General and life-style recommendations
• Bone mineral density by dual-energy-X-ray absorptiometry • Regular low impact physical exercise program
(DEXA) (at starting HPN, then yearly) • Regular and adequate sunlight exposure (UVB radiation from a
• Serum and urinary Ca, Mg and P (every 4 months; additional tanning bed or other UVB emitting device might be considered)
measurement according to the clinical feature) • Maintain protein-calorie nutritional status
• Serum 25-hydroxyvitamin D, PTH and markers of bone turnover • Diet rich in dairy food (depending on the underlying intestinal
(yearly; additional measurement according to the clinical feature) functions)
• Serum 1,25-dihydroxyvitamin D (in case of suspected vitamin D • Avoid cigarette smoking and limit alcohol intake
toxicity) • Estrogen replacement therapy in perimenopausal and
• Serum aluminium and other micronutrients (according to the postmenopausal period (depending on the underlying risk for vein
clinical suspicion) thrombosis)
• Bone biopsy (with/without) double tetracycline labelling (if Correction of the underlying disease-related factors
doubtful diagnosis between osteomalacia and osteoporosis) • Treatment of chronic inflammation
• Limitation of bone damaging drugs
• Prevention and treatment of metabolic acidosis
Diagnosis and Follow Up (Table 3)
• Oral calcium supplementation (500–1000 mg bid)
• Oral magnesium supplementation (Mg oxide 12–24 mmol/day)
The guidelines for CIF of the European Society of Enteral Parenteral nutrition-related factors
and Parenteral Nutrition (European Society of Clinical • Fluids: as required to maintain fluid balance
Nutrition and Metabolism) (ESPEN) [48] recommend that • Infusion rate: slowing the infusion rate may decrease hypercalciuria
for routine purposes both diagnosis and monitoring of MBD • Sodium: as required for maintain Na balance; excess urinary Na
may induce hypercalciuria
is based on a combination of bone densitometry scanning
• Minerals (Ca, P, Mg): as required of maintain balance; Ca/P ratio to
(Dual-Energy X-ray Absorptiometry, DEXA) and biochem- be adjusted to precent hypercalciuria as well as formation of
istry. DEXA is used for the definition of the degree of MBD calcium-phosphate crystals in the admixture
at starting HPN and its evolution during the treatment, • Acetate: as required to maintain normal serum bicarbonate
whereas biochemical parameters are important for the Amino acids: balance between requirement for protein synthesis and
assessment of bone turnover and the investigation of the to avoid amino acid induced hypercalciuria
• Vitamin D: daily iv with multivitamin vials, 220 IU of
potential pathogenetic mechanism (Table 1). DEXA cholecalciferol or 200 IU of ergocalcipherol; PN infusion <7 day/
assessment is usually made at lumbar spine, representing tra- week: add oral or im vitamin D supplementation as required
becular bone, and/or at hip, with femoral neck, representing • Vit K supplementation: as required to maintain normal prothrombin
cortical bone. The result of DEXA is expressed as a number time
of standard deviations from mean BMD value of young adult • Aluminium contamination of the PN admixture: <25 μg/L
Drug therapy (published protocols)
reference mean (T-score) and of age and sex-matched healthy
• Biphosphonates: clodronate, 1500 mg iv every 3 months;
subjects (Z-score). The severity of MBD as osteopenia or pamidronate, 30–60 mg im/monthly or 90 mg iv every 3–6 months
osteoporosis has been defined by the WHO Study Group • Denosumanb: 60 mg sc/yearly
[49] on the basis of the T-score value. The relative risk of any
fracture has been estimated to be 1.4–1.6 for every decrease
in BMD of 1 SD below the BMD Z-score [2]. Also in HPN rosis be promptly addressed, as well as factors with a pos-
patients the predictive value of the BMD for the assessment sible negative impact on bone health, i.e. chronic
of fracture risk has been suggested [4]. DEXA measures inflammation, infections, drugs and other relevant factors
BMD independently of the presence of osteomalacia or related to the underlying disease, in all patients on long-
osteoporosis; bone histology is mandatory when a differen- term HPN.
tial diagnosis is needed. For BMD monitoring, DEXA is rec- Research and treatment of the general and underlying
ommended at yearly interval and biochemical assessment, disease related factors is absolutely important. HPN associ-
serum concentrations and 24 h urinary excretion of minerals ated MBD can be prevented by the optimisation of the par-
(Ca, P, Mg) every 4 months and the measurement of serum enteral solution. Aluminium contamination should be less
PTH and 25-hydroxivitamin D every year. than 25 μg/L [26]. The amounts of minerals should aim to
maintain the normal serum concentrations and 24-h urinary
excretions. The Ca/P ratio in the solution should be always
Prevention and Treatment (Table 4) carefully observed, although, the optimal ratio cannot
always be achieved due to problems of stability in the solu-
The potential pathogenetic mechanisms determine the pre- tion. It has been observed that supplying at least 15 mEq
vention and treatment of MBD. The ESPEN guidelines [48] calcium and 30 mmol phosphorus on a daily basis can pro-
recommend that general risk factors for developing osteopo- mote retention of these elements [37]. Berkelhammer et al.
[39], reported a positive calcium balance giving 12 mEq of Joint Diseases and Enterophatic Arthritis
calcium and 45 mmol of phosphate; according to other stud-
ies the phosphate amount should be 33–42 mmol [38]. Thus, Two case reports described patients with chronic hypomag-
to achieve a positive calcium balance it seems to be required nesemia induced by SBS who developed symptomatic chon-
a Ca/P ratio ranging from 1 mEq of calcium to 1 or 2 mmol drocalcinosis due to deposition of calcium pyrophosphate
of phosphate. However, chronic excess of phosphorus can dihydrate (CPPD) crystals in hyaline and fibrous cartilage
lead to bone loss as a result of secondary hyperparathyroid- [58, 59]. Magnesium deficiency in SBS is the consequences
ism. Amino acids and sodium should not be added in of intestinal malabsorption, increased renal losses and inad-
amounts greater than losses [12]. The recommended intra- equate supplementation. Malabsorption is due to the loss of
venous vitamin D for adults is 200 IU/day [1]. In some bowel absorptive area, especially ileum and proximal colon,
patients, hypercalciuria may be reduced by slowing the to low 1,25-hydroxy-vitamin D levels leading to abnormal
infusion rate [12]. jejunal Mg absorption and to Mg bounding by fatty acids
The ESPEN guidelines recommend as the primary step derived from both high dietary fat intake (long-chain triglyc-
for treatment of metabolic bone disease to optimize the erides) and bacterial fermentation of malabsorbed carbohy-
program for parenteral nutrition with the required supple- drates. In patients with dehydration, increased renal losses of
ments of vitamin D, calcium and phosphate. Further, med- Mg result from hyperaldosteronism. Oral supplementation
ical treatment may be useful to increase bone mineral of Mg may cause intestinal motility and diarrhoea, which
density and lower fracture risk. Recently, the American can further compromise adequate Mg absorption.
Society for Parenteral and Enteral Nutrition (ASPEN) has Magnesium is a cofactor for alkaline phosphatases, an
expressed concern as to whether the daily dose of 200 IU/ enzyme playing a key role in converting inorganic pyro-
day in the current PN products is adequate to maintain phosphates to orthophosphate. Moreover, Mg increases the
normal serum concentrations of 25-hydroxivitamin D in solubility of CPPD crystals in vitro. Thus, hypomagnese-
most patients requiring long-term PN [50]. Oral or intra- mia could facilitate intra-articular elevation of extracellular
muscular vitamin D supplementation, as well as exposure inorganic pyrophosphate and/or reduced saturation product
to sunlight or UVB emitting device could be required [29, of CPPD, thus favouring crystal nucleation of CPPD. The
51]. Bisphosphonates provided intravenously at regular clinical presentation of chondrocalcinosis is characterized
intervals (Clodronate, Pamidronate, or Zolindronic acid), by acute or chronic arthritis (attacks of pseudogout, typi-
may support bone mineral health in patients with cally in knees and ankles). The diagnosis relies on radio-
osteopenia. logical finding of thin linear calcification of the cartilage.
An ESPEN survey on the current practice of MBD man- CPPD crystals can be identified by polarizing light micros-
agement in patients on HPN for CIF reported that zolidro- copy. The prevalence of CPPD increases with age (10–15%
nate, alendronate pamidronate and clodronate were the most for people in the 6 and 7 decades of age), whereas in
common used [52]. So far, there are only one randomised younger individuals several disease can cause CPPD depo-
controlled study and a few prospective observations about sition disease, such as hemochromatosis, hyperparathy-
the use of biphosphonates in patients on HPN. The study of roidism, hyperparathyroidism, hypomagnesemia or
Haderslev et al. [53] showed that intravenous clodronate hypophosphatemia [60]. The treatment of CPPD in SBS
could decrease the urinary excretion of markers of bone patients consists in the correction of Mg deficiency by par-
resorption and maintain BMD at lumbar spine in patients on enteral supplementation of Mg associated with correction
HPN after 12 months, but has no significant effect in increas- of vitamin D deficiency, administration of opioids to slow
ing BMD. Improvement of BMD at both spine and hip has bowel transit, and colchicine as a long-term therapy instead
been observed with the use of intravenous pamidronate [8, of steroids, when required [59].
54]. The case-report reported normalized BMD after The underlying disease of patients with CIF may compli-
18 months in a patient on HPN for short bowel syndrome cate with enteropathic arthritis or enteroarthritis (EA). In
with osteoporosis, treated with the subcutaneous administra- 8–36% of patients who underwent intestinal bypass surgery
tion of the recombinant PTH, teriparatide [55]. Another case for obesity, polyarthralgia and sometimes arthritis has been
report suggests that BMD may be also improved by growth reported to occur weeks or years following surgery, as a post-
hormone used to treat short bowel syndrome [56]. A recent operative complication of this technique. Arthritis affected
study reported an improvement of BMD assessed by DEXA knee, wrist, ankle, shoulder and finger joints [61].
in patients on long-term HPN, after 12 months of treatment Inflammatory bowel disease (IBD) represents a good
with denosumab, a fully human monoclonal antibody that model for the pathological events that may predispose to the
inhibits bone resorption by neutralizing receptor activator of development of EA. EA may be diagnosed before, simulta-
NF-κB ligand (RANKL) (a mediator for osteoclast forma- neously or after the diagnosis of IBD, with a prevalence
tion and function) [57]. ranging between 17% and 39%. The main clinical features
are peripheral arthritis (women, 25–45 years old, asymmet- home parenteral nutrition (HPN) in adult patients. Clin Nutr.
ric mono-oligoarthritis mostly in lower limbs, episodic and 2009;28(4):467–79.
6. Cohen-Solal M, Baudoin C, Joly F, Vahedi K, D’Aoust L, De
recurrent, frequent exacerbations) and axial arthritis (men, Vernejoul MC, Messing B. Osteoporosis in patients on long-term
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Group (ESSG) criteria. In established disease, these clinical Staun M. Vitamin D status and measurements of markers of
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2003;52(5):653–8.
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disease. Corticosteroids are recommended for patients with Nutr. 1990;14(2):139–42.
12. Klein GL, Coburn JW. Parenteral nutrition: effect on bone and min-
mild exacerbations; cyclic intra-articular injections of ste- eral homeostasis. Annu Rev Nutr. 1991;11:93–119.
roids might have also beneficial effects. Sulfasalazine and 13. Saitta JC, Ott SM, Sherrard DJ, Walden CE, Lipkin EW. Metabolic
5-aminosalicylic acid can reduce mild peripheral arthritis, bone disease in adults receiving long-term parenteral nutrition: lon-
particularly in patients with ulcerative colitis, but have no gitudinal study with regional densitometry and bone biopsy. JPEN
J Parenter Enteral Nutr. 1993;17(3):214–9.
effect on the evolution of joint damage; conversely, metho- 14. Cohen-Solal M, de Vernejoul MC. [Bone remodeling]. Therapie.
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especially in patients with Crohn’s disease; Etanercept, Shaffer J, Hebuterne X, Beau P, Guedon C, Schmit A, Tjellesen
instead, seems to be effective only to control joint symptoms L, Messing B, Forbes A, ESPEN-HAN Working Group. Clinical,
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G, Ambrosino P, Esposito C, Scalera A, Castiglione F, Scarpa
Intestinal Adaptation
Julie Bines, Jason Yap, Kelly Tappenden,

Key Points trointestinal hormones and peptide growth factors (e.g.

growth hormone, (GH), Insulin like growth factor-1
1. Intestinal adaptation involves behavioural (hyperphagia), (IGF-1), glucagon-like peptide-2 (GLP-2), epidermal
structural (morphological or anatomical) and functional growth factor (EGF), peptide YY) and the gut
changes. microbiome.
2. Due to the practical and ethical challenges in conducting 6. Pharmacological approaches may be used to promote
clinical studies following massive small bowel resection adaptation by enhancing intestinal growth and/or func-
current understanding of the adaptive response has mainly tion; these include fibre (pectin), glutamine, short chain
been derived from animal models. Animal studies usually fatty acids (SCFAs), long-chain fatty acids (LCFAs), GH,
involve a jejunal resection and rarely a jejunostomy, glutamine, EGF, GLP-1 and 2 analogues and
whereas in man an ileal ± colon resection is more aminoguanidine.
common. 7. Surgical approaches to resolve mechanical barriers and
3. Patients with a jejunostomy show no jejunal structural or enhance gut function are aimed at optimising the gut
functional adaptation over time. environment and facilitate the adaptative response.
4. Patients with a jejunum in continuity with a colon usually
undergo a functional adaptive response that may continue
to occur for 2–3 years. There may be a degree of struc-
tural adaptation. The colon also adapts both structurally Introduction
and functionally.
5. The mediators for adaptive changes include nutrition, Intestinal adaptation is a physiological response following
intestinal secretions (especially pancreaticobiliary), gas- intestinal resection aimed at restoring the digestive and
absorptive capacity of the remaining bowel to meet meta-
bolic and growth requirements. Following intestinal resec-
J. Bines (*)
tion, a number of mechanisms also contribute to
Department of Paediatrics, University of Melbourne,
Parkville, VIC, Australia malabsorption; such as gastric acid hypersecretion, impaired
motility with rapid transit of intestinal content, bacterial
Murdoch Children’s Research Institute, Parkville, VIC, Australia
overgrowth and excess water secretion when presented with
Department of Gastroenterology and Clinical Nutrition, Royal
an osmotic load [1]. The severity of malabsorption is influ-
Children’s Hospital, Parkville, VIC, Australia
e-mail: [email protected] enced by the primary indication for intestinal resection, the
residual length and segment of the remnant intestine [2]. For
J. Yap
Department of Gastroenterology and Clinical Nutrition, Royal example, resection of the peptide YY producing distal ileum
Children’s Hospital, Parkville, VIC, Australia and proximal colon compromises the inhibitory function
e-mail: [email protected] known as the “ileal and colonic brakes” that would normally
K. Tappenden delay gastric emptying, slow small intestine transit time and
Department of Nutrition and Kinesiology, University of Illinois at influence early satiety [3–6].
Chicago, Chicago, IL, USA
In an effort to compensate for the malabsorption due
to the loss of intestinal length; altered diet a) and slowing of
J. M.D. Nightingale
intestinal transit in occurs. The stomach and colon contrib-
e-mail: [email protected] ute to absorptive function that normally would be performed

436 J. Bines et al.
by the small intestine [7]. The remaining small intes- intestinal failure, weight loss post-surgical resection is no
tine undergoes adaptation changes to recover absorptive and longer considered an acceptable clinical outcome.
functional capacity. Intestinal adaptation involves a broad
range of changes, including changes in behaviour (hyperpha-
gia), morphologic (structural and ultrastructural) and func- Morphologic Adaptation
tional changes in the residual bowel [8]. Evolving knowledge
of the molecular mechanisms involved in regulating the Stassoff is credited as being the first person to report small
adaptive response provides the opportunity to identify tar- bowel ‘hypertrophy’ and increased absorption in the remaining
gets and novel therapies to stimulate and enhance the adap- small intestine of dogs after a large resection of small intestine
tive response. [10]. After a predominantly jejunal resection in animals (some
Due to the practical and ethical challenges in conducting ileum and colon left intact), there is structural adaptation with
clinical studies following massive small bowel resection, dilatation and elongation of the remaining intestine (compensa-
current understanding of the physiology of the adaptive tory hypertrophy), and the villi become longer, crypts deepen
response has mainly been derived from animal models. and the cell number over a given length of villus increases (epi-
Studies in rodent models have been used extensively for thelial hyperplasia) [11–14], but the size of the enterocytes do
studies describing intestinal adaptation whereas the large not change. These changes are much more marked in an ileal
animal models, such as the porcine model are considered to compared to a jejunal remnant [12, 13].
more accurately reflect human gastrointestinal physiology The morphologic features of the adaptive response involve
and nutrition. Differences in the age and maturation stage at all layers of the bowel wall, including muscular hypertrophy
time of resection may impact elements of the adaptive (increased bowel diameter and thickness, increase in length),
response and studies from neonatal and growing animals mucosal hyperplasia (increased cell proliferation resulting in
may more accurately reflect the response in infants and deepening crypts and lengthening of the villi) and angiogen-
children. esis (new blood vessel development) (Fig. 1) [15]. There is
also an increase in cellular DNA, RNA and protein content
[16]. Early crypt proliferation is regulated by IFRD1 (Tis7)
Hyperphagia which is a transcriptional co-regulator that alters the tran-
scription of target genes (including cyclin D1 and hedgehog
An early clinical feature of adaptation is an increase in food signalling pathway genes including Gli1, Hhip, Gli2) through
intake (hyperphagia) that occurs in compensation for the interaction with the mSin3B complex and histone deacety-
macronutrient malabsorption. Hyperphagia is reported in lases [16, 17]. In Tis7−/− mice undergoing mid-small bowel
70% of adult SBS patients and is defined as an oral intake resection, crypt cell proliferation was reduced at 72 h and
>1.5 times their resting energy requirements. Hyperphagia this was associated with inhibition in the expression of the
may indirectly contribute to the morphological and func- target genes [17]. Inhibition of expression of hedgehog sig-
tional adaptation of the remnant bowel through the provision nalling commences soon after resection and is maintained
of luminal nutrients. The development of hyperphagia in for up to 2 weeks following 50% small bowel resection in
SBS patients, particularly after colonic continuity is re- mice [18].
established (by re-anastomosis), is considered a good prog- Morphologic adaptation commences 24–48 h after resec-
nostic indicator. The mechanism controlling hyperphagia is tion in mice with colon in continuity and is characterized by
not well understood. In rodents jejuno-colonic anastomo- a rapid expansion of putative enterocyte stem cells at 48–72 h
sis has been associated with elevated levels of serum ghrelin that continues for up to 7 days before returning to baseline by
and peptide YY [9]. Ghrelin promotes appetite while PYY 6 weeks [19]. Concurrent with the expansion of the putative
suppresses it. In addition, the hypothalamic mRNA levels of stem cell population in the crypts, gut epithelial secretory
orexigenic Neuropeptide Y (NPY) and Agouti-related pep- cells, including goblet cell and Paneth cell proliferation, con-
tide (AgRP) were noted to be markedly elevated following tinue for up to 28 days post-resection [20, 21]. Interestingly,
jejuno-colonic anastomosis in rodents, suggesting that the the rate of enterocyte apoptosis is modestly increased and
gut-brain axis is involved in intestinal adaptation. Similar thought to maintain the crypt-villus axis in the presence of an
serum changes of serum ghrelin and peptide YY were con- increased enterocyte proliferation [22]. The colon also
firmed in humans with a jejuno-colonic anastomosis; and undergoes morphological and functional adaptation follow-
there was also a failure to suppress post-prandial ghrelin ing small intestinal resection. In a mouse model of 60% jeju-
secretion [9]. nal ileal resection, colonic adaptation was observed with a
Historically, weight loss to reduce nutritional requirement twofold increase in colonic mass and crypt depth. These
was hypothesized to be a compensatory mechanism follow- changes were observed despite the absence of enteral nutri-
ing massive intestinal resection. With the widespread avail- tion, indicating non-nutritive factors influence colonic adap-
ability of parenteral nutrition support in patients with tation [23]. In the piglet model, early and late features of the
Intestinal Adaptation 437
↑ Intesnal dilataon ↓Intesnal transit
↑Intesnal length ↑Fluid, electrolyte & nutrient absorpon

↑Gastrointesnal secreons
↑Crypt depth
↑Gastrointesnal hormone secreon
↑Villus height
↑Epithelial secretory cells (goblet & Paneth cells)

↑Angiogenesis
↑Epithelial migraon (crypt to p)
↑ Cellular DNA, RNA & protein content
↑Apoptosis
↑Expression of apical transporters (Na/H exchanger, SGLT1,
↑Mucosal surface area ↑mRNA of absorpve genes (L
↑Absorpve enterocyte numbers but not % of total ↑Pro

↑Capillary growth ↑Expression of notch signaling pathway (rat)
↑Muscle hypertrophy
↑Plasma
↑IFRD1 (Tis7) transcripon co
Fig. 1 Features of the adaptive response
adaptive response in the colon were reported, with early have been observed in adults with enterocyte hyperplasia of
changes of increase enterocyte numbers and late changes of 70–75% increase in villus height 2 years after jejuno-ileal
increase cell proliferation. Goblet cell and enteroendocrine bypass surgery in comparison to controls [34].
cell numbers were continuously elevated at all time points of Colonic adaptation following small bowel resection in
adaptation. Increased nutrient complexity enhanced colonic humans is poorly documented. Joly et al. studied the colon of
adaptation in this model [24]. 12 adult hyperphagic patients with jejuno-colonic SBS [35]. In
In humans, various case reports have described dilatation patients with SBS compared to controls, the crypt depth and
of the stomach, duodenum, jejunum, ileum and colon after a the number of cells per crypt were 35% and 22% higher respec-
massive small bowel resection [25–31]. However, there is a tively, resulting in increased absorptive surface [35]. There was
risk that some reports may reflect bowel dilatation proximal no change to the apoptosis/proliferation ratio per crypt. This is
to an anastomotic stricture and not morphological adapta- the first convincing human study of colonic adaptation in SBS.
tion. An increase in bowel length was reported in one case
[25]; whereas another case report, with a carefully docu-
mented set of observations described over the 5 years from atients with Jejunum–Colonic Anastomosis or
P
the original resection, demonstrated no change in residual Jejunostomy
bowel length [32]. This patient had a mesenteric infarction
requiring resection leaving 105 cm of small intestine (95 cm In small and large animal models, adaptation in the duode-
jejunum and 10 cm terminal ileum) and a functioning colon num and jejunum proximal to the site of a large small bowel
remaining in situ. She subsequently had four caesarean sec- resection has been observed, supporting a possible role for
tions over 5 years; on each occasion bowel length and diam- circulating growth factors in the adaptative response [1].
eter was measured [32]. There is also limited clinical data on However, there is little data from human studies to suggest
the microscopic features of adaptation following resection, there is significant morphological adaptation in the jejunum
with the majority of data derived from paediatric studies. In of patients with residual jejunum anastomosed to a function-
33 premature infants who underwent small intestinal resec- ing colon. Two reports of jejunal biopsies from four patients
tion for necrotising enterocolitis (NEC), there was a 32% and with jejunum anastomosed to colon showed epithelial hyper-
22% increase in villus and crypt depth respectively from plasia [36, 37], and a larger study of ten patients showed, not
baseline, recorded at the time of small bowel stoma closure hyperplasia, but atrophy in most patients [38]. There is a lack
at a mean 74 days (range 61–90 days) after primary resection of data on the impact of a proximal jejunal end-stoma on the
[33]. The change in villus height (in mainly ileum) correlated adaptive response in animal models due to the practical chal-
with length of small bowel resected. Similar observations lenges. No structural features of adaptation have been
438 J. Bines et al.
observed in biopsies from the distal duodenal mucosa in tation in humans are limited for practical and ethical reasons,
patients with an established jejunostomy [39]. including the fact that massive intestinal resection is uncom-
mon, patients are often critically ill and may have a variety of
primary aetiologies resulting in the need for resection.
Functional Adaptation Functional adaptation has been observed in children and
adults post-resection if the ileum and/or colon are retained,
The remaining intestine may also undergo adaptive changes as evidenced by achievement of intestinal autonomy in par-
to increase absorptive capacity of fluid, electrolyte and nutri- enteral nutrition dependent patients, sometimes several years
ents. A key measure of functional adaptation is an increase in following resection [2, 48–51].
the absorption of macro- and/or micro-nutrients over a given
length of bowel that occurs over time or when compared
with normal subjects. Functional adaptation may occur as a atients with Jejunum–Colonic Anastomosis,
P
result of structural changes (such as an increase in entero- Ileostomy or Jejunostomy
cytes or enteroendocrine cells), a slowing of transit time or a
range of intracellular events (e.g. increased transport and/or There is limited evidence for structural (morphological)
enzyme activity) (Fig. 1) [40]. However these changes are adaptation in patients with a jejunostomy; however, there is
site specific and there is no clinical evidence that remaining evidence for functional adaptation in patients with jejunum
jejunum acquires any of the specialized transport functions anastomosed to a functioning colon and in patients with an
of the ileum (e.g. vitamin B12 or bile salt absorption). ileostomy. In patients with jejunum in continuity with a
The expression of over 60 proteins have been reported to functioning colon there is a small reduction in faecal weight
change in response to massive small bowel resection in a in the 3 months following a small bowel resection [14].
piglet model [41]. Animal studies have demonstrated an There is also increased jejunal absorption of macronutrients,
increase expression of transporter proteins including the api- water, sodium, glucose and calcium with time [36, 51–54],
cal sodium glucose cotransporter (SGLT 1), NA+/H+ associated with an increased chance of the patient being able
exchanger and Na+/K+ adenosine triphosphatases [41–43]. to stop parenteral nutrition [51, 54, 55]. Patients who have an
Fatty acid transporters L-FABP, FABP-6 and I-FABP are up ileostomy following a colectomy (usually for ulcerative coli-
regulated as early as 2 weeks post resection and gradually tis) have a reduction in stomal output over the first 4 months
increase over 6 weeks in parallel with the increase in total after surgery [56–58]. This is not the case, however, when
villus area [44]. Serum bile acids and serum triglycerides there has also been an ileal resection. In a study of patients
were observed to increase with the changes in FABP. The who had an ‘ileostomy’ after an ileal resection, Hill et al.
upregulation of L-FABP, a known determinant of bile acid showed, that there was no decrease in ileostomy water,
metabolism in the liver is speculated to be hepatoprotective sodium and potassium losses over the period from 11 days to
against parenteral nutrition-associated liver disease. The 6 months after the resection [58]. Nightingale et al. demon-
increase in transporter function is consequent to both villus strated no change in the nutritional or fluid requirements of
cell hyperplasia (e.g.: SGLT1) and functional adaptation on patients with a jejunostomy from 6 to 24 months after their
a per cell basis (e.g. enterocytes express increased digestive last resection [59]. Thus there is no clinical or experimental
enzymes and transporters). The overall net result of these evidence for functional adaptation in jejunostomy patients.
changes is to increase the digestive and absorptive capacity
of the residual intestine [1, 41]. The translocation of luminal
bacteria to mesenteric lymph nodes, blood, liver and spleen Timing of Adaptive Changes
in animal resection models have been linked to abnormalities
in intestinal barrier permeability [45]. Increased paracellular In animal models, features of the adaptive response are
permeability occurring after small bowel resection has been observed within hours following a surgical resection. In the
linked to increased activation of toll-like receptor-4 in a rat, there is an increase in mucosal DNA synthesis within
mouse model [46]. 24–36 h after a bowel resection. Villus epithelial hyperplasia,
Data describing the features of functional adaptation in probably occurring as a result of increased crypt cell produc-
humans is sparse and inconclusive. Glucose absorption in tion rather than villus tip cell loss, is evident at 1–2 weeks
adults post-resection has been reported to be increased but and maximal at 1 month [13].
these studies could not differentiate between increased In 1959, Pullan described three clinical phases (“Extensive
absorptive capacity as a result of enterocyte proliferation, Mucosal Disease: Coeliac Disease and Eosinophilic
versus enhanced functional protein expression, or a combi- Enteritis” chapter) after massive small bowel resection in
nation of both. Whereas results of dipeptide and tripeptide patients with the colon remaining intact. Following the large
transporters PepT1 expression in the human colon have been fluid losses that occurs (phase 1), in phase 2 the emphasis
conflicting [35, 47]. Suffice to say, studies of intestinal adap- shifts from fluid balance to nutritional support, and over the
next 12–24 months as diarrhoea improves, the amount of Table 1 Factors influencing intestinal adaptation in humans
nutritional support can be reduced or even stopped. It is dur- Structural Functional
ing this phase that most adaptation occurs. In phase 3 there is Factor adaptation adaptation
no further clinical improvement and no major adaptive Patient related factors [1,
2, 6–8, 15]
changes occur [60]. Age [33, 50] Potential for
While major adaptive changes are clinically evident within >increase in length
a few weeks in those with a retained colon, the full clinical in young
benefits may take years to be complete. For example, intesti- Underlying disease ↓with ongoing ↓with ongoing
mechanism inflammation inflammation
nal calcium absorption may continue to increase for more
Co-morbidities ↓with chronic ↓chronic
than 2 years after the resection [54]. If parenteral nutrition is pathology pathology
still required 2 years after a bowel resection, the chances of ↓with multisystem ↓with multisystem
subsequently being able to wean from parenteral nutrition disease and/or disease and/or
without additional intervention is limited (~6% of patients) specific drugs specific drugs
[55]. Data from adults on home parenteral support suggests Factors related to
remaining intestine [1,
that no further changes in parenteral nutrition requirements
12, 13, 15]
occur after 3 years following resection [1]. Of 57 patients Site of resection/ Maximum
who have bowel continuity restored after a small bowel resec- segment remaining adaptation requires
tion due to mesenteric infarction, 20 (35%) patients were suc- presence of ileum
cessful weaned from PN within 1 year, 29 (50%) patients Extent of resection ~
100 cm of SI or
60 cm SI with
weaned within 2 years and 44 (77%) patients with 5 years residual colon
suggesting that adaptation can continue to occur for up to 5 needed to wean
years in a favourable intestinal environment [51]. There is no from PN
reliable measure to determine who will successfully adapt or Stoma present
when maximum adaptation has occurred, although predic- Jejunostomy [36–39, Nil significant Nil significant
50]
tions can be made based on a range of clinical factors includ-
ICV absent [1] ↑risk of bacterial Loss of inhibition
ing age, underlying disease, the length and section of bowel overgrowth on gastric
remaining and other co-morbidities. There is currently no emptying and SI
accurate biomarker to monitor the adaptative response. transit
Plasma citrulline has been proposed as a useful clinical Colon present [56–58] ↑crypt depth,
↑cells per crypt,
marker to assess changes in enterocyte cell mass. However ↑surface area
the accuracy of plasma citrulline to monitor the progress of Integrity of remaining ↓with ongoing ↓with ongoing
the clinical adaptive response remains controversial [61, 62]. intestine inflammation and inflammation and
disease disease
Dysmotility [17, 25–31, Dilatation, ↑risk of
174–177] bacterial
Mediators of Intestinal Adaptation overgrowth
Nutritional factors
The mediators of intestinal adaptation are multiple and con- [63–78]
tribute individually to overall intestinal adaptation. These Composition (e.g. diet Stimulation of Stimulation of
include delivery of intraluminal nutrients, anatomic factors complexity, protein, intestinal growth intestinal function
short chain fatty acids,
and gastrointestinal resections (Table 1). More recently, pectin, glutamine, long
research and clinical advances have focussed predominantly chain triglycerides)
on identifying trophic factors that successfully induce rapid Modification of
adaptation and eventual enteral autonomy (Table 1). intestinal transit
Nutritional status Support mucosal Maintain mucosal
integrity and repair barrier function
Gastrointestinal
Intraluminal Nutrients secretions [79–84]
Pancreatic [79, 80] ↑volume of
The presence of food within the intestinal lumen (‘luminal secretions
nutrition’) is the most potent stimulus for intestinal epithelial Biliary [98, 99, 173] ↑volume of Alteration in bile
secretions acid profile
cell proliferation [63]. In the absence of luminal nutrients
Hormones and peptide
mucosal atrophy and a decrease in digestive enzyme and growth factors
transport function is observed. The mechanism whereby (continued)
food induces adaptation is not entirely known, however,
increased dietary complexity and some nutrients, including
440 J. Bines et al.
Table 1 (continued) intravenous short chain fatty acids (SCFA) have been shown
Structural Functional to enhance intestinal adaptation in rats [75, 76]. The tolera-
Factor adaptation adaptation bility of high fat diet in humans to allow for intestinal adap-
Growth hormone [131, Conflicting data ↑absorptive tation is limited by steatorrhea, especially in those with the
132] capacity (PN
weaning) colon in continuity. While the data for pectin derived SCFA
IGF-1 [119–126] ?downstream did not achieve statistical significance for increased fluid
effector of GLP-2 absorption in the colon.
GLP-2 [85–106] ↑crypt cell ↑absorptive Colostrum, which is rich in growth factors (including
proliferation, capacity (↓fluid EGF) and antibacterial peptides, enhanced adaptation in a
↑villus height, and PN
↑surface area requirement) piglet short bowel syndrome model but in a randomized
↑absorptive cross-over study in nine children with short bowel syndrome
capacity was not associated with improved intestinal function [77, 78].
↑Tolerance of
enteral nutrition
Epidermal growth factor No change in
Intestinal Secretions
[110–116] intestinal
permeability
Peptide YY [127–130] ↓gastric emptying, In addition to providing nutrition to the intestinal mucosa,
SI transit feeding into the gut stimulates pancreatic secretions, stimu-
↓stimulated lates factors essential for bile acid transport and gastrointes-
intestinal secretion
tinal hormone secretion (i.e. glucagon like pepetide-2
Gut microbiome Production of
short chain fatty
(GLP-2)) and plays a key role in the intestinal adaptive
acids response. In animal models of biliopancreatic bypass, the
Dysbiosis [166–171] ?enterocyte Impairment of mucosa of the bypassed limb maintained normal morphol-
turnover T-cell proliferation ogy despite exposure only to bilio-pancreatic secretions [79].
?alternation in The intensity of the adaptation in the bilio-pancreatic limb is
enteric nervous
system function markedly less in comparison to animals subjected to massive
and gut motility small bowel resection alone [80]. Sequential experiments
Microbial-derived introducing bile with or without pancreatic secretions high-
metabolites lighted the compounding effect of pancreatic secretions to
potentially impact
intestinal adaptation [81]. Bile delivered to the ileum
a range of
functions increased the adaptive hyperplasia of the ileum, regardless of
PN parenteral nutrition, SI small intestine pancreatic secretions. The addition of pancreatic secretions
further augmented the adaptation process in the distal small
bowel. Bile salt dependent lipase (BSDL) in pancreatic
glutamine, pectin, short chain fatty acid (SCFA) and long secretions has been identified to have proadaptive activities
chain fatty acids, have a specific trophic effect [64]. likely mediated by the Wnt signalling pathway in the entero-
Glutamine, a non-essential α-amino acid has been studied cytes [82]. The presence of nutrients in the colon may be
extensively with mixed results [65]. Glutamine is the major important in promoting small intestinal adaptation. A colonic
substrate for mitochondrial in enterocytes with the majority infusion of glucose in rats caused jejunal adaptation as mea-
of absorbed glutamine metabolized by the intestine. sured by an increase in the crypt cell production rate, muco-
Glutamine has many functions in the intestine including mod- sal wet weight, DNA and protein content per unit length of
ulating tight junction expression and inhibition of apoptosis small intestine [83]. Based on this observation the authors
[65–67]. Nevertheless, there is sparse evidence of glutamine postulated that plasma enteroglucagon is a colonic derived
supplementation improving adaptation, with lower enterocyte growth factor that stimulates small bowel growth [83]. The
protein and DNA levels observed in participants treated with reduction of colonic carbohydrate fermentation induced by
glutamine when compared to controls [68, 69]. administration of metronidazole in rats was associated with
Fats, especially long chain triglyceride, appear to promote decreased small intestinal adaptation [84].
intestinal adaptation [70, 71]. Whether polyunsaturated or
saturated long chain fat is of greater benefit remain to be
convincingly established. Studies of rats fed high polyun- Glucagon-Like Peptide-2
saturated fatty acid showed greater increase in DNA, protein
and mucosal weight [72]. While, two other studies of high Glucagon-like peptide-2 GLP-2) is a 33 amino acid proglu-
saturated fat diet showed increase in the transport of glucose, cagon derived peptide released by the enteroendocrine L
increase villus height and crypt depth [73, 74]. Similarly, cells located predominantly in the ileum and proximal colon
[85]. GLP-2 is released in response to stimulation by luminal In adults and children, the exogenous administration of
nutrients such as glucose, fatty acids and dietary fibre [86]. long acting GLP-2 (teduglutide) has been found to improve
The half-life of GLP2 is approximately 7 min before it is measures of intestinal growth and function. Twenty-four
cleaved to the inactive GLP-2(3-33) by DPP-IV [87, 88]. The weeks of treatment with teduglutide resulted in a reduction
DPP-IV resistant GLP-2 analogue, Teduglutide has greater (≥20%) in PN requirements in 63% of adults who had
bioactivity because of the longer circulating half-life [89]. required 3 days or more per week of PN compared with
GLP-2 is also cleared by glomerular filtration [90]. 30% who received placebo (p < 0.01) [107]. Improvement
The intestinotrophic effects of GLP-2 are both morpho- was associated with an increase in small bowel villus
logic and functional. Administration of GLP-2 or its ana- height and total surface area in responders. Twelve months
logues induces crypt cell proliferation, villus hypertrophy after cessation of teduglutide, 15 of 37 (40%) of patients
and inhibits enterocyte apoptosis resulting in an increase of required an increase in PN volume, 15 of 37 patients (40%)
absorptive surface in both the small and large intestine of maintained the same PN volume and 7 patients had a fur-
animals [91–94]. The functional gains following the admin- ther reduction in PN volume, including 3 patients who
istration of GLP-2 include increase glucose transport via ceased PN (8%). In the post-hoc analysis of the phase 3
activation of the SGLT-1 and GLUT-2 transporters, increase study of teduglutide in patients with short bowel syn-
expression of numerous brush border digestive enzymes drome, the greatest benefit on parenteral volume and nutri-
and facilitates the intestinal absorption of lipids and secretion was observed in patients with higher baseline
tion of chylomicrons [92, 95]. In addition to the intestinal requirements, including patients with a jejunostomy or
structural and functional changes, GLP-2 decreases gastric ileostomy [108].
emptying and proximal gut motility, decreases intestinal The early experiences with teduglutide treatment in chil-
permeability with enhanced tight junction protein expres- dren with short bowel syndrome associated intestinal failure
sion and has local intestinal anti-inflammatory effects that have been encouraging [109]. Following 12 weeks of tedu-
are mediated via vasoactive intestinal polypeptide [96, 97]. glutide administration in children, 3 of 15 subjects (20%)
GLP-2 treatment is associated with alterations in the who received 0.05 mg/kg/day and 1 subject of 14 subjects
hepatic expression of genes involved in bile acid synthesis (7%) who received 0.025 mg/kg/day developed independence
at a transcriptional level, including an up regulation of from parenteral nutrition although 4 weeks after discontinua-
Farnesoid X receptor (FXR), cytochrome P450, family 7, tion of teduglutide 2 of the 4 subjects had resumed PN. At a
subfamily A, polypeptide 1 (CYP7A1), multidrug resis- dose of 0.05 mg/kg/day for 12 weeks, PN volume reduced a
tance-associated proteins 2 (MRP2) and MRP3 [98]. The median of −1.3 L/week (−11.0, 1.0), and PN energy content
differences in bile acid profile observed with GLP-2 treat- of −17 (−45, 53) kcal/kg/day, while enteral energy intake
ment may explain the improvement of parenteral nutrition- increased by a median of 7 (−1, 63) kcal/kg/day. With more
associated cholestasis reported following treatment with prolonged therapy with teduglutide, changes in PN volume
GLP-2 [98, 99]. observed at 12 weeks were maintained through to a total of 24
The intestinotrophic effects of GLP-2 are mediated via weeks treatment [109]. It remains unclear whether teduglu-
the Glucagon-like peptide-2 receptor (GLP-2R) mainly tide has a role in augmenting early intestinal adaptation
localized to the intestine, with limited expression in the cen- immediately following massive intestinal resection.
tral nervous system. The highest expression of GLP2R is in
the jejunal, with expression in enteroendocrine cells, enteric
neurons, subepithelial myofibroblasts, vagal afferents and Epidermal Growth Factor
colonic submucosal glia [100, 101]. The expression of
GLP-2R in different cell compartments of the intestinal sug- The epidermal growth factor (ECF) family of peptides
gests that GLP-2 may act indirectly via multiple mediators include EGF, transforming growth factor-alpha (TGF-α),
[102]. heparin binding growth factor (HB-EGF), neuregulin and
In preclinical models, elevated GLP-2 levels were associ- neuregulin-2. The major sites of EGF synthesis are the sali-
ated with adaptation, while immunoneutralization dimin- vary glands and kidney [110]. The normal small intestinal
ished morphological adaptation in rats with proximal epithelium does not synthesize EGF except in duodenal
intestinal resection [103, 104]. Conversely, the adaptive Brunner’s gland in response to injury. The main EGF recep-
potential in distal intestinal resection is diminished in com- tor (EGFR) is present on the majority of epithelial and stro-
parison to proximal resection, possibly due to removal of the mal cells, with EGFR expressed on the basolateral surface of
ileum and a significant proportion of the intestinal L cell enterocytes [110]. Activation of EGFR results in numerous
mass in the ileum [105]. While, chronic administration of downstream cellular signals involved in enterocyte prolifera-
exogenous GLP-2 in rats with proximal intestinal resection tion and apoptosis, while selective inhibition of EFGR abro-
demonstrated increases in growth, digestive, and absorptive gates the adaptive response after massive intestinal resection
capacity and barrier function of the remnant intestine [106]. [111, 112].
442 J. Bines et al.
EGF therapy has been shown to promote morphological Peptide YY

and functional intestinal adaptation in rodent models of SBS
[113, 114]. Enteral EGF administration in the rat intestinal Peptide YY, like GLP-2, is produced by the L cells of the
resection model increases villus height, crypt depth, attenu- ileum and colon; it slows gastric emptying and small bowel
ates enterocyte apoptosis and decrease permeability to mac- transit and may be responsible for the ‘ileal’ and ‘colonic’
romolecules. In unresected piglets, EGF administration brakes [127]. At physiological doses in man, peptide YY
stimulated weight gain and reversed the weaning induced increases small bowel transit time and reduces stimulated
loss of glucose cotransporter SGLT1 [115]. EGF down- intestinal secretion [128]. Peptide YY serum levels are high
stream signalling is important for the trophic effects of in patients with a retained colon and low in patients with a
GLP-2 in the intestine. The collective information from jejunostomy, thus it may be responsible for part of the func-
experimental models of mutated EGFR mice, GLP-2R tional adaptation that occurs in patients with a retained colon
knockout or EFGR receptor inhibitors indicate EGF signal- [3]. It is unlikely to be responsible for any structural changes
ling is required for the trophic effects of GLP-2, although the as it does not induce gut growth in rats fed only with paren-
exact mechanism remains to be fully elucidated [101, 116]. teral nutrition [129, 130].
Interestingly, the combined administration of EGF and
GLP-2 to neonatal piglets with short bowel syndrome
resulted not only in the known trophic effects of the hor- Growth Hormone
mones, but also lengthening of the bowel, particularly in the
absence of the ileum [117]. Growth hormone (GH) is a polypeptide produced by the
There is limited experience of EGF therapy in humans. In somatotroph cells of the anterior pituitary gland. GH secre-
a study of 5 paediatric patients, enteral administration of tion from the pituitary is under neural control from the hypo-
EGF for 6 weeks resulted in improved both carbohydrate thalamus via growth hormone releasing hormone (GHRH),
absorption and enteral energy intake but not weight gain somatostatin and ghrelin [131]. Negative feedback on GH
[118]. secretion is exerted by IGF-1 and by GH levels. IGF-1 inhib-
its GH secretion by influencing GHRH and somatostatin pro-
duction in the hypothalamus. GH acts via the GH receptor
Insulin-Like Growth Factor-I (GHR) in its target cells and stimulates IGF-1 production
locally. In the intestine, GHR is localized throughout the
Insulin like growth factor-1 (IGF-I) is secreted by many intestinal epithelium, lamina propria, muscularis mucosa,
cells in the body, including the gastrointestinal tract. The submucosa and muscularis propria, indicating the potential
circulating IGF-1 is predominantly synthesized by the for GH therapy within the intestine [132].
liver and its secretion is regulated by growth hormone Results from preclinical animal experiments of GH therapy
(GH), insulin and protein/caloric intake [119]. Unlike following massive intestinal resection have been conflicting.
GLP-2, circulating IGF-I concentration doesn’t increase Early data from GH deficient and hypophysectomy rats dem-
following massive intestinal resection. The adaptive onstrated impaired intestinal adaptation while GH supplemen-
growth effects of IGF-I are thought to be pleiotropic as a tation normalised this process [133–135]. Data from a number
result of its paracrine/autocrine and endocrine effects on of animal models of GH supplementation in short bowel have
the different compartments of the intestinal tract [120– demonstrated trophic effects, including an increase in jejunal-
123]. In transgenic mice with IGF-I over-expression in the ileal length, villus height, ileal cell proliferation and ileal vil-
myofibroblasts, a 50% increase in intestinal length was lus height [136–138]. Conversely, other studies did not
reported post-resection suggests that IGF-1 plays a role in demonstrate GH-induced morphologic adaptation in rats [139,
intestinal lengthening post-resection [122]. Following 140]. Although the evidence to support structural adaptation
exogenous administration of IGF-I an increase in intesti- following GH treatment is conflicting, GH has been shown to
nal wet weight, villus height and crypt depth in the jeju- increase the functional capacity of the residual intestine. The
num and intestinal lengthening is observed [124]. administration of GH in animal models resulted in significant
It is suggested that IGF-I is a downstream effector of increases of brush border transport of glutamine and leucine,
GLP-2 in the intestine based on data from IGF-I knock-out increase glucose transport across ileal mucosa, and stimulated
mice and IGF-I receptor null animals [125, 126]. In the IGF-I sucrase and maltase activity in the small intestine [141, 142].
knock out mice, administration of GLP-2 failed to increase The clinical experience of GH supplementation with or
intestinal weight, morphometry or enterocyte proliferation without glutamine in human intestinal failure is probably of
[125]. Similarly, IGF-I receptor null mice did not exhibit historical interest especially in the current era of alternate
increase crypt-cell proliferation following chronic exposure intestinotrophic therapeutic options. Initial data from non-
to GLP-2 [126]. randomized controlled studies were encouraging with a
modest reduction in PN requirement in a third of patients spermine) which are responsible for inducing epithelial
with about 50% of subjects eventually weaning from PN hyperplasia [163]. The concentration of polyamines in jeju-
[143–146]. However, randomized controlled double blind nostomy fluid increases with refeeding [164]. It is postulated
cross-over studies of GH therapy with or without glutamine that this occurs in response to the presence of nutrients,
supplementation, albeit with small sample sizes, demonstra- increased mucosal blood flow, a neural or a humoral response
ble no improvement in absorptive capacity of the residual [164]. Aminoguanidine, which inhibits diamine oxidase and
intestine [147–150]. reduces polyamine breakdown, has been used successfully in
animals to induce epithelial hyperplasia and increased nutri-
ent absorption [165].
ther Potential Mediators of Intestinal
O
Adaptation
Intestinal Microbiome
Keratinocyte growth factor (KGF), also known as FGF7, is a
potent mitogen and exerts its effects via the FGF receptor 2 The gut microbiome contributes a wide range of metabolic
which is expressed by various types of epithelial cells, and biochemical activities that support the host to digest,
including the intestinal epithelium [151]. KGF expression is absorb, metabolise and excrete nutrients. Following massive
strongly upregulated following acute and chronic injury. In intestinal resection, the intestinal microbiome changes in
animal models of massive intestinal resection, KGF adminis- response to the new luminal environment [166]. Independent
tration augmented small intestinal growth, including muco- of the surgery, multiple factors contribute to the change in the
sal thickening, villus length and modestly increased both microbiome including stress response, use of antibiotics, fast-
small intestinal and colonic crypt depth [152]. KGF adminis- ing and exposure of the intestinal lumen to oxygen.
tration also improves the functional indices of adaptation Experimental models have shown intestinal resection reduces
such as basic ionic transport, alanine and glucose absorption the diversity of the microbiome in the remnant bowel, specifi-
[153, 154]. cally a predominance of gram-positive Firmicutes phyla and
Other potential trophic mediators that have been studied a decrease of Bacteroides [167, 168]. Gnotobiotic animal
include vasoactive intestinal peptide (VIP), vascular endo- models have smaller intestinal crypts, lower proliferation
thelial growth factor (VEGF), hepatocyte growth factor index but taller villi post intestinal resection [169, 170].
(HGF) and oral insulin [155–158]. Both VIP and VEGF have Following the introduction of microbes into gnotobiotic mice,
been identified to be downstream mediators of GLP-2 func- there was an increase in both crypt depth and enterocyte pro-
tion, therefore upstream GLP-2 administration possibly proliferation. Microbiota induced inflammation was associated
vides adequate stimulation of both VIP and VEGF pathways with significantly deeper crypts, taller villi and proliferation
for intestinal adaptation [155, 156]. Oral insulin has been index in interleukin-10 deficient mice, while genes involved
studied in a small human trial involving ten paediatric sub- with adaptive and innate immunity were up-regulated follow-
jects [159]. Although two infants were weaned of PN, the ing intestinal resection in zebrafish [169, 171]. These obser-
role of oral insulin remains uncertain complicated by the sig- vations suggest a possible synergistic effect between the
nificant degradation of insulin in the stomach. immune system, microbiota and intestinal adaptation.
There is limited data of R-spondin1 in short bowel syn- Metabolites generated from the breakdown of luminal
drome. However, it is a peptide of interest because of its nutrients by intestinal bacteria play an important role in
potent and specific proliferative effects on intestinal crypt intestinal adaptation. Short chain fatty acid (SCFA), the most
cells mediated via the wnt signalling pathway [160]. In vivo studied metabolite of commensal colonic bacteria fermenta-
experiments using exogenous administered R-spondin1 lead tion has been shown to improve adaptation in the small and
to expansion of many intestinal parameters including small large bowel, enhance intestinal barrier function and modu-
intestinal diameter, weight, crypt density and intestinal stem late energy salvage [75, 76, 172]. Specifically, butyrate
cell numbers [161]. In rats with induced colitis, exogenous appears to be the main SCFA responsible for the increase
R-spondin1 administration ameliorated the intestinal inflam- structural and functional changes in the early adaptation
mation while preserving the mucosa integrity in both small [173].
and large bowel by stimulating epithelial cell mitosis [162].
Intestinal Maladaptation
Aminoguanidine
The goal of intestinal adaptation following massive intestinal
Within the epithelial cell, ornithine is converted by ornithine loss is the eventual return of enteral homeostasis. Clinically
decarboxylase to polyamines (putrescine, spermidine and this is reflected in the successful transition from the state of
444 J. Bines et al.
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expression in models of jejuno-colonic short bowel syndrome. Sci
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Part V
Assessment and Treatment of Intestinal Failure
Assessment of Nutritional and Fluid
Status
Kirstine Farrer and Sorrel Burden
Key Points electrical impedance analysis, and computer tomography

1. Traditionally nutritional screening is done using a mea- or air displacement plethysmography. These techniques
surement of body mass index, percentage weight loss and are usually only performed in a research setting.
the likelihood of being able to eat/drink. 7. Underhydration is detected by a rapid weight loss, thirst,
2. A nutritional assessment additionally includes measure- fall in postural systolic blood pressure, low urine output,
ments of body composition and a review of the dietary and a rise in serum urea and creatinine.
intake. 8. Overhydration is commonly due to excessive amounts of
3. In many countries “subjective global assessment” is used intravenous saline being given and causes rapid weight
and it includes weight change, dietary input, gastrointes- gain, pitting oedema of the extremities, ascites, pleural
tinal symptoms, underlying disease, functional capacity effusions and a raised jugular venous pressure. It many
and physical examination. take 10 or more days to excrete the saline load.
4. The Global Leadership Initiative on Malnutrition (GLIM)
is being increasingly used and incorporates five criteria
for malnutrition 3 are phenotypic criteria (non-volitional
weight loss; low body mass index; and reduced muscle Introduction
mass) and 2 etiological ones (reduced food intake/assimi-
lation and inflammation/disease burden). The diagnosis Nutritional health is maintained by a state of equilibrium in
of malnutrition is based upon the presence of at least one which nutrient intake and an individual’s requirements bal-
phenotypic criterion and one etiologic criterion. ance. Protein-energy malnutrition occurs when net nutrient
5. Body composition can be measured in the clinical envi- intake (nutrient intake corrected for abnormally large faecal
ronment with anthropometric measurements such as mid or urinary losses) is less than requirements. Protein-energy
upper arm circumference (MUAC), triceps skin fold malnutrition leads to a succession of metabolic abnormali-
thickness (TSF), and mid arm muscle circumference ties, physiological changes, reduced organ and tissue func-
(MAMC). Muscle function may be assessed using hand tion, and loss of fat mass and skeletal muscle mass.
grip strength (hand-held dynamometer). Concurrent stresses such as trauma, sepsis, inflammation and
6. More detailed assessments of body composition are avail- burns will accelerate loss of tissue mass and function [1–3].
able including: dual-energy X-ray absorptiometry, bio- Nutritional screening aims to quickly detect patients who
may be or be at risk of becoming malnourished. A nutritional
assessment is a more detailed evaluation of intake, body
function/losses and needs. It is performed beside an assess-
K. Farrer (*) ment of hydration.
Salford Care Organisation, Part of the Northern Care Alliance NHS
The assessment of hydration is of immediate importance
Group, Salford, UK
e-mail: [email protected] and a nutrition support team may spend more time in manag-
ing hydration issues than managing the nutritional support.
S. Burden
University of Manchester and Manchester Royal Infirmary, This is because sick patients including those who have, sep-
Manchester, UK sis or inflammation or refeeding, often retain salt and water
University of Manchester and Salford Royal Foundation Trust, while patients with stoma or fistulae or drains may lose much
Manchester, UK fluid. A patient’s hydration is assessed by observing weight
e-mail: [email protected] changes, fluid balance, postural systolic blood pressure, skin/

454 K. Farrer and S. Burden
mucus membrane turgor, central venous pressure and bio- ferences; sagittal abdominal diameter; limb measurements
chemical measures. (mid-upper arm and calf circumferences) and skinfold thick-
This chapter will briefly address nutritional screening ness [10]. Body composition measurements aim to assess
then will concentrate on methods of doing a nutritional individual components of the human body including fat,
assessment before summarizing how subjective global muscle, bone and water content. Body composition measure-
assessment (SGA) [4] and Global Leadership Initiative on ments that are available include bioelectrical impedance,
Malnutrition (GLIM) [5] are performed. It completes with ultra sound, computed tomography, magnetic resonance
hydration assessment and some of the abnormalities imaging, air displacement plethysmography, isotope dilu-
encountered. tion, dual-energy X-ray absorptiometry and whole body
counting/neutron activation.
Biomarkers in nutritional assessment aim to identify indi-
Nutritional Screening cators of nutritional status and can be assessed by any bio-
logical specimen that is derived from dietary intake or
There are a number of screening tools that incorporate these metabolism [11], including measuring serum, plasma or
criteria including the UK Malnutrition Universal Screening urine levels. Functional measurements aim to determine
Tool (‘MUST’) [6] (Fig. 1). The Mini Nutritional Assessment muscle strength as a potential indicator of body muscle sta-
(MNA) includes more information than ‘MUST’ and is often tus or function [12]. There are also a number of question-
used in older adults. In addition to percentage weight loss naires available to determine overall assessment derived
and BMI the short form includes food intake, mobility, neu- from a combination of measurements, visual observations
ropsychological status and a measurement of calf circumfer- and points about disease type and severity [13]. Finally, there
ence [7]. are numerous nutritional screening tools available some of
which have been validated.
Nutritional Assessment
Anthropometric Measurements
Nutritional assessment involves a more detailed careful eval-
uation of a patient’s nutritional status and is a broader topic. ody Mass Index and Percentage Weight Loss
B
It is important for two reasons. Firstly for it to be of clinical Body weight is a simple measure of total body components
importance the ideal method should be able to predict and although is useful for identifying changes, within indi-
whether the individual would have an associated morbidity viduals, is of limited use without interpreting in conjunction
and mortality risk in the absence of nutritional support. with height and age. Weight is usually used to calculate body
Unfortunately, disease and nutrition interact so that disease mass index (BMI) or Quetelet index and is BMI is calculated
may cause secondary protein-energy malnutrition, or pre- as weight in kilograms divided by height in meters squared
existing protein-energy malnutrition may adversely influ- [14] (Appendix 1). A BMI indicating an individual is under-
ence the underlying disease. Secondly the measurement of weight is <18.5 kg/m2 and a normal BMI within a healthy
nutritional status is essential for determining the provision of range is 18.5–24.99 kg/m2 [14]. A BMI indicating undernu-
nutritional interventions and subsequent monitoring of inter- trition has been shown to correlate with an increase in all-
ventions administered [8]. Assessment of nutritional status is cause mortality [15]. However, measurements of body
required to determine requirements for nutritional support weight in patients in hospital cannot be seen in isolation
and accurately assess energy and protein requirements if pre- without considering fluid balance and hydration status. Both
dictive formulas are being employed [8, 9]. Monitoring the dehydration and over hydration are well recognised conse-
provision and adequacy of nutritional support treatment quences of illness particularly in the critically ill, postopera-
plans is also reliant on being able to assess changes in nutritive period, liver disease, cancer and renal failure, which can
tional status and body composition. lead to oedema and ascites [16].
Nutritional assessment methods encompass a variety of Unintentional weight loss greater than 10% is a good
different types of measurements looking to determine very prognosticator of clinical outcome [17, 18] (Appendix 2)
different aspects of the human physical form. These include However, it may be difficult to determine true weight loss.
anthropometric measurements, body composition measure- However, weight loss is often subject to memory recall and
ments, biomarkers and measurements of functionality. this has been shown to vary considerable in relation to the
Anthropometry is the measurements of the human body and length of time weight history is required, gender, age and
forms in integral part of assessment of nutritional status in also BMI [19, 20]. Furthermore, the nutritional significance
clinical practice. Anthropometric measurements include of changes in body weight can again be confounded by
measurement of whole body weight, height, body mass changes in hydration status, particularly an increase in extra
index, trunk measurements including: waist and hip circum- cellular fluid.
Assessment of Nutritional and Fluid Status 455
Fig. 1 Malnutrition Universal Screening Tool ‘MUST’. (Reproduced with the kind permission of BAPEN (British Association for Parenteral and
Enteral Nutrition). For further information on ‘MUST’ see www.bapen.org.uk’)
id-arm Muscle Circumference

M by the reproducibility and error in the measurements, while
Triceps and subscapular skinfold thickness provide an index the latter is dependent upon the relevance of the reference
of body fat and have been described in detail [21, 22]. Mid- data or standards available.
arm muscle circumference (MAMC) provides a measure of Body composition measurements have been divided into
muscle mass and can be calculated from skinfold thickness a five-level model to provide a structural framework [34].
and mid upper arm circumference (MUAC) (Appendix 3). The five levels include atomic, molecular, cellular, tissues-
MUAC has been used to identify chronic energy deficit and organs and whole body. Each of these levels measure differ-
has been found to be of prognostic value in relation to mor- ence components to determine body composition that can
tality in patients who are in hospital [23, 24]. include fat mass: fat free mass; total body water; body cell
The reliability of skinfold thickness is debated and there mass; bone mineral; skeletal muscle or total body protein
has been some debate about the reproducibility of these mea- [34]. The most frequently used measurements of body com-
surements. The measurements have been shown to be more position use the 2-compartmental model which measures fat
reliable in thinner people where there is less fat to measure mass and fat free mass [35]. It is important to note that some
and more reproducible when the same observer performs models measure a component of fat free mass then calculate
sequential measurements [25]. Experienced practitioners can fat free mass and then secondarily derive fat mass (e.g. bio-
achieve a high rate of reproducibility and more so then those electrical impedance) whereas the other techniques measure
observers who are less experienced, although there is mea- fat mass then subsequently calculate fat free mass (e.g. ultra
surement error in reproducibility between people [26]. sound) [35]. This is important when evaluating the precision
There are references ranges that can be used for skin fold of measurement and the potential for the degree of error
thickness, MUAC and mid arm muscle circumference based incurred during the measurement.
on population distributions (Appendix 4). Values less than the In healthy weight stable subjects there are relatively con-
fifth percentile have been used to classify individuals as under- stant relationships between these components which are cor-
nourished, although due to changes over time within popula- related with each other.
tions, older reference values have been questioned [27, 28].
The most commonly used standards for triceps skinfold Isotope Dilution
thickness and mid-arm muscle circumference are those Total body water, measured by, is usually the largest molecu-
reported by Jelliffe [29], which are based on measurements lar level component. Water maintains a relatively stable rela-
of European male military personnel and low-income tionship to fat-free body mass and thus measured water
American women, and those reported by Frisancho [30] isotope dilution volumes allow prediction of fat-free body
which are based on measurements of white males and mass and fat (i.e. body weight minus fat-free body mass).
females participating in the 1971–1974 United States Health The relationship between total body water and other body
and Nutrition Survey. The use of these standards to identify composition components may change with disease and this
protein-energy malnutrition in many patients is problematic should be considered when interpreting data from hospital-
because of the restricted database and the absence of correc- ised or chronically ill patients. The usual approach is to mea-
tion factors for age, hydration status and physical activity on sure a dilution volume using one of three isotopes, tritium,
anthropometric parameters. Several studies have demon- deuterium, or 18O-labelled water. This first step allows esti-
strated that 20–30% of healthy control subjects would be mation of a dilution volume of one of the three isotopes. In
considered undernourished based on these standards [28, 31] the second step it is assumed that the proportion of fat-free
and that there is poor correlation between the Jellife and body mass as water is constant at 0.732. This allows calcula-
Frisancho standards in classifying patients [28]. Although tion of fat-free body mass and fat [36].
attempts have been made to create standards for diseases
such as renal dialysis patients [32] the validity of standards ual-Energy X-Ray Absorptiometry
D
have been questioned and interpretation of data may be lim- Dual-energy X-ray absorptiometry (DEXA) is a method
ited by inter-rater variability [33]. developed originally for the measurement of bone density
and mass. Systems today also quantify soft tissue composi-
tion, and it is possible to measure total and regional fat, bone
Body Composition mineral and bone mineral-free lean components with
DEXA. The method is based on the attenuation characteris-
Assessment of nutritional status based on body composition tics of tissues exposed to X-rays at two peak energies.
involves detecting the loss (or gain) of body components Mathematical algorithms allow calculation of the separate
relative to previous measurements and relating these values components using various physical and bio logical models.
to standard reference ranges bases on healthy populations or Software can be used to measure regions separately if
data derived from specific populations. The former is affected desired. A typical whole body scan takes approximately
30 min and exposes the subject to ~1 mrem radiation. This areas can be calculated from CT images described by Prado
method provides an accurate and practical means of measur- et al. [43], including the quantification of muscle within a
ing bone mineral mass and offers the opportunity to study Hounsfield unit (HU) range of −30 to +150, and fat
appendicular muscle mass. within −190 to −30.
The value obtained for muscle mass area (cm2) is lin-
ioelectrical Impedance Analysis
B early related to whole-body muscle mass [42], and can be
Bioelectrical impedance analysis (BIA) is a method of esti- standardised according to height by dividing muscle area
mating body fluid volumes by measuring the resistance to a by height2 to provide a skeletal muscle index, which can be
high frequency, low amplitude alternating electric current compared to cut off values for the identification of low
(50 kHz at 500–800 mA). The amount of resistance mea- muscle mass [43, 44]. Low muscle mass derived from CT
sured (R) is inversely proportional to the volume of electro- images was found not to correlate with survival in a cohort
lytic fluid in the body, and to a lesser extent on the proportions of patients on home parenteral nutrition with intestinal fail-
of this volume. A regression equation is then developed ure [45].
based between a reference measurement of fat-free body Magnetic resonance imaging can be used to assess body
mass (i.e. isotope dilution) and the measured R, height and composition and is useful as it does not expose individuals to
other variables. Recent research in this area has focused on radiation. MRI images for whole body assessment with a full
separate measurements of extra- and intracellular water. In set of images to evaluate full body composition can take
healthy adults it is possible to predict total body water within about 30 min. However, there is validation work enabling the
2–3 L however; these prediction may not be reliable in indi- use of a single slice at lumbar vertebra 4 and 5 to assess skel-
viduals with medical conditions that effect fluid balance etal muscle mass and adipose tissue [46].
including renal and cardiac disease. So caution needs to be
taken where fluid shifts are a likely occurrence in disease ir Displacement Plethysmography
A
states [37]. This is four compartmental method of measuring body compo-
In a cohort of patients with intestinal failure BIA had sition. Participants are asked to wear swim wear and a cap over
good agreement with air displacement plethysmography their hair. All jewellery is removed as well as glasses. Participant
(ADP) as a criterion measure when measuring body compo- weight is taken on the Air displacement plethysmography
sition [38], which is in accordance with previous data mea- (ADP) scales before they enter the capsule. Participant is asked
suring percentage fat in 41 healthy participants using ADP to sit in the ADP chamber, remain relaxed and breathe nor-
and BIA where good agreement was shown [39]. Phase angle mally. The door is closed and the participant is asked to remain
derived from BIA has been shown to be predictive of mortal- as still as possible during a 30–50 s period, whilst the machine
ity and hospital length of stay in people with intestinal fail- takes a reading. The measurement is taken twice unless the
ure on home parenteral nutrition [40]. machine instructs a third measure to be taken. Body fat mass
and fat free mass is calculated by the ADP machine software
omputed Tomography and Magnetic Resonance
C (BODPOD). The BODPOD uses the principles of whole body
Imaging densitometry to determine body composition.
These methods measure components at the tissue-system This method of assessment was offered to patients receiv-
level of body composition, including skeletal muscle, adi- ing home parenteral nutrition with short bowel syndrome,
pose tissue, visceral organs and brain. Computed tomogra- although in a research environment the uptake was very low
phy (CT) systems measure X-ray attenuation as the source [38]. It was suggested that this was due to the requirement to
and detector rotate in a perpendicular plane around the sub- wear swimwear which was possibly due to individual’s being
ject. Magnetic resonance imaging (MRI) systems measure self-conscious about body image due to the presences of a
nuclear relaxation times from nuclei of atoms with a mag- stoma [47]. In addition, in this study the BODPOD was
netic moment that are aligned within a powerful magnetic located at a different location so travel may have been a fac-
field. tor in the low uptake for this measurement [38].
The use of CT and MRI imaging is becoming more popu-
lar in research and clinical practice internationally. The Ultrasound
development of computer software packages that allows Ultra sound is a fairly fast noninvasive method of assessing
body composition to be determined from CT and MRI body composition in clinical practice and research, it is rela-
images is now readily available. These software packages tively inexpensive and also portable device are available. It
have been reviewed and been found to be highly correlated does not subject people to any radiation so suitable for
for the measurement of cross sectional muscle area [41]. sequential measurements. Ultra sound uses high frequency
The level of the third lumbar vertebra (L3) is often used as a sound waves that travel in the form of cyclical waves greater
reference point and this has been found to correlate well than 20 KHz [48]. A transducer produces pulses of ultra-
with whole body composition [42]. Fat and muscle mass sounds that are transmitted through the skin and when the
beam comes into contact with a tissue interface of either skin, 3. What reasons are given for the change in dietary
fat, muscle or bone an echo is sent back though the transducer intake? Has appetite changed? Is there a disturbance in
[48]. These echoes are then processed by the transducer and taste, smell, or the ability to chew or swallow food?
turned into signals. It is these signals that are represented by Has there been a change in mental status or increased
waves. To perform an ultrasound scan the transducer is moved depression? Has there been a change in the ability to
over the skin where gel has been applied and for a single site prepare meals? Are there gastrointestinal symptoms,
measurement this movement is approximately 5 cm. However, such as early satiety, post-prandial pain, nausea, or
whole thigh or calf can be scanned depending on what is vomiting? Is the patient taking medications that affect
required. The image is then read on a screen using software. food intake?
Some packages have been designed for the purpose of mea- 4. Is there evidence of malabsorption? Does the patient have
suring fat, muscle and bone and reliability and validity data gastrointestinal disease? Has there been a change in
are available for the A Mode ultrasound [49, 50]. bowel habits?
Ultra sound has been compared to air displacement pleth- 5. Are there symptoms of specific nutrient deficiencies
ysmography (ADP) in a small number of patients with intes- including macro-minerals (e.g. sodium, potassium, cal-
tinal failure and showed for fat free mass measured by cium or magnesium), micronutrients and water?
ultrasound in comparison to ADP there was a moderate intra-
class correlation (ICC) (ICC 0.659, 95% confidence interval
−0.27 to 0.92), although this was poor for fat mass (ICC
−0.005, 95% CI −0.73 to 0.65) [38]. Physical Examination
The physical examination corroborates and adds to the find-

Clinical Assessment of Nutritional Status ings obtained by history:
The clinical assessment of nutritional status involves a Anthropometric Assessment

focused history and physical examination in conjunction Current body weight should be compared with previously
with selected measurements of body composition or labora- recorded weights, if available (Appendix 1). Weight for
tory tests. Laboratory tests can identify specific nutrient defi- height should be compared with reference values for BMI
ciencies and body composition measurements can assess the (Appendix 2). A search for evidence demonstrating deple-
incidence of sarcopenia, myopenia or sarcopenic obesity. A tion of body fat and muscle masses should be made. A gen-
full nutritional assessment can also potentially identify those eral loss of adipose tissue can be judged by clearly defined
who are at risk of becoming malnourished or developing bony, muscular and venous outlines, and loose skinfolds.
future nutritional abnormalities. The presence of hollow cheeks, buttocks and perianal area
suggests body fat loss. An examination of the temporalis,
deltoids, and quadriceps muscles should be made to search
History for muscle wasting.
The nutritional history should evaluate the following Fluid Status

questions: An evaluation for dehydration (hypotension, tachycardia,
postural changes, mucosal xerosis, dry skin, and swollen
1. Has there been a recent change in body weight, particu- tongue) and excess body fluid (oedema, ascites) should be
larly in the last 3 months and was the change intentional made (see below).
or unintentional?
2. Is dietary intake adequate? An assessment of habitual eating valuation for Specific Nutrient Deficiencies
E
and current dietary intake should be assessed by a dietitian in Rapidly proliferating tissues, such as oral mucosa, hair, skin,
relation to overall nutritional adequacy and specific micro- and bone marrow are often more sensitive to nutrient defi-
nutrient intakes. An assessment of nutrient supplements ciencies than are tissues that turn over more slowly.
being taken needs to be undertaken and their contribution to
nutrient intake including both macro and micronutrient Laboratory Tests
intakes. A diary documenting food intake may be useful The results of the history and physical examination may lead
when the history is inconclusive and this can be in the form to a suspicion of specific nutrient deficiencies, which can be
of a paper diary or one of a number of digital applications further corroborated by appropriate diagnostic laboratory
that are available to use on SMART phones or tablets [51]. tests.
Functional Assessment Table 1 Features of subjective global assessment

History
and Grip Strength
H 1. Weight change and height
Handgrip strength is a measure of muscle function or strength Current: Height ________ cm
and is used in research and clinical practice. Handgrip mea- Weight ________ kg
Overall loss in past 6 months: ________ kg
sure has been seen to be valid in hospitalised patients and
________ %
reliable when undertaken in the sitting or supine position Change in past 2 weeks (use + or −): ________ kg
[52]. Handgrip strength has been shown to correlate with ________ %
outcome in hospitalised patients, surgery and cardiovascular 2. Dietary intake change (relative to usual intake)
disease [53, 54]. No change
Change: Duration ____ days
iomarkers: Serum Proteins
B Type: Suboptimal solid diet
Hypocaloric liquids
There is no laboratory test that is both sensitive to and spe-
Starvation
cific for protein energy malnutrition. Historically albumin Supplement: (circle)
and pre albumin have been used as markers of nutritional Nil
status and to identify energy and protein malnutrition. Vitamins
However it has since been recognised that hepatic proteins Minerals
are not good markers of nutritional status, but measurements 3. Gastrointestinal symptoms that persisted for >2 weeks
of disease even though there is evidence of correlation None
Nausea
between mortality, morbidity and recovery from disease.
Vomiting
During a critical illness, factors that alter serum albumin and Diarrhoea
prealbumin may include the following: the acute-phrase Pain: At rest
response; hydration (intravascular volume) status; disease On eating
state; clinical condition; leakage of albumin from intravascu- 4. Functional capacity
lar to extravascular spaces; and severe zinc deficiency. No dysfunction
Evidence has demonstrated that serum levels of these pro- Dysfunction: Duration____ days
Type: Working
teins do not change in relation to the intake of protein. They
sub-optimally
should not be used in clinical environments to assess disease Ambulatory but
related malnutrition but are useful as a tool to indicate sever- not working
ity of disease [8, 55]. It is imperative that the dietitian inter- Bedridden
prets hepatic protein levels in the context of overall health 5. Disease and its relation to nutritional requirements
and lifestyle [8, 56]. Primary diagnosis: ___________________________
Metabolic demand (stress):
No stress
ubjective Global Assessment
S Moderate stress
World-wide the Patient-Generated Subjective Global High stress (burns, sepsis,
Assessment (PG-SGA) is often used. It is a clinical method severe trauma)
for evaluating nutritional status, termed subjective global Physical status (for each trait specify: 0 = normal, 1 = mild deficit,
assessment (SGA), encompasses historical, symptomatic 2 = established deficit)
Loss of subcutaneous fat
and physical parameters [4, 13, 57]. This approach defines
Muscle wasting
undernourished patients as those who are at increased risk Oedema
for medical complications and who will presumably benefit Ascites
from nutritional therapy. The basis of this assessment is to Mucosal lesions
determine whether nutrient assimilation has been restricted Cutaneous and hair changes
because of decreased food intake, or malabsorption, whether SGA Grade __________
any effects of protein-energy malnutrition on organ function A: well nourished; B: moderate or suspected protein-energy
malnutrition; C: severe protein-energy malnutrition
and body composition have occurred, and whether the indi-
vidual’s disease process influences nutrient requirements.
The specific features of the history and physical examination (>10%). The pattern of loss is also important and it is possi-
used in the SGA are listed in Tables 1, 2, 3, and 4. ble for a patient to have significant weight loss but still be
The history used in the SGA focuses on five areas. The considered well-nourished if body weight (without oedema
percentage of body weight lost in the previous 6 months is or ascites) recently increased. For example, a patient who
characterized as mild (<5%), moderate (5–10%), and severe has had a 10% body weight loss but regained 3% of that
weight over the past month, would be considered well- not precise, but are merely a subjective impression of the
nourished. Dietary intake is classified as normal or abnormal degree of subcutaneous tissue loss. The second feature is
as judged by a change in intake and whether the current diet muscle wasting in the temporal areas and in the deltoids and
is nutritionally adequate. The presence of persistent gastroin- quadriceps, as determined by loss of bulk and tone detectable
testinal symptoms, such as anorexia, nausea, vomiting, diar- by palpation. A neurological deficit will interfere with this
rhoea and abdominal pain, which have occurred almost daily assessment. The presence of oedema in the ankle and sacral
for at least 2 weeks, is recorded. The patient’s functional regions and the presence of ascites are noted. Co-existing
capacity is defined as bedridden, suboptimally active, or full disease such as renal or congestive failure will modify the
capacity. The last feature of the history concerns the meta- weight placed on the finding of oedema. Mucosal and cuta-
bolic demands of the patient’s underlying disease state. neous lesions are recorded, as are colour and appearance of
Examples of high-stress illnesses are burns, major trauma the patient’s hair.
and severe inflammation, such as acute colitis. Moderate- The findings of the history and physical examination are
stress diseases might be a mild infection or limited malignant used to categorize patients as being well-nourished (category
tumour. A), having moderate or suspected protein-energy malnutri-
The features of the physical examination are noted as nor- tion (category B), or having severe protein-energy malnutri-
mal, mild, moderate, or severe alterations. The loss of subcu- tion (category C) (Table 5).
taneous fat measured in the triceps region and the mid-axillary The rank is assigned on the basis of subjective weighting.
line at the level of the lower ribs. These measurements are Equivocal information is given less weight than definitive
data. Fluid shifts related to onset or treatment of oedema or
ascites must be considered when interpreting changes in
Table 2 Subjective global assessment—clinical observations of loss body weight. In general, a patient who has experienced
of subcutaneous fat stores
weight loss and muscle wasting but is currently eating well
Physical and is gaining weight is classified as well nourished. A
examination Normal Mild/moderate Severe
Under eyes Slightly Somewhat Hollow look,
patient who has experienced moderate weight loss, contin-
bulging area hollow look, depression, ued compromised food intake, continued weight loss, pro-
slightly dark dark circles gressive functional impairment, and has a ‘moderate-stress’
circles illness is classified as moderately undernourished. An indi-
Triceps Large space Some depth to fat Very little space vidual, who has experienced severe weight loss, continues to
between fingers tissue, but not between fingers
ample. Loose or fingers touch have poor nutrient intake, progressive functional impairment
skin and muscle wasting is classified as severely undernourished
Ribs, lower Chest is full, Ribs obvious and Indentation independent of disease stress. Baker et al. [57] and Detsky
back, side of ribs are not indentations are between ribs et al. [4] found that the use of SGA in evaluating hospitalised
body trunk visible, slight not marked. very obvious,
to no Crest somewhat iliac crest very
patients gives reproducible results and there was more than
protrusion of prominent prominent 80% agreement when two blinded observers assessed the
the iliac crest same patient.
Table 3 Subjective global assessment: clinical observations of loss of muscle mass

Physical examination Normal Mild/moderate Severe
Temple Well defined muscle Slight depression Hollowing depression
Clavicle Not visible in males, may be Some protrusion; may not be all the Protruding/prominent bone
visible but not prominent in way along
females
Shoulder Rounded Not square in appearance, acromion Square appearance, bones
process may protrude slightly not all prominent
areas
Scapula/ribs Bones not prominent no Mild depressions or bone may show Bones prominent
significant depressions slightly not all areas significant depression
medially
Quadriceps Well defined Depression/atrophy medially Prominent knee. Severe
depression medially
Interosseous muscle between thumb Muscle protrudes could be flat in Slightly depressed Flat or depressed areas
and forefinger (back of the hand) females
Table 4 Subjective global assessment—clinical observations of fluid work as a teacher and is active. On physical examination,
retention there was no loss of subcutaneous fat stores; her ribs are not
Physical visible and there is no protrusion of the iliac crest. There are
examination Normal Mild/moderate Severe no signs of muscle wastage; her shoulders are rounded and
Oedema None Pitting oedema of Pitting beyond
the temple shows no signs of depression. She is classified as
extremities/pitting to
knees, sacral oedema
knees, possible sacral
if bedridden may SGA—‘A’, ‘well nourished’.
oedema if bedridden also have generalised
oedema Case 2
Ascites Absent Present (may only be Present (may only be A 40-year-old man with an acute exacerbation of Crohn’s
present on imaging) present on imaging)
disease had lost 10% of his body weight within the previous
2 weeks. His weight is 65 kg, height 1.83 m, BMI 19.4 kg/m2
Table 5 Subjective global assessment—categories and he was drinking liquids to avoid gastrointestinal discom-
Category Well-nourished no decrease in food/nutrient intake; <5% fort associated with ingesting solid food (vomiting, nausea
A weight loss; no/minimal symptoms affecting food intake; and diarrhea). He was ambulatory, but he was not going to
no deficit in function; no deficit in fat or muscle mass OR
an individual with criteria for SGA, B or C but with work. On physical examination, he had slight loss of subcu-
recent adequate food intake; non-fluid weight gain; taneous tissue manifested by a reduced buccal fat pad (on the
significant recent improvement in symptoms allowing facial cheek), his ribs are obvious and iliac crest somewhat
adequate oral intake; significant recent improvement in prominent and loose skinfolds over the arms. His acromion
function; and chronic deficit in fat and muscle mass but
with recent clinical improvement in function. process protrudes slightly and his interosseous muscle on the
Category Mildly/moderately malnourished definite decrease in back of his hand is slightly depressed. He is classified as
B food/nutrient intake; 5–10% weight loss without SGA ‘B’—‘moderate or suspected protein energy
stabilization or gain; mild/some symptoms affecting food malnutrition’.
intake; moderate functional deficit or recent deterioration;
mild/moderate loss of fat and/or muscle mass OR an
individual meeting criteria for SGA C but with Case 3
improvement (but not adequate) of oral intake, recent A 67-year-old man with oesophageal cancer had minimal
stabilisation of weight, decrease in symptoms affecting food intake for almost 3 months. His weight was 55 kg,
oral intake, and stabilisation of functional status.
height 1.77 m and BMI 17.6 kg/m2. He has lost 15% of his
Category Severely malnourished severe deficit in food/nutrient
C intake; >10% weight loss which is on-going; significant body weight during the previous 4 months and is continu-
symptoms affecting food/nutrient intake; severe ing to lose weight—1 kg per week. He was able to move
functional deficit OR recent significant deterioration around the house but had marked muscle weakness and
obvious signs of fat and/or muscle loss. Cachexia—If fatigue and did not walk outdoors. Hi oral intake is
there is an underlying predisposing disorder (e.g.
malignancy) and there is evidence of reduced muscle and restricted to fluids 1.5 L/day (soup, ice-cream and milk).
fat and no or limited improvement with optimal nutrient On physical examination, he lacked subcutaneous fat tis-
intake, this is consistent with cachexia sarcopenia—If sue, had hollow temples, dark circles under his eyes, del-
there is an underlying disorder (e.g. aging) and there is toid wasting, square shoulders, prominent knees, and mild
evidence of reduced muscle and strength and no or
limited improvement with optimal nutrient intake pitting oedema. He is SGA ‘C’—severe protein energy
malnutrition.
Illustrative Cases
lobal Leadership Initiative on Malnutrition
G
Case 1 (GLIM)
A 55-year-old woman was admitted to the hospital for elec-
tive resection of a colon carcinoma. Her weight was 65 kg, In 2016 the global consensus for diagnosing malnutrition in
height 1.65 m and BMI 23.9 kg/m2. She had lost 10% of her adult patients was launched; commonly known as the Global
initial weight over a 6 month period before admission. Leadership Initiative on Malnutrition (GLIM) [5]. Nutritional
However, she recently gained weight after therapy with screening is the first line of nutritional assessment and is now
nutritional supplement drinks providing an additional informed by the Global Leadership Initiative on Malnutrition
600 kcal + 25 g protein per day and these have subsequently (GLIM) where appropriate criteria are specified for pheno-
been stopped as her dietary intake is classified as ‘normal’. types and aetiological criteria (Table 6). A global team of
She has no adverse gastrointestinal symptoms or pain. experts agreed on five criteria for malnutrition which
Current weight 68 kg (BMI 25 kg/m2). She continued to include non-volitional weight loss; low body mass index;
Table 6 Thresholds for severity grading of malnutrition (both need mortality, morbidity and patient reported outcome measures.
one phenotypic criteria) [5] There is a vast literature on the reliability and validity of
Weight loss BMIa measurements of body composition and nutritional status
In last Beyond Muscle covering multiple measurement techniques. It is the skill in
6 months 6 months kg/m2 mass application of these techniques in different settings that facil-
Stage 1 itates appropriate assessment and monitoring of individuals
Moderate 5–10% 10–20% <20–22a,b Mild/ and ensuring the monitoring is the role of a dietitian/regis-
malnutrition moderate
deficit tered nutritionist.
Stage 2
Severe >10% >20% <18.5 Severe
malnutrition <20 if aged 70 deficit Assessment of Fluid Status
years or over
Aetiological criteria
Reduced food intake or assimilation
Water and salt are critically important constituents of the
• 50% of ER >1 week, or any reduction for >2 weeks, or any chronic body, and disturbances of salt and water have quicker and
GI condition that adversely impacts food assimilation or absorption more profound effects on health than nutrients. Body water
Inflammation comprises 73% of the lean body mass but 54% of body
• Acute disease/injury or chronic disease-related weight because fat does not contain water. Consequently,
a
20 in less than 70 years old and 22 if more than 70 years old obese persons have less water in relation to body weight. Of
b
Lower BMI in Asian population <18.5–20 total body water, 40% is the volume in which chloride is dis-
tributed and is extracellular; 60% resides in cells and is
called the intracellular water in which body potassium and
and reduced muscle mass as phenotypic criteria, and magnesium is distributed. The assessment of fluid status
reduced food intake/assimilation and inflammation/dis- depends upon recognizing that body fluids are composed of
ease burden as etiologic criteria. It was proposed that the isotonic saline and free water. The changes in the normal
diagnosis of malnutrition be based upon the presence of at saline content alters the volume of the extracellular fluid and
least one phenotypic criterion and one etiologic criterion. leaves the electrolyte concentration unchanged, while
Conclusions About Nutritional Assessment changes in free water alter the osmolarity and change plasma
Protein-energy malnutrition results in a continuum which sodium concentration.
starts when an individual fails to eat sufficient oral diet to Clinically the hydration status is assessed by:
meet their nutritional requirements. There are numerous
methods to assess nutritional status and body composi- 1. History of conditions which can cause deficits or
tion and some methods are suited to research and others overload.
to clinical practice. Measurements can now be used to 2. History of symptoms suggestive of abnormal fluid
start identifying malnutrition, sarcopenia, sarcopenic status.
obesity and myopenia. However, there is also the need to 3. Physical examination.
assess risk of those individuals who are likely to become 4. Biochemical tests.
malnourished in the future, because prevention is better
than cure.
The identification of risk of malnutrition and malnutrition
should follow with the appropriate intervention being made nderhydrated (Hypovolaemic, Extracellular
U
available to correct macro and micro nutrient deficiencies. Fluid Depletion)
Appropriate assessment and monitoring of disease related
malnutrition allows the correct intervention to be adminis- This is common especially when there are large losses such
tered with the ultimate aim of effecting change in an indi- as diarrhoea, large stomal/intestinal fistula output and/or
vidual’s disease trajectory, whilst influencing overall vomiting. When the changes are mild with less than 10%
reduction of extracellular fluid volume (ECF), the patients Table 7 History and clinical features of hypovolaemia/ECF depletion
may have very few complaints except for rapid weight loss. History Symptoms Physical signs
When there is a greater reduction of ECF then there are Losses of fluid: Weakness, thirst, Weight loss
symptoms of marked weight loss, dizziness and palpita- vomiting and dizziness,
diarrhea postural
tions on changing from a recumbent to an erect posture,
Renal disease Symptoms Dry mucous membranes
weakness, thirst and fainting. On examination there is pos- with diuresis
tural tachycardia and fall in systolic blood pressure on Diuretic Reduced skin turgor
changing posture. In normal individuals or those with <7% therapy Reduced central venous
volume depletion the pulse will rise by 10 beats/min, the pressure
systolic pressure will fall by 5–10 mm and the diastolic will Postural changes in pulse >10
beats/min and a fall in systolic
rise by 5–10 mm when the posture is changed from a pressure >15 mm
recumbent to an erect state. With greater loss of the ECF
the pulse rises by 20 beats/min and the postural change in
systolic pressure will be 20 mm or more without a similar Table 8 Changes in plasma electrolytes with conditions resulting in
compensatory rise in the diastolic pressure. Weight loss loss of ECF
always occurs, with severe depletion (>15%) the jugular Clinical
venous wave is not seen even when the patient is lying flat. condition Sodium Potassium Chloride Bicarbonate
Vomiting Normal Low Low High
The changes in blood pressure may be missed unless the
Jejunostomy Normal Normal Normal Normal
blood pressure is taken only after waiting for 10 min after losses
change of position. The clinical features of ECF volume Pancreatic Normal Normal High Low
depletion are summarized in Table 7 and the electrolyte fistula
changes in Table 8. Ileostomy Normal Normal or Normal or Normal or
low high low
On biochemical testing the plasma sodium concentra-
Diarrhoea Normal Low High Low
tion is normal unless the patient has been drinking water
to quench thirst, in which case the plasma sodium may fall
below the normal range (hyponatraemia). When patients containing fluids or in the perioperative period). Two liters of
have a short bowel, losses of fluid from a jejunostomy, 0.9% saline given to healthy volunteers reduced the albumin
which is isotonic will cause serious volume contraction by about 10 g/L and it took 2 weeks to return completely to
but leave the plasma sodium, potassium, chloride and normal [58]. Thus humans have poor mechanisms for excret-
bicarbonate concentrations normal. Losses from other ing a sodium load. Saline overload causes rapid weight gain,
sites can change the plasma electrolyte picture as indicatedswelling of the extremities and abdomen, and breathlessness.
in Table 8. In addition renal urine electrolytes will show On examination there may be one or more of the following:
a marked reduction in sodium concentration <10 mmol/L. acute weight gain, pitting oedema (pretibial or if bed bound
of thighs or sacral area), ascites, raised jugular venous pres-
sure and pleural effusions. In this condition the plasma elec-
Overhydrated (Hypervolaemic, Increased trolytes will be normal unless the patient has received
Extracellular Fluid) diuretics and continues to drink water or receive fluids with-
out sodium (e.g. isotonic glucose). These patients need saline
This commonly occurs when excessive saline is given intra- intake restricting, or very occasionally are given intravenous
venously (e.g. after vigorous resuscitation with sodium- albumin with or without a loop diuretic.
Appendix 1
Appendix 2
Appendix 3 MID-ARM MUSCLE CIRCUMFERENCE (MAMC)

50 49 49 48 47 47 46 46 45 44 44 43 42 42 41 41
49 48 48 47 46 46 45 45 44 43 43 42 41 41 40 40
48 47 47 46 45 45 44 44 43 42 42 41 40 40 39 39
47 46 46 45 44 44 43 43 42 41 41 40 39 39 38 38
46 45 45 44 43 43 42 42 41 40 40 39 38 38 37 37
45 44 44 43 42 42 41 41 40 39 39 38 37 37 36 36
M 44 43 43 42 41 41 40 40 39 38 38 37 36 36 35 35
I 43 42 42 41 40 40 39 39 38 37 37 36 35 35 34 34
D 42 41 41 40 39 39 38 38 37 36 36 35 34 34 33 33
A 41 40 40 39 38 38 37 37 36 35 35 34 33 33 32 32
R 40 39 39 38 37 37 36 36 35 34 34 33 32 32 31 31
M 39 38 38 37 36 36 35 35 34 33 33 32 31 31 30 30
38 37 37 36 35 35 34 34 33 32 32 31 30 30 29 29
37 36 36 35 34 34 33 33 32 31 31 30 29 29 28 28
36 35 35 34 33 33 32 32 31 30 30 29 28 28 27 27
C 35 34 34 33 32 32 31 31 30 29 29 28 27 27 26 26
I 34 33 33 32 31 31 30 30 29 28 28 27 26 26 25 25
R 33 32 32 31 30 30 29 29 28 27 27 26 25 25 24 24
C 32 31 31 30 29 29 28 28 27 26 26 25 24 24 23 23
U 31 30 30 29 28 28 27 27 26 25 25 24 23 23 22 22
M 30 29 29 28 27 27 26 26 25 24 24 23 22 22 21 21
F 29 28 28 27 26 26 25 25 24 23 23 22 21 21 20 20
E 28 27 27 26 25 25 24 24 23 22 22 21 20 20 19 19
R 27 26 26 25 24 24 23 23 22 21 21 20 19 19 18 18
E 26 25 25 24 23 23 22 22 21 20 20 19 18 18 17 17
N 25 24 24 23 22 22 21 21 20 19 19 18 17 17 16 16
C 24 23 23 22 21 21 20 20 19 18 18 17 16 16 15 15
E 23 22 22 21 20 20 19 19 18 17 17 16 15 15 14 14
22 21 21 20 19 19 18 18 17 16 16 15 14 14 13 13
21 20 20 19 18 18 17 17 16 15 15 14 13 13 12 12
20 19 19 18 17 17 16 16 15 14 14 13 12 12 11 11
C 19 18 18 17 16 16 15 15 14 13 13 12 11 11 10 10
M 18 17 17 16 15 15 14 14 13 12 12 11 10 10 9 9
17 16 16 15 14 14 13 13 12 11 11 10 9 9 8 8
16 15 15 14 13 13 12 12 11 10 10 9 8 8 7 7
15 14 14 13 12 12 11 11 10 9 9 8 7 7 6 6
14 13 13 12 11 11 10 10 9 8 8 7 6 6 5 5
13 12 12 11 10 10 9 9 8 7 7 6 5 5 4 4
12 11 11 10 9 9 8 8 7 6 6 5 4 4 3 3
11 10 10 9 8 8 7 7 6 5 5 4 3 3 2 2
10 9 9 8 7 7 6 6 5 4 4 3 2 2 1 1
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0
TRICEPS SKIN FOLD THICKNESS CM
MAMC = Mid − arm circumference − ( 3.14 × Triceps skin fold thickness )
The mid-arm circumference and triceps skin fold mea- mion (shoulder tip) and the olecranon process (elbow) on
surement are made mid-way between the tip of the acro- the relaxed extended left (non-dominant) arm
ppendix 4 MID-ARM MUSCLE

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Radiology in Intestinal Failure
Arun Gupta, Alex Fitzhugh, Chun Wah So, Aia Mehdi,

Anmol Gangi, Michele Marshall,
and Rajapandian Ilangovan
Key Points 8. Diagnosis of obstruction or ischaemia can be challeng-

1. The radiologist is a key member of the intestinal failure ing. If there is a strong clinical suspicion of either and
multidisciplinary team and helps with both diagnostic the initial radiology report doesn’t match the clinical
and therapeutic procedures. concern, urgent review by a specialist Gastro-intestinal
2. The choice of radiological technique depends upon the radiologist maximises the chance of making a correct
availability of equipment, the expertise of the local radi- diagnosis.
ology department, and whether the patient is acutely 9. A barium follow through (BFT) alone or in combination
unwell or stable with chronic problems. with a CT scan will usually give the information required
3. A plain abdominal radiograph is useful in the acute set- (length and quality of bowel) for mapping bowel before
ting to diagnose obstruction, ileus, perforation and the reconstructive surgery.
extent/severity of colitis, and can be helpful in monitor- 10. Contrast fluoroscopy (with bowel distension) is good to
ing progress. determine the patency, length and quality of out of cir-
4. Computerised tomography (CT) is usually the best cuit bowel prior to distal feeding or reconstructive
choice in an acute setting where it is easily accessible, surgery.
quick to perform, can be relatively easier to interpret and 11. Mapping a fistula tract is dependent on its location,
allows an extra-intestinal assessment including the state accessibility and complexity, and upon the general state
of the abdominal wall. of the patient. A CT and /or BFT can provide an accurate
5. Magnetic resonance enterography (MRE) produces high overview, with fluoroscopy (fistulogram) or focussed
quality images of the small bowel, but it can be challeng- MRI adding more detail.
ing to obtain high quality images in all patients. Patient 12. Expert review of all current and previous imaging,
movement, bowel peristalsis or inability to maintain a including those obtained in other institutions, may pro-
breath hold can result in sub-optimal non-diagnostic vide an understanding of complex anatomy not discern-
images, so careful patient selection is needed. ible on a single examination or modality, and can guide
6. Ultrasound (US) is user dependent, but with appropriate further imaging.
expertise, US scans can provide greater resolution and
information than is possible with other imaging modali-
ties, particularly in thin patients or when the probe can
be placed close to the pathology. Introduction
7. Intra-abdominal sepsis is usually detectable by CT, but a
multi-modality approach may be needed. Drainage can Diagnostic imaging and interventional radiology is used fre-
be achieved by CT or US guidance, depending upon quently in managing patients with IF. The radiologist should
which provides the best accessibility or visibility of the be regarded as part of the multidisciplinary team caring for
collection. the patients with IF. They are able to help define the initial
diagnosis of perforations, sepsis, ischaemia and obstruction/
ileus. Small bowel obstruction can easily be misdiagnosed as
ileus, and similarly reversible bowel ischaemia can be missed
A. Gupta (*) · A. Fitzhugh · C. W. So · A. Mehdi · A. Gangi as signs can be non-specific. Using a variety of modalities
M. Marshall · R. Ilangovan they can accurately map the remaining bowel (length and
St Mark’s Hospital, Harrow, UK
quality) and abdominal wall before reconstructive surgery.

470 A. Gupta et al.
An increasing number of therapeutic procedures, from drain- Fluoroscopy

ing sepsis to inserting enteral and parenteral feeding lines,
require radiology input and a dynamic and collaborative Until recently fluoroscopy relied on the fluoroscopic proper-
interface with the radiology department will facilitate best ties of crystalline media, converting x-rays to collectible
clinical practice. This chapter covers the imaging modalities, light to form a visible image. Modern digital fluoroscopy
the radiological assessment of relevant conditions, and tech- units now use digital flat panel detectors that convert the
niques for bowel and fistula mapping. transmitted x-rays directly into electrical current allowing
higher resolution images and potentially lower radiation
doses. Fluoroscopy has the distinct advantage over most
Imaging Modalities other modalities of allowing the operator to provide func-
tional assessment by acquiring dynamic (‘cine’) images.
lain Films: Conventional and Digital
P Fluoroscopy utilising either barium based or iodinated
Radiography (CR & DR) (water-soluble) contrast remains a useful tool in the IF
patient. Water soluble contrast can safely be administered via
Radiography is the oldest imaging modality, and its persis- any route, including vascular or where there is risk of enter-
tence in spite of the many advances in medical imaging is ing the peritoneal cavity, whereas barium is generally only
testament to its extensive utility. Its most common role lies safe to administer into the lumen of the GI tract.
in the assessment of the acutely unwell patient, with par- Barium is generally preferred when opacifying the GI
ticular advantages including ease of access (such as the tract, as it provides more detail and does not become so
potential for portable films for the unstable patient) and a diluted in the distal bowel, which can minimise the interpre-
relatively low radiation dose (usually <0.5 mSV). Plain tation difficulties due to overlapping bowel segments [1]. In
films can often be more readily interpreted than other addition the greater density and other properties of barium
modalities, allowing rapid identification or exclusion of may increase the sensitivity in identifying a fistula. Barium
major pathology. should be avoided where acute, non-mature enteric fistulae
Abdominal radiographs (AXRs) are most commonly are suspected, and generally should not be given within
requested for emergency presentations such as suspected 3 months of acute fistulation. Water soluble contrast may be
bowel obstruction, though may also demonstrate other useful in these circumstances and when there is a risk of
pathologies such as colitis and perforation leading to pneu- acute perforation or if surgery may be performed soon after
moperitoneum. They are used in the diagnosis of small bowel the study. This is because barium can precipitate peritonitis if
ileus (either post-operative or related to other systemic pro- it enters the peritoneal cavity either at the time of the radiol-
cesses), and pseudo-obstruction. Serial AXRs are useful and ogy examination or through inadvertent spillage during sur-
accurate for monitoring colonic disease and dilatation in gery if residual barium remains in the bowel.
ulcerative colitis.
AXR following water-soluble contrast (e.g. oral Barium Follow Through
Gastrografin®) can be used in prognostication of acute After a period of fasting (between 4–12 h), to ensure the small
small bowel obstruction, helping to predict which patients intestine is empty, a barium follow through (BFT) involves
can be managed conservatively. Our institution utilises ingestion of barium suspension (typically 300–600 mls of
100 mL of contrast diluted with an equal volume of water 50% w/v BaSO4). In addition, some centres use aerogenic
with films taken at 4 and if necessary 24 h post-ingestion. powder (30 min before the examination) but this is only nec-
Post operatively, some centres may also administer water- essary if mucosal detail is required. Ingestion of oral barium
soluble contrast orally for its potential therapeutic effect (to is followed by imaging every 10–15 min until the barium has
stimulate bowel peristalsis), as well as for its use as a diag- passed through the ileocaecal valve into the colon.
nostic aid. Whilst historically BFT studies have been the mainstay
The position of enteral support devices such as nasogas- for evaluation of the small bowel, expertise is reducing in
tric (NGT) and nasojejunal (NJT) tubes as well as central many parts of the world, particularly where CT or MR
venous catheters (peripherally inserted and internal jugular) enterography (CTE or MRE) are readily available.
can be readily assessed with radiography. An improperly Nonetheless, the examination still has significant utility in
sited NGT may be ineffective at decompressing the stomach particular circumstances, and can provide greater assessment
and represent a risk of aspiration. of mucosa and fold pattern for example (Fig. 1), not easily
Chest radiographs are used to identify complications appreciable on other tests. Increased fold density, and subtle
related to acute IF, such as pneumonias (aspiration or noso- global or segmental fold thickening as seen in vascular insuf-
comial), or an erect film when a perforated viscus is ficiency or low protein states, can be important signs or indi-
suspected. cators of underlying pathology or disease response.
Radiology in Intestinal Failure 471
Fig. 2 Water soluble contrast enema. The rectum and colon are filled
with contrast and there is reflux into the terminal ileum. Note the con-
Fig. 1 Barium follow through which demonstrates the alteration in
trast in the bladder (arrow) and renal collecting systems due to iv con-
fold pattern seen in some conditions such as idiopathic sprue, coeliac
trast given earlier for a CT
and other malabsorptive states
Cine images and serial evaluation over the course of sev- Contrast Enemas
eral (usually 2–4) hours can demonstrate evidence of evolv- Water soluble contrast enema studies, are performed by ret-
ing or intermittent obstruction (most commonly due to rograde administration of approximately 500 ml of dilute
adhesions) or dysmotility which can be difficult to differenti- contrast into the rectum (Fig. 2) or an ileal pouch. They are
ate on static modalities such as CT and MRI (although newer used to assess the integrity of anastomoses, length and diam-
MRI techniques described later which are still evolving may eter of a stricture and identify any fistula related to a number
allow similar dynamic evaluation). of causes such as complications of prior pelvic surgery, as
Contrast is generally given orally to assess the ‘in circuit’ well as neoplastic or inflammatory disease.
bowel, but can be instilled via the afferent orifice of a defunc-
tioning loop or an end stoma as well as via the efferent stoma Other Procedures
orifice to assess the downstream ‘out-of-circuit’ bowel (‘loo- Fluoroscopy may be used in siting enteral support devices
pogram’). A combination of these techniques can help deter- (nasojejunal tubes and radiologically inserted gastrosto-
mine residual lengths of in situ bowel when planning further mies), insertion of and assessment of vascular devices
surgery (either for stoma formation or restoring continuity), (peripherally inserted or central venous catheters for total
to identify and localise the origin of fistulae (entero-enteric parenteral nutrition), and in placement of trans-jugular intra-
and entero-colic), evaluate strictures, and determine suitabil- hepatic portosystemic shunt (TIPSS) for portal
ity for distal limb feeding in patients with short bowel. hypertension.
Fistulography
A contrast fistulogram may be obtained by cannulating the Computed Tomography
cutaneous opening of a suspected entero-cutaneous fistula
and contrast injected in order to demonstrate its communica- Modern (spiral) multi-detector computed tomography (CT)
tion to bowel. This examination and other techniques to eval- utilises an x-ray source and sensor array directly opposite it
uate fistula are also described later in the chapter. mounted on a gantry. Through software it effectively creates
472 A. Gupta et al.
a three-dimensional volume of data as it rotates around the Table 1 Water soluble luminal contrast in CT
patient. It is now widely accessible and has become the most Indication Protocola Considerations
frequently utilised cross sectional examination in most radi- Small 250–1000 ml over More than 500 ml is usually
ology departments. This is in part due to its widespread bowel 45–60 min and scan impractical in small bowel
after 45–60 min obstruction and a more realistic
availability, but also its excellent diagnostic utility and it volume of 250–500 ml helps
offers advantages for both patient (often more convenient reduce risk of patient vomiting
compared to an MRI) and radiologist (greater consistency of Large 1000 ml over 60 min If scan is for a distal colonic/
obtaining a high quality scan) compared to other imaging bowel and scan after 2–4 h rectal anastomosis, rectal
contrast may be more
options. Intravenous iodinated contrast is routinely used and successful
further augments the versatility of CT, allowing better dif- Rectum Depends on height of Consider need for a pre-contrast
ferentiation between structures and clear visualisation of anastomosis, but scan to define anastomosis level
vasculature. ~100–300 ml injected
via Foley catheter in
Though CT of the abdomen and pelvis carries a relatively
the rectum
high radiation dose (5–10 mSv), the short scanning time Catheter balloon:
(less than 10 s in modern scanners) and out-of-hours access generally avoid
available in most acute hospitals, make it the superior modal- inflating if recent
anastomosis
ity for the acutely unwell patient compared to MRI, where
diagnostic images are reliant on patients’ ability to remain Considerations:
Enteric tubes should be clamped
still and follow breathing instructions. Timings may need to be increased in suspected obstruction or shortened
Contrast enhanced CT (CECT) utilises intravenous con- in patients with short bowel
trast, which can be optimised with specific contrast phases, a
Contrast dilution: 1:10 is sufficient for most cases in CT, e.g. 50 ml
mainly by using unenhanced, arterial (at 30 s), and portal contrast in 500 ml of water
venous (at 70 s) phases, the choice of phases being deter-
mined by which structures are being investigated. The wide- more complex patients. Indications for positive oral contrast
spread use of CECT increases the ability to identify in IF include: better delineation of bowel anatomy in the
ischaemia, arguably at earlier stages, which in turn may complex surgical abdomen, to aid differentiation of bowel
improve prognosis, [2] and this in addition to a range of other from adjacent collections, or to demonstrate points of fistula-
benefits likely justifies the increased use. tion and anastomotic compromise/leak.
Studies may be further augmented by use of very dilute Though most commonly given orally or via a nasogastric
water-soluble or barium oral contrast media, which acts as a tube, luminal contrast may alternatively be administered via
‘positive’ contrast. A dilution of 1 part contrast to 10 parts a stoma, rectally via a catheter, or even through a suspected
water is effective for most cases (see Table 1 below). Dilution entero-cutaneous fistula. It is naturally important to consider
of oral contrast is required to optimise the density for CT, as the patient’s anatomy and what route of contrast will feasibly
undiluted contrast used for other x-ray examinations results reach the area of concern, particularly relevant in patients
in “streak” artefact, significantly compromising the image with defunctioned bowel.
quality. Therefore CT should generally be avoided soon after CT-fistulography may be performed in cases where an
enteric gastrografin® administration due to residual relatively external opening is present and prolonged fluoroscopic fistu-
undiluted contrast. Such a situation may arise when a CT is lography is not practical, or when greater anatomical detail
requested for example following an abdominal radiograph, and relationships to adjacent structures is required, though it
taken 4 h after oral intake of gastrografin, which demon- lacks the benefit of dynamic cine imaging. The fistula is can-
strates features of small bowel obstruction (SBO). In these nulated and dilute contrast injected (1:10) with the volume
circumstances, a delay in CT scanning should be considered used informed by previous imaging and surgical history,
if feasible, to allow either absorption or dilution of the lumi- though this can be difficult to predict. A single CT can be
nal contrast to avoid excess artefact. immediately acquired, usually with intravenous contrast [3].
Due to the risks of barium entering the peritoneum in
enteric perforation, water soluble contrast is used in most CT CT-Enterography
examinations, particularly in acute settings, and barium is CT-Enterography (CTE) is a specific modification to the
generally reserved for specific indications such as allergy or standard CT technique to allow detailed assessment of the
other contraindication to water soluble contrast. In recent small bowel. The protocol involves oral administration of
years, routine use of any oral contrast is reducing, in part due 1.5–2 L of a contrast agent such as dilute mannitol solution
to the increased logistical complexity and delay required (or a similar alternative) to act as a neutral or low-density
before scanning, and additional cost and therefore it is usu- luminal contrast (so appears the same as water) and provide
ally reserved for answering a specific question or concern in small bowel distention. This is followed by intravenous con-
trast timed in the enteric phase, which is obtained by scan- Magnetic Resonance Imaging
ning at 50 s post-intravenous contrast administration, the
timing of which maximises mucosal enhancement [4]. An advantage of magnetic resonance imaging (MRI), com-
The administration of oral contrast is usually started pared to the imaging options described above, is the lack of
around 45 min prior to CT, following a 4–12 h fast. ionising radiation. MR scanners employ very powerful
Immediately prior to the scan, an intravenous injection of an magnets and receiving coils to create the images. The
anti-spasmodic agent (most commonly Hyoscine strength of these magnets is measured in units of Tesla (T).
butylbromide (Buscopan®)) is given to reduce small intestine In theory, the more powerful the magnet, the better or
muscular tension. Relatively rapid image acquisition and the quicker the images can be obtained. Most MR scanners in
use of antispasmodics reduce motion artefacts caused by clinical use currently have a 1.5T magnet. The most power-
respiratory and gastrointestinal peristalsis respectively. CT ful MRI magnets available for routine clinical indications
has the advantage of providing volumetric data, allowing are 3T. Unfortunately they can have greater problems with
multiplanar imaging reconstruction and the ability to use artefacts and more practical limitations than 1.5T scanners,
image analysis software (for example vascular and bowel including increased risks of localised heating causing tis-
luminal software) which can allow 3D virtual reconstruction. sue damage. As manufacturers find solutions to overcome
CTE provides the additional benefits over radiography of a these problems, increasingly 3T scanners are becoming
combined luminal assessment and evaluation of extramural more widely available in hospitals, leading to the potential
structures and other organs. for significant improvements in the quality of MR
Specific indications include assessment of strictures, imaging.
inflammatory bowel disease, fistulae, small bowel and mes- When high quality MR scans are obtained, they can pro-
enteric root tumours, and obstruction related to above men- vide excellent anatomical detail, in addition to assessments
tioned conditions or other causes including adhesional of disease activity (Fig. 3). Newer functional MR techniques
disease. The necessity for the patient to ingest a large volume can evaluate other parameters such as motility (described in
of fluid generally limits the use of CTE to well outpatients. more detail later).
a b
Fig. 3 MRE (a) Coronal T2 sequence showing Terminal Ileum mural on the (b) coronal T1 post contrast image, there is mural stratification
thickening, with fat hypertrophy causing loop separation and penetrat- of the thickened TI (circled)
ing disease demonstrated by adjacent mesenteric abscess (circled) and
474 A. Gupta et al.
MR Enterography receive ultrasound waves with a frequency ranging between

MR Enterography (MRE) shares some elements of patient 2 and 20 MHz. Changing the frequency of ultrasound waves
preparation with CTE, including the requirement for the will alter the penetration and resolution of the images. The
patient to drink up to 1.5 L of oral solution, after a period of higher the frequency, the better the resolution is, however the
at least 4 h of fasting. There are a number of oral solutions depth of penetration decreases. Utilising the highest fre-
available [5], but the most commonly used in the UK are quency probes (15–20 MHz), sub-millimetre resolution can
mannitol or Lactulose based solutions. The choice of oral be achieved, but the structures being evaluated must be
solution will generally be determined by local preference. within 3–4 cm of the probe to obtain this resolution. It is
Most oral contrast has an increased osmolality compared to therefore easy to understand why US can be optimal when
water, which reduces absorption in the small bowel, but as a scanning thin patients, and conversely may be of limited
direct consequence, this often leads to the commonest side value in patients with high BMI or where the probe can’t be
effect which is diarrhoea. MRE also requires intravenous placed close to the site of the pathology. Views may also be
injection of an anti-spasmodic agent (Hyoscine butylbro- limited if there is gas between the probe and the area to be
mide (Buscopan®)) to reduce small intestine muscular con- visualised (e.g. in bowel or in enteric perforation causing
traction, and to reduce motion artefacts caused by free gas). In addition, the quality of images can be poor in
gastrointestinal peristalsis. Any movement is a significant patients who are tender, preventing the operator from press-
problem during many MR sequences, and therefore any ing the probe deeper into the abdomen, which is often
bowel, respiratory or patient motion can markedly degrade required to optimise resolution. US scanning may also be
the images. hindered by overlying dressings, stoma bags and subcutane-
Most MRE protocols generally utilise a gadolinium based ous oedema, though communication between referring clini-
intravenous contrast agent, which can be an advantage in cians and radiologists and good patient preparation can help
those patients who have an allergy to iodine based agents optimise studies.
required for CT. US of the bowel can provide real time evaluation of fea-
Most radiology departments have access to MR scanners, tures such as motility, and correlation with areas of patient
but availability in some centres may be more limited com- tenderness can allow accurate localisation of pathology.
pared to CT or other modalities. The time taken to acquire an Most centres don’t require patients to drink any oral solu-
MR scan is longer compared to CT, which can be a factor in tion, or cannulation for intravenous agents, which means
determining how quickly or easily an MR scan can be that typically US is less intimidating for children than an
arranged, particularly in the acute setting. MR enterography MRE. As a consequence, many centres now advocate the
usually requires the patient to be in the scanner room for up use of US as a first line or as a complementary test to MRE
to 45 min (compared to 10 min scanner room time for many [6], for younger children in particular. However, it should be
CT scans), or longer if additional sequences are utilised. This borne in mind that US is very operator dependant, and so
relatively long scan time is also one of the reasons MRI is unsurprisingly its use is dependent on the availability of
usually a more expensive scan than other imaging appropriately skilled operators (radiologists, sonographers
modalities. or other clinicians).
To avoid respiratory motion artefact, the patient is asked
to hold their breath for up to 20 s during most MRE
sequences, whilst the images are acquired. Most MRE proto- ommon indications for Imaging
C
cols will include around 8–10 breath hold sequences. If a in Intestinal Failure
patient is unwell, claustrophobic or finds it difficult holding
their breath (particularly in older or younger patients), under- Sepsis
going an MRE can be quite challenging or even unpleasant.
As a result, achieving high quality MRE examinations con- Radiology plays an essential role in the localisation of sep-
sistently is difficult as it requires full compliance. It is there- sis, particularly given that patients may present atypically
fore helpful for clinicians to be aware of these issues when due to their impaired immunity and failure to thrive may be
discussing imaging requests with their radiologist to decide the only manifestation [7].
when MR is the most appropriate imaging option. Contrast-enhanced CT is a highly sensitive test and has
the benefits of being quick to perform and well tolerated
except in the most unstable patients. Positive oral contrast
Ultrasound can be crucial in problem solving in the complex abdomen,
and particularly in helping to differentiate bowel from intra-
Ultrasound (US) is made up of mechanical waves that can abdominal collections.
transmit through different materials like fluids, soft tissues Radiation dose from studies should be minimised, but this
and solids. Medical ultrasound machines generate and must be balanced against the benefits of identifying and then
potentially draining infected collections, given the high mor- by mechanical or functional causes [8]. In the UK it accounts
tality rates associated with sepsis [3, 7]. for nearly half of all laparotomies performed, with an associ-
Ultrasound can provide greater anatomical detail for eval- ated 30-day mortality rate of 7% [9]. Effective treatment
uation of the biliary system than CT and is superior in dif- depends on a rapid and accurate diagnosis, requiring a com-
ferentiating cholecystitis from physiological gallbladder prehensive approach with imaging often playing a pivotal
oedema. Its portability also means it is useful in assessing role.
patients who are too unstable to attend for CT. Definitions of SBO [10]:
Fluoroscopy’s dynamic aspect can be helpful in identify-
ing suspected fistulae which may be driving sepsis, 1. Complete/high grade obstruction: no fluid or gas passes
particularly those that are more subtle and less apparent on beyond the site of obstruction
static cross-sectional studies [3, 7]. 2. Partial/low grade obstruction: some fluid or gas is able to
MRI generally has a more limited role in the acutely pass beyond site of obstruction
unwell IF patient, when clinical questions can usually be 3. Closed loop obstruction: a segment of bowel that is
answered with other modalities, and is therefore generally obstructed at two points along its length and is at risk of
confined to problem solving following other imaging. ischaemia
Pelvic sepsis is one exception where MRI can be superior 4. Strangulated obstruction: indicates that blood flow has
to CT, as the relative lack of respiratory motion that makes been compromised.
abdominal MR imaging difficult, can allow for detailed
analysis of pelvic structures. Optimal MRI scans of the The causes of SBO can be divided into three main
main pelvic cavity require meticulous attention to detail categories:
and close co-operation between clinician, radiologist and
radiographer to utilise the full potential of modern MRI 1. Intrinsic: inflammatory disease, neoplastic, vascular, hae-
scanners. In these circumstances, pelvic MRI can be suc- matoma, intussusception
cessful in identifying the source of sepsis, when other tech- 2. Extrinsic: adhesions, hernia, haematoma, endometriosis
niques have failed. 3. Intraluminal: gallstones, bezoars, foreign bodies
Once the underlying site of sepsis has been detected,
imaging can be used for planning further management. Traditional teaching states that three main aetiologies
Percutaneous radiological drainage (either under CT or US) account for most causes of mechanical SBO: adhesions, her-
may provide a safer alternative to surgery and allows antimi- nias and neoplasia [10]. Adhesions are the most common
crobial rationalisation following culturing of aspirate. cause of obstruction, and account for 50–80% of SBO cases
Collections, often rim enhancing on CT scans, are common [8, 11, 12]. Whilst hernias remain common in developing
in the early days after surgical intervention especially in countries, Crohn’s disease has now replaced hernias in
undernourished patients, due to a reactive and exudative pro- Western society as one of the most common causes of SBO
cess in the peritoneum. The presence of an enhancing rim [8, 12].
alone is not sufficient to define an infected collection, and its
shape is equally important, looking for imaging features to
indicate whether it is under tension and becoming spherical Identification of Obstruction
and deforming, or if it conforms to the peritoneal recesses.
Clinical assessment is critical, and in the post-operative period As well as confirming a diagnosis of SBO, imaging can be
collections should only be drained if symptomatic with swing- used to determine its site and cause, and identify any associ-
ing fevers or localising pain or persistently elevated/rising ated complications [10].
inflammatory markers. If there is an enteric leak driving the Plain film radiography is advocated as the initial exam-
collections then in most circumstances a fistula will develop ination due to widespread availability and low cost,
along the drainage track. Consideration should therefore be although it has a reported accuracy ranging from 50 to
given to the location of the drain with respect to an amenable 60% [12]. A more recent study reported sensitivities of
site for placing a stoma bag later. Small inter-loop collections around 80% [13]. However, in a setting of IF where sur-
should generally be left to evolve, unless they are amenable to gery is not imminent, and removing diagnostic uncer-
trans-gastric or other safe drainage option. tainty may change management, then cross-sectional
imaging is warranted. Multi-detector computed tomogra-
phy (CT) has become the mainstay of imaging where
Small Bowel Obstruction available, with a sensitivity of 82–100% [8]. Ultrasound is
often unhelpful due to intraluminal bowel gas obscuring
Small bowel obstruction (SBO) is a common condition the view of deeper structures, rendering the images
occurring when normal transit of bowel contents is prevented non-diagnostic.
476 A. Gupta et al.
lain Abdominal Radiograph Findings

P need for a delay in the examination [10]. Similarly, CTE,
The hallmark of SBO is the presence of dilated bowel loops which requires ingestion of a large volume (usually at least
(>3 cm) proximal to the obstruction. There are a range of 1 L) of oral contrast, is therefore not usually performed in an
other findings in radiographs for SBO, including a ‘string of acute setting.
beads’ sign, secondary to slow resorption of intraluminal air, Intravenous contrast is administered, and the patient
with residual small bubbles trapped between the valvulae scanned in the portal venous phase (60–70 s delay) which
conniventes [14]. However, aside from inguinal hernias and provides optimal assessment of most abdominal and pelvic
gallstone ileus, the cause of SBO is rarely seen on a radio- structures and also achieves good enhancement of the bowel
graph, and hence further cross-sectional imaging is usually wall.
obtained. The diagnosis of SBO on CT is determined by the pres-
ence of dilated small bowel loops (>3 cm diameter) proximal
CT Technique and Findings to a transition point, with normal calibre or collapsed loops
CT is the preferred investigation for SBO, given its speed distally. The colon is often decompressed, depending on the
and sensitivity. It has a greater ability to determine the site of degree of SBO.
the transition point, its cause and exclude a closed loop The ‘small bowel faeces’ sign is the presence of particu-
obstruction. The transition point is the point of abrupt calibre late material with gas bubbles in the small bowel, similar to
change (Fig. 4). If a clear transition point is identified, then the appearance of stool in the colon. This is presumed to be
the cause can almost always be determined or inferred. secondary to delayed transit, with increased fluid absorption
Traditionally, positive oral contrast was administered in and accumulation of undigested food as a result of obstruc-
patients suspected of having SBO. An advantage to this tion or stasis [15, 16]. Whilst studies disagree about whether
approach includes a prognostic element, based on the obser- its presence correlates to the degree of obstruction, it serves
vation that if the contrast passes distally into the decom- as a useful aid in finding the transition point [17].
pressed bowel, then high grade SBO is excluded. However, The many causes of SBO have differing appearances;
many centres now scan without oral contrast, because (a) some of the most common causes are outlined below:
nauseated patients may vomit potentially leading to aspira-
tion; (b) in SBO the retained intraluminal fluid serves as an Adhesions
excellent neutral contrast agent, without the need for addi- Adhesions are bands of fibrous tissue which connects sur-
tional positive oral contrast; (c) its omission eliminates the faces or organs within the peritoneal cavity that are normally
a b
Fig. 4 Coronal (a) and axial (b) CT shows large bowel obstruction due to transverse colon cancer associated with a clear transition point (arrow)
and collapsed colon distal to this
separated [18]. Almost all are secondary to surgery, with a caused by a single adhesive band, but internal hernias or iatro-
minority caused by peritonitis. The adhesion itself is usually genic defects in the mesentery are also recognised causes [10].
not visible on CT and as such, typically is a diagnosis of CT findings of closed loop obstruction depend on the ori-
exclusion; its presence is inferred when there is an abrupt entation of the loop relative to the plane of imaging. Fluid-
transition point or sharp angulation of bowel loops, in the filled dilated loops with a U-shaped or C-shaped configuration
absence of an alternative identifiable structural cause [10]. (in longitudinal section) and a corresponding radial distribu-
On a BFT, absence of movement of the bowel with respiration tion (in an orthogonal plane) [21] can be best identified by
or on extrinsic compression increases the level of confidence using multi-planar reformatting for image review. Fusiform
for adhesions but this assessment is limited by large body tapering at the site of obstruction (“beak” sign) may be pres-
habitus and presence of fistula or stoma. Similar observa- ent [21]. A “whirl” sign, representing rotated intestinal ves-
tions can also be made with MRI on cine sequences or on sels surrounded by mesenteric soft tissue, fat and bowel
US, but again both of these modalities may be challenging in loops has also been described [21, 22]. Strangulation occurs
large or unwell patients. in 10% of patients with closed loop obstruction, leading to
Whilst BFT and CT remain the key examinations for ischaemia [23] and the earliest sign of this is oedema and
identification of adhesions in clinical practice, a review of associated effects in the affected segmental mesentery
multiple studies has shown that both transabdominal ultra- together with venous engorgement/dilatation.
sound and dynamic MRI can achieve a diagnostic accuracy
between 76% and 92%. Ultrasound can identify adhesions Post-operative Ileus
by assessing movement of small bowel, small bowel mor- Post-operative ileus (POI) is the impairment or arrest of gas-
phology and visceral glide. Dynamic MRI on the other hand trointestinal motility following surgery. Despite its reported
can be assessed during breathing or straining to assess vis- incidence rate of 10–30% for abdominal surgery [24–29]
ceral slide. However, one large limitation of most of these with resultant increase in morbidity and length of stay, there
studies is a lack of blinding, as surgeons were made aware of remains no internationally accepted standard definition of
findings prior to intraoperative correlation [19]. POI, nor any consistent distinction between the ‘normal’
physiological period of dysmotility and the prolonged patho-
Crohn’s Disease logical entity [30, 31].
When SBO occurs due to the acute presentation of Crohn’s, Whilst clinical presentation of mechanical obstruction
this is characterised by stenosis of the bowel lumen, usually and POI are similar in early stages, key differences in radio-
secondary to the transmural inflammation. Affected seg- logical findings may sway the diagnosis. A reported feature
ments may demonstrate wall thickening and hyper- on abdominal radiographs is gaseous distension of both the
enhancement (Fig. 3), associated with mesenteric small bowel and colon. However, this finding is not reliable,
hypertrophy, vascular engorgement and lymphadenopathy as the colon is difficult to visualise when it is fluid-filled, or
[20]. Classically, the adjacent fat appears clean homoge- if the patient has had a colectomy [32]. CT is more definitive,
neous and black in contrast to the oedematous fat stranding usually demonstrating dilated bowel loops similar to SBO,
seen in other inflammatory conditions. SBO may also mani- but without an abrupt transition point, often gradually taper-
fest in chronic disease, seen on imaging as stenotic strictures ing to normal calibre distally.
but without evidence of active inflammation. In cases of prolonged ileus, there should be a low thresh-
old for considering alternative underlying pathologies such
Hernias as anastomotic leak, perforation or collection – all of which
Hernias are classified by the anatomic location of the defect can be seen on CT.
through which the bowel protrudes [8]. They are broadly
classified as either internal or external, with external being Gut Ischaemia
the most common. Common hernia sites include the inguinal Ischaemia can increase the morbidity and mortality associ-
canal, the femoral canal and the anterior abdominal wall. ated with SBO. The physical examination and laboratory
The hallmark of SBO secondary to a hernia is the presence of findings are not specific and imaging findings can support a
dilated bowel loops with a transition point at the entrance in diagnosis of ischaemia in the correct clinical context.
to the hernia sac and decompressed bowel exiting from the Accuracy of CT varies amongst studies, with a reported
sac [10]. 83–100% sensitivity and 61–93% specificity [33–35].
CT technique for ischaemia remains a contested issue,
Complicated SBO: Closed Loop Obstruction with some centres advocating for ‘triple phase’ approach
A closed loop obstruction is a segment of bowel that becomes (unenhanced, arterial and portal venous), stating that (a) the
obstructed at two points along its length, essentially leading to unenhanced study allows for a point of reference when deter-
its isolation from the remainder of the bowel. Commonly, it is mining bowel enhancement and (b) unenhanced increased
478 A. Gupta et al.
bowel wall density reflects haemorrhagic transmural necro- on the arterial phase. There may be extensive background
sis [36]. However, others argue that unenhanced CT is not atherosclerotic disease. Bowel enhancement is absent or
required for diagnosis of ischaemia, with its low sensitivity decreased due to cessation of arterial supply, with bowel
[37]. Most centres opt for a dual phase approach, with an wall thickening rarely occurring unless reperfusion occurs
arterial phase to assess the arterial vasculature and portal [38]. Perhaps most useful, is the identification of a differ-
venous phases to assess bowel wall enhancement and mesen- ence in bowel enhancement within a segment of bowel,
teric/portal venous system. compared to adjacent proximal and distal bowel, and may
be matched by reduction or absent enhancement of the sup-
T Findings: Arterial vs Venous Ischaemia
C plying arterial vessels. The bowel wall may become thinner
The appearances of bowel ischaemia on CT include: bowel as ischaemia progresses, leading to pneumatosis as infarc-
wall thickening (>3 mm); mesenteric oedema and/or fluid in tion develops (Fig. 5) [39]. Mesenteric inflammatory
the mesentery or peritoneal space; decreased bowel wall stranding and ascites are rare but can occur with infarction
enhancement; pneumatosis (intramural gas) with or without and perforation [39].
associated gas in the mesenteric/portal veins [10].
Pneumatosis is a late sign and is suggestive of infarction. The Venous
vasculature should be carefully scrutinised, with accompa- Venous occlusions accounts for 5–10% of bowel isch-
nying knowledge of the arterial supply and venous drainage aemia [39]. Impairment of the venous drainage increases
of the bowel. the hydrostatic pressure, leading to extravasation of fluid
into the bowel wall and mesentery [39]. Thrombus in the
Arterial mesenteric venous system is usually visible [40]. Bowel
Arterial thromboembolism can be seen as a filling defect wall thickening, fat stranding and ascites are commonly
within or occlusion of the supplying artery, best visualised present [38].
a b
Fig. 5 CT demonstrates extensive pneumatosis indicating bowel there is portal venous gas associated with liver infarction (circle). Axial
infarction. On the coronal image (a), there is gas in the wall of the stom- CT (b) there is gas in the wall of most the visible small bowel (arrows)
ach (upper arrow), and in the small bowel (lower arrow). In addition
Management only an appropriate option when surgery is indicated for

Whilst historically management of acute mesenteric isch- some other reason and length assessment is carried out by a
aemia has focussed on a surgical approach, with restoration surgeon familiar with the technique. Whilst knowledge of
of blood flow and resection of necrotic bowel, endovascular intestinal length is crucial for future decisions, direct mea-
treatment (EVT) is now playing an important role [38]. A surement may not be available due to: surgery being per-
variety of techniques including catheter directed thromboly- formed in an emergency situation, variation in surgical
sis, embolectomy and stenting can be employed to treat acute expertise, a hostile abdominal environment, or simply an
thrombotic superior mesenteric artery occlusion [41]. inability to review detailed patient records. Therefore, mea-
Anticoagulation or low molecular weight heparin is recom- surement of small intestinal length by non-invasive radio-
mended as first line treatment for venous thrombosis, EVT graphic examination is a common route for developing
can be considered in certain scenarios if patients deteriorate patient specific management plans.
despite medical treatment [42].
In summary, there are a wide range of CT findings which Barium Follow Through
may or may not be present depending on the stage of isch- Two studies have demonstrated a correlation between bowel
aemia, and sometimes these changes may be reversible, length assessment measured by BFT and clinical prognosis
exacerbating the challenge in making a timely diagnosis, and [50, 51]. It is a relatively cheap and widely available study
explaining why there is such a wide range of diagnostic but is limited by 2D imaging, wherein collapsed or superim-
accuracy for identification of ischaemia by CT. Clinicians as posed/overlapping bowel segments and loops may result in
well as radiologists must be mindful of the difficulty in underestimation of the length when remnant bowel length is
excluding bowel ischaemia even with good quality imaging. over 150 cm. Moreover, patients in the post-operative con-
Clinicians and radiologists should have a low threshold to text can frequently suffer from adhesions and sometimes
seek early specialist GI radiology review, as perhaps the related to this, pelvic bowel loop aggregation, both of which
most efficient route to addressing any diagnostic uncertainty, may further reduce accuracy if overlapping loops can’t be
if there is a discrepancy between the initial imaging report separated. Application of an opisometer can improve the
and clinical suspicion of ischaemia. accuracy of BFT length assessment [54]. Overall the BFT-
surgical measurement correlation was found to be moderate
(r2 values <0.75) [1, 55], including in studies of SBS patients
Assessing Length of Small Bowel [54].
In our institution, BFT compares favourably with intra-
An accurate understanding of the length of small intestine operative measurements of bowel length, particularly with
remaining is particularly important in patients requiring residual lengths of less than 150 cm, and may allow a more
repeated small intestine resection, which may result in short accurate assessment of length, compared to CTE or MRE.
bowel syndrome (SBS) [43]. The morbidity and mortality of One of the limitations of BFT is that it is only able to
SBS is directly related to remaining small intestine length measure in circuit bowel length. In order to accurately assess
[44], with the degree of malabsorption being influenced by length of the out of circuit bowel, a further examination is
the length of remnant small intestine as well as the status of often required, such as a distal loopogram, with barium or
the patient, their colon, underlying disease process and other water soluble contrast introduced per catheter, to the afferent
absorptive organs [45–48]. Remnant small intestine length is limb or fistula, to access the out of circuit bowel.
an important indicator for management decisions including
autologous small intestine lengthening procedures [49–51], CT Enterography
and can be an important factor in assessing likelihood of The use of CTE had a statistically significant correlation
patients surviving without parenteral nutrition [52]. with surgical measurement and outperformed BFT with
Therefore, accurate measurement of the remnant small intes- regards surgical measurement correlation, in a small study of
tinal length is important for clinical prognostication and SBS patients [54].
treatment planning.
MR Enterography
Intra-operative Measurements of small intestine length are performed on a
Intra-operative measurement of small intestinal length by an range of rapid image-acquisition techniques, usually utilis-
experienced gastrointestinal surgeon, which involves mea- ing assessments on a range of sequences obtained as each
suring along the anti-mesenteric border (without stretching can have a different advantage or drawback for measurement
the bowel) from the ligament of Treitz to the end of the small of length (Fig. 6). On some studies, MRE has been shown to
intestine using known lengths of suture material and a ruler, more accurately correlate with surgical measurement than
is regarded as the gold standard [53]. However it is usually CTE [54, 56] but may be very operator dependent.
480 A. Gupta et al.
paradoxically, the time required to measure bowel length is

often less when compared to CT or MR. CTE has been
shown on some studies to be superior to BFT and to strongly
correlate with surgical measurement. In our institution, CT is
gradually becoming the most common technique utilised for
assessment of length, in part because many of the patients
will have had a CT at their base hospital prior to being
referred to our unit.
In general the longer the remaining length of bowel, the
longer it will take to complete this process, and the harder it
may be to get an accurate measurement of the length. In
addition, in patients who have multiple collapsed or adhesed
segments, measurement may be difficult or of limited value
on a single examination. However, many of these patients
will have had at least 2 or more scans at different times, typi-
cally associated with acute admissions. In such patients, an
accurate measurement may only be obtained by analysis of
multiple different examinations at different times, assuming
segments that are poorly visible on one exam, are better visu-
alised and hence more easily measured on a different exam
obtained at a different time.
Fig. 6 This is a single coronal image from a T2 sequence of a normal Assessment of Quality of Small Bowel
MRE. The majority of the small bowel is well distended, and the quality
allows a good assessment of bowel length, when following the course The quality of small bowel and the disease affecting it are
of the small bowel on all of the images in this sequence important determinants of its ability to carry out its functions
of absorption and motility, which are linked to morbidity
Novel Techniques even when bowel length is maintained [3].
Preliminary studies have evaluated the use of software aided Fluoroscopic examination with luminal contrast is an
manual [56] and algorithm based automated [57] methods of effective technique for short bowel segments (<150 cm) [58]
small intestine measure on MRE images. Although the latter and contrast can be introduced via multiple routes including
has so far only been conducted in mice studies, the results orally, via stoma or fistula or per rectum. As a dynamic study
are promising and in the future may provide a useful adjunct it allows a more targeted examination than other modalities,
to improve accuracy of non-invasive methods [57]. and is particularly helpful in assessment of the distal out of
The measuring tools available on all PACs software allow circuit bowel where there has been a defunctioning stoma
accurate measurement of bowel length with all of the modal- created, or an enterocutaneous fistula (ECF). There is a sig-
ities described above. However, despite the ability of CT and nificant benefit in watching and controlling luminal disten-
MR to view the bowel in multiple planes, the course of the sion and in the assessment of fistulae tracts in real time.
bowel may weave in and out of the standard planes, neces- Often, studies using a variety of modalities and instilla-
sitating a very time consuming process of measuring multi- tion routes may be required to assess bowel segments inde-
ple short segments, by repeatedly changing planes to follow pendently to overcome issues such as under-distended or
all the twists and turns of the entire small bowel. In practical overlapping loops, maximise accuracy and provide as much
terms, whichever technique is utilised, time is required to detail as possible to optimise management decisions.
meticulously navigate the course of the bowel, either while Cross sectional (CT/MRI) imaging has the added benefit
acquiring the images (BFT) or when analysing them on of global intestinal and extra-intestinal assessment; mural
PACs. A BFT is still readily available in many centres and and mesenteric pathologies can be occult at luminal imaging
can be inexpensive, but may be limited by 2D imaging, adhe- such as fluoroscopy or capsule endoscopy but may be appar-
sions, aggregation, pelvic pooling and overlapping bowel ent on CT which is now the mainstay of imaging assessment
loops, and potentially requires more radiologist time to per- in most centres due its sensitivity and ubiquity. CT is per-
form the exam. However if good quality images are obtained, formed individually or adjunctive to fluoroscopy, for cases
with complex post-surgical anatomy. Water soluble oral con- invasive and non-ionising assessment of gut motility [65].
trast is often used with CT to delineate fistulation, sinuses or Diffusion weighted imaging, a technique already widely
to demonstrate collections where these are suspected. CTE used in other systems notably neuro-imaging, provides an
protocol with bowel distension (as described earlier) is often alternative to intravenous contrast for functional evaluation
the optimal technique for assessment of mucosa, wall thick- which is particularly valuable in patients with renal impair-
ness and bowel lumen calibre, particularly if strictures are ment, when unenhanced CT would be of limited use. MRE
suspected [59]. has a high sensitivity and specificity for assessing disease
It is important to be aware of the normal cross sectional activity in Crohn’s disease [58, 60] and when it includes
appearances and parameters of small bowel: fold patterns “cine” sequences, can be particularly useful in assessing and
varies between jejunum, possessing feathery thin closely demonstrating strictures and complex adhesions.
spaced folds (valvulae conniventes), and ileum which dem-
onstrates a lesser density of folds. On CTE normal small
bowel wall thickness should be less than 3 mm when the apping Distal Bowel for Distal Feeding
M
lumen is distended [60]. Intravenous contrast enhancement and Pre-operative Assessment
is assessed at multiple phases timed following high flow
bolus administration of contrast; bowel mucosal enhance- With the improvement in clinical nutrition, critical care med-
ment is optimally assessed in the enteric phase (50 s follow- icine and minimally invasive bowel sparing surgery, there
ing contrast injection) [61, 62] but can also be adequately has been great progress in the management of enterocutane-
assessed on portal venous phase imaging (70 s) [63], whilst ous fistulae. However, high output fistulae pose a clinical
arterial phase (30 s) is useful for assessment of vascular challenge with associated malnutrition and organ dysfunc-
compromise. tion due to high volume loss of water and electrolytes [66].
Features of acute inflammation include: mural hyper- This is particularly significant in the setting of patients with
enhancement, bowel wall thickening and stratification (with a short bowel or small intestine dysfunction, where the
mural hyper-enhancement being the most sensitive CT imag- absorptive capacity of the remnant gut is reduced.
ing sign of active inflammation in the setting of Crohn’s dis- The conditions for utilisation of enteric nutrition are
ease [61]. Mural stratification describes the laminated intestinal continuity and a minimum length of 75 cm of
appearance to the bowel wall, the appearance occurring due bowel [67]. In these patients imaging assessment with a
to the presence of mucosal hyper-enhancement with submu- combination of CT and fluoroscopy, is often used to map the
cosal thickening and hypo-attenuation due to oedema/ distal bowel and assess integrity prior to feeding; including
inflammatory infiltration. Intramural fat can be a normal measurement of the length of the distal bowel, the continuity
finding in the ileocaecal valve but can be a sign of chronic or otherwise of the remaining segments, as well as the mural
inflammation elsewhere [60]. and luminal status.
Inflammatory changes in Crohn’s disease are frequently Fluoroscopy can be in the form of a loopogram where a
on the mesenteric aspect of the bowel and can be penetrating, stoma allows access to distal bowel or fistulogram if a fistula
with a spectrum ranging from ulceration to fistula, appearing is present which may be a suitable entry point for distal feed-
as hyper-enhancing transmural/extra-mural tracts within the ing. The calibre of the distal bowel is assessed and, in par-
mesentery. Mesenteric hypertrophy produces a characteristic ticular, strictures and obstruction should be excluded as these
expansion of the mesenteric fat easily identified on CT with a may prohibit distal feeding (Fig. 7) or surgical anastomosis
clean and sharp appearance of fat creating a striking contrast for restoring continuity. The orientation, fold pattern and
to the increased size and prominence of the mesenteric vascu- lumen calibre of the excluded distal bowel may appear
lar arcades and producing a classical comb sign in an affected abnormal on the imaging assessment however it is worth not-
hyperaemic bowel segment. Beyond the acute stages, chronic ing that the imaging appearances may also underestimate
intestinal inflammation and deposition of extracellular matrix structural and functional changes of bypassed segment
protein are contributory factors to small bowel fibrosis; on related to altered blood flow, motility, hormones, secretions
imaging this is suggested by the presence of wall thickening and mucosal surface area.
in the absence of mural oedema or hyper- enhancement, Fistuloclysis involves insertion of a balloon Foley cathe-
upstream dilatation and delayed enhancement [64]. ter into the fistula and advancement of the catheter under
Many of the features described above can also be seen on fluoroscopic guidance to a depth of 5 cm into the distal intes-
MRE (Fig. 3). Cine MRI is an evolving technique described tinal lumen followed by insufflation of the balloon catheter.
further in the next section, may in the near future may be a The proximal intestine lumen is intubated with a double pipe
more widely available adjunct to MRE in providing a non- to collect intestinal fluid [67].
482 A. Gupta et al.
a b
Fig. 7 (a) Distal loopogram to assess colon pre distal feeding, shows same patient after a period of distal feeding shows increased calibre of
narrowing of the descending colon (arrow) with a clear transition from the descending colon
normal to reduced calibre. (b) A water soluble contrast enema, in the
Motility Assessments Fistula Tract Mapping
Dynamic small bowel imaging, which allows assessment of Fistulography

motility, is an evolving area of research, and includes various A fistulogram has been considered the best way of mapping
techniques which increasingly are being used in routine MRI a fistula tract when there is an external opening. Contrast is
small bowel protocols. Small single centre studies have injected through the external opening and images are
shown that motility assessment protocols not only increases acquired using fluoroscopy [75]. One key limitation is the
lesion detection rate compared with conventional MR limitation in visualisation of adjacent or extramural pathol-
enterography, [68] but that motility also is altered in distant ogy [76]. When an external opening cannot be identified,
macroscopically non-affected segments with active Crohn’s other contrast techniques described below and elsewhere can
disease (CD) [69]. Active inflammation, penetrating disease be carried out per stoma or per rectum to identify the luminal
and a fixed stricture are associated with decreased small origin of the ECF.
bowel motility [70]. Terminal ileum motility correlated with
histology findings for active and chronic CD but did not arium/Water Soluble Contrast Follow-Through
B
allow differentiation between active and chronic disease, A small bowel follow through (SBFT) study can help to
[71] and during flares, small bowel motility correlated with delineate the fistula tract when fistulography is inconclusive
blood markers including calprotectin and CRP [72]. The and to assess the bowel both proximal and distal to any fis-
length of inflammatory segments and wall thickening on the tula. Utilising barium rather than water soluble contrast may
other hand did not correlate with the frequency of contrac- increase the sensitivity for detection of tracts. However,
tions [73]. SBFT may fail to locate the tract if contrast passes through
Several studies have investigated the quantification of quickly or if the tract is small or occluded. As a consequence
small bowel motility. One study has shown that quantifica- of this and the inability to evaluate occluded or incompletely
tion of small bowel motility is repeatable and sensitive to patent fistula, SBFT may have a lower accuracy than CT and
changes in response to drug therapy [74]. MRI [77].
a b
Fig. 8 (a) Coronal CT showing multiple loops converging towards a appreciated on the axial CT (b) which shows the EC tract reaching the
EC fistula. The increased mucosal enhancement and wall thickness external opening (arrowed)
indicates active disease (arrows). The whole of the EC fistula is fully
CT perianal protocols. If patients are prone to repeated CT imag-

CT allows high spatial resolution images of the fistula tract ing then MRI can have an important role to minimise radia-
and its relationship to adjacent structures (Fig. 8). Positive oral tion dose, in patients that are not acutely unwell or can
contrast can help to better identify bowel loops especially in manage the requirements of an MRI scan (Figs. 9 and 10).
cases where patients lack intra-abdominal fat. Furthermore, if
contrast opacifies the tract, it not only makes identification of Ultrasound
a fistula tract easier, it also confirms patency. Another option is Ultrasound can have a similar diagnostic accuracy as fluoro-
carrying out CT fistulography with injection of dilute contrast scopic contrast studies for identifying fistulas, reaching up to
material through the external opening prior to CT. Care should 87% sensitivity and 90% specificity, however ultrasound has
be taken to ensure that very dilute contrast is used as the con- the additional advantage of identifying other extra-luminal
centration required for per-oral or per fistula techniques on disease e.g. collections. In those departments with better
fluoroscopy are too high for use in CT where considerable access to US than other imaging modalities, it may provide a
artefacts will be generated. The typical appearance of an ECF quick and convenient assessment or provide additional infor-
is a tubular structure extending from a bowel loop anteriorly mation to aid the interpretation of other tests. The use of
towards the peritoneum, crossing subcutaneous tissues hydrogen peroxide inserted through the skin opening can
towards the skin. Loops of bowel can become adherent to the increase the sensitivity of detecting the internal opening
anterior abdominal wall converging towards the fistula tract. [78].
MRI Malignancy and ECFs

MRI has an established role in perianal and other pelvic fis- In instances when patients have spontaneous or unexpected
tulating disease, but can also be used in the assessment of ECF, underlying malignancy needs to be excluded. Although
cutaneous fistulae throughout the abdomen and pelvis. Use rare, any mass like areas with irregular or asymmetric wall
of high resolution T2 scans (Fig. 9) focussing on the region thickening with an abrupt transition on CT and MRI should
around an external opening or expected site of fistula (based raise the suspicion of neoplasia. Malignant transformation
on prior imaging) is often the most effective way of identify- associated with longstanding ECF or other fistulating inflam-
ing a tract. It is critical that Hyoscine Butylbromide or other matory disease is well recognised and not only should
gut paralytic agent is given at the start of the examination to patients be appropriately counselled, where surgery or cura-
ensure bowel movement artefact is minimised. Heavily T2 tive therapy is not an option, but consideration of surveil-
weighted, fat saturated and post contrast sequences can also lance imaging is important. Both squamous and
help to delineate tracts, and are therefore routinely used in adenocarcinomas are described and the prognosis is poor.
484 A. Gupta et al.
a b
Fig. 9 (a) High resolution axial MR T2 sequence shows entero-enteric MRI T2 sequence shows entero-enteric fistula (circled), with changes
fistula (arrowed) and this also communicated with a gas containing extending to the dome of the bladder where there is wall thickening
abscess in the muscle of the anterior pelvic wall (elipse). (b) Sagittal (arrow) and the gas filled collection in the anterior pelvic wall (ellipse)
Abdominal Wall Assessment Assessment should specifically comment on the presence

or absence of an abdominal wall hernia. If one is present, the
Detailed assessment and reporting of the abdominal wall is following features should be noted; its location, size of
important in IF patients as often these patients have had pre- abdominal wall defect (maximum length and width in cm),
vious surgeries and may have a stoma, cutaneous fistula, her- contents, assessment of loss of domain, complications of the
nia, or abdominal wall collection. No dedicated imaging of hernia, abdominal wall thickness and quality and evidence of
abdominal wall or modification of the imaging techniques is previous surgery (including presence of mesh). The report
necessary. Most of the necessary information regarding the should also highlight if there are any adhesions and the loca-
abdominal wall can be obtained by focused specialist review tion of any fistula or stoma in addition to the standard report
of previous cross-sectional imaging, especially CT scan. of the abdomino-pelvic viscera [79].
a b
Fig. 10 (a). Contrast enema shows abnormal filling of the small bowel was done, but the site of fistula (arrow) was still hard to identify, until
(thin arrows), with only small volume of contrast in the descending reviewed in conjunction with the CT (c), which more clearly shows the
colon (broken arrow), but the site of fistula was not visible. An MR (b) entero-rectal fistula (circled)
486 A. Gupta et al.
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Insertion, Types and Care of Enteral
Feeding Tubes

1. Enteral nutrition (EN) is given for no or insufficient oral
intake when it is safe to do so and when there is adequate Most patients receiving enteral nutrition will have oral
functioning small bowel present. (intake) failure most commonly due to neuromuscular disor-
2. Nasogastric tubes need the tip position carefully checking ders, head/neck cancer and occasionally cardio-respiratory
with an acidic aspirate (pH < 5) and if doubt a chest diseases or dysmotility/malabsorption problems. If those
radiograph. with IF cannot absorb adequate macronutrients and fluid
3. Gastrostomy tubes are most commonly and most safely with an increased intake, dietary/fluid modifications and sip
inserted at endoscopy. feeds, then enteral feeding may be needed. EN may be given
4. Jejunal tubes may be inserted at the bedside (with or to utilize the gut for longer periods (e.g. with an overnight
without an electromagnetic devise), during an endoscopy, enteral feed) [1, 2]. Enteral feeding is usually preferred to
using radiological screening or at surgery. parenteral nutrition as it is more physiological, less expen-
5. After gastrostomy insertion feeding may start after 2–4 h, sive, prevents biliary sludge formation and originally was
the tube should be on very gentle tension for a week, then thought to be associated with less severe complications than
this is relaxed and the tube rotated daily and pushed in parenteral nutrition (PN); however with the safer administra-
2–10 cm once a week. tion of PN, EN may have a similar incidence of severe com-
6. Distal feeding into defunctioned bowel or a fistula is done plications [3] or more (e.g. after pancreaticoduodenectomy
via a small diameter feeding catheter or balloon catheter [4]). It was thought to maintain the gut barrier function to
providing there is no distal obstruction. The feed may prevent endotoxin and bacterial translocation [5–7] which
provide all the nutrition required (complete) or a small could lead to sepsis and multi-organ failure; however the evi-
amount to stimulate motility and be trophic to the mucosa. dence for this is not convincing [8]. Previous metabolic and
7. A buried gastrostomy internal flange (bumper) occurs if septic problems with PN may have related to overfeeding
there is much traction on a gastrostomy tube. A buried and hyperglycaemia, and less careful attention to the care of
internal flange can, if patent, sometimes be removed by the feeding catheter. Now less energy is given especially in
stiffening and pushing the tube inwards, and/or dilating critical care so metabolic problems are less frequent; great
or cutting (with an endoscopic needle knife) the gastric care is given to the aseptic care of parenteral feeing catheters
tissue to free the internal flange. so septic complications are much less frequent.
EN is usually contraindicated if there is mechanical bowel
obstruction, peritonitis or ischaemia, or if there has been a
recent major gastrointestinal haemorrhage. Percutaneous
abdominal tubes are relatively contra-indicated if a coagu-
lopathy or if a patient has ascites (accumulation needs to be
prevented for 7–10 days after the procedure to allow adher-
ence of the gut to the abdominal wall) or the presence of a
ventriculo-peritoneal shunt (as it can be infected and cause
meningitis) [9, 10].
EN and PN may be used together when PN is being
J. M.D. Nightingale (*) weaned, but generally should not be used together in the

Table 1 Routes for providing enteral nutritional support

Nasal tube
Nasogastric (NG)
Nasoduodenal/jejunal (ND/NJ)
Pharyngostomy/oesophagostomy
Gastrostomy Naso-gastric or
naso-jejunal tube
Percutaneous endoscopic (PEG)
Percutaneous radiological gastrostomy (PRG) (also called a
Pharyngostomy
radiologically inserted gastrostomy (RIG)) Hyoid bone
Surgical (includes percutaneous laparoscopically assisted Oesophagostomy
Trachea
gastrostomy (PLAG))
Duodenostomy/jejunostomy
Percutaneous endoscopic gastro-jejunostomy (PEGJ)
Direct percutaneous endoscopic jejunostomy (D-PEJ)
Percutaneous radiologically inserted via gastrostomy (PRGJ or
RIGJ)
Surgical (open (using a needle catheter) or laparoscopic)
Distal feeding
Enteroclysis and fistuloclysis
Gastrostomy
long-term as the management of both becomes very complex
and time consuming.
This chapter outlines the methods of inserting enteral Jejunostomy
feeding tubes and advises upon their subsequent care.
Fig. 1 Enteral routes for feeding into upper gut

Access Routes to the Gut
There are many ways to access the gut (Table 1, Fig. 1) [11].
Direct feeding into the colon/rectum has been successful in zine have been given). The stomach tolerates hypertonic
the past [12] but is not currently used. If there is a mucus feeds, higher feeding rates and bolus feeding better than the
fistula or fistula connecting to defunctioned ileum or colon, small intestine. After abdominal surgery, owing to increased
saline, a peptide feed or the effluent from a high stoma may sympathetic activity, the stomach may take 1–2 days to
be instilled into it to help with fluid/nutrient balance. This regain its motor function and the colon may take 3–5 days,
distal feeding can give all the nutritional requirements or can but the motor and absorptive functions of the small bowel
give a small amount of feed to help the bowel function/ usually remain normal [13, 14]. Thus post-pyloric feeding
mucosal growth before continuity is surgically re-established. may be started safely within 12 h of surgery/trauma, espe-
This procedure can be unpleasant and technically demanding cially if the patient is already undernourished. Many units
(“Distal Feeding and Hydration” chapter). wait for at least 24 h to allow for the ‘ebb phase’ of hypome-
tabolism and some surgeons delay for 5 days, often to ‘pro-
tect a distal anastomosis’ [15, 16]. Clinically the return of
Nasoenteric Feeding hunger, the passage of stomal or rectal wind and the presence
of bowel sounds suggests the return of gut function. It is
An enteral feed may be given by a tube passed through the helpful if access for feeding, via the gut, is achieved at the
nose into the stomach, duodenum or jejunum (nasogastric, time of surgery (e.g. by a nasojejunal tube or needle jejunos-
nasoduodenal and nasojejunal feeding). It has become tradi- tomy). Post-pyloric/jejunal feeding is indicated when there is
tional to insert enteral feeding tubes through the nose rather altered gastric anatomy (e.g. gastrectomy, gastric bypass or
than the mouth as it is thought to be more comfortable for the Whipple’s procedure), gastroparesis, high risk of aspiration
patient and eliminates the possibility of the tube being bitten. or an intolerance of gastric feeding [10].
Fine bore naso- or oro-enteral tubes are chosen for short- The passage of a tube through the nose can induce the
term feeding (up to 4–6 weeks) and a gastrostomy or jeju- patient to cough and so the procedure is considered an aero-
nostomy tube for long-term enteral feeding. sol (less than 5 μm diameter) generating procedure and
Feed may be delivered into the stomach if there are no FFP3 masks and visas should be worn if the patient has or
problems with aspiration or inadequate/delayed gastric emp- is at risk of having a disease spread by an aerosol (e.g.
tying (e.g. if opioid or anticholinergic drugs including cycli- COVID) [17].
Insertion, Types and Care of Enteral Feeding Tubes 491
Nasogastric Tubes smaller tubes may suffice (e.g. infants may be fed boluses
via a 4 FG tube with no problems). Only if there is a need to
Nasogastric tubes are generally marketed for single use; give drugs through the tube, or if gastric juice needs to be
however, the manufacturers of some tubes advocate cleaning aspirated regularly in adults, is a larger tube required.
and re-passing of the same tube on the same patient if it is
accidentally dislodged. The maximum rate of flow through Length
an enteral feeding system depends mainly upon the tube The total length of a nasogastric tube varies between 40 and
diameter and length, and less upon the viscosity and tem- 90 cm and is selected to ensure a manageable amount of
perature of the feed [18]. They are generally only used for external tubing. The longer the tube, the greater is the resis-
4–6 weeks [11]. tance to flow [18]. A weighted tip on a nasogastric tube does
not make the tube easier to pass or less likely to become
Material displaced [19].
Fine-bore nasogastric tubes are made of polyvinyl chloride
(PVC), latex, polyurethane or silicone, and are available in a
variety of sizes and lengths. Polyurethane is preferred to Insertion of Nasogastric Tubes
polyvinyl chloride (PVC) and latex as it is more resistant to
kinking. Polyurethane allows the tube wall to be thinner than The method of insertion is outlined in Box 1. The tube
with silicone, so that while its outer diameter is the same its must not be forced, and special care must be taken if a
internal diameter is larger, so allowing high flow rates. tube is considered necessary in a patient with mucositis or
Nasogastric tubes made from PVC tend to lose plasticizers oesophageal varices. The tube may be passed through the
after a few days; they become brittle and rarely can cause mouth if there is a severe rhinitis. Soft, pliable nasogastric
pressure necrosis of soft tissues. PVC tubes are damaged by tubes made of polyurethane or silicone generally have a
radiotherapy. PVC tubes require changing after 7–10 days,
whereas polyurethane or silicone tubes can remain in situ for
a month. Many tubes are impregnated with a water-activated Box 1 Passing a Nasogastric Tube at the Bedside
lubricant to help insertion, and most are radio-opaque.
This is considered a clean procedure. Equipment: non
Diameter sterile gloves and plastic apron, tray, sterile/boiled
Large-bore Ryles tubes, used for gastric drainage, are water, glass of water ± straw, tissues, sterile paper
uncomfortable and may be associated with rhinitis, oesopha- towel, sterile receiver (galipot), receptacle for aspirate,
geal reflux, and oesophageal strictures. Fine-bore tubes (1.4– hypoallergenic tape or other fixative, glass of water,
4.0 mm diameter, 4–12 Fr) are more comfortable and cause lubricating jelly, nasogastric tube (CE marked), enteral
less trauma to the nasopharynx and oesophagus. Fine-bore syringes of 10 and 50 mL, pH indicator strip (CE
tubes are more easily displaced by coughing or vomiting marked), measuring tape.
than large-bore tubes, and there is a greater chance of them Method
being accidentally inserted into a bronchus, especially in an
unconscious patient. The presence of an endotracheal tube 1. Explain the procedure and arrange a signal for
does not preclude the tube being accidentally passed down patient to give if he/she wants the procedure to
the trachea into the lung. stop.
Quoted tube size is based on external diameter; the inter- 2. Check that the nostrils are patent by asking the
nal diameter is usually about 1 mm less. The diameter of a patient to sniff with each nostril occluded in turn.
tube is the single most important limitation to flow, and an 3. Wash hands and dry hands, apply hand rub and
increase in internal diameter from 1 to 2 mm results in a assemble the equipment.
tenfold increase in flow. The limitation to flow is rarely clini- 4. Put out the equipment. Sterile paper towel onto
cally relevant; for example an 8 FG 100 cm long tube con- trolley/tray then put onto it the NG tube, galipot
nected to a giving set and a feed container will discharge and enteral syringes. Ensure the glass of water,
100 mL of 24 °C solution (viscosity 4.25 cps which is similar lubricating jelly, hypoallergenic tape and pH paper
to/higher than most feeds) at a pressure of 75 cm water are near.
(about the height of a drip stand) within 5 min [18]. The fine- 5. Put on gloves
bore tubes used in clinical practice vary from 1.4 mm (4 FG) 6. Position the patient upright and do not tilt the head
for small infants, to 2.7–4.0 mm (8–12 FG) for older children backwards (if insertion is difficult it can be helpful
and adults. All commercially available feeds can be adminis- to put the head forwards and/or turn it to one side).
tered with good flow through an 8 FG tube though even
7. Measure the distance from the nose to an earlobe

to the xiphisternum (NEX distance which is
50–60 cm in adults) then add 5–10 cm to this.
8. Mark the tube (if not marked) with the measured
distance. If there is a guidewire in the tube, remove
it and flush the tube with 10 mL water, then rein-
sert the guidewire; this allows the wire to be with-
drawn freely. Check that the guidewire does not
protrude through the end of the tube and that it is
freely mobile within the tube.
9. The clearest nostril may be sprayed with ligno-
caine. Lubricate the tube with a small amount of
lubricating jelly (or water).
10. Gently slide the tube backwards along the floor of the
clearest nostril. At a distance of 10–15 cm the tube
can usually be seen at the back of the pharynx. If pos- Fig. 2 A NG tube accidentally placed in the right lung
sible, at this point ask the patient to take a mouthful
of water and hold it. Ask the patient to swallow and
at that moment advance the tube 5–10 cm, stop when guidewire to aid insertion, while those made of PVC do
the swallowing stops and repeat 3–6 times. If the not. There is still a small risk of misplacement (1.3%)
patient becomes distressed, continually coughs or [20], oesophageal or pulmonary perforation. In the UK
becomes blue, remove the tube. If there is difficulty intrapulmonary or pleural placement of a nasogastric tube
passing the tube, the patient can turn his/her head with administration of feed or medication or fluid is con-
either way by 90° and flex the head. sidered a “never” event that must fully investigated
11. When the mark (at 50–60 cm in adults) is reached, (Fig. 2) [21]. Due to the trauma involved for staff when
stop advancing the tube and gently remove the guide- these never events are investigated it is advised that two
wire. If does not remove withdraw tube gently and staff are present at the insertion to confirm the tube posi-
twist as it may be coiled Do not attempt to replace the tion (with a pH indicator strip). There is a high rate of
guidewire when the tube is in situ as it may exit from nasogastric tubes ‘falling out’. This ‘non-elective removal’
the side of the tube and cause a perforation. has been reported to be as high as 25% within the first
12. Check the tube position by aspirating 2–5 mL gastric 24 h [20].
juice and check that the pH is less than 5.5 or below
using pH indicator strips (CE marked for human
aspirate). If so, the tube is in the correct position and Checking Position of Nasogastric Tubes
can be secured at the nose and feeding begun. If not,
the tube may not be in the stomach or the stomach The intra-gastric position of a nasogastric tube should be
may not be producing acid (e.g. if the patient is tak- confirmed before using the tube for feeding or administering
ing a proton inhibitor drug); a chest radiograph is medication. This should be carried out every time the tube is
needed to confirm that the tube has not entered the used; failure to do so could result in feed or medication being
lungs. Auscultating for bubbles is unreliable as bub- delivered to the lungs. Only checking the gastric pH and
bles can be heard even if the tube is in the lung. chest X-ray are acceptable methods.
13. Document the procedure: time, indication, consent
verbal/written, tube type, size and two health care Aspiration
workers should sign to confirm the pH reading and Two to 5 mL of gastric juice is aspirated through the naso-
the position of the tube. If a chest radiograph is gastric tube using a 50 mL syringe. A 50 mL syringe exerts
needed the name of the clinician confirming the less negative pressure and so is less likely than a smaller
correct position should be recorded. syringe to create a vacuum and cause damage. The aspirate
is checked, using a pH indicator strip (CE marked), and
Additional comments should show an acidic fluid with a pH of between 1 and
5.5 [23–25]. Care in interpreting the pH is advised if little
• If the patient is heavily sedated or has had a general fluid is aspirated and much lubricating jelly has been used,
anaesthetic, the head can be flexed to 30° and the as lubricating jelly has an acidic pH. Fluids aspirated from
larynx lifted anteriorly [22]. the respiratory and intestinal tract or from a patient receiv-
ing a proton pump inhibitor should all have an alkaline 2. Monitoring bubbling at the end of the tube
pH. However some of the occasions in which the tube has The end of the tube can be left in a glass of water as the
been accidentally inserted into the lung in UK have had an tube is inserted. If the tube then enters the lung, there may
acidic pH documented. In future, a means of both measuring be bubbles in the water. Again this is not a method that
pH and detecting a gastric (e.g. pepsin) or intestinal enzyme can be relied upon.
(e.g. trypsin) may become available. 3. Monitoring for respiratory distress
Tubes can be inserted into the lung with no patient dis-
Chest/Abdominal Radiography tress (until feed is given) especially in neurological
Abdominal radiography is the definitive way to confirm the disorders.
correct position of a radio-opaque nasogastric tube. Most 4. Observing the appearance of NG tube aspirate
tubes have radio-opaque markings, or contain a radio-opaque The aspirate from the lung can look similar to that
compound (e.g. bismuth trioxide). Although it is a reliable from the stomach/duodenum.
method, it is only indicative of the position of the tube at the 5. Testing the acidity/alkalinity of aspirate using blue litmus
time of X-ray, and is therefore not necessarily correct at the paper
time the patient starts feeding, when aspiration should again Only pH indicator strips (CE marked for human aspi-
be done. It may be used as a check on initial placement of the rate) are considered accurate. A pH of less than 5 is taken
tube if an acidic gastric juice cannot be aspirated. Due to the to indicate a gastric aspirate. However rarely bronchial
occurrence of “never events” some units advocate chest secretions, especially if infected, can cause a similar low
radiographs on all patients with a neurological disease or pH.
impaired consciousness. Many community hospitals, and
patients at home, do not have access to X-ray facilities and so
do not have this checking system. When tubes are dislodged Problems
frequently (e.g. in patients with neurological problems),
repeated X-rays are not practical and the radiation exposure No aspirate in syringe.
becomes unacceptable. An additional problem is that feeding If this occurs, check that the correct/usual length of tub-
is delayed while a patient is waiting for a radiograph and its ing is visible externally and that the tube is firmly secured
interpretation. to the face. If a longer length of tube than expected is visi-
The features on a CXR that show correct position of a ble, the tube may have slipped back and thus needs to be
naso/oro-gastric tube are: The naso-gastric tube should removed or resited. If the tube appears to be of correct
remain in the midline through thorax down to the level of the length, it may be that the tip is not in contact with gastric
diaphragm, it bisects the carina, and is clearly visible below contents; in this case, the position of the patient can be
the left hemi-diaphragm (unless situs inversus). Its tip should changed (i.e. to lie on the left or right side, sit up, etc.) and
be approximately 10 cm beyond the gastro-oesophageal aspiration again attempted. Alternatively, if some oral
junction (i.e. within the stomach). Figure 2 shows a mal- intake is possible, the patient can be given a drink to
placed NG tube. increase the volume of the gastric contents before another
attempt is made to aspirate the stomach. If these methods
Laryngoscopy fail, the tube may be advanced a short distance (2–5 cm)
If the patient is unconscious, the tube can be visualized passing and aspiration again tried. This may not be possible with
into the upper oesophagus using a laryngoscope or endoscope. some polyurethane tubes.
Tests of NG tube position not to be relied upon Aspirate is not acidic.
This may occur if the patient is taking antacids, H2 antag-
1. Auscultation onists or proton pump inhibitors. A confirmatory chest radio-
Air is injected into the stomach via the nasogastric graph may be needed.
tube and at the same time the observer listens with a
stethoscope over the upper abdomen (‘whoosh’ test);
bubbling should be heard and the site where they are Nasoduodenal and Nasojejunal Tubes
loudest is noted. This method can be falsely reassuring
and bubbles may be heard (in the epigastrium) when the Post-pyloric feeding may be indicated when there is delayed
tube is incorrectly in the lung base. This technique should gastric emptying (gastroparesis) or an increased risk of aspi-
not be relied upon. ration (large hiatus hernia). Nasoduodenal/jejunal tubes may
A feeding tube can be attached to a specially adapted be single lumen (as for a nasogastric tube but of a longer
stethoscope; if the tube is in the trachea or bronchi, loud length) or double lumen, allowing feeding into the small
breath sounds are heard [26]. intestine while aspirating gastric secretions.
Insertion of Nasoduodenal/Jejunal Tubes 10 mL as compared to 40 mL if the tube is in the stomach.

A more reliable method is to aspirate fluid which should
Post-pyloric tube placement may be difficult, and various show a pH change from less than or equal to 4 in the stom-
techniques have been adopted. They may be inserted at the ach, to greater than or equal to 6 in the duodenum/small
bedside (Box 2), radiologically, in endoscopy or at an opera- bowel.
tion. Post pyloric feeding compared to gastric feeding in In an intensive care setting the blind insertion of an NJ
critically ill patients resulted in a 30% lower rate of pneumo- tube had a 43% successful placement rate and was most
nia and an increase in the amount of nutrition delivered to likely to be successful if the greater curve of the stomach was
these participants [11, 27, 28]. cephalad (higher) than L1-L2 disc [32]. The success rate and
time to insert a tube using endoscopy or fluoroscopy was the
Bedside Placement same (95% taking about 15 min) [33].
A randomized prospective trial in 1993 showed that tubes
with weighted tips were less likely than unweighted tubes to
Box 2 Methods for Passing a Nasojejunal Tube at the
pass through the pylorus [34]. This may be because a
Bedside
weighted tip naturally falls into the antrum to a level below
When the tube is in the stomach (60 cm), the guidewire that of the pylorus.
inside the tube can be removed and a 30° bend made
3 cm from the tip. The wire is then carefully replaced. Self-Propelling Tubes
This allows the tube to be rotated to assist its passage A nasojejunal tube which develops a spiral coil when the
through the pylorus [29]. In addition, when the tube is guidewire is removed (e.g. Bengmark) can be inserted into
at 60 cm, the patient is turned onto his/her right side the stomach and in most patients will pass spontaneously into
and the tube advanced to about 70 cm. This usually the small bowel, probably being carried there by the fasting
results in passage of the tube; if not, the stomach can migrating myoelectrical complex. This type of tube may stay
be rapidly inflated with 500–1000 mL of air before the in position more reliably than a straight tube [35, 36].
tube is advanced further [30]. Rotating the tube clock-
wise and giving 10 mg intravenous metoclopramide Electromagnetic Guided Tubes
may also help the tube pass the pylorus [30]. Sometimes Electromagnetic bedside feeding devices (e.g. Cortrak®) are
referred to as the 10-10-10 method as 10 mg metoclo- increasingly being placed with over 60% successful place-
pramide is given, then there is a wait of 10 min before ment [37]. They have an electromagnetic stylet that can be
advancing the tube 10 cm. The tube position should be tracked and provide a display of the path of the feeding tube
checked radiologically with a plain abdominal radio- during placement. The system consists of an LCD monitor
graph or ideally screened so that the tube tip is posi- unit, specific nasoenteral feeding tubes each containing a
tioned at or beyond the duodeno-jejunal flexure. stylet with a transmitter, and a signal receiver unit. Thus they
provide real-time location information on the tube tip place-
ment. There is as with all naso-enteric tubes a risk of acci-
dental placement into the lung [38].
It may be advantageous to give metoclopramide (10-10-10 as
above) or erythromycin (cisapride in the past) just prior to Other Techniques
any insertion procedure to increase gastric emptying and Other methods for placing a transpyloric tube include the use
help the tube pass the pylorus. Neostigmine may also be of ultrasound or a magnet on the tip of the tube and on the
used, but careful cardiac monitoring is needed as it may abdominal wall (88% achieved transpyloric feeding) [39].
cause a severe bradycardia. The Kangaroo™ feeding tube with IRIS technology uses
Auscultation and aspiration techniques may be used to direct vision via an integral 3 mm camera as the tube is
attempt confirmation that the tube is situated beyond the placed and may have a role in the future.
pylorus, but they are not conclusive [31]. If air is injected
down the tube during insertion, the loudest place that bub- I mage Guidance Insertion
bling is heard (with a stethoscope) is initially on the left side Image guidance (fluoroscopic) techniques are generally suc-
of the abdomen (in the stomach) then, when the tube is past cessful [40, 41], more so than blind placement and almost as
the pylorus, on the right side of the abdomen. In addition, often successful as endoscopic placement [33, 41].
the volume of air that can be aspirated from a post-pyloric Radiologists may be familiar with the technique as it was
tube, after 60 mL air has been instilled, is usually about used to perform a small bowel enema examination.
Endoscopic Insertion the longer-length tubes can be positioned further into the
Endoscopic placement may be difficult [42]. If the nasoen- intestine and allow more free tube outside the nose; they do
teral tube is grasped with forceps and taken to the distal not block more frequently than shorter ones [45].
duodenum/proximal jejunum using a paediatric colono-
scope, it easily becomes displaced during withdrawal of
the endoscope, even when the guidewire has been left ecuring a Nasoenteric Tubes with a Nasal
S
within the tube. It is technically easier to position a long Loop (Bridle)
guidewire through an endoscope into the jejunum, and
then withdraw the endoscope completely to leave the A nasoenteric tube can be secured with a non-allergenic fixa-
guidewire in situ. The wire can be re-routed through the tive on the maxilla, and the tube can be hooked over the ear.
nose (using a short tube passed through the nose and out of A technique of making a nasal loop (bridle) for confused
the mouth). The lubricated nasoenteric tube is passed over patients was described in 1980 [46]. A catheter is passed
the guidewire into the jejunum while being careful to through one nostril and brought out of the mouth (as done
maintain the same length of guidewire outside the patient initially for re-routing a tube from the mouth to the nose).
(Figs. 1 and 3). Surgical ribbon is taped to the catheter coming out of the
Many NJ tubes are passed through an endoscope, ideally mouth. The catheter is pulled gently back out of the nose and
using an ultrathin transnasal gastroscope [43], but if a normal a 15 cm length of ribbon is left emerging from one nostril.
gastroscope is used rerouting from the mouth to the nose is The procedure is repeated through the other nostril, and the
required, however it is easy for the tube (especially if not ribbon is cut 15 cm from the nose. Thus ribbon passes into
kept stiff with a guidewire) on withdrawal to form a loop in one nostril, goes round the nasal septum, and exits through
the stomach and this may cause the enteral tube to fall back the other nostril. The ends of the tape are tied through tape
into the stomach. fastened round the nasoenteric tube [47]. Subsequently a
An endoscopic nasoenteral feeding tube may have a clip simpler way of inserting the nasal loop was by inserting
placed at the end of the tube to anchor it to the jejunum and magnets attached to the distal ends of the catheter and a
this results in fewer repeat endoscopies than standard endo- probe (magnetic retrieval system). After inserting the cathe-
scopic naso-enteral tube placement [44]. ter into one nostril and the probe into the other, the magnets
come in contact posterior to the vomer bone, the probe is
withdrawn pulling the catheter and tape out of the nostril
Post Insertion of Jejunal Feeding Tube leaving tape passing round the back of the nasal septum. The
end of a feeding tube is securely connected with the tape
A plain abdominal radiograph should be taken 8–12 h after [47]. A nasal loop inserted in this way on an intensive care
insertion to confirm position, except in pregnant women or unit resulted in less tube displacement 10% (4 of 40) com-
patients in whom a tube is replaced at home. A polyurethane pared with 36% (18 of 50) whose tube was secured by tape
tube of 105–145 cm can be expected to last about 10 days; only [48].
Fig. 3 (a) Passage of a b

endoscope (lateral view) into
small bowel and guidewire
emerging. (b) Endoscopically
placed nasojejunal tube in situ
beyond the DJ flexure
Cervical Pharyngostomy Gastrostomy Feeding

and Oesophagostomy
A gastrostomy may be inserted surgically, endoscopically or
A tube with its insertion in the neck above the cricoid carti- under radiological/ultrasound guidance. It means that the
lage is termed a pharyngostomy; one below the cricoid is an patient can be fed without having to swallow and is likely to
oesophagostomy. Either may be performed after maxillofa- receive a greater amount of the prescribed feed than from a
cial surgery, often performed for head/neck cancer. These are nasoenteric tube [54, 55]. Gastrostomy feeding devices are
basically blind procedures that carry not only the risks of any currently made from polyurethane or silicone, and may vary
operation but also the risk of pharyngeal or oesophageal in diameter from 9 Fr to 26 Fr. As with nasogastric tubes, the
leaks or salivary fistulas. The tubes are just as visible as smallest diameter that is adequate for feeding is chosen. Thin
nasoenteric tubes and are extremely uncomfortable for the tubes are cosmetically most acceptable to patients.
patient, as whenever the neck is moved it pulls on the tube. Gastrostomy tubes differ in appearance, but share most of the
Now that percutaneous endoscopic or radiologically guided same features. An inner radio-opaque fixation device (a soft
enterostomies can be made, usually prior to surgery, pharyn- flange or a balloon) sits against the anterior stomach wall. It
gostomy and oesophagostomy are rarely performed except prevents the tube from being accidentally pulled out and, as
in the very rare circumstance that, for anatomic reasons, a long as it is held securely against the gastric mucosa, it pre-
nasoenteric tube, gastrostomy or jejunostomy cannot be vents leakage of gastric contents. An external fixation device
placed. is positioned comfortably against the skin and is adjusted to
Cervical pharyngostomy was first described by Shumrick accommodate weight changes. It prevents migration of the
in 1967 [49]. It can be performed using open dissection, a tube through the pylorus, and also prevents leakage and sore-
percutaneous approach [50], or a combination of both. The ness due to excessive inward/outward movement of the tube.
pyriform sinus is located with an index finger passed down Before a gastrostomy is inserted an INR is checked, the
the lateral pharyngeal wall until below the hyoid bone; a procedure may proceed if it is less than 1.5. Clopidogrel is
right-angle forceps is inserted through the mouth and pushed usually stopped 7 days before the procedure and warfarin 5
out in this position. A small stab incision is made through the days [9].
skin, then mainly blunt dissection is used to reach the for-
ceps, which are pushed out of the side of the neck. Tape is
grasped and pulled back into the pharynx, Kelly forceps hold Endoscopically Placed Gastrostomy
onto the tape, so are pulled from outside the neck into the
pharynx, the proximal end of an already in situ orogastric An endoscopic gastrostomy can be inserted, under light seda-
tube is grasped by the Kelly’s forceps and pulled out through tion (e.g. midazolam 2.5 mg) and using local anesthetic, in
the skin incision [51]. If a long-term pharyngostomy is over 95% of adult patients. A gastrostomy placed at endos-
required, a more definitive incision is made along the ante- copy is a less expensive procedure than one placed at open
rior border of the sternocleidomastoid muscle, and it and the operation. It may not be possible to insert an endoscopic gas-
carotid sheath are retracted laterally. The exit site is made as trostomy safely if a patient has had a gastrectomy, has ascites,
before but the pharyngeal mucosa is sutured to the cervical hepatomegaly, a neoplastic/infiltrative disease of the gastric
skin. wall, an obstructing oesophageal lesion, a coagulation prob-
Cervical oesophagostomy was described by Klopp in lem or is in the later stages of pregnancy. It may be difficult if
1951 [52]. The approach is usually on the left side of the the patient is obese and if it is not possible to bring the ante-
neck as the oesophagus lies to the left of the midline in this rior gastric wall into contact with the anterior abdominal wall.
area. A formal dissection requires a 4–6 cm oblique supracla- All techniques involve gastric insufflation to bring the
vicular incision. The sternocleidomastoid muscle is retracted stomach wall into apposition with the abdominal wall, per-
laterally after careful open dissection that does not damage cutaneous placement of a tapered cannula into the stomach,
the thyroid or its vessels, trachea, recurrent laryngeal nerve, passage of guidewire/thread into the stomach, placement of
carotid sheath and contents or thoracic duct. A tube is then the gastrostomy and verification of its position. There are
inserted through a 5 mm incision in the lateral wall of the two ways in which an endoscope can be used to help position
oesophagus. The tube feeds into the stomach and either exits a gastrostomy tube: by a pull (traction) or a push method in
through the lower end of the incision or from a separate stab which the endoscopist mainly observes the procedure. The
incision [53]. tubes inserted by the pull method is commonly referred to as
For both procedures the position of the feeding tube tip a PEG (percutaneous endoscopic gastrostomy). The pull
can be checked as for other nasoenteric tubes. technique was introduced in 1980 [56] and takes only
15–20 min to perform (Box 3) [57–59]. The original push

technique was similar to the pull technique except that a seen, the endoscope light power is turned to full bright-
300 cm flexible-tipped guidewire was inserted into the stom- ness and A1 observes if the light can be seen through
ach instead of a thread, the wire was snared and brought out the abdominal wall. Sometimes, on transillumination a
through the mouth, and the gastrostomy tube was then shadow from the transverse colon can be seen and this
pushed over it down through the mouth and into the stomach area must be avoided. These two techniques locate the
[59]. The push technique has subsequently been used to refer route that the PEG’s sheathed trocar (with air valve)
to a technique (used by radiology and endoscopy) in which will take to enter the stomach. Originally, the site cho-
the stomach is first fastened to the abdominal (gastropexy) sen for a gastrostomy was one-third of the distance
and then a trochar is inserted and through its sheath a balloon from umbilicus to left costal margin in the mid-clavic-
gastrostomy is inserted (see below). No significant differ- ular line. Although the PEG can be inserted anywhere
ences have been found between the push and pull techniques in the abdomen, the rectus abdominis muscles and
in terms of procedure time or complications [59, 60]. abdominal creases are best avoided.
Antibiotics are usually given (e.g. a single dose of 2.2 g 4. A1 washes and dries hands, opens the dressing
co-amoxiclav 30 min before the procedure) to reduce the risk pack, and puts on sterile gloves. Antiseptic solution
of a peristomal wound infection [43, 61]. An antiseptic is poured into a small container. Five milliliters of
mouthwash before the procedure may also be beneficial. 1% lignocaine solution is drawn up.
The external fixation device (disc/plate) is made of non- 5. A1 cleans a 15 cm area of abdominal skin and puts
irritant material and provides a secure external grip on the a small dressing towel below the intended insertion
catheter, keeping it in contact with the skin; it also prevents the site. Using a small, then a long injection needle, the
tube from kinking/looping. It may alter the tube angle by 90°. skin and route to the stomach (including perito-
neum) are anaesthetized with about 2–3 mL of 1%
lignocaine solution. The longer needle can often be
Box 3 Pull Method for Placing a Percutaneous seen by A2 to enter the stomach. If this can be done
Endoscopic Gastrostomy (Fig. 4) there is rarely any problem in subsequently insert-
ing the sheathed trocar. The PEG set is opened and
1. The procedure is explained to the patient/relative/ tipped onto the open dressing pack.
carer and written informed consent obtained. The 6. A1 makes a 1–3 mm vertical skin incision about
platelets and INR may need to be corrected if there 5 mm deep with a pointed scalpel. The sheathed
is a risk of bleeding. The patient is fasted for 6 h trocar is carefully inserted along the line by which
before the procedure. Prophylactic antibiotics may the long needle entered the stomach; it is advanced
be given half an hour before the procedure. Some with short jabs. Sometimes the needle can only be
units may stop H2 antagonists/PPI for 1–3 days made to fully enter the stomach with the help of
before the procedure, and some carefully clean the biopsy forceps used by A2. When 1–2 cm of needle
mouth with an antiseptic mouthwash immediately are inside the stomach, the trocar is removed to
before the procedure. leave the sheath in place; the latter may need a cap
2. The PEG inserter (A1) sets up a trolley near to the over it to prevent air escaping.
endoscopy table and examines the patient’s abdomen 7. A narrow long thread is inserted down the sheath. A2
for scars and enlarged organs. The size and position of catches this in the stomach with biopsy forceps or a
the aorta is noted. The patient is sedated with an intra- snare and withdraws the thread up into the endo-
venous injection of a short-acting benzodiazepine. scope. A1 must take care that not all the thread is
The gastric smooth muscle is relaxed by an intrave- pulled up into the endoscope. The endoscope is with-
nous injection of 20 mg hyoscine butylbromide. drawn and the thread is left coming out of the mouth.
3. The endoscopist (A2) performs a full upper gastroin- 8. The PEG is held by A1 and tied to the thread. A1
testinal endoscopy, noting in particular any evidence of then pulls the PEG down through the mouth into the
a hiatus hernia or oesophagitis (duodenal biopsies and stomach and, using gentle traction, pulls the dilating
test for Helicobacter pylori may be done). The patient end of the PEG out onto the abdominal wall.
is turned onto the back. The stomach is distended with 9. The dilating end of the PEG is cut off and attach-
air. A1 pushes a finger gently into the epigastric region ments made according to the manufacturer’s
about halfway between xiphisternum and umbilicus, instructions. The patient returns to the ward with
A2 sees if this is visible in the gastric antrum. The site clear written instructions about subsequent care for
of maximum indentation is chosen. If no indentation is the next 2 weeks.
a b c
Fig. 4 (a) Sheathed needle entering the stomach at the start of a pull PEG insertion. (b) Biopsy forceps capture the thread. (c) Internal flange at
end of the procedure
roblems After PEG Insertion

P stitches (or T fasteners) into the stomach to anchor it to the
Complications requiring surgery occur in fewer than 5% of anterior abdominal wall (gastropexy). Then after making a
patients; the procedure-related mortality rate is 0.3–2% [62– small stab incision (2 mm) a trocar with a peel away sheath
64]. Most deaths are caused by the underlying illness. The over it is introduced into the stomach (e.g. Pexact®). Under
main problems are infection of the insertion site and peristo- endoscopic observation the trocar is removed, a balloon gas-
mal leakage [65, 66]. Other rare early problems include peri- trostomy inserted through it, filled with water, the peel-away
tonitis, septicaemia, tube dislodgement, pulmonary aspiration, sheath is split and removed before gentle traction is applied
bowel perforation, gastro-colic fistula and necrotizing fasci- to the balloon which is fixed to the abdominal wall. Originally
itis [67]. Bleeding problems should be avoided if coagulation a needle was inserted with Seldinger wire then serial dilators
abnormalities are corrected before the procedure. were pushed over this to make a tract for a balloon gastros-
Poor wound healing may occur if the patient is under- tomy to be inserted [74].
nourished (e.g. cancer/HIV infection) [66, 67], immunosup-
pressed or taking steroids or have EDS. Mortality is higher Radiologically
during the first month in patients with previous aspiration or
urinary tract infections or those who are more than 75 years Percutaneous Radiological Gastrostomy (PRG)
old [68]. A percutaneous radiological gastrostomy (PRG) is also
A benign pneumoperitoneum is common and can be seen referred to as a radiologically inserted gastrostomy (RIG) or
on abdominal or chest X-rays in as many as 38% of patients percutaneous fluoroscopic gastrostomy (PFG). PRG can be
[69, 70]. It is important to recognize this as a normal find- used as alternative techniques for the placement of a feeding
ing—it does not mean that the patient has a significant bowel tube into the stomach, if an endoscopically guided tube place-
perforation. ment cannot be performed. Of 180 tube attempts a failed gas-
In the long term, aspiration pneumonia may occur in 23% trostomy tube placement occurred in 15.7% of PEGs and
of patients [71]. 1.9% of RIGs. Post-procedure aspiration was recognized after
10.5% PEG and 0% PRG attempts [74]. Originally the risk of
peritonitis, balloon failure and hence tube displacement, and
Direct Puncture Gastrostomy Insertion mortality was lower for a PEG than a PRG [75–77]. However
with time the outcome of a PRG has improved and is associ-
Endoscopically (Push Technique) ated with an equal number or even less complications than a
A different technique for inserting a PEG without the tube PEG [78, 79]. A study of 133 patients who underwent PRG
passing down the oesophagus can be done endoscopically. placement found a 1.5% incidence of major complications
This may reduce the chance of entry site infections as the requiring operative intervention and a 3% incidence of minor
tube has not passed through the mouth and may also pre- complications [76]. Both PEG and PRG are effective for long-
vent the seeding of an oropharyngeal or oesophageal tumor term EN support in selected individuals, PRG may be a better
to the PEG site (risk 0.3–0.5% with a standard pull PEG) option in patients with motor neurone disease especially if
[72, 73]. they have significant respiratory impairment [80]. PRG can be
The endoscopic technique involves distending the stom- performed as an outpatient procedure [81, 82].
ach with air via the endoscope, an assistant injects local The technique for insertion of a PFG is very similar to
anaesthetic into the abdominal wall, and introduces 2–4 that performed endoscopically (Box 4) except that it starts
with distending the stomach with air via a nasogastric tube Surgical Gastrostomy
and using ultrasound to position the fasteners (gastropexy)
before inserting the trocar; the rest of the procedure is the A surgical gastrostomy may be fashioned at the time of
same [82]. Often a PFG or PFGJ (percutaneous fluoroscopi- other abdominal surgery using the Stamm technique [85]; a
cally placed gastrojejunostomy) succeeds when a PEG has laparoscopic technique has also been described [86]. The
not been possible [9, 83, 84], though it does not allow the Stamm technique uses concentric submucosal purse-string
upper gastrointestinal tract to be carefully inspected. sutures (two rows) that invaginate the serosa about a
mushroom-tipped tube passed into the anterior stomach
Box 4 Radiological Method of Placing a Percutaneous wall at the junction of the body and antrum. An exit sepa-
Gastrostomy rate from the laparotomy incision is made for the tube. The
gastric serosa is sutured to the peritoneum and transversalis
A gastrostomy tube can be placed using ultrasound or fascia [87].
X-ray guidance (fluoroscopically) or both. A surgical gastrostomy is rarely performed as percuta-
neously inserted gastrostomies are quicker to accom-
1. Ultrasound may be used to determine the position of plish, avoid a general anaesthetic, and usually have a
the liver and transverse colon relative to the stom- lower incidence of stomal leakage and wound infection
ach. Occasional injections of air into the colon via a [88–90]. Two studies have shown no difference in the
rectal tube can be used to delineate the transverse complications following a PEG, laparoscopic or open
colon, but too much gas makes ultrasound difficult. gastrostomy [90, 91]. A PEG or, rarely, a balloon catheter
2. A nasogastric tube is passed into the stomach, and can be inserted at the time of surgery, though the latter
the stomach is distended with air. may be difficult to connect to a giving set and may not
3. Upon selection of a site in the mid-body of the last as long.
stomach, an aseptic technique is used, gloves are
worn, the skin is cleaned and the area draped with
towels. The skin, subcutaneous tissues and perito- Button Gastrostomy
neum are injected with local anaesthetic.
4. The abdominal wall is punctured with a needle When a gastrostomy tract has become established, the
through which a T fastener is passed to anchor the catheter may be replaced with a button-type gastrostomy,
anterior gastric wall to the abdominal wall. One to especially in children [92]. The button-type gastrostomy
four of these may be inserted. (14–28 FG) consists of a small catheter with an internal
5. The abdominal wall between the anchoring clasps water or saline balloon containing 5–20 mL. It is anchored
is punctured with a needle inside a sheath. Using externally with a flange, and the button opening is flush
fluoroscopic guidance, the needle is inserted into with the skin. The button has a duckbill anti-reflux valve,
the stomach and then withdrawn, leaving the sheath which prevents leakage of gastric contents. A feeding
in place. extension clicks into it when in use, and a cap fits into it
6. A water-soluble contrast agent may be injected to when not in use. It has the advantage of being level with
confirm the position of the sheath within the the skin and so more convenient and cosmetically
stomach. acceptable.
7. A wire is passed into the stomach and the sheath When inserting a button for the first time, the length of the
removed. The opening may be dilated using pro- abdominal wall tract is measured by inserting a balloon cath-
gressively larger dilators. A catheter (pigtail or bal- eter with measurements along its side. The balloon is inflated
loon type) is passed into the stomach over the wire. with 5 mL air and pulled back, the length of the tract is mea-
The wire is removed and the threads to a pigtail sured and a suitable size button is selected. If the shaft length
catheter released or a balloon inflated. is too long, the balloon does not sit close to the gastric
8. Contrast may again be injected through the catheter mucosa. This may cause leakage of the stomach contents
to try to ensure that there is no leakage into the peri- around the button shaft. If the shaft is too short, skincare may
toneal cavity. If a jejunal tube is needed a catheter be difficult and soreness can result. If the tube is tight or
can be inserted through the pylorus into the duode- painful, a lateral abdominal X-ray is performed to check that
num or jejunum. the balloon is in the stomach, not the peritoneal cavity. The
9. An external flange (fixing device) is attached and balloon volume should be checked every 7 days, as there is
sutured to the skin. always a small loss of volume.
Post-pyloric Feeding develop pneumonia than one with a PEG [97]. Tube block-
age, leakage, migration or fracture occurred in 53% of PEGJs
Percutaneous Gastrojejunostomy compared to 24% of PEGs with a mean follow-up of 275
days [95]. Designs of jejunostomy tube with a distal flexible,
If a percutaneous endoscopic gastro-jejunostomy (PEGJ) is non-weighted tip that can easily be grasped with biopsy for-
to be done, a large (e.g. 15 FG) gastrostomy tube is inserted ceps may be better; though the connection of the jejunos-
and through this the jejunostomy tube is passed with a stiff- tomy tube to the gastrostomy tube can still become detached
ening wire in its centre. The patient is re-intubated with a and result in the tube falling into the gut.
long endoscope (e.g. a paediatric colonoscope), the end of
the jejunostomy tube is grasped by biopsy forceps, and the
tube is taken slowly (using the push-pull techniques of colo- irect Percutaneous Endoscopic Jejunostomy
D
noscopy) about 30–50 cm distal to the pylorus (at or beyond (D-PEJ)
the duodeno-jejunal flexure). The endoscope is withdrawn to
the gastric body while the forceps are advanced to keep the A technique similar to PEG insertion can be used to insert a
jejunal tube in position. The biopsy forceps let go of the tube direct percutaneous endoscopic jejunostomy (D-PEJ) in
and are gently shaken as they are withdrawn to try to prevent patients who have had a gastrectomy. Sometimes a paediatric
the jejunostomy tube from returning into the stomach. When colonoscope can be positioned in the distal duodenum, the
the forceps have been fully withdrawn, the stiffening wire is duodeno-jejunal flexure or beyond, and under radiological
removed from the jejunostomy tube. The view from the guidance a needle inserted into the bowel just distal to the
endoscope will show the tube passing through the pylorus. scope. If thread can be introduced through a medium-sized
An abdominal radiograph is done to confirm the post-pyloric needle (the large introducers supplied with a PEG set are usu-
position of the jejunostomy tube tip. Only when the tip is ally too big and do not penetrate the bowel) then a PEG-type
considered to be in a satisfactory position is the tube cut and tube can be inserted in the usual way (to prevent the thread
connected to the inner gastrostomy tube. Some tubes allow being cut, the needle must be completely withdrawn as the
the stomach to be drained at the same time as the jejunal feed thread is pulled into the endoscope). Radiological screening
is given. If the tube cannot be placed endoscopically, it may also helps to prevent other structures (especially the trans-
be done radiologically (PFGJ or RIGJ), which may be easier verse colon) being entered with the needle. The procedure
if the PEG has been inserted through the greater curve of the may also be done using double balloon enteroscopy [98].
stomach.
The procedure can be done through a gastrostomy tube
using an ultra-thin endoscope [43, 93]. Surgical Needle Jejunostomy
There have, in the past, been many difficulties with PEGJ
tubes [71–73, 94–96]. In particular, PEGJ tubes often become It is difficult at surgery to manipulate a nasoenteric tube
displaced back into the stomach [96] (Fig. 5) or become dis- round the duodenum and into the jejunum. It can be difficult
connected and the whole tube passes through the PEG and to both aspirate the stomach and feed into the small bowel at
down the gut. A PEGJ does not necessarily prevent aspira- the same time, though tubes are available to do this. For these
tion [94], though a patient with a PFGJ is less likely to reasons a needle jejunostomy is often inserted at the time of
Fig. 5 (a) PEGJ in situ. (b)

a b
PEGJ tube that has become
displaced back into the
stomach
Fig. 6 (a, b) Insertion of a a b

needle surgical jejunostomy
and the Witzel tunnel
operation (Box 5) (Fig. 6) [99–103]. A laparoscopic method

of inserting a needle jejunostomy has been described [104].
bowel and distension observed; if there is resis-
Complications are common, especially tube dislodgement or
tance the needle is withdrawn and another attempt
obstruction [103, 105], and the outcome is no better than for
is made to enter the bowel lumen.
a well-placed and cared-for surgical tube jejunostomy [106].
4. If present, the flexible J end of the guidewire is
The bowel can kink at the catheter entry point, so causing
identified and put into the catheter (but not so that
obstruction, or leakage can occur. The incidence of aspira-
it protrudes from the catheter). The catheter (with
tion pneumonia is still high at about 16% [104]. The tube is
guidewire) is then advanced through the needle
always left in for 3–5 weeks, even if feeding has stopped, so
into the bowel lumen.
that a tract can become established and the purse-string
5. The needle is removed while grasping the catheter
suture holding the tube will have dissolved. This may take
within the bowel; the catheter is advanced for
longer if the patient is taking steroids. There are many types
20–45 cm. If necessary, the J end of the guidewire
of surgical gastrostomy tubes some have a Dacron cuff that
may be advanced to just beyond the distal end of
can embed 1–2 cm from the exit site in a similar way to that
the catheter to help passage. Care is taken to pre-
on a Hickman-type catheter.
vent the catheter from kinking or curling within
the bowel. The guidewire is removed and the
purse-string is tied.
6. In addition to the submucosal tunnel, a short
Box 5 Surgical Placement of a Needle Jejunostomy (2–3 cm) Witzel tunnel is often made by suturing
At the end of the laparotomy a needle jejunostomy two parts of the sero-muscular layer (from the
may be inserted. This takes about 20 min. same circumference) together around the catheter,
so covering the catheter. The sutures must not be
1. A loop of jejunum about 10–30 cm distal to the tight enough to cause occlusion of the catheter or
duodeno-jejunal flexure or gastrointestinal anasto- to cause tissue necrosis.
mosis is selected and orientated. The distance 7. A second sheathed hollow needle that can be split
should be sufficiently great to allow tension-free (or that has a sheath that can be split) is inserted
apposition to the abdominal wall. through the left abdominal wall at a position where
2. A 1 cm diameter purse-string absorbable suture is there will be no tension on the bowel. The catheter
placed on the anti-mesenteric border of the jeju- is fed through this (or if necessary the needle is
num at the site selected for jejunal catheter inser- removed) and the needle (or introducer) is split
tion. The ends are left untied. and removed.
3. A submucosal tunnel is created on the anti- 8. The jejunum is stitched to the anterior abdominal
mesenteric border using a 12–14 gauge hollow wall using 2–3 sutures around the catheter.
needle with a retractable obturator. With the obtu- 9. The catheter is placed in an external fixative device
rator withdrawn, the needle is pushed into the (retainer) which is sutured with non-reactive
sero-muscular layer within the purse-string suture. monofilament sutures to the skin.
The obturator is advanced and the blunt end used 10. The site may be covered with a clear dressing and
to create an intramural tract for 2.5–5.0 cm before any attachments are connected to the catheter.
the obturator is withdrawn and the sharp needle is Catheter patency is confirmed using 20 mL air,
advanced into the lumen. If the needle tip position saline or contrast.
is uncertain, 10 mL of air can be injected into the
Distal Enteral Feeding hydrogel or glycogel dressing may be used as alternative to

classical aseptic wound care in the first weeks. After healing
Distal enteral feeding includes feeding through the distal occurs 10–14 days after placement (longer if malnourished
limb of an enterocutaneous fistula (fistuloclysis) or through a or taking steroids) the dressings (if one is needed) are
defunctioned distal small bowel stoma/mucus fistula (entero- changed once or twice a week [11]. The traction is loosened
clysis). The distal feeding (DF) may be complete/total (CDF) after 3–5 days and after 7–10 days the external flange (also
where the aim is to administer all nutrition and hydration called a fixing plate or fixing device) is undone and the gas-
(±chyme) via the enteral tube or just trophic (TDF) where it trostomy tube rotated (not if a gastroenterostomy tube) then
aims only to provide enough nutrition/hydration to maintain pushed in (2–10 cm) [11] and, and the skin cleaned and dried
bowel structure and function usually before a surgical re- [11, 43]. The tube is pulled with very light traction and the
anastomosis [107] (“Distal Feeding and Hydration” chap- external flange is reattached and the distance from the inter-
ter). Proximal and distal contrast studies of the bowel are nal flange to the abdominal wall skin noted. There may be
done before starting DF to ensure there is no disease, obstruc- 0.5–1 cm between the skin and the external flange. If the
tion or leak present in the distal bowel. The feeding is done external flange is positioned while the patient lies supine, it
by inserting an enteral feeding tube (fine bore nasogastric may be tight when sitting/standing and have to be loosened.
tube or balloon gastrostomy) more than 5 cm into the distal The external flange may also need loosening as the patient
intestine. A polymeric or semi-elemental feed or chyme may puts on weight. If the tube is kept too tight and not rotated,
be given, ± added salt through the distal feeding tube. The epithelial overgrowth (buried bumper) may occur [108, 109].
action of DF in addition to providing nutrition/fluid, is by The skin around a gastrostomy or jejunostomy tube is
neural and humeral mechanisms, to reduce upper gastroin- kept clean and dry to prevent soreness/infection; the use of
testinal secretions and motility, and thus proximal stomal/ gauze and talcum powder is discouraged. Creams are kept
fistula output and so reducing the amount of nutritional/fluid off the tube as these can cause the external flange to slip. If
support needed. the external flange slips when dry, it should be replaced.
TDF consists of a small volume (100–500 mL/24 h) bolus If a nine FG PEG is used, the skin incision is so small that
being given once or twice daily into the distal bowel. It helps early PEG problems are very rare [110]; however visceral per-
maintain the bowels anatomical structure and motility (pre- foration with peritonitis, fasciitis, and pericatheter leaks are
venting gut atrophy), so making a surgical re-anastomosis reported [111] in addition to bleeding [43] Leakage of gastric
more likely to be successful (easier anastomosis, faster post- contents onto the skin should not occur if the stoma is healthy
operative return of function and a lower chance of an anasto- and the external flange correctly positioned. When it does hap-
motic leak); but parenteral support may still be needed while pen, however, it can result in extreme soreness partly because
this continues. of the low pH of the gastric juice. It requires a review of the
tube and skin care to prevent recurrence. The skin can be pro-
tected by zinc oxide based barrier skin protectants, foam
are of a Patient Receiving Enteral Feeding
C dressing and giving a proton pump inhibitor drug. The forma-
tion of granulation tissue may be prevented by regular rotation
kin Care
S of the tube. Silver nitrate can be gently applied to areas of
excessive granulation tissue but can burn the surrounding skin,
It takes 2–4 weeks after insertion for the anterior gastric or so an antibacterial/steroid creams are often preferred.
jejunal wall to become adherent to the abdominal wall and For showering, bathing and swimming the tube is capped
then an intraperitoneal leak is improbable. After insertion and the site should be covered with a water proof dressing.
very low traction without tension should be applied to the
tube and the distance from the internal flange to the skin
recorded (usually 2–4 cm) for 1 week. It is a common error Mouth Care
for the traction to be completely removed after insertion and
this can allow a leak/bleed to occur as the stomach has not Patients, especially those who have no oral intake, are
adhered to the anterior abdominal wall. This is suggested by advised to clean their mouth with a mouthwash and to brush
pain and an increase in the distance between the internal teeth and gums twice daily. They may need artificial saliva if
flange and abdominal wall. Each day, after the insertion of a their mouth is very dry. Some patients like to have something
percutaneous gastrostomy or jejunostomy, the site should be to taste (sweet) in their mouths when they receive their
cleaned gently with unperfumed soap and water and the tube EN. For patients on an intensive care unit, the normal or
gently rotated by 90°, but not pushed inwards (till 7–10 induced production of saliva can be useful because of sali-
days). The gastrostomy tube of a gastrojejunostomy should va’s natural bactericidal activity. Lemon and glycerine swabs
not at any stage be rotated as it can dislodge the jejunostomy are avoided as they lower the pH in the mouth to 2.3–3.9,
tube. A loose absorbent dressing may be applied. Glycerin which can cause decalcification of teeth.
To prevent blockage, the tube should be kept clean by

flushing with water (usually 30–50 mL of fresh tap water,
cooled boiled water or sterile water in accordance with local
policy) before and after administering feed or medication. A
50 mL syringe is used for flushing, fitting either directly onto
the feeding tube or onto the side port of a giving set. The
quantity of water used to flush the tube should be sufficient
to clear the tube and meet the patient’s fluid requirements.
Some units recommend that the tube be flushed weekly with
a carbonated drink (e.g. Coca Cola®, 7 Up®, or a sodium
bicarbonate solution) or pineapple juice, followed by cooled
boiled or sterile water, to prevent blockage. Drugs should not
be given through an enteral feeding tube, if possible; if such
administration is necessary, they should be obtained in liquid
form after establishing compatibility. When more than one
medication is required, the tube should be flushed after each
medication to prevent the two from mixing within the tube.
Box 6 How to Set Up an Enteral Feed
1. Check the expiratory date on the feed, which

should be at room temperature. Record the time/
date the feed was set up. Invert the feed container
2–3 times.
2. Wash and dry your hands. (Some units recom-
mend putting on gloves.)
3. Remove the cover from the feeding container and
clean the inferior surface with spirit.
4. Close the giving set clamp/roller, then spike the
Fig. 7 Diagram of an enteral feed being given through a gastrostomy. feeding container and attach the giving set.
Most systems no longer have a drip chamber 5. Invert the container and hang it on the drip stand.
For gravity feeding, the feeding container should
Care of the Feeding Tube be 1 m above the proximal end of the feeding tube.
6. Remove the distal cap from the tubing and slowly
Enteral feeding can start 2–4 h after a percutaneous feeding open the roller/clamp to prime the giving set.
tube has been inserted, there is no evidence to support giving 7. Flush the feeding tube with the prescribed quantity
water alone at first [11]. (usually 50 mL) of cooled boiled or sterile water.
Enteral feeding tubes are used for the administration of 8. Connect the giving set to the feeding tube.
feeds, water and, if necessary, medications (Box 6) (Fig. 7); 9. Insert the drip chamber or length of tubing into the
they may become blocked by feed or medication solidifying pump.
within the tube. Feed may block the tube if there is a failure 10. Set the pump rate, unclamp the giving set and run.
to flush the tube, interrupted feeding (e.g. due to a pump mal-
function) or if the feed is of a high viscosity and contains Approximate drip ratesa
mL/h drips/min
whole protein. Acidic fluids with a pH of less than 5 (e.g.
125 35
gastric acid or fruit juices) and the warmth of the body may
100 28
cause casein-derived feeds to coagulate and thus block the 75 21
tube. However, feeds containing free amino acids, small pep- 50 14
tides (elemental or peptide feeds), egg albumin or whey pro- 25 7
teins do not coagulate at a pH of less than 5 [18, 112] and
mL / h ×17
thus can be used if recurrent blockage occurs. Crushed tab- drips / min =
lets and potassium and iron preparations are especially likely 60
to block tubes. Many drugs are in a hyperosmolar solution a
The drip rate is affected by viscosity of feed, temperature of
feed and giving set material. It is not necessary to know this for
which, in addition to making line blockage more likely, may
most modern pumps
cause nausea and diarrhoea [113].
It may be possible to clear a blocked tube by flushing with Feeding Regimen

warm water, a carbonated drink, pineapple juice or sodium
bicarbonate solution. Cranberry juice is less effective than tarter Regimens/Feeding Rates
S
Coca Cola® or water in preventing blockage [114]. An alka- A gastrostomy or jejunostomy is not used for 2–4 h after
linized solution of pancreatic enzymes (Viokase® at pH 7.9 insertion (though longer after surgery/trauma), then fed is
with sodium bicarbonate) is effective in unblocking most given at 20–45 mL/h for the next 12 h, before being increased
lines [115], and the same mixture has been advocated for (sometimes over 2–4 days) to the amount needed to meet the
giving after a feed and a water flush to prevent tube blockage patient’s requirements [120]. Some units starts the feed at
[116]. This solution can be made by adding 5 mL of water to 25 mL/h and increases it every 4 h in 25 mL/h increments
one crushed tablet of Viokase® and one of sodium until the calculated rate is reached. With an overnight feed
bicarbonate. the rate rarely exceeds 150 mL/h. Often a jejunal feed is
Before the enteral feeding tube is connected to a giving started at a slower rate 10 mL/h and gradually increasing and
set, air is expelled. Some ‘backflow’ of gastric contents into reaching the target by day 6.
tube is normal and is a reassuring sign of the correct position With continuous infusions in patients who have had some
of the tube within the stomach, though it may be perceived oral intake in the last week, starter regimens that either dilute
by a carer to be a problem. [121] or reduce the feed volume [122] are not necessary and
Some types of gastrostomy or jejunostomy tube have a may prolong the period of negative nitrogen balance.
clip/clamp on the tube to prevent leakage when the feeding However, if vomiting/bloating or diarrhoea (not related to
ports are open. If left closed when the tube is not in use, these antibiotic therapy) occurs, the feed rate may be reduced for a
clamps can cause damage to the tube, which may eventually trial period.
break at the point where the clamp was located.
It may be possible to replace certain parts of an enteral Energy/Composition
feeding tube (e.g. the Luer lock end) if damaged. If high-energy feed is given, hepatic steatosis, osmotic
diarrhoea, refeeding syndrome, uraemia or hyper-capnia
may occur. Care must be taken not to overfeed a patient
Gastric Aspirates who is being ventilated as the energy requirements are
likely to be up to 1000 kcal/24 h less than calculated; a
It is uncommon for a nasogastric tube to be inserted rou- feed with less carbohydrate is usually given. Ten to 30%
tinely after abdominal surgery to ‘decompress the stomach’ of tube-fed patients will have hyper-glycaemia [123] and
as patients with a tube in place have more infective compli- may need to be given an oral hypo-glycaemic agent or
cations and it is longer before they can take food orally [117]. subcutaneous insulin before starting the feed. It is impor-
Sedative drugs and high circulating catecholamine levels tant not to underfeed patients. Keeping a patient ‘nil by
delay gastric emptying. If a gastrostomy or nasogastric tube mouth’ while waiting for investigations, stopping feeding
has been inserted post-operatively or in an intensive therapy because of a high nasogastric aspirate, cardiac problems
unit, the residual volume should not prevent feeding from or the tube ‘falling out’ can all worsen the problems of
starting, but care must be taken when aspirating more than undernutrition.
200 mL from a nasogastric tube or 100 mL from a gastros- If a patient has a non-functioning gut and full nutrient
tomy tube [118]. If, more than 2 h after starting to feed, there requirements are being met by parenteral nutrition, minimal
is an aspirate of more than 200 mL or more than 2 times the enteral feeding (10 mL/h) with or without added glutamine is
hourly feeding rate, gastric emptying is likely to be delayed often given on the basis that it may preserve the gut’s barrier
and extra care is needed, however the feed does not necessar- function and prevent villous atrophy, however there is no
ily need to be stopped. Some intensive therapy units aspirate good evidence in man that it reduces bacterial translocation
all the gastric contents every 4 h and replace [124].
200 mL. Metoclopramide 10–20 mg three times a day (0.1– Most commercial feeds contain 1.0–1.5 kcal/mL and are
0.2 mg/kg in children) orally or intravenously, domperidone nutritionally complete. In the long term, a feed containing
10 mg four times a day, erythromycin 125–250 mg four fibre (fructo-oligosaccharide) is often given as it may result
times a day (3 mg/kg in children over 1 h) or, rarely, neostig- in a normal formed stool. If a patient is being fed into the
mine 1 mg may all be used to increase the gastric emptying jejunum and a polymeric diet has caused symptoms of dump-
rate. Cisapride 10 mg four times a day used to be helpful but ing syndrome, then an isoosmolar peptide feed may be given.
has unfortunately been withdrawn. If a high gastric aspirate
is preventing feeding, jejunal feeding should be considered. Feeding Method
A fine-bore feeding tube used to aspirate gastric fluid is Gravity, a pump or a syringe can be used to deliver a feed,
much more likely to become blocked as the acid coagulates which may be given continuously, intermittently or by
casein-derived protein [119]. boluses.
Continuous feeding keeps the intragastric pH high/neutral Drugs

[125]; this used to be thought to protect against haemorrhage Drugs should be given in liquid form and the tube flushed
from ‘stress ulceration’ in critically ill patients. If the gastric before and after use with 30 mL water [11]. Care should be
contents are not acidic, however, they will not be bactericidal exercised if digoxin and fibre, or warfarin and vitamin K/E
and the stomach can become colonized by enteral bacteria are given together as they may make digoxin and warfarin,
[126, 127]. The gastric contents can reflux up the oesopha- respectively, less effective. Sucralfate that is allowed to mix
gus and spill over into the lungs where micro-organisms can with enteral feed in the stomach or in an enteral tube can
cause pneumonia and an increased mortality [128]. form a solid mass and so block the tube. Phenytoin can inter-
Administration of an H2 antagonist (cimetidine) increased act with protein, so it is given 2 h before or 2 h after enteral
the risk of patients on a ventilator developing pneumonia feeding.
[129]. Bile reflux into the stomach raises gastric pH and ulti-
mately predisposes to colonization of the lower respiratory Contamination of Feeds
tract by gastric bacteria [130]. Four Gram-negative bacteria An enteral feed is an ideal culture medium and can easily
(Escherichia coli, Enterobacter cloacae, Klebsiella pneu- become contaminated. The feeding tube itself is also an
moniae and Serratia marcescens) are mainly responsible for important reservoir for bacteria, including those that are
stomach-to-airway colonization. At a pH of less than 2.7, all multi-resistant [136]. The factors that determine whether
4 bacterial species are killed within 90 min [131], thus a contamination will cause a problem are the dose of infecting
period free from a feed that allows a normal low gastric fast- organism, the route of administration (stomach or jejunum)
ing pH to be reached should be beneficial. An additional and host resistance, which is reduced in elderly, undernour-
problem in ventilated critically ill patients is that their gastric ished or immunosuppressed patients.
motility is disrupted, making them more likely to have viable Unacceptable contamination of a feed is said to occur
bacteria in their stomach [132]. when there are more than 104 colony-forming units per mL
The time a patient should be rested from a feed has not of feed, and levels greater than this have been associated
been determined; Bonten et al. showed that colonization of with diarrhoea [137]. In ventilated patients the organisms
the stomach, oropharynx and trachea was the same with 4 h that contaminate a feed have often come from the gut [130].
fasting every 24 h as with continuous feeding [133]. With 8 h Contamination is common if a feed is hung for more than
fasting every 24 h, the incidence of pneumonia on an inten- 24 h [138]. It is important that asepsis is maintained in the
sive therapy unit fell from 54% to 12% [134]. A break in preparation and delivery of a feed, especially for those
feeding (probably of 4–8 h) allows both the stomach pH to patients on the intensive therapy unit, immunocompromised
return to normal and catch-up time to ensure that all of a feed patients, patients taking proton pump inhibitors or H2 antag-
is given. onists, and neonates. Hand washing is the single most impor-
Continuous and intermittent feeding is usually done tant measure to prevent contamination. A mask should be
via a pump (and no drip chamber), which provides a resis- worn if the carer has a cold, sore throat or respiratory tract
tance to flow, so preventing excessive amounts of feed infection. No part of the system that comes into contact with
abruptly being delivered into the stomach/small bowel. the feed should touch the hands, clothes, skin or any non-
Whole protein feeds may be of high viscosity but the disinfected surface [139, 140]. The number of manipulations
pump does not need to generate a high pressure [18]. It to a feed should be kept to a minimum. A recessed spike on
would be cheaper and simpler for most patients to use the giving set helps to reduce the chance of contact and thus
gravity feeding with a variable or fixed resistance to con- contamination of the feed. Bottles with a ring pull that needs
trol the feeding rate. decanting should be avoided as the feed is usually poured
In bolus feeding, boluses of 200–400 mL feed are gener- over the area the thumb has touched to remove the ring. If a
ally given (though 800 mL has been used) into the stomach feed has to be decanted it should be hung for a short time.
over 20 min (range 15–60) [135]. Bolus feeding would seem Acidifying an enteral feed preserves gastric acidity and
more physiological and akin to what happens in real life. reduces gastric colonization in critically ill patients and thus
Bolus feeding may cause bloating and diarrhoea and, if given may reduce the incidence of pneumonia [141].
into the jejunum, may cause a dumping type syndrome.
Bolus feeding can be done by pouring the feed into an
inverted 50 mL syringe which has had the plunger removed. Patient Position
The syringe is then either connected directly to the feeding
tube or via an extension tube and the feed is run in slowly. If Patients should always be fed in the semi-supine position
the rate is too slow the plunger can be replaced and the feed (propped up) for nasogastric or gastrostomy feeding and for
gently injected. The syringes can be washed between uses, 30 min after finishing, as there is a high and often unrecog-
depending upon local policies but they do need to be replaced nized risk of aspirating the feed. While this position does not
weekly as they become hard to use. prevent aspiration, it reduces its frequency and severity [19].
Equipment label the delivery system to prevent its contents from being
accidentally administered intravenously, especially as
Pumps adapters that change male Luer lock or push-in connections
Most pumps in Europe give a flow rate that varies from 1 to to female ones are available. ‘All parts, joints and connec-
300 mL/h and they comply with European Device Standards. tors of an enteral giving set and catheter shall withstand a
It is suggested that no more than 500 mL be given over 4–6 h linear tensile strength of 15 N without disconnection, rup-
without a pump. An enteral feeding pump should not be able ture or cracking’ and there should be no leakage when the
to generate a pressure of more than 15 psi, and syringes system is pressurized to a minimum of 150 kPa with water
smaller than 50 mL should not be used as they can exceed for 2 min [144].
this pressure. A parenteral nutrition pump should never be
used as this generates high pressures. Pumps may have Giving set/nutrient containers/syringes There may be
alarms for occlusion, air in the line or low battery. local policies concerning the feed administration sets and
Several small portable pumps with carrying packs are handling procedures. The feed administration set and nutri-
available and allow feeding to occur while the patient is ent containers are discarded after a single use while syringes
mobile. may be washed and reused.
Drip Stands
A large hospital drip stand is often provided, but small bed- Disconnecting an Enteral Feed
side stands are available. The LITRE (Looking Into The
Requirements for Equipment) group in United Kingdom has An enteral feed is disconnected after hands have been
designed a small portable drip stand that can be used for car- washed; the tube is flushed with cooled boiled or sterile
rying a feeding bag for enteral or parenteral nutrition. water, then capped off. All feeding equipment except syringes
is discarded. An open nutrient container can be refrigerated
Dry Goods and reused for 24 h only.
The feeding catheter connects to a flexible giving set, which
in turn connects to the nutrient-feeding bag (Fig. 7).
Discharge Planning
Feeding tube The position of the feeding tube should be
regularly checked by looking at the markers on its side to Before discharge from hospital, the patient/carer must be
ensure that it has not slipped out. Some jejunal feeding sys- trained in the setting up/taking down of a feed, flushing the
tems allow the stomach to be drained while feeding contin- tube, giving medication through the tube, care of the exit
ues into the jejunum. Tubes with a balloon may not last as site, prevention and treatment of tube blockage, and repair of
long as those with a flange and may need to be changed every the hub. They must understand some basic anatomy and
3–6 months or according to the manufacturer’s instructions physiology as well as how to set up and operate the pump (if
[43]. A PEG tube may last for 2 years, a jejunostomy tube for used). They must have made arrangements for delivery so
a shorter time of about 6 months. There is no difference in that there is an uninterrupted supply of the feed/dry goods.
blockage between an 8, 10 or 12 FG feeding tube, though it They should have contact numbers in case of illness or if
is harder to aspirate fluid from the smaller tube [142], and they have problems with the equipment. They should have
leakage and peristomal infections were not significantly follow-up appointments arranged. All patients, those receiv-
more common with a 20 FG compared to a 12 FG tube [143]. ing enteral nutrition, are reviewed at least annually by a spe-
A radiologically placed gastrostomy will last about 6–12 cialist nutrition team.
months.
Connectors ENFit is the global enteral feeding device con- Monitoring

nector design that complies with International Standard
(ISO 80369-3). ENFit devices will not be compatible with a When an enteral feed is first started, especially if the patient
Luer connection or any other type of small bore medical is very undernourished, haemoglobin, clotting, sodium,
connector, so preventing the accidental intra-venous admin- potassium, urea, creatinine, liver and bone chemistry and
istration of an enteral feed. Unlike current parenteral and magnesium are measured, as is a random urinary sodium
oral syringes with male syringe tips that fit into female con- concentration. Within the first 24 h of starting the feed the
nectors, the ENFit devices are the opposite. They have a serum phosphate and potassium are measured. These tests,
female tip on the syringe that will fit around a male connec- along with serum magnesium, are done at least weekly for 2
tor on feeding tubes. All the same, care should be taken to weeks, then every 2–12 months depending upon the clinical
condition of the patient. Refeeding problems are common the abdominal wall. Another option is to dilate the tract with
with enteral feeding largely due to the incretin effect dilators of gradually increasing diameter and to insert a but-
(“Refeeding Problems” chapter). ton or balloon-type gastrostomy.
The patient is ideally weighed daily in hospital, but often
this is not possible; mid-arm muscle circumference and hand Elective/Planned Removal
grip dynometry may be determined and measured every Planned removal may be by cutting the tube and allowing it
week until discharge, then every 2–4 months. After discharge to pass, or careful endoscopic A gastrostomy tube with an
weight, muscle mass/strength, hydration, food intake, com- internal fixation device that deflates can be removed by with-
plications and quality of life are assessed with routine blood drawing air/water from it and gently pulling. If it does not
testing that may include serum transthyretin (pre-albumin) come out easily, however, it may need to be removed in the
[11]. same way as a tube with a non-deflating internal fixation
device. If a gastrostomy tube is pushed inwards to check that
it is free, then pulled upon and transected as near to the skin
Psychosocial Implications as possible, it will usually pass through the gut with no prob-
lems [145]; however, in a few cases (2%) the tube does not
It is difficult for a patient to feel that he/she is part of the fam- pass [146]. This method may be appropriate if the patient has
ily if he/she cannot eat; fortunately, patients with intestinal a normal gut (no Crohn’s disease or distal strictures). If a
failure are usually able to eat normally and use the feeding as gastrostomy tube with a rigid internal fixation device is
a way of getting extra energy, usually at night. They can lead removed endoscopically, the tube is pushed 1–2 cm inwards
a moderately normal life and can bathe/shower/swim 2–4 and a polypectomy snare is put over the internal fixation
weeks after a gastrostomy or jejunostomy has been inserted. device and tightened round the tube. The tube is cut about
5 cm from its skin entry point and the endoscopist withdraws
the scope and tube. The patient is usually kept nil by mouth
Problems of Enteral Tubes for 12 h following tube removal. Abdominal fistulae rarely
develop, even in patients with Crohn’s disease [147].
The long-term problems include over granulation of tissue at When a PEG/PEJ tube needs replacement because of
the exit site, tube blockage, aspiration, leakage around entry breakage/leakage that cannot be corrected with repair kits/
site or at the connection and discharge at exit site and buried replacement parts, it can usually be done endoscopically. The
bumper. All are covered in “Enteral Nutrition” chapter but PEG can be transected about 10 cm from the exit site and the
buried bumper which occurs due to too much traction being new double-looped introducing thread of the new PEG pushed
applied to a percutaneous enteral feeding tube is discussed in through the lumen of the old PEG and into the stomach. The
here. closed polypectomy snare from the endoscope is pushed
through this loop, and then opened; this traps the thread round
the snare. The snare is then put round the internal fixation
ccidental and Elective Tube Removal/
A device and closed; the thread is caught in this and, when the
Replacement PEG is removed, the thread will again come out of the mouth
ready to be attached to a new PEG. An alternative way is to cut
Accidental Removal a 1 mm hole 5–10 mm from the end of the cut PEG; the intro-
A percutaneously inserted tube should not be removed, nor ducing thread from the new PEG set is put through the newly
reinserted along the new tract until at least 4 weeks after cut side hole and tied. The old PEG can then be removed,
insertion, as a fibrous tract needs to have become established using a polypectomy snare, as already described. The thread
to prevent intraperitoneal leakage [11, 43]. If a tube becomes will emerge from the mouth and the new PEG is attached to
displaced in the first 4 weeks then a full new insertion needs this and pulled into position in the usual way.
to be done. If the tube is inadvertently displaced more than 4 When a PEG is removed it is sometimes replaced with a
weeks after initial placement, direct replacement can be button, especially in children.
safely attempted (within 12 h) before the tract closes [11]. A
flexible guidewire is often the easiest way of finding the
tract. Its soft end can be inserted into the tract. An endosco- Burried Internal Flange (Buried Bumper)
pist can see the wire emerge in the stomach and can catch it
with a polypectomy snare or grasping forceps. The wire is Traction on an enteral tube (and without pushing it in each
pulled up into the endoscope, which is withdrawn to leave week) particularly one with a flat disc can result in the gastric
the wire coming out of the mouth. A new PEG is tied to this mucosa growing over the disc and eventually occluding it.
and pulled into position in the usual way by the assistant at While the tube may rotate it will not push into the stomach
ageal balloon dilator which is inflated (10–12 mm) when

the first 2 cm of dilator is seen in the stomach. This balloon
dilator both acts as a stiffener so the tube can be pushed
inwards and it may disrupt some of the overgrown tissue
so allowing the tube to enter the stomach. If this is not suc-
cessful radial incisions with an endoscopic needle knife
onto the internal flange can aid the balloon’s passage into
the stomach [43, 149]. If it does not pass it is worth leaving
the tube alone on no traction and repeating the procedure a
week later, and often the tube relocates easily into the
stomach. Another technique with good results reported is
to cut the PEG tube short close to the abdominal wall and
pass biopsy forceps through the PEG; then through an
endoscope pass a snare which is grasped by the biopsy for-
ceps and pulled out; a 2 cm piece of the old PEG tubing is
placed through the snare and closed to create a t-piece
which is pulled by the endoscope; thus the PEG should
emerge into the stomach [150]. A new PEG can usually be
reinserted through the old tract.
If the PEG tube cannot be seen at all an abdominal CT
Fig. 8 Burried bumber. As the white of the internal flange (bumber) scan may help identify its position.
can be seen, it should be possible to remove
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Formulation and Administration
of Enteral Feeds
Gil Hardy and Hazreen Abdul Majid
Key Points actions (DNI) and managed by the multidisciplinary

1. Enteral nutrition (EN) is generally accepted to be the NST.
first choice for nutrition support of most patients. 8. To avoid tube blockage, the tube should be flushed with
However, EN and/or parenteral nutrition (PN) are both water before and after feeding. Tubes should also be
equally efficacious, if prescribed and used flushed before and after any medication is
appropriately administered.
2. There is no good evidence for trophic EN. It is suggested 9. Quality assurance procedures should be followed to
to give either EN or PN. A combination of both may be avoid contamination of EF during administration, but
used when converting from PN to EN or when EN is most contamination may not be clinically relevant unless
insufficient to meet energy requirements, at the discre- a patient is immuno-suppressed, is taking drugs to inhibit
tion of the multidisciplinary nutrition support team gastric acid production, or is being fed directly into the
(NST). small bowel.
3. After the stomach, all parts of the gut can absorb water, 10. Protein deficiency decreases absorption of vitamin A,
macro-nutrients, minerals and vitamins, so some nutri- dietary fat decreases calcium absorption, copper and
tion from EN will be absorbed in all parts of the small zinc supplements inhibit iron absorption, whereas vita-
and large intestine. min C enhances absorption of non-haem iron.
4. Distal enteral tube feeding (DETF)/fistuloclysis whereby 11. Do not aim to achieve the full energy target with early
EN or gastrointestinal secretions (chyme) is adminis- EN. Early feeding that exceeds actual energy expendi-
tered through an enterocutaneous fistula in the distal ture is harmful. Hypocaloric early EN appears to be safe
bowel can be effective. and can frequently meet protein targets.
5. Enteral feeds (EF) divide into three main formula types, 12. There are published practical guidelines for prescribing
standard (whole protein), peptide (semi-elemental) and and administering EN for paediatric and adult, surgical
specialized formulas. EF then further sub-divides into, and critically ill patients.
oral/sip feeds and tube feeds.
6. Most liquid EF are ultra high temperature (UHT) steril-
ised, but heat processing can destroy some vitamins (e.g.
all B vitamins especially thiamine and vitamin B6, folic Introduction
acid and pantothenic acid) and heat-sensitive amino acids
(e.g. glutamine and cysteine). Extra vitamins and some In considering the nutritional support of hospital patients the
individual amino acids may need to be supplemented. general, almost obligatory, rule that has been promulgated in
7. Enteral feeding tubes (EFT) are increasingly used as recent years is ‘if the gut works, use it’. However with the
vehicles for administering medications, but pharmaceu- recent advancement in research, it is crucial to ensure at least
tical advice should be taken to avoid drug-nutrient inter- the patients are fed [1]. Delivering early nutrition therapy,
generally within 48 h in the ICU [2], primarily by the enteral
G. Hardy (*) route, is now seen as a proactive therapeutic strategy that
Clinical Nutrition, Ipanema Research Trust, Devonport, may reduce disease severity, diminish complications,
Auckland, New Zealand
decrease length of stay (LOS) in the ICU, and favourably
H. A. Majid impact patient outcomes [3]. Nutrition support via enteral
Nutrition and Dietetics, Faculty of Medicine, Centre for Population
nutrition (EN) and/or parenteral nutrition (PN) for patients is
Health, University of Malaya, Kuala Lumpur, Malaysia

514 G. Hardy and H. A. Majid
Table 1 General principles and precautions for using early EN (EEN) gastrectomy [6] and after hepatic resection [7]. There are
in critically ill patients at risk of intolerance
fewer septic complications [5] and natural killer cell activ-
Starting and Start EN at a slow rate (10–20 mL/h) while ity is higher in patients fed with EN compared with PN [7].
continuing EEN carefully monitoring abdominal/gastrointestinal
symptoms
The frequently quoted paper in favour of EN, by Moore
Increase EN slowly once previous symptoms are et al. [8], is a meta-analysis of eight studies (six unpub-
resolving and no new symptoms occur lished). Their analysis shows no difference between EN
Do not increase EN in cases of intolerance or and PN in non-infectious complications, mortality rates or
new symptoms, such as pain, abdominal length of hospital stay. However, more septic complica-
distension or increasing intra-abdominal
pressure. In these circumstances EN should be
tions were noted with PN in patients who had had abdomi-
either continued at a slow rate or ceased nal trauma. A comprehensive review of published
depending on the severity of symptoms and prospective randomized controlled trials by Lipman [9]
suspected underlying sinister pathology (e.g. concluded that with the exception of reduced septic mor-
mesenteric ischaemia)
bidity in abdominal trauma (which was offset by an
Energy target Do not aim to cover full energy target with
during EEN EEN. The optimal energy and protein target in increased incidence of EN-related complications) the only
the early phase of acute critical illness is not significant difference between EN and PN was the lower
known. EEN that exceeds actual energy cost of EN. A more recent study of critically mechanically
expenditure appears harmful and should be
ventilated patients concluded that ventilator-associated
avoided [12, 13], whereas hypocaloric EEN may
be safe [14–16] pneumonia rates, ICU and hospital lengths of stay, ICU
Monitoring and In case of gastric retention without other new and hospital mortality rates of patients receiving PN were
protocolised abdominal symptoms use prokinetics and/or not significantly different than those receiving EN [10].
management of GI postpyloric feeding in a protocolised way [17]. A balanced approach to the route of nutrition support ther-
dysfunction during Monitoring gastric residual volume (GRV) is
EEN typically conducted to observe signs of feeding apy is appropriate. It is important to consider the nutritional
intolerance, but a meta analysis of 4 RCT support requirements of each individual patient, then choose
provided no evidence that returning residual the most appropriate route of delivery for that patient.
gastric aspirates provides more benefits than Guidelines, as proposed by Blaser et al. [11] for successfully
discarding them [18] (chapter “Insertion, Types
and Care of Enteral Feeding Tubes”). feeding critically ill patients suggest giving early EN in order
During introduction and increasing the rate of to meet nutritional goals (Table 1). It is important that indi-
EN, measurement of intra-abdominal pressure vidualised approach to be used to ensure nutritional
(IAP) provides an additional numeric value to optimization.
detect negative dynamics of IAP during EN in
patients with severe abdominal pathology,
hypoperfusion or fluid overload
Individualized For patients with diminished consciousness and History, Ingredients and Manufacturing
approach inadequate swallowing, precautions to prevent
aspiration of gastric contents may be useful,
Various mixtures of milk, egg, beef or chicken broth, wine,
including considering post pyloric feeding
Premorbid health and course of the acute illness brandy and pancreatic tissue have been administered to
may differ between patients with similar patients rectally since Ancient Egyptian times [19]. John
diagnose; therefore an individual approach Hunter in 1790 successfully used a ‘tube’ passed through
should always be applied the mouth into the stomach to feed a patient who was
unable to swallow due to ‘paralysis of the muscles of
crucial with no superiority for either, if prescribed and used deglutition’. The ‘tube’, which was designed by a watch-
appropriately. EN is claimed to: be physiological, improve maker, consisted of eel skin wrapped round a flexible
gastrointestinal function, prevent bacterial translocation and whalebone and was attached to a pig’s bladder which acted
improve patient outcome while being less expensive than as a reservoir. Hunter recommended that jellies, eggs
PN. beaten with a little water, sugar and wine or milk should be
There is no documented evidence for reduced bacterial given as food [20].
translocation or improved intestinal function in humans, Today whole protein enteral feeds (EF) are made from
although there are animal data [4] which show that intesti- milk components (e.g. calcium caseinates) or soya protein
nal mass, mucosal weight, villus height and disaccharidase isolates as the predominant protein sources, various oils (e.g.
activity all decrease in animals fed with PN compared with soya, corn or safflower) as lipid sources, and ingredients
EN. Although there is no direct evidence that patient out- derived from corn starch (e.g. maltodextrin), sucrose, and
come or safety is better, there are studies which show glucose as sources of carbohydrate. Some have insoluble
fewer complications with EN compared with PN. These and/or soluble fibre added. The protein sources in semi-
include patients with pancreatitis [5], following a total elemental EF (peptide or elemental diets) are based upon the
Formulation and Administration of Enteral Feeds 515
products of hydrolysis of milk components (caseinates, whey is catalysed by heat, light, high pH and the presence of cop-
protein and lactalbumin) or soy protein, with some specific per and/or iron. Whilst vitamin C is partially protected by the
amino acids and medium-chain triglycerides added. Most EF addition of bisulphite, thiamine destruction is accelerated.
intended for use as sole source of nutrition, are fortified with Vitamin E is relatively stable to heat but oxidized in the pres-
essential vitamins, minerals and trace elements. Some also ence of air. Average nutritional claims for the content of EF
contain other nutrients such as choline, taurine, arginine and are those which are declared on the label.
glutamine. Most liquid, ready-to-use feeds are filled aseptically
Manufacturers of EF invariably endeavour to achieve into cartons, plastic containers or glass bottles. These are
maximum nutrient content in minimum volume. then subjected to ultra-high temperatures (UHT) to kill
Technological challenges for new product R&D involve any bacteria present. A temperature of about 143–152 °C
packaging development to ensure the final product maintains is maintained for 5–10 s. The resultant sterile feed will
nutritional, microbiological and organoleptic integrity. keep for several months but variable losses of vitamin C
Sensory assessment is important during the product develop- and folic acid may occur during storage. It is difficult to
ment stage. The elderly have different perceptions of taste give precise values for expected losses, and they will be
and smell to younger people, and it is now known that further accentuated when the containers are opened and exposed
alterations occur during hospitalisation. Sensory testing is to air. However, if they are kept in the closed carton in
initially conducted ‘in-house’ but then usually involves con- which they are transported, the contents will be protected
sumer and patient panels that must be conducted according from light and oxygen. The process of freeze drying has
to the Medical Nutrition Industry Code of Conduct [21]. been used for over 50 years, and was refined during World
Finally, extensive stability testing in the laboratory is required War II in order to supply huge quantities of dried plasma
to establish shelf life, pilot production runs and larger scale- and penicillin to the armed forces. It is now used exten-
up for industrial processing. sively in the pharmaceutical industry as one of the best
methods for preserving biological materials and for pro-
tecting heat-sensitive drugs. It has also been successfully
Stability adopted for producing some EF.
Manufacturers generally fortify EF to levels designed to
The stability of macro- and micro-nutrients depend upon the compensate for losses, which occur during processing. In
exposure of the EF to heat, pH, light and air (Table 2). Heat addition, most manufacturers have rigorous quality assur-
processing to produce a sterile liquid feed can destroy some ance programmes designed to test levels of all nutrients dur-
vitamins (e.g. all B vitamins especially thiamine and vitamin ing the ‘quarantine’ period after products are manufactured,
B6, folic acid and pantothenic acid) and heat-sensitive amino but before they are released for sale, to ensure that nutrient
acids (e.g. glutamine and cysteine). Hence glutamine and levels, which are listed on the labels, are accurate. Most com-
cysteine are absent from most commercial EF. The amount panies also conduct routine stability trials to determine the
of vitamin and amino acid lost will depend on the time for average levels of nutrients over the shelf-life of the product.
which heat is used to destroy harmful organisms. Thiamine Feeds can usually be stored at room temperature unopened
is more stable to heat at low pH, but when the pH is high, for up to 1 year.
losses are considerable. Riboflavin is unstable at high pH and
is light-sensitive. Vitamin A losses can occur if light and air
are not rigorously excluded. Vitamin C is the least stable of Formulations
all the vitamins; it is readily oxidized in air, a process which
The type of EN formulation used, as for PN, is directly
Table 2 Vitamin and amino acid stability in EF dependent on the nutrient needs and goals of therapy for the
Heat patient [22]. EF divide into three formula types, standard
Vitamins (whole protein), peptide (semi-elemental) and specialized
B vitamins (especially thiamine and B6), folic acid and formulas. EF then fall into two different categories, oral/sip
pantothenic acid feeds and tube feeds:
Amino acids
Cysteine and glutamine
Light
Vitamin A and riboflavin Oral (or Sip) Feeds
pH
Riboflavin and thiamine at high (alkaline) pH Most prescribable sip feeds are nutritionally complete and
Air can be used as sole source of nutrition. However, in general
Vitamins A, C and E all oxidize they should only be used to supplement a patient’s diet to
Table 3 Nutritional considerations for enteral feed constituents Table 4 Classification of prescribable enteral products in UKa
1. Protein source (whole protein, peptides or amino acids) 1. Oral supplements (sip feeds)—to provide greater nutritional
2. Carbohydrate content and source (e.g. lactose free) value and/or energy density to the diet
3. Fat content and source (long-chain triglycerides (LCT) vs. 2. Polymeric tube feeds—nutritionally complete feeds with high/
medium-chain triglycerides (MCT)) whole protein, maltodextrin, LCT, PUFA/ MUFA, immune
4. Energy density modulating formula and often fibre
5. Energy distribution (i.e. % of energy supplied by protein, 3. Elemental/peptide feeds for sip and/or tube feeding—mono/
carbohydrate and fat) oligo-peptides and mono/oligo-saccharides which may be more
6. Fibre content, type and source easily digested and absorbed (but have a high osmolality,
7. Renal solute load especially the elemental diet)
8. Electrolyte composition 4. Disease-specific formulae—for short bowel, liver or renal failure
9. Lactose/gluten content 5. Modular diets (e.g. powdered carbohydrate or protein
10. Vitamin and mineral content (i.e. volume required to supply supplements—to individualize a patients diet)
RNI) 6. Feeds for inborn errors of metabolism (e.g. phenylketonuria)
11. Osmolality 7. Infant formulas (e.g. lactose free feeds or those which do not
12. Viscosity contain cow’s milk)
13. Palatability and patient acceptance
a
This list is not exhaustive and does not include gluten-free foods or
low protein foods
achieve optimum nutrition. There is a wide range of ‘ready- milk proteins provide useful data, they do not take into
to-use’ commercial sip feeds. account imbalances in protein amino acid patterns, different
digestion rates and absorption of specific amino acids and
losses during processing. Published data based on actual
Tube Feeds protein and EAA requirements for humans that accommo-
date age and lifestyle factors, allow reasonably accurate
Tube feeds are administered as nutrition support via a naso- amounts to be determined. Nevertheless, most enteral and
enteric tube (for short term) or via a percutaneous endoscopic parenteral products have a lower protein quality value when
gastrostomy (PEG) or jejunostomy (for long term). They are compared to egg or milk.
nutritionally complete and can be safely given as the sole
source of nutrition. These include whole protein feeds for
patients with ‘normal’ gut function, peptide feeds often used Glutamine
for jejunal feeding, and specialised feeds (free amino acids
hence hyperosmolar) to treat some patients with malabsorp- Glutamine is key for immune function as the primary fuel for
tion such as Crohn’s disease. Some of the nutritional consid- proliferation of lymphocytes, production of cytokine, and
erations relating to EF are shown in Table 3. macrophage phagocytic and secretory activities [24].
A comprehensive list of prescribable EF (classified as Glutamine is also the precursor for amino acids, proteins and
‘Borderline Substances’) can be found in the British National nucleotides synthesis, and also ammonia genesis in the kid-
Formulary (BNF) [23]. Unlike in the USA, very little EN neys [25]. Since glutamine is available abundantly from ani-
‘compounding’ is carried out in UK pharmacy departments. mal and plant-based protein sources, individuals consuming
EN products can be classified into seven groups (Table 4). a balanced diet can easily meet their nutritional requirements
for glutamine. However during periods of metabolic stress or
catabolic conditions, such as critical illness, sepsis, burns,
Protein post-surgery, and malnutrition; glutamine becomes condi-
tionally essential, as the demand for glutamine increases
In the UK it is common to refer to protein requirements for drastically. Recent research has shown that glutamine can
EN and nitrogen requirements for PN. The eight essential positively affect gut health by supporting the gut microbi-
amino acids (EAA) (in adults: isoleucine, leucine, lysine, ome, gut mucosal wall integrity, and by modulating the
methionine, phenylalanine, threonine, tryptophan and inflammatory response [26]. Because glutamine is heat
valine) cannot be manufactured by the body but can be used labile, standard EF do not contain adequate amounts of glu-
to make the non-essential amino acids (NEAAs), which pro- tamine, due to losses during the manufacturing process.
vide most of an individual’s metabolic need for nitrogen. Therefore, glutamine may be provided to those individuals
The quality of protein is as important as the quantity. Whilst as modular supplements in the form of the more heat-stable
chemical scores based on reference standards for egg or glutamine dipeptides.
Arginine fatty acid) and other polyunsaturated fatty acids (PUFAs) as

they cannot be synthesized de novo, and have to be con-
Just like glutamine, arginine is also a conditionally essential sumed from the diet.
amino acid during metabolic stress and trauma, due to the In peptide-based enteral formulas, fractionated coconut
increased protein turnover and energy requirements of the oil is often added as a source of medium-chain triglycerides
immune system. Arginine is involved in various metabolic (MCTs) for better absorption. MCTs are absorbed directly
pathways. It is converted into biologically active compounds into the lymphatic system, hence, may minimize steatorrhea
such as ornithine, nitric oxide, polyamines and citrulline. in patients with malabsorption.
Hence, arginine is involved in the modulation of immune
function, regulation of blood flow, angiogenesis and also
wound healing [27]. Arginine is stable to heat processing and Vitamins and Minerals
can therefore be formulated into EN regimens. All protein-
based enteral feeds contain theoretically between 3 and 5 g Enteral formulas whether to be used as sip or tube feeds, that
arginine per 1000 kcal (4200 kJ) whilst some have been fur- are intended for use as sole source of nutrition; are fortified
ther enriched with additional free amino acid. Lower infec- with essential vitamins, minerals and trace elements ade-
tion rates and reduced hospital stays have been reported with quate to supply the RNI in volumes about 1–2 L [31]. The
these arginine-enriched diets, but it remains difficult to inter- RNIs are a guide to the requirements for healthy individuals,
pret the potentially beneficial effects of arginine therefore may not be representative of the micronutrient
supplementation because of its co-administration with other requirements of metabolically-stressed patients, who will
immune-stimulating nutrients during many trials [28]. have increased requirements for nutrients due to changes in
metabolism. Therefore, some enteral formulas contain higher
amounts of micronutrients, which will be beneficial for
Nucleotides patients, in account for the increased nutrient requirements
[32]. Recommendations for adult and paediatric daily micro-
Nucleotides plays an important role in the structural integrity nutrient requirements in EN and PN have been published by
of DNA and RNA, especially in the development of immune ASPEN [33] and ESPEN [34] and for paediatric require-
system, and differentiation of rapidly growing cells, such as: ments by ESPEN/ESPGHAN [35].
skin, intestinal mucosal, lymphocytes, etc [29]. During peri-
ods of rapid growth, tissue injury, infection and certain dis-
ease states, the physiological demand for nucleotides beyond Osmolality
de novo synthesis [30]. Hence, they are also incorporated
into immune-enhancing formulas. Osmolality is the measure of the size and quantity of ionic
and molecular particles within a defined volume, usually in
the measure of mOsm/kg of water. A standard enteral for-
Carbohydrate mula of approximately 300 mOsm/kg of water is considered
“isotonic” as it falls within the normal physiologic range of
Carbohydrate is an essential component of enteral feeds, the human body. However, with energy and nutrient-dense
however Recommended Nutrient Intakes (RNIs) have not formulas, the osmolality of the formula increases as more
been published [24]. Most enteral feeds are designed to molecular particles are present within the same amount of
supply a non-protein calorie to nitrogen ratio of between volume. Generally, commercially available enteral feeds are
94:1 and 154:1. These proportions of energy and protein tolerated by most individuals. Tolerance to higher osmolality
help to ensure that the carbohydrate in the feed is used for formula may vary according to different medical conditions
energy. and gut integrity. Patients with gastrointestinal diseases or on
jejunal tube feeding may experience intolerance such as
osmotic-induced diarrhoea, when given high osmolality
Lipids enteral feeds at a high rate. Therefore, it is advisable to start
the enteral feeds at a lower infusion rate and advance gradu-
Lipids are included in most enteral feeds as they act as a ally, and to monitor the patient for gastrointestinal intoler-
source of energy to help meet energy requirements and to ances. Patients with a high output jejunostomy may need a
minimize endogenous protein catabolism. Unlike carbohy- solution with an osmolality near to 300 mOsm/kg and a
drate and protein, lipids do not contribute to osmolality. sodium content of 90–120 mmol/L (chapter “Management
Enteral formulas contain essential fatty acids like alpha- of a High Output Stoma, Jejunotomy or Uncomplicated
linolenic acid (omega-3 fatty acid), linolenic acid (omega-6 Enterocutaneous Fistula”). In some units additional sodium
is added (using aseptic procedures) to the feeding bag prior which occurs at low pH, is usually the cause of blockage and
to administration, but this will increase the osmolality. may be aggravated by the administration of medications
through the tube. To avoid tube blockage, the tube should be
flushed with water before and after feeding, and some advo-
Feeding Routes/Administration cate every 4 h during feeding. Tubes should also be flushed
before and after any medication is administered and certain
The choice of feeding route is determined by alimentary tract medications should never be mixed as this may cause EF to
function, previous gastrointestinal surgery (e.g. gastrec- become unstable, thus increasing the potential for the tube to
tomy), accessibility of the gastrointestinal tract (GIT), prac- become blocked (see below). Along with other measures
ticality of using the GIT and patient preference. In patients (chapter “Insertion, Types and Care of Enteral Feeding
who are able to eat, but unable to meet their nutritional Tubes”), a suspension of pancreatic enzymes and bicarbon-
requirements with everyday food and drink, fortified foods ate can prevent tube blockage and decrease the rate of tube
or sip feeds can help to increase intake of energy, protein and occlusion tenfold [38] (e.g. a Creon® capsule dissolved in
other nutrients. 10 mL 8.4% sodium bicarbonate).
In those who are unable to eat, but have a functioning
GIT, tube feeds may be administered via a nasogastric tube
in the short-term, or a gastrostomy or jejunostomy in the Diarrhoea
long-term. Nasogastric feeding is the most common form of
tube feeding, and can be used to meet total nutritional Much research has been undertaken to understand and define
requirements, or to complement oral or parenteral nutrition. the pathogenesis of enteral feeding-related diarrhoea. Factors
A gastrostomy (most commonly a PEG) or jejunostomy is such as antibiotics, high osmolality feed, lactose intolerance,
used for patients who are expected to require tube feeding for contaminated feeds, laxatives and overflow incontinence
longer than about 3 weeks. Jejunostomy feeding is used have all been implicated (chapter “Intestinal Adaptation”). A
when the stomach cannot be used (e.g. if patient has had a systematic review of 26 studies has shown that diarrhoea can
gastrectomy) and the patient has otherwise a functioning be moderated by fibre in patients receiving EN [39] and fibre
GIT. Jejunostomy feeding has been successfully used to feed is well tolerated within 72 h of feeding in ICU [40]. However,
patients after liver transplantation [36]. In patients who do the addition of prebiotics (fermentable fibre), which lead to
not have adequate functioning gut, or whose nutritional goals specific changes in the composition and/or activity of gut
cannot be met by EN, parenteral feeding is indicated. microbiota that benefit the well-being and health of the host)
in minimising diarrhoea in ICU settings remain inconclusive
[41]. In addition, a meta-analysis of 30 trials with 2972
Delivery Techniques patients had shown the potential use of probiotics in reduc-
ing VAP infections but high quality clinical trials are needed
For most tube-fed patients, a feeding pump is used to deliver in a broader selection of patients to substantiate this interest-
the feed. Pump controlled feeding can be continuous or ing and low cost approach for diarrhoea prevention [42].
intermittent. In the hospital setting, continuous feeding is the
most common. For patients who require feeding at home,
intermittent feeding allows more flexibility and freedom. In dministration and Compatibility of Drugs
A
addition, when feeding is stopped for 4 or more hours each with Enteral Nutrition
day, the gastric pH drops to below 2.5 and this has the addi-
tional advantage of having an antibacterial effect. Gravity or Providing optimal nutrition therapy is as vital to patient out-
bolus feeding, which supplies 100–400 mL of feed over come as prescribing the correct drug, but as our knowledge
10–30 min several times a day, can be used with stable of clinical nutrition and pharmaconutrition has expanded, so
patients who may find it better psychologically. However, if too have the complexities of the nutrition and drug therapies
not introduced carefully, it can increase the incidence of diar- that patients are prescribed. The two extremes of nutritional
rhoea, cramps, nausea, bloating and/or abdominal discom- status i.e. malnutrition and obesity, can both influence drug
fort [37] (chapter “Enteral Nutrition”). disposition and drug absorption when administered with EF
in infancy and childhood; pregnancy and lactation; and espe-
cially in the elderly. Around 10% of the population in most
Tube Blockage western countries is over the age of 65 but this relatively
small percentage of patients uses more than a third of all
Tube blockage can occur in enterally fed patients and may medicines prescribed. Moreover, polypharmacy or multiple
lead to the EFT needing to be replaced. Protein coagulation, drug therapy and malnutrition are more prevalent in older
people. It is estimated that over 40% of home enteral tube tion, whereas vitamin C enhances absorption of non-haem
feeding (HETF) patients are over 70 years old and the major- iron by binding and solubilising ferric iron. Another example
ity will have a permanent feeding device with only 20% of DNI involves warfarin, whereby the effect of medication
using nasogastric tubes. is dependent on the vitamin K content of the EF. In such
As a result of the heightened awareness of the benefits of cases, once feeding has been established and the patient will
home artificial nutrition (HAN) support, EF are now increas- be on long term EN, INR should be monitored routinely and
ingly seen as a useful vehicle for administration of medica- dosage of warfarin should be adjusted accordingly [43].
tions. However, interactions between drugs and nutrients in Most drugs contain excipients that could also interact with
an EF can cause an alteration of the pharmacokinetics of the an EF. Sorbitol, used as a solubilizing agent and as a sugar-
drug or nutrient (bioavailability, distribution, metabolism, free sweetener in liquid formulations can cause severe
excretion) leading to compromised nutritional status. Drug- cramping and diarrhoea. It has now been eliminated from
nutrient interactions (DNI) can be categorised as: physical, some drugs, such as paediatric antibiotics, but it is wise to
pharmaceutical, pharmacological, physiological, pharmaco- check with the drug manufacturer. Nevertheless, it must be
kinetic or pathophysiological and may occur when certain remembered that these actions will breach the product
medications are administered together with EF, causing licence of the drug. Consequently, adding an oral medication
reduced absorption of the medication or nutrients, or tube directly into the EF is generally discouraged in favour of
blockage. Factors contributing to DNI have been compre- direct enteral bolus or via the EFT after consultation with the
hensively listed by Rollins in Table 5 [43]. The clinical con- pharmacist.
sequences of an interaction are related to alterations in the DNI in patients on EN can be avoided or minimised by
disposition and effect of the drug or nutrient and can include the following: avoid mixing drug and the EF formula, change
nutritional deficiencies, drug toxicity or loss of therapeutic the route of administration, change the drug dosage form to
efficacy. a therapeutic equivalent, change the EN formula, use mini-
Typical DNI usually occur during absorption in the gas- mum drug dose, dilute the drug and flush EFT before and
trointestinal tract. For example, there is a reduction in after dosing. Liquid solutions or liquid suspensions of drugs
absorption of phenytoin when an EF is being administered at are preferred and can be administered directly via the
the same time. Hence, adjustments to the timing of feeds and EFT. Tablets or capsules, need to be either crushed and dis-
phenytoin administration are needed, whereby the EF is solved, or opened and dissolved in water before administer-
stopped for 2 h before administration of intravenous phenyt- ing through the EFT. When administering medication via the
oin; and plasma levels of phenytoin need to be monitored EFT, it is advisable to flush with 20–30 mL of water before
routinely [43]. Additionally, protein deficiency decreases and after the medication is administered. If adding more than
absorption of vitamin A, dietary fat decreases calcium one drug, flush the EFT with 10 mL of water between the
absorption, copper and zinc supplements inhibit iron absorp- different medications. Mixing drugs together and adding
medications directly into the EF is generally discouraged in
favour of direct enteral bolus. Modified or extended release
Table 5 Factors contributing to drug-nutrient interactions (adapted tablets, enteric coated tablets or capsules, cytotoxics, and
from [43])
hormones should not be administered as the pharmacoki-
Administration Tube characteristics size, length, material
netic properties (bioavailability, distribution, metabolism,
related
Regimen Continuous, cyclic, intermittent or bolus excretion) of the medication may be significantly altered.
Flushing fluid (e.g. water) frequency and The US Pharmacopoeia [44] contains release characteris-
volume tics of drug dosage forms and data on DNI with EF or
Site of feeding Gastric, duodenal or jejunal EFT. The BPNG Handbook of Drug Administration via
Medication Tablet, capsule, solution, elixir (contains Enteral Feeding Tubes provides legal, practical and technical
alcohol), syrup (contains sugar), suspension
Osmolality and viscosity of liquids
aspects that clinicians should consider for safe and effective
Excipients: sorbitol, alcohol, stabilizers prescribing and administration of drugs via EFT [45].
Absorptive Acid, base, hydrophilic or lipophilic Whenever possible a licensed formulation should be used but
environment the individual drug monographs in the book provide guid-
Therapeutic index Important if narrow ance on alternative medications when appropriate.
Formula Protein content - intact, hydrolysed, caseinate, Nevertheless, it must be remembered that administering a
isolated milk protein, soy, whey
Components affecting GI motility: lipid
crushed or opened oral drug or an intravenous drug via an
content, osmolality, viscosity EFT usually falls outside the drugs product licence. There
Vit K content could be a risk of inaccuracies in dosing, tube blockage or an
Disease related Visceral protein and GI motility/digestive adverse patient reaction—in which case the drug manufac-
factors enzymes and mucosal absorption turer is no longer accountable, but the responsible health pro-
fessional could be liable for any adverse reaction experienced directly related to the type and number of manipulations of
by their patient. The ASPEN Enteral Nutrition Handbook [1] the system and the use (or non-use) of aseptic techniques
contains the latest recommendations on safe practices and [54]. Nurses often do not wash their hands before handling
new information on preparation, labelling, and dispensing of EN systems but micro-organisms detected in patient’s feeds
EN. It provides a step-by-step, practical guide to caring for can be transferred from nurses’ hands or from patients them-
patients receiving EN therapy. The ASPEN website [46] also selves [55, 56]. Typical organisms isolated from EF include
has useful references including updates on the ASPEN the skin contaminants Staph. epidermidis and Gram-negative
ENFit® project to standardise enteral connections in accor- bacilli. Retrograde spread of organisms from the patient, via
dance with the ISO standards [47]. The US FDA is in the the giving set, to the EN container have been reported [57].
process of developing guidance for the pharmaceutical Microbiological contamination of EFT may be due to the
industry on oral drug products for ETF. The draft guidance, practice of flushing the tube with tap water [58]. The practice
which is out for public consultation, will cover in vitro test- of flushing and rinsing giving sets when changing EN con-
ing and labelling recommendations for manufacturers to tainers is common in the USA, but rinsing may be unneces-
ensure oral drug quality and bioequivalence when evaluating sary if the sets are changed at least every 24 h [59].
a drug’s suitability for administration via an EFT [48]. Historically, hang-time for paediatric formulas has been only
Administration of drugs via an EFT has implications for 4 h, but by using sterile closed EN systems hang times may
all members of the multidisciplinary NST. In particular, the be extended up to 24 h [49].
pharmacist has several responsibilities to ensure the correct Several policies and procedures intended to minimize EN
drug formulation is prescribed and that clinical colleagues contamination have been published in USA and Europe [48].
are aware of the legal implications of using an unlicensed Anderton et al. [60] published guidance notes for the British
drug. Rational drug or nutrition therapy requires clinical Dietetic Association and recommended that at no time should
management based on accurate interpretation of symptoms, any internal part of the nutrient container or giving set be
correct diagnosis and sufficient knowledge about drugs to allowed to come into contact with hands, clothes or sur-
select the right medicine and administer it in the right dose rounding surfaces. Contamination is more likely in patients
for the optimum length of time by the most appropriate route. on an ICU if EF are reconstituted or diluted with non-
More comprehensive education on DNI in EN will enable pasteurized water rather than with sterile water.
health care providers to better manage their patient’s clinical Contamination of a EF may not be clinically relevant unless
outcome. a patient is immuno-suppressed, is taking drugs to inhibit
gastric acid production, is being fed directly into the small
bowel or if there is an enteropathic organism in the feed. As
Feed Contamination such patients may not be immediately identified, it is there-
fore recommended that EFs are always prepared and admin-
Safety must be a primary focus for the preparation and istered using aseptic technique.
administration of an EF. According to the ASPEN Safe
Practices for Enteral Nutrition Therapy Task Force [49]
before any drug is considered for administration via an EFT, ther Feeding Options That Need
O
the pharmacist should be consulted, who can ensure that Microbiological Monitoring
national equivalents of OSHA and NIOSH [50, 51] are com-
plied with for the use of hazardous drugs in hospital settings. Blenderised food is becoming increasingly popular with
Additionally, the patient should be assessed to determine HEN patients. It involves administering liquidised or pureed
whether they can tolerate and manage oral administration of table food vi an EFT. There may be physiological benefits
the prescribed licensed medication. Detailed practice recom- such as improvement in symptoms of vomiting, reflux and
mendations have been compiled by ASPEN [49]. abnormal bowel habits for some tube-fed individuals.
Microbial contamination of EF can occur during prepara- Additionally, the parents and carers of some tube-fed chil-
tion, decanting and assembly of mixed or ready-to-use prod- dren report social and emotional benefits. Nevertheless, this
ucts, or more commonly during the subsequent manipulation mode of EN has been met with caution, by some profession-
of the feeding system and might be a source of nosocomial als who consider there could be increased risks of nutrient
infection [52, 53]. It has been assumed that micro-organisms deficiencies, blockage of EFT or infection, in comparison to
present in a feed administered into the gut (especially the commercial EF. The UK BDA has produced a position state-
stomach), will be destroyed by gastric acid and digestive ment designed to inform dietitians and ensure effective,
enzymes, in the same way as food. Hence, infection control evidence-based patient care [61].
procedures have remained less stringent for EN than those Chyme reinfusion (CR) into the distal gut is known to
for PN. However, the risk and magnitude of contamination is improve nutritional status of patients with high output enter-
ostomies but use has been limited by complicated equip- 15. Arabi YM, et al. Permissive underfeeding or standard
enteral feeding in critically ill adults. N Engl J Med.
ment, safety concerns and low patient acceptance. However,
2015;372(25):2398–408.
recent clinical experiences in Europe and Australasia [62] 16. Casaer M, Van den Berghe G. Permissive underfeeding of
have demonstrated that the procedure can be microbiologi- standard enteral feeding in critically ill adults. N Engl J Med.
cally safe, reduce dependency on PN and improve gut reha- 2015;18(2015):1.
17. Blaser AR, et al. Gastrointestinal function in intensive care patients:
bilitation before surgery (chapter “Distal Feeding and
terminology, definitions and management. Recommendations of
Hydration”). the ESICM working group on abdominal problems. Intensive Care
It is important for a multidisciplinary NST, ideally com- Med. 2012;38(3):384–94.
prising a physician, dietitian, pharmacist, nurse and a micro- 18. Wen Z, et al. Is discard better than return gastric residual aspi-
rates: a systematic review and metaanalysis. BMC Gastroenterol.
biologist, to have an ongoing quality assurance programme
2019;19:113.
for EN and PN. The team approach to quality assurance with 19. Randall RJHT, Caldwell MD. In: Randall RJHT, Caldwell MD,
the key participation of the pharmacist and/or microbiologist editors. The history of enteral nutrition, in clinical nutrition: enteral
has been previously advocated by Anderton, [63] who pro- and tube feeding. Philadelphia: WB Saunders; 1990.
20. Hunter J. A case of paralysis of the muscles of deglutition cured by
posed an adaptation of the food industry’s Hazard Analysis
an artificial mode of conveying food and medicines into the stom-
Critical Control Point (HACCP) system for the preparation ach. Trans Soc Imp Med Chir Know. 1793;1:182–8.
and administration of EF that has been successfully employed 21. British Specialist Nutrition Nutrition Association Medical Nutrition
over the years [64]. Industry Code of Conduct. 2020.
22. Randall HT. Sixth annual Jonathan E. Rhoads lecture. Enteral
nutrition: tube feeding in acute and chronic illness. JPEN J Parenter
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Access for Parenteral Support
Arun Abraham, Geert Wanten, and Jeremy M.D. Nightingale

1. Assessment prior to the insertion of a central feeding
catheter consists of examining for evidence of previous Venous access is essential for providing parenteral support
venous thrombosis or its predisposing factors (dehydra- (PS) (nutrition and/or fluids and electrolytes) to patients with
tion and sepsis). Intestinal Failure (IF). PS is required when the gut is not
2. Reviewing current medication including anti-coagulants. functioning, is functioning insufficiently, is being left to
3. The choice of catheter is influenced by the underlying ‘rest’ or if enteral nutrition is unsuccessful [1]. Successful
diagnosis for Intestinal Failure (IF), predicted duration of outcomes for the management of PS venous catheters relate
parenteral support (PS), the frequency and composition not only to obtaining venous access but more importantly to
of the PS mixture, intravenous medication needed, the the skilled after care of the catheters provided initially by
person who will be setting up the infusion, the patient and nursing staff (chapter “Nursing Care of Patients Receiving
IF team preference. Home Parenteral Support”). This chapter provides a practi-
4. A catheter needed for long-term home PS is usually tun- cal guide about central and peripheral feeding catheter inser-
nelled to reduce the risk of dislodgement. tion. It is helpful for all members of a nutrition support team
5. If possible ultrasound is used to help placement of all (NST)/ IF team to have an understanding of the consider-
central feeding catheters commonly into the jugular or ations made in obtaining and maintaining venous access.
subclavian veins.
6. The routes for parenteral nutrition can be described
according to the position of the catheter tip as large, Indication of PN
medium or small vein feeding.
7. A central vein catheter tip needs to be at the atrial/caval The most common indication for intravenous nutrition support
junction. If more proximal the risk of thrombosis is short term reversible (type I) IF during the peri-operative
increases. phase, however the duration of nutritional support is widely
8. An arteriovenous fistula is an effective way to give paren- variable from a few days in the initial post-operative days
teral support and should be considered if many catheter- when an ileus may occur, to a several weeks for those who are
related blood stream infections (CRBSI) have occurred. severely malnourished due to underlying disease or requiring
gut rest. Some of these patients may progress to having
medium term reversible (type II) intestinal failure depending
upon the severity of the underlying disease. In some cases,
patients with an abdominal catastrophe need long-term (type
A. Abraham (*)
III) IF as a consequence of an extensive bowel resection usu-
Salford Royal Hospital, Manchester, UK
e-mail: [email protected] ally due to a disease process or ischaemia.
G. Wanten
Treasurer Dutch Registry for Intestinal Failure and Transplantation,
Intestinal Failure Unit, Department of Gastroenterology and Preserving Venous Access
Hepatology, Radboud University Medical Center,
Nijmegen, The Netherlands
Preservation of venous access is important both for fluid/
J. M.D. Nightingale nutrition delivery and medication administration. An intrave-
nous catheter may need to be changed due to a catheter-

524 A. Abraham et al.
related blood stream infection (CRBSI), venous thrombosis cause a high osmolality which in theory could lead to irrita-
or due failure of the device. An underlying pro-thrombotic tion of the vein’s endothelium and so predispose to thrombo-
condition (e.g. inflammation, dehydration or a coagulopa- sis but surprisingly this has not been shown in one study [3].
thy) that will contribute to a hypercoagulable state and thus The amino acids used in parenteral nutrition may have a low
venous thrombosis should be detected and managed. pH and can affect the final pH of the admixture and this may
Dehydration which is often due to fluid losses and/ or poor increase the risk of thromboembolism. Therefore on theo-
compliance with the oral must be avoided as in addition to retical grounds parenteral nutrition, especially if long-term
predisposing to venous thrombosis makes venous detection and of high osmolality (greater than 600 mOsmol/kg), and/or
more difficult [2]. Medication (e.g. cyclizine) inserted into a with low pH may be best delivered into the circulation at a
PS catheter can cause damage and an increased the risk of point of maximal dilution (e.g. the vena cava/atrial
occlusion. Venous thrombosis is often irreversible and there- junction).
fore contributes to a loss of venous access. Thrombosis of
more than two major veins is an indication for discussion
about an isolated small bowel transplant (chapter “Intestinal Central and Peripheral Vein Nutrition
Transplantation”). Preserving access is very relevant to a
small number of long-term (type III) IF patients who may The routes for parenteral nutrition can be described accord-
require renal replacement therapy. ing to the position of the catheter tip as large, medium or
small vein feeding (Table 1, Fig. 1). Previous descriptions
have addressed the site of catheter insertion as either central
PN Composition
Table 1 Parenteral nutrition routes
The lower osmolality of some formulations of parenteral Type of
nutrition may be compatible with a short term peripheral Catheter tip Venous insertion site nutrition
infusion (small vein), however there are limitations with Large vein Subclavian/jugular/cephalic vein Central
many of these formulations as they do not meet the higher Brachial vein in cubital fossa Central
(PICC)
energy/volume requirements needed by some patients (lower Medium Brachial vein in cubital fossa Peripheral
volume and glucose content). Some of the components of vein
parenteral nutrition (especially glucose and electrolytes) can Small vein Vein on back of hand Peripheral
Fig. 1 Schematic venous

anatomy and sites for large
and medium vein cannulation
for the administration of
parenteral nutrition
Access for Parenteral Support 525
or peripheral. This may lead to confusion as peripheral nutri- size and the silver acts as an antimicrobial [13]. Antimicrobial
tion may be given through a short cannula with its insertion catheters are not routinely used in current practice due to
site and tip in a small vein (e.g. on the back of the hand or on limited difference in outcome [14, 15].
the forearm), or via a catheter inserted into the basilic vein A central catheter internal diameter is variable but usually
with its tip in the axillary vein. 6.6–9.6 FG and a PICC is 2–6 FG. To avoid thrombosis the
Nomenclature is most clear when both insertion site and catheter vein ratio should be 45% or less [16, 17].
catheter tip position are named (e.g. with peripherally
inserted central catheters (PICCs)). PICCs are long small
diameter catheters inserted into the basilic vein in the cubital Choice of Catheter
fossa with their tip at the superior vena caval (SVC)/right
atrial (RA) junction. The choice of catheter is influenced by the underlying diag-
nosis for IF, predicted duration of PS, the frequency and com-
position of the PS mixture, intravenous medication needed,
Catheter Materials (Types and Size) the person who will be setting up the infusion, the patient and
IF team preference. In acute IF the choice of catheter for
The ideal catheter material is flexible, strong, chemically patient care may be different to that of patients requiring a
inert, non-thrombogenic, radio-opaque and does not kink. It catheter for PS at home. At the onset of IF after an abdominal
should have a measurement scale on its side. The wall of the catastrophe, due to their physiological and metabolic instabil-
vein may be damaged by pressure, if the catheter material is ity, a patient often requires access for multiple therapies. The
relatively inflexible, and this can lead to thrombosis [4]. onset may be more insidious when IF is limited to an episode
Small diameter flexible catheters that effectively float in the of illness that fails to resolve or when there is a decline in gut
bloodstream are less likely to cause injury. function on a background of chronic illness. The dependence
The chemical composition of a catheter has not changed and on intravenous support may changes after surgery that either
remains an important factor in causing thrombophlebitis of resects bowel or brings more into continuity.
peripheral veins. Most plastics contain additives that may pro- The Bard Groshong valve is a three-way valve incorpo-
duce a chemical phlebitis. Rubber, polyethylene, polyvinylchlo- rated into the tip of a large-vein catheter which, in the absence
ride, Teflon® and uncoated polyurethane are all thrombogenic of a negative or positive pressure, remains in the closed posi-
[4–8]. For parenteral nutrition either a polyurethane-hydromer tion. It opens inward when negative pressure is applied for
or silicone elastomer (also called silicone rubber or silastic) aspiration and outward with positive pressure used for infu-
catheter is used because they are biologically relatively inert. sion. It should prevent blood from the venous circulation
When compared, thrombophlebitis occurred less frequently entering the lumen, so making catheter occlusion less com-
with a polyurethane-hydromer coated catheter [9–11]. mon, and should reduce the risk of air entering the catheter.
The coating of a polyurethane-hydromer catheter con- While generally performing well, [18] they were no better
tains a hydrophobic polymer made from polyvinylpyrrol- than Hickman-type lines in terms of CRBSI or thrombosis
idone and anisocyanate prepolymer. When a hydromer-coated formation, and they malfunctioned more frequently [19].
catheter is wetted, water is absorbed onto the coating and the For long-term home PN a tunnelled catheter is preferred
resulting gel acts as a barrier between the blood and the cath- as the risk of dislodgement after 2 weeks is minimal (Fig. 2)
eter material so that platelets do not adhere to it. This gives [20].
the practical advantage that when wetted by body fluids (e.g.
blood) the catheter becomes slippery, which makes the pas-
sage of the catheter through a peripheral vein relatively easy Peripherally Inserted Central Catheter
and so less likely to cause trauma to the vein. It also has the
advantage of being physically stronger than a silicone elasto- In patients with acute IF, a multiple lumen peripherally
mer catheter, allowing its external diameter to be reduced; in inserted central catheter (PICC) may be considered initially
addition, it does not easily kink. Thus polyurethane-hydromer and then later changed to a tunnelled catheter if long-term
catheters are used when the insertion site is a medium or home PN is appropriate. As they are relatively easy to insert
small vein. Silicone elastomer catheters, which are soft and and remove, there is a growing tendency to use a PICC to
flexible, are commonly used for long-term central vein feed- deliver HPN for a short time (e.g. less than 3–6 months).
ing where they can last for 10 years without problems. However, they remain less ideal for long-term parenteral
Some catheters have an antimicrobial (e.g. minocycline) feeding due to the risk of dislodgement of the catheter as
incorporated into the material [12]. Other catheters have an there is no cuff to anchor the catheter to soft tissues. The exit
extra cuff (VitaCuff®) containing collagen impregnated with site position on the arm restricts normal arm movement mak-
silver ions; the collagen cuff swells to 2–3 times its original ing daily living activities difficult and almost impossible if
Fig. 2 Types of catheter for

a b
long-term PS. (a) Cuffed
single lumen feeding catheter
for long-term use with
insertion needle attached. (b)
Implantable port for
long-term feeding (or
medication) with external
insertion needle attached
the patient is doing the procedures themselves. There is an Table 2 Key features included in the WHO surgical checklist [26]
increased incidence of thrombosis when a larger diameter Confirmation of patient, surgical site
PICC is used and if there is an underlying malignancy [21]. Comorbidities and medications identified (anticoagulation)
In other countries such as Canada there is an established Allergies specified
practice in using PICC for HPN [22]. They are not suitable Sedation and local anaesthetic identified
for patients who use crutches or a wheelchair. Infection precautions
Equipment (instruments/ultra sound/X ray compatible table)
confirmed
Post procedure care identified
Implanted Subcutaneous Port
An implanted subcutaneous port is used by some centres for long-term catheter). He/she will then mark at least two
HPN [23]. The first fully implantable venous access device or appropriate sites with permanent ink that will not come off
reservoir device (port) appeared in 1982 [24]. Since that time when the skin is cleaned.
they have gained in popularity and are now used widely and
have few complications [25]. They consist of a vascular cathe-
ter attached to a subcutaneous port. The port segment is a cone- Place for Procedure
shaped chamber made of stainless steel, titanium or plastic
covered with a self-sealing compressed silicone septum that Ideally a large vein feeding catheter is inserted in the radi-
can be punctured up to 2000 times by a non-coring needle. ology department using ultrasound and fluoroscopy.
Ports are available in single or dual lumen configurations with Long-term tunnelled catheters (e.g. a Hickman type cath-
a pre-attached or attachable silicone rubber or polyurethane eter or implanted port) are most commonly inserted.
catheter. The advantage of an implantable port over other cath- Fluoroscopy is useful to ensure the tip of the catheter is at
eters is the cosmetic appearance as it is concealed under the the cavo-atrial junction at the time of placement.
skin and therefore would be an ideal solution for those who Placement of a catheter with the help of fluoroscopy or in
prefer the appearance, do not require frequent infusions or wish interventional radiology should especially be considered
to swim. However, if patients require daily infusions the advan- to assess and navigate venous anatomy if changed by
tage of concealed lumen is lost when the Huber needle is left in thrombosis or if there have been several catheter
situ for 5–7 days a week. Daily puncture of the skin overlying placements.
the port can lead to ulceration and imflammation of the skin
over time. Port site infections can easily lead to CRBSI; salvag-
ing a port when infected is difficult partly due to the reservoir WHO Surgical Safety Checklist
and they usually have to be completely replaced [23].
For any invasive procedure it is recommended to have a
checklist to decrease errors or misadventure and a version
Preparation of the WHO surgical safety checklist is most commonly
used [26]. All members of team are present for the WHO
Marking of Catheter Exit Site check list to appraise patient factors and discuss any issues
anticipated for the procedure. The key features within the
The nutrition nurse specialist will discuss with the patient the sign in, time out and sign out headings are listed below
possible sites for the catheter to exit the skin (especially if a (Table 2) [26].
Venous Anatomy Assessment out transillumination, can be used. For deeper veins NIR can
be combined with ultrasound imaging (photoacoustic imag-
Multiple visible veins on the chest are suggestive of collater- ing). There are smartphone apps being developed that pro-
als (Fig. 3) and should raise concerns about chronic occlu- vide an NIR function.
sion. A large dilated internal jugular vein seen on ultrasound
should raise concern about occlusion of central large veins.
Patients who have had multiple central venous catheters, Equipment
prolonged intensive care stay, multiple episodes of sepsis, or
an indwelling catheter for a few years, or have a thrombo- Ultrasound
philia disorder, or are transitioning from paediatric to adult Ultrasound has changed the practice of insertion of central
services are at risk of compromised vascular access. Their venous catheters with a significant decrease in incidence of
venous anatomy may be assessed with the help of a CT (or complications [28]. A linear probe with high frequency is
MRI) venogram. There should always be a high index of sus- used. The probe is placed in a horizontal as well as longitu-
picion for a venous thrombosis; however assessment of dinal plane to assess the anatomy (Fig. 4a, b). When the
venous anatomy for a long term HPS patient is undertaken probe is placed in horizontal plane the vascular structures
only when there is a clinical concern. A comprehensive appear circular, whereas when the probe is placed in a longi-
review of venous anatomy is important prior to undertaking tudinal plane it appears as tubular. Veins are collapsible and
a placement of a new catheter for an existing HPN patient. It therefore can be compressed when pressure is applied.
is also useful to have upper limb venograms in high risk Arteries may be compressed; however there is a distinct pul-
patients prior to placement of PICC. satile appearance to them. Further confirmation is possible
with help of Doppler. The blue colour on Doppler (blood
New Methods flowing away from the probe) identifies the veins. Red colour
For non-invasive venous imaging there are developing tech- on Doppler identifies the artery with blood flow in the oppo-
niques that use the property of haemoglobin (concentration site direction. If the veins are not collapsible with absence of
and oxygenation) as a strong absorber of visible and near- flow (there is no colour on Doppler) a thrombus must be con-
infrared (NIR) light (650 and 950 nm) to show the size and sidered (Fig. 5).
site of veins. For visualising superficial veins (e.g. for venous The ultrasound setting should be confirmed to avoid auto-
cannulation/PICC insertion) NIR imaging [27], with or with- matic time out.
Fig. 3 Collaterals on the

a b
upper chest wall due to
previous superior vena caval
thrombosis. (a) Difficult to
see and (b) very obvious
a b
Fig. 4 (a) Picture of neck showing position of the internal jugular vein (IJV) (SCM sternocleidomastoid muscle). (b) Ultrasound of IJV showing
size of vein horizontally (CC common carotid artery) and (c) longitudinally
Fig. 5 (a) The direction of a b

flow red towards the probe
and blue away. (b) Thrombus
in IJV (internal jugular vein)
and common carotid artery
(CC) posteriorly
Local Anaesthetics/Sedation
Most of the tunnelled CVCs can be inserted under local check. The skin is cleaned with Chlorhexidine in alcohol
anaesthetic. A volume of 15–20 ml of 1% lidocaine is solution [30–33] and allowed to dry. The site is kept sterile
required particularly for the tunnel. Local anaesthetic vol- by applying sterile drapes exposing the lateral side of neck
ume can be increased if 0.25% levobupivacaine hydrochlo- as well as the exit site. Head drapes are useful to cover hair
ride (Chirocaine®) is used however it is preferred not to use and head to maintain a sterile field. The surgical drapes
local anaesthetic with adrenaline. The syringes used for local must be adjusted on side of the face to avoid covering
anaesthetic should be clearly labelled to avoid the error of patients face completely as this would cause anxiety for
accidental flushing of catheter with local anaesthetic. Some patients. The introducer needle is primed with 10 ml
patients would prefer to have the procedure done under seda- syringe with approx. 5 ml of saline in the syringe. It is
tion or general anaesthetic due to discomfort or anxiety. important to ensure there are no air bubbles in the syringe
General anaesthetic would be essential if a patient cannot lie to help assess if there has been a puncture of lung during
still. Prophylactic antibiotics are not routinely administered. the procedure.
onsent and Exit Site

C
Patient is consented and the exit site marked. Discussion with Internal Jugular Veins
patient about exit site is important as the catheter can be insitu
for a significant period, therefore patient preference should be When internal jugular veins (IJV) are used, the point of entry
considered with regards to clothing and ability to care for the of catheter should be as low as possible into the root of the
catheter. The exit site should be away from the crease of axilla neck. If the point of entry is higher in the neck this would
as the skin flora from axilla are different from those on the lead to an acute angulation of catheter when the catheter is
chest wall [29]. Males patients should have their chest hair tunnelled under the skin which can lead to occlusions of
trimmed. If the femoral vein is used the exit site may be catheter in the future. A catheter placed as low as possible in
marked on the lower abdomen or thigh. If a patient is very IJV will curve anterior to the clavicle forming an arch when
confused and at risk of pulling the catheter, it can be tunnelled tunnelled under the skin which is apparent in a lateral view
onto the back between the scapulae. chest X-ray.
IJV’s are commonly used to support acute care and a
Position quad lumen central venous catheter (CVC) may be in situ
The patient is placed in supine position with table tilted with as the patient recovers and requires support for long term
slight head down. The table should be compatible with X-ray parenteral nutrition. A tunnelled CVC may be placed in the
fluoroscopy. Patient may be monitored with an ECG tracing, as opposite side or the same side if the quad lumen CVC is
well as pulse oximetry. ECG monitoring is useful to detect early placed in a more cranial position. The placement of two
arrhythmias caused by the guide wire (if placed into the heart). catheters in the same vein for a prolonged period of time
can compromise flow in the vein which can lead to throm-
bosis, [17, 34] and if one catheter becomes infected, there
I nsertion of Large Vein Central Venous is a risk of it infecting the other. It is often less difficult to
Catheter pass the guidewire from the right side than the left. There
is some suggestion that the right side has lower risk of
The operator assess venous anatomy to confirm the site of thrombosis than the left, possibly due to the catheter being
insertion and then washes hands with surgical scrub, puts angulated at the junction of the SVC and brachiochephalic
on sterile gown, gloves and completes the instrument vein [35].
Subclavian Vein Femoral Vein
Subclavian veins (SC) have always been considered as the Non tunnelled CVC’s placed in a femoral vein are considered
vein of choice for PN [36]. as the catheter exit site is not to have very high risk of CRBSI. However, for tunnelled
obviously visible, is relatively easy to tunnel from the CVC’s, there is very little difference in rate of CRBSI between
insertion site and was thought to have a lower incidence of the femoral and other sites [37–39]. The catheter can be tun-
CRBSI. However the introduction of ultrasound reduced nelled on to the antero-lateral part of thigh or onto the lower
the risk of insertion related complications (pneumotho- abdominal wall taking care to avoid any large collaterals that
rax/haemopneumothorax and arterial puncture) [28]. As it may have appeared due to a supra-cardiac thrombosis. The risk
was technically more difficult, with ultrasound, to find of a more distal thrombosis with a tunnelled femoral CVC is
and cannulate the subclavian vein there has been a move unknown, partly because most patients needing a femoral cath-
towards the preferred first insertion site being the internal eter have had a thrombosis and are already anticoagulated.
jugular vein. There is very little difference in the risk of
CRBSI from whichever vein a tunnelled CVC is inserted
[37]. However, many patients would prefer to have a cath- ardiac and Transhepatic Insertion of a Central
C
eter in the SC for cosmetic reasons as the catheter is not Catheter
visible over the clavicle (Fig. 6). Rarely a SC catheter
may be compressed between the first rib and clavicle Rarely all major veins are thrombosed and it is necessary for
(pinch off syndrome). the cardiothoracic surgeons to insert a feeding line through a
Fig. 6 A recently places (a)

internal jugular and (b) a b
subclavian long-term
Hickman type feeding
catheter. Note the visible
catheter in its tunnel above
the clavicle in the jugular
insertion
right anterior thoracotomy and through the right atrial append- (Box 2) or surgically using the cephalic vein (Box 3) and
age into the right atrium [40, 41]. A catheter may be inserted the insertion of an implantable port (Box 4). ECG guid-
radiologically through the liver and into the inferior vena cava. ance (especially if from an electrode at the tip of the cath-
This technique has mainly been reported in children [42]. eter) has helped in knowing when the tip of a catheter is
within the right atrium. A catheter tip in the right atrium
near the sino-atrial node may cause an atrial tachycardia
Large Vein Catheter Insertion (often when feed is given) [43]. In most care settings a
catheter is placed with radiological screening and the use
Boxes 1–4 show the detail about inserting a catheter into a of ultrasound guidance. In the rare circumstances when
large vein: using ultrasound/radiology (Box 1), directly this is not possible bedside placement may be performed
into the subclavian vein without ultrasound/radiology (Box 2).
Box 1. Ultrasound Aided Cannulation of a Large Vein ing. The needle is removed, and ECG tracing is
1. A sterile probe cover is used to cover the ultrasound checked to ensure the rhythm is unchanged and the
transducer. Venous anatomy is confirmed by composition of the guide wire is confirmed with
pressing the vein. The trajectory of insertion needle fluoroscopy.
noted, and skin marked for local anaesthetic. Local 3. The guide wire is secured, and the skin is incised at
anaesthetic is checked and administered about a the site of cannulation by 0.5 cm. It is good practice
1 cm under the skin raising the level of the skin to have the full length of the needle under direct
with some blanching. When infiltrating local anaes- view. This is possible when the needle is introduced
thetic care must be taken to avoid any small air along the longitudinal plane. However, in some
bubbles which can cause the images to be compro- anatomical locations a horizontal plane is more
mised. The ultrasound probe is used to familiarise suitable, in such circumstances when the needle is
the operator with the anatomy. introduced along the horizontal plane it is impor-
2. The introducer needle is used to pierce the skin tant to ensure the tip of the needle is always under
under direct vision. The linear probe is placed hori- direct view. It is not possible to have the full length
zontally across the vein and needle is positioned at of the needle under direct view when introduced
the midpoint of the linear probe (usually marked on along the horizontal plane and therefore there is a
the probe). This allows a clear view of the posterior greater risk of piercing the posterior wall of the
wall and surrounding structures. There are many vein due to difficulty in assessing the tip of the nee-
methods used for cannulation with ultrasound. dle. The images seen in horizontal plane can easily
Most commonly used is the “crepe” method where led to error in confirming the tip of the needle and
needle is placed at a small angle to the probe and therefore the probe must be adjusted regularly to
advanced under direct vision. The probe is tilted as confirm the tip of the needle by identifying the
the needle is advanced to ensure the tip of the nee- absence of the needle (Fig. 8).
dle is always in view (Fig. 7). It is important to 4. The dilator with a peel away sheath is now inserted
assess the tip of the needle constantly in relation to over the guidewire using a Seldinger technique.
the vein. In patients who are underfilled or in older When inserting the dilator resistance is felt at the
patients with tougher venous wall the introducer site of cannulation. The dilator is advanced firmly
needle may not cannulate the vein despite complete with constant pressure, after a few seconds the
indentation of the anterior wall of the vein. resistance gives way and the dilator can be pushed
Continuous firm pressure with the needle will in without any significant resistance. If excess
enable to pierce through the anterior wall of the resistance is felt ensure the skin incision is adequate
vein. Cannulation is confirmed by free flow of prior to advancing again.
venous blood into syringe on aspiration and the 5. Once the dilator is inserted and guide wire secured, a
needle is then tilted towards the skin. The syringe is subcutaneous tunnel needs to be formed. Local
disconnected keeping the needle steady and guide anaesthetic is infiltrated subcutaneously from the
wire is passed. Absence of pulsatile bleeding from exit site to the entry site (cannulation of vein) with a
the needle before insertion of guide wire is reassur- series of injections. An incision is made at the
marked exit site and the line tunnelled with help of a easier to withdraw later as long at the cuff is not
tunneller (usually a metal rod). The tunneller close (within 3 cm) of the exit site, however if the
attached to the catheter is removed via the wound in catheter is too high it cannot be pushed further
the neck and the catheter pulled through under the inwards. Patients with COPD and kyphosis may
skin. Occasionally some resistance is felt at the cla- require further adjustments to the length of the cath-
vipectoral fascia. The cuff is pulled through approxi- eter due to their distorted thoracic anatomy. The
mately halfway between the clavicle and the marked guide wire and the detachable part of the dilator is
exit site. The catheter is cut from the tuneller and removed, and the catheter is then inserted into the
placed on the chest wall and assessed for positioning vein via the “peel away” sheath. The “peel away”
and length with the help of fluoroscopy before cut- sheath is peeled apart, and catheter tip is positioned
ting the catheter to length. If the procedure is not with help of fluoroscopy.
done under fluoroscopy, measurements can be made In femoral catheter placements the tunnel may be bet-
from the manubrium to predict desired length. If the ter placed in the outer lateral aspect of thigh as
catheter is placed too far into the right atrium it is opposed to on the lower abdominal wall.
Fig. 7 Diagram to show the

different U/S views as the
needle is advanced into a
large vein. This diagram
demonstrates the tip of the Longitudinal view Tip of needle
needle at points (a) to (e) as
the probe is advanced along
the vein. The tip of the needle
should be confirmed by
absence of needle as in point
Cross sectional view a b c d e
(e)
Fig. 8 Diagram to show the

tip of the needle which has
passed through the vein and is
not in position for a guidewire
insertion. It demonstrates the
limitations of a cross sectional
U/S view in which you can
see only a small portion of the
needle and falsely gives the
impression that the tip of the
needle is in the centre of the
vein
Longitudinal view
Tip of needle
Cross sectional view

Box 2. Long-term cuffed Subclavian Catheter Placement injecting local anaesthetic, usually the subclavian
(Subclavicular Approach to Large Vein Catheterization vein will be encountered.
without Radiology Often Done at Bedside or in a Dedicated 5. The operator may change their gloves, then make
Room) a small 1 cm transverse skin incision over the site
The equipment needed is variable but includes a gown, of the intradermal local anaesthetic injection.
gloves, sterile drapes, needles, syringes, dissecting Blunt dissection may be done (closed scissors are
scissors, scalpel, suturing equipment, cleaning solu- inserted and opened) to make it easier for the
tion, local anaesthetic, a feeding line (Hickman or the introduction of a splittable introducer. Then the 18
smaller Broviac type of line), tunneller, split intro- gauge needle from the catheterization pack is con-
ducer, Seldinger wire and needle. nected to a 10–20 ml syringe (some fill this with
1. Patient lies supine, ideally with the head and saline) and advanced in the same way as for the
shoulders positioned lower than the body (some local anaesthetic, with gentle suction being applied
put a small sandbag or rolled pillow between the from the syringe until there is a good flashback of
shoulders). The operator selects the right or left venous blood into the syringe indicating that the
subclavian vein. There is a tendency to choose the vein has been entered. Holding the needle still, the
right as there is less risk of damaging the thoracic syringe is removed and the soft end of the guide-
duct and thus of causing a chylothorax. The side wire is pushed gently down the needle for a dis-
furthest away from any abdominal stomas or fistu- tance of about 30 cm. Hardly any pressure is put
lae is chosen. If the right subclavian vein is on the guidewire. Keeping the guidewire in posi-
selected, the following anatomical landmarks are tion, the needle is withdrawn.
noted: the tip of the left shoulder, supra sternal 6. While the guidewire is left in position and covered
notch, the junction of the lateral one-third and lightly with a piece of sterile gauze, the subcutane-
middle two-thirds of the right clavicle, the site of ous tunnel is made. The tunnel is usually about
the right internal jugular vein and carotid artery. 15 cm long, the exit site is chosen to be approxi-
2. The operator ‘scrubs up’, puts on a sterile gown mately midway between the mid point of the ster-
and gloves, then checks the equipment on the num and the nipple position of a man. The exit site
operating trolley. should be on a flat area of chest, well away from
3. The operator cleans the chosen site with a the moist warm potentially bacteria prone axilla.
chlorhexidine in spirit solution. Sterile drapes are Skin creases should be avoided. This aids security
put over the patient’s hair and round approximate and comfort by making the catheter easier to
30 cm2 of skin, which leaves all anatomical land- anchor, and it reduces the chance of bacterial
marks visible except the left shoulder tip, which infection. Local anaesthetic is inserted at the exit
can be felt. site and along the line of the tunnel with 3–4 injec-
4. Once the skin is dry, a local anaesthetic (ligno- tions. A small 1 cm vertical incision is made at the
caine 1%) is injected intradermally about 1–2 cm exit site. Blunt dissection is performed by opening
below the junction of the lateral one-third and and closing surgical scissors in the line of the tun-
medial two-thirds of the clavicle. An assistant then nel for a distance of about 7 cm from the exit site.
holds the patient’s right hand and pulls gently The tunnel is created by pushing, with a rotating
down towards the patient’s feet. The patient turns action, either a hollow plastic tube into the exit site
their head away from the operator and the head of and up towards the entry site or attaching the feed-
the operating table is lowered. The needle is ing catheter to a sharp-ended metal tunnelling rod
changed to a longer one, reintroduced and passed and pushing this up. Some blunt dissection is usu-
under the clavicle, then it is redirected aiming to ally needed to get the tunnelling instrument out of
pass both under the sternal notch and at the left the entry site. Care should also be taken to main-
shoulder tip for a distance of about 5 cm. The tain a superficial approach so that the Dacron® cuff
syringe aspirates every few millimetres before will easily be felt below the skin. A single pass
may reduce the chances of the patient developing 13. One stitch is put over the insertion and exit site.
a haematoma, infection or pain. The long threads from the exit site are tied round
7. The catheter may be primed with either saline or the catheter to help prevent it from being pulled
heparinized saline, reducing the risk of air enter- out. The entry and exit sites may be sprayed
ing the venous circulation. The catheter is posi- with povidoneiodine. Adhesive sterile gauze
tioned in the tunnel either by putting it into the dressings are placed over the cannulation and
hollow plastic tunneller or it is pulled behind a exit sites (Fig. 2). The catheter is curled round
metal rod. The dacron cuff is positioned halfway or over the dressing and taped to prevent
up the tunnel. It must not be at the exit site as cuffs traction.
situated adjacent to the exit site readily become 14. The patient is advised to stay in bed for 2–3 h for
infected, which can lead to the loss of the the effect of sedation to wear off. A postero-ante-
catheter. rior chest radiograph is taken about 3 h after the
8. The tunnelling rod is removed from the catheter, procedure to check the catheter tip position (Fig. 9)
and the length of catheter needed estimated by and to warn of a pneumothorax. If the catheter tip
lying the catheter on the chest wall in the shape of position is satisfactory then parenteral nutrition
the subclavian vein and SVC (usually about may be started.
15–20 cm of catheter will be needed). The catheter
is then cut. Care needs to be taken not to contami- Providing the catheter is mechanically stable and not
nate the catheter. infected, connective tissue will grow into the inter-
9. The rigid dilator surrounded by the splittable stices of the cuff over the following 6 weeks. Sutures
introducer are advanced over the guidewire, are removed after 2–3 weeks, but if the patient is
checking that the guidewire remains free all the receiving corticosteroids they are left in for at least
time until the wings of the splittable introducer are 5 weeks.
close to the patient’s skin. The guidewire and rigid Insertion of non-cuffed short-term feeding line.
introducer are removed leaving the splittable If a non-cuffed line is used, the tunnel may be
introducer in position. The catheter is then quickly much shorter (5–10 cm). After the subclavian vein
fed through the splittable introducer (forceps may has been cannulated, the central needle is withdrawn
be needed). If the catheter cannot immediately be leaving a plastic sheath in situ, the catheter is fed
fed into the splittable introducer the operator may quickly through this for a measured distance (marks
temporarily place their thumb over the splittable on the catheter usually make this easy). The plastic
introducer to reduce bleeding and prevent air from sheath is removed then the tunnel is made. Local
entering the venous circulation. anaesthetic is applied, but no incision made at the exit
10. The working field may be covered and the catheter site. In order to reduce the risk of piercing the cathe-
tip position checked radiologically. However, with ter with the tunnelling needle, the tunnelling needle
experience the operator can achieve a good posi- without its plastic sheath is pushed from the entry site
tion. The ideal position for the tip is the SVC/RA down the tunnel and out of the exit site. The exit site
junction. may need to be enlarged to about 2 mm. About 5 mm
11. If the position is good, the splittable introducer is of plastic sheath is then pushed gently onto the needle
slowly peeled apart as the catheter is advanced at the exit site. The tunneller needle is gently pulled
into the vein (non-toothed forceps may be needed while the plastic sheath is pushed until the plastic
to prevent the catheter coming out), until the entire sheath exits from the entry site. The tunneller needle
catheter is in place and the sheath has been com- is removed, the catheter is fed down this and the plas-
pletely split and removed. tic cannula withdrawn. The attachments are put on
12. Five millilitres of 50 units/ml heparin is instilled the end of the feeding line, which is then flushed. A
into the lumen of the catheter and the line is either plastic clip, sutured to the skin may be used to hold
capped or connected to a saline infusion. the line in position.
a b c
Fig. 9 Chest radiographs after insertion of a central venous catheter. Ideal placement of a central catheter and (c) good flow of contrast
(a) Catheter tip (arrowed) too proximal and at high risk of causing a (arrowed) shown in a well-placed central venous catheter
central vein thrombosis. It should be replaced and not used for PN. (b)
Box 3. Cephalic Vein Approach to the Subclavian Vein Box 4. Implantable Port Insertion
The cephalic vein lies in the deltopectoral groove and is After the procedure in Box 1 has been done the proce-
well placed for surgical insertion of a long-term venous dure to place a subcutaneous port begins. A subcutane-
feeding catheter. After injecting local anaesthetic, a ous pocket in made by dissecting a subcutaneous space
1–3 cm incision is made approximately 1–2 cm below over the chest wall at the marked site. After the cathe-
the lateral end of the clavicle. The cephalic vein in the ter is inserted, tunelled and the position confirmed the
clavipectoral fascia is identified and is controlled by port is connected the end of catheter and inserted into
proximal and distal ligatures. A subcutaneous tunnel is a subcutaneous pocket. The port may be anchored in
created in the same way as described in the percutane- the subcutaneous space with an absorbable suture.
ous approach, with the tunnelling rod and catheter exit- Immediately after a port has been placed, an access
ing at the subclavicular incision. The required length of needle is placed in the port and heparin is locked into
the catheter is decided and advanced into the cephalic it. This is done because swelling and inflammation will
vein via a venotomy made between the proximal and make access to the port very difficult for the next week.
distal ligatures. The tip of the catheter is located at the It is especially important to do this if the port is not
SVC/RA junction. The ligatures supporting the cathe- going to be used within the next 4 days. When the non-
ter are tied. The lumen is checked by venous aspiration coring needle is in place it must be secured safely and
and flushed with heparinized saline. The clavicular comfortably in place with a sterile gauze dressing.
incision is sutured with a subcutaneous catgut suture
first, then finally with 2–3 silk skin sutures, which are
left in for approximately a week. The exit site of the
catheter is secured using the same method as the percu-
taneous approach.
Unable to Advance Guide Wire Complications of Large Vein Cannulation
Occasionally there is difficulty in advancing the guidewire after Arterial puncture and pneumothorax were common prior
the wire has been inserted into a vein. The tip of the wire may to use of ultrasound in venous access practice. Insertion-
remain at the confluence of brachiochephalics. Manipulation of related complications are reported in 3–12% patients [46]
the wire under fluoroscopy helps to place it in the RA however (Table 3) and are less if they are inserted by a nutrition
if the wire does not fall in place with ease there should be a high team [47].
index of suspicion of an occlusion or stenosis. Ideally an on-
table venogram will help reassess the anatomy and so make
insertion easier. However if this is not possible further attempts Counter Puncture
may be made after a detailed assessment of venous anatomy
with CT or MR imaging. It is not safe to advance a dilator if the The venous wall may have resistance and not give way when
guide wire has not passed into the distal RA. advancing the needle under US guidance resulting in indent-
Venous anatomy on the right side often lies in straight line ing the anterior wall of the vein and approximating on to the
to RA and therefore placement is less complicated. Left posterior wall, predisposing to risk of counter puncture. The
sided catheter placements may require some manipulation of risk can be avoided by applying constant gentle pressure
the catheter particularly at the confluence of right and left with the needle for some time to allow the needle to pass
brachiochephalic veins when the catheter tends to flip through the anterior wall of the vein. The root of the neck has
upwards into the right brachiocephalic vein. The thoracic a neuro vascular bundle as well as the apex of the lung pres-
duct is on the left side and can be damaged during jugular/ ent. Occasionally the subclavian artery lies posterior to IJV
subclavian puncture. The left common iliac veins are often at the root of neck and can be injured by counter puncture
anatomically placed at a steep angle to IVC and hence it is without any immediate signs of bleeding. If the US guiding
easier to use the right side. probe is pressed too hard on the neck, the veins may be col-
lapsed making cannulation difficult.
ecuring the Catheter (Excluding

S
Implantable Port) Venous Wall Tear
The catheter is secured with a 2′0 prolene stitch at the exit The risk of tearing the venous wall is substantial if excessive
site. The sutures at the exit site are kept in place for about force is used with dialator, furthermore “twisting movement
6 weeks to allow the dacron cuff to completely embed in soft along with excessive force” may lead to a spiral tear of the
tissues. Some of the catheters come with a fixation device, vein which is difficult to repair [48]. To prevent this compli-
however when they are used it becomes difficult to clean cation when introducing the dilator, a firm pressure should
around the exit site. This ensures that the catheter does not be applied.
get displaced when used regularly. The entry site the neck is
closed with absorbable sutures.
Malposition
After Catheter Insertion When using a subclavian approach, the catheter can pass up
into the jugular vein, a clue to this is that the patient may
The position of the tip of the central vein catheter is crucial complain of a pain in their ear when the guidewire is
in preventing thrombophlebitis leading to endothelial injury
and a SVC thrombosis. This thrombosis may also be pro-
moted by a low pH and/or high osmolality PS infusion. Table 3 Insertion-related complications of central vein
catheterization
Therefore the tip should be ideally placed at vena cava-atrial
junction [44, 45]. This can be confirmed either by fluoros- • Counter puncture
• Venous wall tear
copy at the time of placement of catheter or by CXR after the
• Malposition (cardiac arrhythmia’s or perforation)
catheter is placed. It is worth noting that in women if the
• Arterial puncture (haemothorax or haemomediastinum)
catheter cuff is placed close to breast tissue, the tip of cathe- • Pneumothorax
ter is different when they are supine compared to that seen on • Air or catheter embolism
an erect CXR. This is due to the movement of the cuff which • Nerve injuries (brachial plexus, phrenic or recurrent laryngeal
is anchored to the soft tissue of the breast. nerve)
• Thoracic duct damage
inserted. If the procedure is done under fluoroscopy the with reduced breath sounds. An immediate post-insertion
guide wire can be positioned correctly. The catheter can chest radiograph may have been normal; hence one is usually
advance into the ventricle or pass into the opposite subcla- done about 3 h after insertion if there is concern of pneumo-
vian vein. The catheter can be redirected using radiological thorax. A small pneumothorax may be asymptomatic and
guidance or it may (especially if cuffed) need to be replaced. can be left alone, larger ones can be aspirated and only rarely
Rarely the guidewire can induce cardiac arrhythmias, if so is a formal chest drain insertion needed [49].
it is withdrawn, or cardiac perforation and tamponade have
been described. Rarely a catheter can be malpositioned in
the pleural cavity or mediastinum and this will cause a Air/Catheter Embolism
pleural or pericardial effusion respectively when the feed-
ing is started. The risk of air embolism is higher in cannulation of supra-
cardiac veins due to change thoracic pressure during breath-
ing. Care is taken to ensure a closed system is always
Artery Puncture maintained during the procedure, furthermore patient is posi-
tioned tilted head down to decrease the risk of air embolism.
There should be a high index of suspicion of arterial puncture If an air embolism is ever suspected (e.g. if the catheter sud-
if blood appears bright red when passing the guidewire in to denly becomes detached) the catheter is clamped as near to
vein. This may be misleading if patient is having a general the skin as possible and the patient is positioned on their left
anaesthetic. Arterial punctures may occur if the needle has side with their head tilted downwards. Rarely part of the cath-
gone through the posterior wall of the vein. If so, the needle is eter can break away and pass as an embolus which may get
removed, and firm pressure applied for 5 min. If the carotid or dislodged in lungs depending on the size of the fragment. An
subclavian artery is injured and the patient’s coagulation sta- attempt should be made to retrieve large fragments wedged in
tus is normal, another attempt can be made on the same side. Right atrium with help of interventional radiology. Small
After passing the guidewire repeat assessment with ultra- fragments that embolise to the lungs can be left alone but if an
sound to confirm placement of wire in the vein will help abscess develops may have to be surgically removed.
decrease the risk of arterial injury with the dilator. Blood can
collect in the pleural space (haemothorax) or mediastinum
(haemomediastinum) following subclavian arterial puncture. Nerve Injuries
If haemothorax is moderate a wide bore surgical chest drain
should be inserted to drain blood from the pleural cavity. If the introduction needle hits the brachial plexus, numbness
Injury to the common femoral artery is managed by and tingling can develop in the arm and/or specific muscles
applying direct pressure over it. Rarely the injury leads to can become weak. The exact pattern of weakness depends
retroperitoneal haematoma. upon which part of the brachial plexus has been damaged. A
The catheter entry site is observed for signs of bleeding neuropraxia can follow and may take several months to
after catheter insertion and blood pressure is monitored. If resolve. Rarely the phrenic nerve is damaged resulting in
bleeding occurs, a pressure dressing is applied over the exit diaphragmatic paralysis; the recurrent laryngeal or vagus
site and coagulation studies may be performed. nerves can also be damaged causing hoarseness.
Haematoma Thoracic Duct Damage
The needle may be dislodged if the guidewire cannot be This can occur from left subclavian vein cannulation and
inserted in to vein after an initial flash back. To avoid a rarely causes a chylothorax.
haematoma and allow a second attempt on the same side it
is better to pull the needle out and apply pressure for 5 min.
eripherally Inserted Central Catheter (PICC)
P
Insertion
Pneumothorax
As nutrient infusions into small or medium-sized veins are
If air is aspirated during cannulation of the subclavian vein associated with a high risk of thrombophlebitis, it is preferable
(or less commonly the jugular vein), a pneumothorax is to site the tip of feeding lines in a large vein. This was first
likely to develop. This is often not apparent until several reported in 1975 [50] and can be done using a long catheter
hours after the procedure when the patient complains of inserted into a medium-sized vein. A PICC is made of radio-
pleuritic chest pain and breathlessness; a physical examina- opaque silicone rubber or polyurethane-hydromer and comes
tion reveals tachypnoea, tachycardia, a hyperresonant lung with a single (4Fr) or dual lumen (5Fr). PICCs are inserted into
the basilic, median cubital or cephalic veins in the ante-cubital

fossa and the tip of the PICC terminates at the SVC/RA junc- 4. The required length of PICC line is measured pre-
tion. Their insertion can be done at the patient’s bedside by a insertion in anticipation of the final tip location.
trained nurse [51]. or at interventional radiology if there are 5. An ultrasound may be used to aid cannulation of
concerns of previous thrombosis or abnormal anatomy related the basilic vein in the mid arm (similarly to the
to deformities such as severe kyphoscoliosis. The common technique for cannulation of large veins) with a
sites for PICC are the upper limb basilic veins. In common with micro-puncture needle (21Gauge).
large vein catheters they may be open ended or have Groshung 6. If cannulation was unsuccessful it is important to
valve incorporated into the tip. Often PICC’s are used at the remove the needle and apply pressure for 5 min to
initial setting of abdominal catastrophe or medium term (type prevent a haematoma and also allowing a second
II IF) whilst the patient recovers and stabilised for parenteral attempt. If there is a haematoma around the vein it
nutrition support. Basilic vein often has a good calibre and runs is better to abandon the procedure and attempt
medially away from the neurovascular bundle, however there again a few days later.
are variations in anatomy such as small basilic vein with most 7. Once cannulation is confirmed with free flow of
of the venous drainage via accompanying veins of brachial venous blood a micro wire is inserted whilst the
artery. In some cases, if patients do have upper limb thrombo- needle is held steady. The needle is removed over
sis, saphenous vein may be considered along with anticoagula- the wire. When PICC is inserted at bed side it is
tion and expert nursing care as access in these circumstances is important to ensure the wire is advanced freely to
high risk. Some PICC’s are compatible with administration of have the assurance that the catheter can be
IV contrast for CT imaging which may be a consideration if advanced. Inability to advance wire freely should
access is difficult. As PICCs are placed by cannulating a periph- raise concerns about abnormal venous anatomy or
eral vein, they are easier to insert, associated with fewer inser- thrombosis therefore further attempts should be
tion complications than centrally placed lines [52]. done only after assessment of venous anatomy and
PICCs remain less ideal for long-term parenteral feeding possibly in interventional radiology.
due to the risk of dislodgement of the catheter as there is usu- 8. A 4 or 4.5 Fr dilator is passed over the guide wire
ally no cuff to anchor the catheter to the soft tissues. The exit and the catheter is placed through a peel away
site position on the arm restricts normal arm movement mak- sheath.
ing daily living activities difficult and sometimes challenging 9. If there are good dilated veins, venous cannulation
for the patient if they are doing the procedures themselves. may be achieved with help of 14g needle and cath-
eter inserted, however this is suitable only for
those catheters where the hub may be attached
Box 5. Insertion Procedure for a PICC after placement of the catheter such as the
The equipment needed includes a gown, gloves, ster- Groshung valved catheters.
ile drapes, cleaning solution, local anaesthetic, PICC 10. In advancing the catheter at the junction of subcla-
line, securing mechanism (Securecath®, Steri-strips® vian and jugulars, there is tendency for the cathe-
and Stat-lock®) and a plastic dressing (e.g. Opsite IV ter tip to follow cranially into IJV. To prevent this,
3000®), Ultrasound and micro puncture kit. The the arm is often abducted and the patient is asked
choice of number of lumens is determined by the fre- to turn their head towards the operator and to flex
quency and type of therapy the patient requires, how- head with chin touching clavicle. Alternatively,
ever it is considered best practice to a use single you may ask another person to press on jugular
lumen if the access is required only for administra- vein whilst advancing catheter.
tion of PS [53–55]. A tourniquet is applied to distend 11. Lubricating the line with sterile normal saline may
the veins. help insertion. The PICC line (Fig. 10a) is then
gradually advanced until the measured point. It is
1. The area of insertion is assessed with ultrasound preferable to insert the catheter slightly longer than
(if available) for a suitable vein before the operator the estimated length as the catheter cannot be
scrubs. The site should be sufficiently above the advanced further at later time if the site of the tip is
bend of elbow or 2–3 cm below to prevent kinking unsatisfactory when the sterile felid is lost, but it
of catheter when bending the elbow. can be easily pulled back in to the correct position.
2. The operator ‘scrubs up’ and puts on sterile gown 12. The catheter is secured (e.g. Secure-cath®, with
and gloves. Steri-strips® and a Stat-lock® dressing). A small
3. Using strict aseptic technique the skin is prepared gauze square or release dressing is placed over the
with chlorhexidine in spirit. entry site, then a plastic dressing (e.g. Opsite IV
Fig. 10 (a) PICC catheter

and (b) its dressing in the
a b
cubital fossa after insertion
infection to the new catheter [61]. It is preferable for patient

3000 ) is applied over the exit site for security, a
® to be apyrexial for a 2–10 days and any possible metastatic
light bandage (or Tubigrip®) is applied again for infection treated prior to insertion of a new tunnelled catheter
security and comfort (Fig. 10b) [62]. The interval between removal of catheter and insertion
13. A chest X-ray is taken to ascertain the position of new has been variable in asymptomatic patients, usually the
the catheter tip. duration is 48 h between the removal of old catheter and
14. If the catheter tip is displaced in IJV, a jet flush of insertion of new catheter, however there is very little evidence
10 ml saline often helps the catheter to fall in to support this practice. Negative blood culture is often con-
place. The catheter may also align itself in SVC sidered to ensure the infection has been treated particularly
over 24 h. If conservative measures fail the cathe- with fungus or staphylococcus aureus CRBSI. Rewiring of an
ter may be rewired at bedside again or with help of infected catheter is often not successful [43], however in
interventional radiology. It is important to note extreme cases where the access is very poor, antibiotics is
that the catheter must not be used when it is not delivered through the infected catheter and later changed over
placed correctly. a guide wire with further delivery of antibiotics via the new
catheter.
Small-Vein Nutrition Exit Site Infection
After the introduction of Intralipid® allowed feeding solu- Failed salvage of exit site infection [43] will require a new
tions to become less hyperosmolar, it again became possible catheter with a new tunnel away from the old tunnel.
to consider parenteral nutrition through a small vein [56]. Sometimes the opposite site has to be considered due to
Small-vein parenteral nutrition is administered through a extent of inflammation or type of organism (pseudomonas)
short plastic cannula inserted into the small veins on the fore- affecting the exit site.
arm, on the back of the hand, or on the scalp of babies. The
limiting feature of this type of parenteral feeding is the high
incidence of thrombophlebitis which means that a cannula Occluded and Fractured Catheter (Rewiring)
does not often remain patent for more than 3 days [57–60]. It
is recommended that a cannula used for feeding in a small Prior to any intervention with catheter it is important to
vein is re-sited every 1–2 days. This type of feeding is rarely assess for possible CRBSI. If there is any suggestion of
used now that PICCs can be relatively easily inserted. CRBSI it is safer to remove the catheter and insert a new
catheter in keeping with CRBSI management. Occlusion of
a catheter is not uncommon and often managed with lock
Managing Access with Complications solutions; but if unsuccessful a new catheter is inserted. A
fracture of the catheter may occur at the exposed part of cath-
atheter Related Blood Stream Infections
C eter and is often managed with a repair. Both scenarios can
(CRBSI) be managed by rewiring a new catheter over a guidewire.
For a short term uncuffed catheter the catheter is dissected at
If catheter is infected and decision is made to remove the the point of insertion and looped out. The proximal end is
catheter, the insertion of a new catheter should take place only secured to prevent dislodgement in to the vein and cut. The old
after adequate treatment of infection to avoid seeding of catheter is removed over guide wire and a dilator inserted.
Occasionally there may be scaring at the site of insertion which Other Considerations
will prevent advancing the dilator, this should be suspected if
there is resistance when the old catheter is pulled out. A new Pacing Wires
catheter is placed subcutaneously with a new tunnel as described
earlier and the catheter inserted. For a cuffed catheter an incision Pacing wires are usually placed in left subclavian. It is safer to
is made over the cuff or at the point of insertion to release the place tunnelled catheters or PICC under fluoroscopy to avoid
catheter from the soft tissue. The catheter is cut after securing it any potential dislodgement. Furthermore, the right side is
with a Halstead mosquito clip. A guide wire is inserted, and the preferable to decrease the number of devices in left brachioce-
old catheter removed over the guide wire. Cannulating with an phalic. The tip of the catheter is placed in proximal SVC as a
18G venflon® into the catheter and flushing may help if the compromise. Infection can cross from an infected PS catheter
guide wire cannot be passed through the catheter. to a pacing wire. It may be less likely to occur when a fibrin
In both these scenarios the tip of the old catheter should sheath fully covers both the pacing and PS catheters.
be sent for culture and sensitivity to determine if there is an
infection and thus will help in guidance of antibiotics if
patient becomes unwell in the near future. Haemodialysis
Patients requiring renal replacement therapy require preser-

Thrombosis vation of venous access for dialysis or venous anastomosis of
graft kidney to iliac veins. Insertion of tunnelled catheter is
In patients with long-term (type III) IF the objective is to preferred to the contralateral side of AV fistula, usually AV
maintain access and prevent further loss of venous access fistula is on the left side and therefore tunnelled catheter on
from thrombosis (chapter “Central Vein Thrombosis”). The Right IJV would be the safest option. PICC is best avoided to
strategy adopted varies depending on the clinical presenta- prevent any thrombosis which may compromise life span of
tion and extend of thrombus. AV fistula.
Acute Thrombosis
In acute thrombosis the patient should be anticoagulated Chemotherapy and PN
with LMWH injections and will require urgent CT or MR
venogram to assess the extent of thrombosis. If the thrombus Oncology patients receiving PN as well as chemotherapy
extents beyond the tip of the catheter; the catheter cannot be will require two separate lumens for infusion one for PN and
used for parenteral nutrition or infusion of crystalloids. one for chemotherapy due to concerns about compatibility of
However, the catheter may be used as an access for thrombo- the oncology medication with PN. This may be delivered
lytic therapy after discussion with a vascular radiologist. If with two separate devices or a dual lumen device. The risk
there is a significant stenosis in SVC or large veins contribut- has to be balanced between thrombosis due two simultane-
ing to thrombosis, angioplasty may be required prior to ous devices versus the risk of CRBSI due to dual lumens
insertion of a new catheter ensuring the tip of the catheter is even though one may not be used in the long-term. The
distal to stenosis [63] (chapter “Central Vein Thrombosis”). choice is determined by the probable duration of PN as well
If the thrombus is proximal to the tip of the catheter and as the number of chemotherapy sessions anticipated.
not causing any significant life or limb threatening symp-
toms the catheter may be used after a 2–5 days of anticoagu-
lation. It is best practice to take blood for a thrombophilia Removal of a Feeding Catheter
screen prior to anticoagulation. In continuing to use the cath-
eter the access is maintained, and the other veins are pre- Prior to removal of any vascular access device it is important
served for use in the future. to have information about catheter insertions, complications
especially CRBSI and venous thrombosis. The clinician must
Chronic Thrombosis also be aware if a patient is anticoagulated or on anti-platelet
Patients with established thrombosis around the catheter medication. Management of anticoagulation around the pro-
may require the catheter to be changed for non-infective cedure will vary depending on the indication for anticoagula-
mechanical problems (fracture or occlusion). It is preferable tion as well as indication for removal of a vascular access
to change the catheter over a guidewire to maintain access if device. These procedures are performed under local anaes-
possible; however, it is useful to review venous anatomy thetic. Implantable ports should be removed in a setting where
with a recent venogram prior to placement of new catheter. surgical dissection can be done with adequate support usually
in a surgical theatre setting. Tunnelled catheters may be

removed in a procedure room by an experienced operator well as comparison with a previous CXR also helps in
with adequate emergency support. A PICC can be removed at assessing if the catheter was removed without fragment-
the bedside, the length of the line removed should be recorded ing. Occasionally the catheter feels adherent on traction
and the catheter tip should be sent for culture and sensitivity. with no movement if they have been in situ for a few
years. This is often due to scarring of the venous wall at
the site of insertion and requires continued gentle trac-
Box 6. Tunnelled Catheter Removal tion for few minutes without fracturing the catheter.
Tunnelled catheters have a cuff that would have embed- Rarely if the catheter is firmly adherent, despite a few
ded to soft tissue under the skin. Removal of the cuff is minutes traction, another incision is required at the site of
essential in removing the catheter completely. The cuff entry to dissect down to the vein. This may require input
may not be placed near the exit site however should be from the vascular services. Once the line is removed
palpable along the line. In some patients the cuff may be from the vein the cuff can be dissected away from the
difficult to palpate due to subcutaneous fat if they are soft tissue with a combination of blunt and sharp dissec-
nutritionally replete particularly if the catheter were tion. Haemostasis is often achieved by applying firm
placed at time of severe malnourished state. A 1–2 cm pressure for a few minutes. Closure of the skin is done
transverse incision is made at the superior aspect of the with an absorbable suture (e.g. 3′0 vicryl); once satisfac-
cuff. The soft tissue is separated with blunt dissection tory haemostasis is achieved however in cases of an
down to the line and cuff. The catheter is grasped with a infected tunnel the wound should be packed to allow for
pair of forceps and the fibrous sheath “usually off white” adequate drainage of infection. It is prudent to send the
around the catheter formed during the time the catheter tip of the catheter for culture and sensitivity so as to pro-
has remained in situ is defined. A careful longitudinal vide microbiological guidance should patient become
linear incision is made along the catheter to avoid tran- febrile/unwell.
section of catheter and this will remove the fibrous sheath On rare occasions when removal of catheter is
and reveal the white of the catheter. The catheter should unsuccessful, and patient requires transfer, it is best to
be grasped with help of Halstead mosquito forceps ligate and fix the catheter to soft tissue at the site of
between the sleeves of the fibrous sheath and pulled with dissection.
gentle traction (Fig. 11). This should enable the catheter When tunnelled femoral catheters are removed it is
to be pulled out of the vein completely. The tip of the prudent to ensure post procedure, patient remains on
catheter should have a clean-cut edge suggesting the bed rest for 4 h to check for delayed bleeding from the
catheter has not fractured. The length of the catheter as sheath or at the site of dissection.
Fig. 11 (a) Catheter a b

identified after incising the
sheath around the catheter just
above the cuff, (b) arrow
shows the sheath as the
catheter is being removed
Box 7. Removal of an Implanted Port

Port-A-Cath can be removed under local anaesthetic
however dissection required in releasing the port is
more extensive. Some patients who are restless or
combative have required sedation with help of anaes-
thetic support. Incision is made over the previous inci-
sion often at the junction of catheter and port. The
fibrous sheath is incised, and the catheter removed like
that of the tunnelled catheters. The port may be
anchored to soft tissues at four corners from the base
of the port to soft tissue with non-absorbable suture.
The fibrous capsule around the port is incised followed
by traction on the port. The sutures if present are cut
whilst the port is on traction to remove the port com-
pletely. There is a capsule firmly adherent to soft tissue
pocket which may be left in situ if there is no evidence
of infection. Removal of the capsule may be consid-
ered if the pocket appears infected and it may be neces-
sary to consider packing the wound to allow drainage
of infection.
Fig. 12 An arteriovenous fistula in the right cubital fossa
rteriovenous Fistulae for Venous Access

A Currently the first choice for an AVF is the autogenous
in HPN Patients radiocephalic shunt on the fore-arm (Fig. 12), or less ideally,
in the lower extremity. When the quality of these peripheral
While CVCs or implantable ports are standard for long-term vessels is insufficient, more proximal fistulae such as the bra-
parenteral nutrition administration, a surgically created arte- chiocephalic or brachio-basilic AVF are considered at the
riovenous fistula (AVF) was the only available type of venous elbow and upper-arm region. In case these options fail, graft
access at the inception of this treatment in the late 1960s. implants may be used as a vascular conduit to construct an
Upon the introduction of intravenous catheters in the 1970s AVF, whenever possible with the use of an autologous trans-
AVFs became rare, also because of their high complication posed vein, most commonly the great saphenous vein (GSV).
rate that was associated with the use of xenologous (bovine) Such graft AVFs may also be created on the thoracic wall.
or prosthetic (polytetrafluoroethylene-like) graft materials For reasons outlined above, the use of prosthetic materials
leading to shunt occlusion and thrombosis [64]. such as PTFE to create AVFs for the purpose of HPN [68] is
From the start of the HPN program in Nijmegen avoided. Importantly, following their creation it usually takes a
(Netherlands) in 1969, besides CVCs there has been a con- maturation period of around 6 weeks before AVFs are available
tinued use of AVFs in patients with a high CVC infection for (self)-puncturing by the patient or caregiver. For follow up
rate. In 1983, a series of 7 patients using AVFs was reported and surveillance patients are provided with a stethoscope to
[64]. Later, the group described their oldest patient who has detect changes in the pitch of the murmur and loss of thrill over
currently remained well on HPN with an AVF for more than the AVF at an early stage that might indicate stenosis, mostly at
45 years [65]. the level of the anastomosis. In this case, balloon dilation of the
The notion that AVFs may still be a valuable alternative stenosis by the interventional radiologist usually can solve the
to CVCs was corroborated in a retrospective analysis of problem. Also for this reason, regular check-ups (usually at
127 HPN patients, comprising 194 AVF access years [66]. 6-month intervals) with evaluation through ultrasound of the
Bloodstream infections (BSI) were extremely rare (0.03/ shunt flow to detect such abnormalities are required, and also to
year) for AVFs compared to tunneled CVCs (1.37/year), rule out severely increased shunt blood flow (which may
although occlusion was more frequent (0.6 versus 0.35/ become more than 3 l/min) that might lead to cardiac failure.
year). Of note later taurolidine locks (not feasible in AVFs) Thus AVFs may be a valuable alternative to other modali-
were started which brought the CRBSI rate down to 0.6/ ties to provide HPN as long as the expertise to adequately
year [67]. address any of the associated complications is available.
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Formulation of Parenteral Nutrition
Regimens
Gil Hardy and Michael Charles Allwood
Key Points (e.g. ascorbic acid and thiamine), adsorption onto the sur-
1. All parenteral nutrition (PN) compounding must be per- face of the infusion bag or administration sets (e.g. vitamin
formed under strict aseptic conditions and under phar- A and E), and by light catalysed photodegradation.
macy control. Consequently, exposure to direct sunlight must be avoided.
2. Multiple chamber bags (MCBs) have the lipid, carbohy- 10. All PN systems, i.e. bags, and ideally the giving set,
drate and protein components physically separated, have should have a light protective covering and an in-line
long shelf lives (e.g. 1 year) and do not need refrigera- 1.2 μm filter. Administration should be well away from a
tion, before mixing, by rolling the bag just before the sunny window or at night.
infusion begins.
3. MCBs can be triple chamber “All-in-One” (AIO), or
double chamber “2 in 1” without intravenous lipid emul-
sion (ILE), Introduction
4. MCBs do not contain trace elements or vitamins which
must be added aseptically or administered separately. Since the first edition of this textbook, the major international
5. ‘Bespoke’ or ‘tailored’ PN bags can be compounded up professional societies, ASPEN (American Society for
to 2–3 weeks before administration but generally have Parenteral and Enteral Nutrition) and ESPEN (European
all the necessary vitamins and trace elements included. Society of Enteral and Parenteral Nutrition (European Society
6. The shelf life of bespoke bags and MCB after mixing of Clinical Nutrition and Metabolism)) have published impor-
under aseptic conditions can be up to 21 days. tant clinical practice guidelines for parenteral nutrition (PN)
7. Interactions between PN components arise from prescribing, preparation and administration [1–3]. AuSPEN
physico-chemical incompatibility and/or chemical deg- (Australasian Society for Parenteral and Enteral Nutrition),
radation that can lead to precipitation, loss of nutritional European Society for Paediatric Gastroenterology Hepatology
or pharmacological efficacy, and possible toxicity due to and Nutrition (ESPGHAN), ESPEN and ASPEN have pro-
hazardous degradation products. The greatest risk of duced clinical guidelines for trace elements and vitamins [4–
precipitation is from the formation of insoluble calcium 8], and international expert consensus recommendations for
phosphate salts. micronutrients in adult and paediatric PN have been recently
8. The most significant limitations on stability of complete published [9, 10]. Additionally, the United Kingdom NHS
AIO PN regimens are high cation concentrations and Pharmaceutical Quality Control Committee has published
poor control of air content and air ingress into PN mix- protocols for assessing PN stability [11]. Where appropriate,
tures during compounding and storage. The use of air the recommendations of these expert bodies will be incorpo-
impermeable bags is essential. rated into this chapter.
9. There is a loss of vitamins and other nutrients from PN PN-is a complex prescription therapy that is indicated in a
mixtures after compounding due to chemical degradation wide spectrum of clinical situations, from surgical and inten-
sive care unit (ICU) patients, who may require short term
nutritional support (for a few days/weeks), to patients rely-
G. Hardy (*) ing on long-term PN for survival because of severe impair-
Clinical Nutrition, Massey University, Ipanema Research Trust,
ment in gastrointestinal (GI) function. A PN regimen
Devonport, Auckland, New Zealand
typically includes 40–50 components, including; amino
M. C. Allwood
acids, glucose and lipids, multivitamins and trace elements.
Pharmacy, University of Derby, Derby, UK

546 G. Hardy and M. C. Allwood
In the past PN has been associated with significant adverse commercial companies or hospital-based, are now common
effects when the therapy is used inappropriately. Safe pre- and have made a major impact on reducing infection risks in
scribing and use is an essential component of PN therapy patients receiving PN. Most adult patients can be supported
that requires a thorough knowledge of indications, require- nutritionally with a range of standardized regimens.
ments for protein and energy, macro and micro-nutrients,
fluid homeostasis and acid-base balance, together with basics
of sterility and infection control and associated complica- Protein
tions. PN is administered with increasing frequency at home
(HPN) or in long-term care facilities. Regardless of the set- Currently available solutions supply all the traditionally
ting or the number of patients receiving the therapy, classifi- termed ‘essential’ and ‘non-essential’ l-amino acids. Some
cation of PN as a high-alert medication requires healthcare paediatric amino acid preparations contain the aminosul-
institutions to develop evidence-based policies and fonic acid, taurine, to alleviate taurine deficiency. However,
procedures to promote safe administration, and to validate the ‘conditionally essential’ amino acids; glutamine and
the competency of those responsible for preparation and cysteine are not usually included because of solubility and/
administration of this complex intravenous therapy [1]. In or potential stability problems. Dipeptide additive solu-
depth education on PN should be included as a standard tions are available as a vehicle for less soluble heat-labile
component of acute care and home care training. This applies amino acids, e.g. glycyl-l-glutamine dipeptide, N(2)-l-
equally to all health professionals caring for PN patients and alanyl-l-glutamine dipeptide and glycyl-l-tyrosine. These
clear communications are essential. are chemically and heat stable but are hydrolysed to free
This chapter outlines the components of a PN regimen, glutamine, glycine, alanine or tyrosine in plasma and tis-
reviews reasons for their choice and clinical requirements, sues [15].
summarises the recommendations from recent guidelines Amino acid solutions are available in concentrations
and expert groups, for safely preparing and administering ranging from 5% to 15% with or without some electrolytes.
PN, and reviews key features relating to the stability and High strength solutions with Nitrogen contents up to 30 g/L
compatibility of PN admixtures. allow more concentrated formulations to be compounded
when administration volume is important. Around the world
protein may be prescribed as either g. protein equivalent/g.
Components of a PN Solution amino acids or g. Nitrogen [16].This may be confusing for
some health professionals and it is now time for some inter-
When PN first became a treatment option in the 1960s (then national agreement on a standard terminology. In the mean-
often called ‘hyperalimentation’) [12], all components were time, the most common method of determining PN efficacy
separately administered from bottles of high strength glu- is to measure nitrogen balance. A factor of 6.23 can then be
cose, protein hydrolysates or amino acids, with or without used to convert Nitrogen to protein/amino acids.
intravenous lipid emulsion (ILE). To some of these macronu-
trient containers, electrolytes and micronutrients were added
by ward staff. Infusion systems comprised multiple lines Energy
with two-or three-way taps, connected to the central venous
access device (CVAD). The risk of the line becoming infected There is no longer debate as to which is the best energy
was high due to contamination from changing infusion con- source. It is generally recognised that glucose, lipids and
tainers and handling the administration lines. Extrinsic con- amino acids are essential energy substrates but may play
tamination was later found to be significantly reduced if PN different roles in certain clinical situation for optimizing
admixtures were compounded under strict aseptic pharma- the efficiency of energy utilization and minimizing meta-
ceutical conditions. Subsequently, the single ‘Big Bag’ and bolic complications. Providing the administered substrate is
all-in-one (AIO) systems for PN were developed and intro- adequately utilized, there is no difference in the efficacy of
duced in the late 1970s [13, 14]. glucose or lipids with regards to protein sparing. Most cen-
As the clinical benefits of the AIO system were increas- tres use an admixture of glucose, amino acids and an ILE
ingly recognized by clinicians, the demand for more nutri- for AIO PN, but some still advocate the separate infusion
tionally complete mixtures and bags with shelf-lives greater of ILE administered weekly to provide essential fatty acids
than 24 h produced new challenges for pharmacists, who (EFA).
needed to ensure the stability and compatibility of these com- It is conventional, though illogical, to describe the energy
plex admixtures. This means that careful formulation and given in PN as “non-protein energy” and the protein/amino
strict mixing protocols must be followed during compound- acid energy is not usually stated, in contrast to enteral nutri-
ing. Pharmacy-operated compounding services, either by tion (EN) where the total energy content of a feed is indi-
Formulation of Parenteral Nutrition Regimens 547
cated. However, it must be remembered that amino acids are derived from OO are less immunosuppressive than LCT. and
metabolically important energy substrates for cells of the FO ILE contain anti-inflammatory long chain omega-3 poly
immune system and should be included in total energy calcu- unsaturated fatty acids (PUFA). Clinical experiences with
lations. Moreover, Nitrogen itself is NOT a source of energy, the newer generation ILE provide evidence that the role of
thus the terms ‘non-nitrogen calories or energy’ are incorrect lipids extends beyond that of energy substrates. Lipids may
and should not be used. influence prostaglandin and leukotriene synthetic pathways
to beneficially modify the patient’s response to illness
[18–20].
Carbohydrate All ILE are emulsified with egg lecithin derived phospho-
lipids to mimic the structure of chylomicrons and contain 5%
Glucose is the carbohydrate of choice for PN and is available glycerol, to ensure the products are isotonic. A variety of ILE
in concentrations ranging from 5–70% w/v, sometimes in with different combinations of MCT/LCT/MUFA/PUFA and
combination with electrolytes. Alternative carbohydrate ω-3FA, are available as 10%, 20% or 30% w/v concentra-
sources do not offer any advantages over glucose. The energy tions. The energy value of lipid is approximately 9 kcal/g,
value of anhydrous glucose is approximately 4 kcal/g. When but glycerol contributes 1 kcal/g. Hence the energy contribu-
glucose monohydrate is used (as in USA) then a figure of tion of a 10% ILE is 1.1 kcal/mL, a 20% ILE is 2.0 kcal/mL
3.4 kcal/g is used. and 30% ILE is 3.0 kcaL/mL.
Advantages Advantages
• Inexpensive and readily available • High energy content

• Effectively metabolized in the presence of insulin • Isotonic allowing peripheral infusion
• Stimulates insulin release so encouraging nitrogen reten- • Source of essential fatty acids (EFA) and vitamin E.
tion in muscles.
Disadvantages
Disadvantages
• Expensive compared to glucose
• Concentrated solutions are hypertonic so preventing • Lipids may interfere with routine blood tests
peripheral infusion • Some patients may have reduced ability to clear lipid
• Hyperglycaemia and glycosuria may occur • Risk of catheter occlusion with complex AIO regimens
• Essential fatty acid deficiency can occur if used as the • Pharmaceutical limitations on stability and shelf life.
only energy source. • Increased susceptibility to microbial growth
Lipid Electrolytes
ILE have low osmolality and allow large amounts of energy Various electrolyte salts are available as small volume paren-
to be administered in a relatively small volume. Historically, teral injections (SVP) for inclusion into PN regimens.
ILE consisted of soya bean oil (SO) long-chain triglycerides Examples are sodium (as chloride or acetate), potassium (as
(LCT) with chain lengths of 16–20 carbon atoms. These chloride or phosphate), phosphate (as mono- and dibasic
products have been used safely and with good clinical accep- potassium salts or organic compounds), magnesium (as sul-
tance for over 50 years. More recently concerns have been phate or chloride) and calcium (as chloride, sulphate or glu-
expressed about the immunosuppressive pro-inflammatory conate). Organic phosphate injections, such as glucose-1
effects of high doses of LCT and the adverse effects of phy- phosphate, glycero-phosphate and fructose-1,6-diphosphate
tosterols, present as impurities in SO. Newer ILE, were reduce the possibility of calcium phosphate precipitation in
developed towards the end of the twentieth century, formu- PN mixtures. The phosphate group on these compounds is
lated from coconut oil (CO) or olive oil (OO) and/or fish oil covalently bonded and thus is not ionized for precipitation as
(FO). Medium chain triglycerides (MCT) with chain lengths insoluble calcium phosphate. Some SVP and particularly
of 6–10 carbon atoms from CO are metabolised via a calcium gluconate, can be contaminated with aluminium,
carnitine-
independent fatty acid transport system [17]. which may be a problem for patients with renal impairment
Mono-unsaturated fatty acids (MUFA) with 9 carbon atoms, and preterm infants [21].
Micronutrients stability of ILE during storage for several days and that ther-
apeutic doses of iron can be suitably admixed with lipid-
While EN products and oral supplements usually include containing (AIO) PN solutions. Nevertheless, these data
sufficient micronutrients to ensure basic nutritional com- have not been confirmed by other researchers and caution is
pleteness, Chemical and temperature stability considerations still advised when considering adding iron to PN [27].
preclude vitamins from being incorporated into PN admix-
tures until closer to the time of administration. Fixed dose
combinations and some individual micronutrients are avail- Vitamins
able commercially as additives for compounding to meet
specific clinical requirements. When micronutrients are A number of commercial multivitamin preparations for par-
administered intravenously they are 100% bioavailable and enteral use are available which provide the recommended
undergo the same metabolic and elimination pathways as daily requirements of vitamins Products with higher thia-
corresponding minerals provided by oral feeding. mine content may be advantageous when thiamine defi-
ciency is anticipated or when a relatively carbohydrate-rich
feeding regimen is used, in order to avoid refeeding syn-
Trace Elements drome (RFS). A continuing problem is the loss of vitamins
from PN mixtures after compounding, whether due to chem-
Over a dozen trace elements are thought to be essential to ical degradation, light catalysed peroxidation, by exposure to
biological functions, but only 9 are routinely supplemented ultraviolet light, adsorption onto the surface of the infusion
in PN regimens. Metabolic rates after elective surgery may bag or administration sets. Because of these potential chemi-
increase by 10–20% and with severe sepsis by up to 50%. cal losses the patient may not receive an adequate vitamin
When the metabolic rate increases there is a greater require- intake according to the prescription to maintain vitamin sta-
ment for trace elements, partly because all essential trace tus. Light protection of the PN container and exclusion of air
elements are involved in enzyme-catalysed reactions, many during compounding can help to minimise these losses [28,
of which are central to intermediary metabolism. There are 29].
also multiple sites from which large amounts of zinc, copper,
manganese can be lost from fistula or diarrhoea during sur-
gery or trauma [22]. Water
The provision of precise amounts of micronutrients is
therefore difficult due to uncertainty about how much to give Water makes up most of a PN regimen with the quantity
and in what chemical form. In addition, the amino acid and varying according to a patient’s needs. If large amounts are
other PN products may be contaminated with trace elements. needed this is usually given in conjunction with isotonic
Contamination has been reported for zinc, copper, manga- sodium chloride, which is usually lost from the body with
nese, chromium, selenium and most recently iron [23, 24]. water.
Contamination levels vary between manufacturers and
between lots from the same manufacturer. Consequently a
daily amount to prevent clinical deficiency states must be Peripheral Parenteral Nutrition Formulations
provided in accordance with the guideline recommendations
referenced earlier [4–10]. When central vein access is limited, peripheral parenteral
Standard PN solutions do not contain trace elements nutrition (PPN) should be considered for ≤5–7 days but can
because of the aforementioned chemical stability consider- be given for up to 14 days if required. PPN can provide a
ations and need to be added to the PN solution shortly before safe, efficient and cost-effective short term route for nutrition
administration to the patient. Trace elements may interact delivery in a variety of clinical situations [30]. The most
with vitamins, amino acids and other trace elements. Because important complication limiting the use of PPN is thrombo-
these interactions become more significant when concentra- phlebitis, largely due to administering high osmolarity solu-
tions differ markedly from recommended daily intakes, tions into a small calibre vein. The major contributors to the
administration of supplemental trace elements in a fixed osmolarity are glucose, amino acids and electrolytes with a
combination single solution, has been advocated in order to greater incidence of thrombophlebitis noted from increasing
maintain balance [25]. electrolyte content, especially potassium. Consequently,
The compatibility of trace elements, especially iron, with standard PN regimens are not suitable for peripheral admin-
lipid-containing PN remains controversial. Tu et al. [26] istration as their hyperosmolarity increases the risk of throm-
showed that the addition of small quantities of trace elements bophlebitis when infused into smaller veins. The likelihood
(including some iron) does not affect the physicochemical of thrombophlebitis is reduced when the PPN regimen con-
tains ILE [31] and has an osmolarity of less than 900 mOsm/L Standard commercially available ‘ready-to-use’ PN prod-
[32, 33]. Given the low electrolyte composition of PPN, due ucts may be viable options to aseptically compounded PN
to limitations with osmolarity, the patient’s electrolyte levels products, when compliance with USP Chapter <797> and
should be checked prior to administration in order to mini- other national guidelines is not feasible [1]. Multi chamber
mise the risk of refeeding syndrome (RFS). Good adminis- bags (MCB) are designed to reduce the risk for instability or
tration and monitoring procedures, based on evidence-based precipitation. Macronutrient components of the PN formula-
practices, with careful surveillance for the signs of thrombo- tion are separated in individual chambers by a seal, until just
phlebitis that include warmth, tenderness and pain in the prior to activation and administration. The contents of the
affected area, often accompanied by redness and swelling, chambers should be mixed and any additives made asepti-
can ensure the success of PPN. The addition of heparin and cally under pharmaceutical conditions, prior to dispensing
hydrocortisone to infusions has been used to reduce the the PN prescription. If MCB are used in home care then
incidence of peripheral vein thrombophlebitis. Timmer and patients and/or caregivers shall be provided with thorough
Schipper [34] have shown that the ‘osmolality rate’ (osmo- training regarding the procedure for properly mixing the
larity × infusion rate) correlates more with peripheral vein contents before use [1, 37, 41].
thrombosis than osmolarity alone.
Stability and Compatibility of PN Solutions

Compounding Standards and Regulations
Since PN solutions are complex mixtures, there are two cat-
All PN compounding must be performed under strict aseptic egories of interactions between components that can poten-
conditions and under pharmacy control. In the UK PN is a tially take place in compounded PN admixtures:
Prescription Only Medicine and all hospital pharmacy com- physico-chemical incompatibility leading to precipitation,
pounding units are strictly controlled by the Medicines and and chemical degradation leading to loss of nutritional or
Healthcare products Regulatory Agency (MHRA). pharmacological efficacy, and possibly enhanced toxicity
Pharmacies must have a Manufacturer’s licence for com- from hazardous degradation products. Avoiding precipitation
pounding licensed PN products with a marketing authorisa- and minimizing degradation requires an understanding of the
tion (MA), or a Specials licence for compounding small major reasons why they occur in certain PN regimens. The
batches of unlicensed products or a Section 10 exemption chemical composition and physical properties of PN admix-
from licensing [35, 36]. Within Europe, individual countries tures vary greatly between regimens depending on the amino
have their own regulations controlling compounding phar- acid source, ILE type, the particular electrolyte salts used,
macies [37] and in the USA, ASPEN recommends that all the relative concentrations of ingredients and the final vol-
healthcare organisations with ‘in-house’ compounding facil- ume. In describing the potential chemical and physical inter-
ities shall comply with USP Chapter <797> standards [38]. actions that can take place, it is important to realize that each
Those hospitals without licensed Aseptic Units may con- regimen is chemically unique. Extrapolation of stability data
tract their PN compounding to an outside manufacturer or from one to another regimen requires a full understanding of
compounder. A decision to outsource PN compounding all the factors that can influence stability.
requires that the commissioning pharmacy should exercise
due diligence to monitor that the outsourcer operates within
the jurisdiction of the MHRA, or in the USA follows USP Physical Incompatibility
<797> guidelines.
Procedures involved in providing a PN compounding ser- Electrolytes
vice are described in detail by Austin and Stroud [35] and a The most common cause of precipitation in PN mixtures is
useful Summary table of twelve recommendations for order- due to calcium phosphate insolubility [35–37]. Factors influ-
ing, order review, compounding and labelling/dispensing of encing the solubility of calcium phosphate in PN admixtures
PN is included in the ASPEN Clinical Guidelines [33]. Risk are multi-factorial, but the most important variable is pH
management advice for health professionals performing PN [42]. The final pH of a mixture is influenced by the following
compounding, by the NHS Pharmaceutical QA Committee factors:
[11], include considerations of the compounding processes, The amino acid product. Differences in pH, that can vary
the final container choice, stability, exclusion of air and light from around pH 5 to greater than 7 are important due to the
protection, storage temperature and infusion period. strong buffering capacity of individual amino acids that are
Controlling impurities such as Aluminium, that has been the major controllers of pH in the final PN admixture [43].
regulated in the USA for over 20 years [39], is now a BP The phosphate source. Inorganic phosphates are strong
requirement for UK manufacturers [40]. buffers but potassium dihydrogen phosphate injection (acid
phosphate) has a very low pH c.5 while disodium hydrogen dissociation of calcium gluconate, so paradoxically, PN
phosphate has a pH around 8. Thus, the choice of phosphate admixtures containing calcium gluconate stored in the refrig-
injection can have a marked effect on final pH of the PN erator are less likely to precipitate, compared with PN
mixture [42]. admixtures at room temperature. More importantly, is the
possible risk of precipitation in the administration set, as the
he Buffering Capacity of Amino Acids
T PN infusion warms to body temperature, especially within
and Inorganic Phosphate the canopy of a neonatal cot. Consequently, a limit of 76 mg
The chemical equilibrium for inorganic phosphate salts in Ca per kg and a molar Ca:P ratio of 1.3:1 is recommended
water is shown in Fig. 1. Note that pH is the controlling fac- for neonatal PN regimens [33]. Note also the concerns about
tor for which phosphate species actually predominate in any high aluminium levels in calcium gluconate injection as pre-
particular solution. In PN admixtures, the optimum pH lies viously indicated [39].
between 5 and 7 but will depend on the amino acid source, Other factors that can also affect calcium phosphate solu-
final concentration and phosphate source. At pH 5, the bility in PN admixtures are summarized in Table 1.
dihydrogen-phosphate salt predominates, while at pH 7, the
predominate salt is the mono-phosphate species [42]. ther Possible Causes of Precipitation
O
Calcium mono-hydrogen phosphate is 60 times less solu- There are some other possible causes of precipitation, but all
ble than the dihydrogen salt. As the pH increases, there is an are far less likely than calcium phosphate. Most are associ-
increasing likelihood of precipitation. Since the most impor- ated with trace elements and usually take many days to
tant cause of precipitation in PN admixtures is the formation become evident [46, 47]. In contrast, calcium phosphate pre-
of insoluble calcium phosphate, the calcium source needs to cipitates appear within 24 h of compounding. Significant
be considered [42]. trace element interactions can cause precipitation in PN
Parenteral Calcium comes in two forms, as inorganic or admixtures. These include:
organic salts: calcium chloride and calcium sulphate for
injection, which are fully ionized in aqueous solution, or cal- • Copper and sulphide (a degradation product of cysteine
cium gluconate injection which is only partially ionized in found in Vamin®, Vaminolact® and Primene products [47].
aqueous solution. These salts behave differently in PN • Iron and phosphate (only reported with Synthamin® with
admixtures, and precipitation is most likely with the chloride electrolyte-containing PN mixtures) [47].
salt. Calcium gluconate is therefore preferred to reduce the • Selenium and vitamin C at acidic pH [48].
risk of precipitation in PN mixtures [44] But there is a further
complication. The degree of ionization of calcium gluconate In summary, the greatest risk of precipitation is from forma-
is only slightly influenced by pH, but is substantially affected tion of insoluble calcium phosphate salts. In clinical prac-
by temperature [42]. Raising the temperature increases the tice, it is normally possible to achieve adult nutritional
Fig. 1 Speciation of 2 H3PO4

phosphate salts in parenteral
nutrition mixtures
pH < 5+ 2 H+
2 H2PO4
pKa1 = 7.2 2 H+
2 Ca2*+ 2 HPO42– 2 CaHPO4 - 2 H2 (s)

(insoluble)
2 H+
3 Ca2+ 2 HPO43– Ca3(PO4)2 (s)

(insoluble)
requirements without running the risk of calcium phosphate phospholipid ‘tails’ around its surface. Consequently, charge
precipitation. Nevertheless, in neonates and small children, repulsion maintains the emulsion in a stable state [49].
because of their greater needs for these essential compounds, Since the average globule size is around 3–400 nm (0.3–
it is very difficult to formulate PN regimens without creating 0.4 μm), small enough to pass through the smallest capillar-
a potentially incompatible admixture. Insolubilities can be ies, the essential requirement of any ILE after being added to
minimised by using an organic source of phosphate, such a a PN admixture, is that this size does not increase to the
sodium glycerophosphate [45] with covalently bonds so extent that it might block these capillaries. This forms the
there are no free phosphate ions present. Thus, the risk of basis for deciding if the AIO regimen remains within accept-
forming an insoluble salt with calcium is minimised, so able limits. Most ILE contain added sodium oleate (c. 0.3%)
phosphate requirements for neonates and small children are as an additional surfactant to enhance the physical stability
more easily achieved. of the emulsion. Such ILE are also more stable and can toler-
ate both lower and higher concentrations of amino acids and
I ntravenous Lipid Emulsions glucose after dilution in a PN regimen [50].
It is now routine practice to include intravenous lipid emul- In compounding a PN admixture, ILE is mixed with a
sions (ILE) in most PN formulations. An intravenous oil-in- whole range of other compounds, which, crucially, include
water emulsion is manufactured using a homogenization electrolytes and specifically, cations. These positively charged
process to form a very fine emulsion, egg lecithin being the ions can neutralize the negative surface charges of the oil glob-
emulsifying agent. Each lipid particle is kept separate by the ules. The particles start to come together as aggregates and
fact that the surface is covered in the negative charges of form small clumps. Since oil is lighter than water, these aggre-
gates tend to float to the surface and form a ‘cream’ layer (just
Table 1 Factors that effect calcium phosphate solubility in PN like the “top-of-the-milk”) (Fig. 2). Gentle shaking can dis-
mixtures perse these clumps. Therefore, the formation of a cream layer
Factor Likely effect Reason for effect is not normally considered hazardous because the particles
Magnesium Reduces Magnesium phosphate more remain discreet. However, if the particles start to coalesce to
concentration likelihood of soluble than calcium phosphate form larger oil globules, this is more hazardous, but can usu-
precipitation salts [33]
ally only be detected by careful particle-size analysis [51].
Amino acid May decrease or Some amino acids specifically
source increase bind calcium and reduce salt
solubility and/or formation, thus enhancing Causes of destabilisation in AIO PN mixtures
precipitation solubility [43]
Organic Removes risk of Phosphate is in an organic • HIGH concentrations of calcium and magnesium
phosphate calcium covalent form (e.g.
precipitation glycerophosphate or glucose • LOW pH
phosphate) and so calcium • LOW relative volumes of ILE
phosphate does not precipitate • LOW concentration of amino acids
[45] • HIGH ratio of acidic to basic amino acids
Fig. 2 Stages of All-in-One

PN admixture instability over
time
Freshly prepared Creaming Flocculation Cracking

Safe to Use Unsafe to Use
Factors that enhance stability of AIO admixtures Na/K <200 mEq (mmol)/LNB: Stability information
should never be extrapolated between PN admixtures
• HIGHER glucose concentrations, but within an upper with different commercial sources of amino acids and/
limit or ILE.
• Second emulsifying agent—sodium oleate
In fact, it requires relatively large concentrations of cat-

ions to significantly reduce these surface charges, but diva- Chemical Degradation
lent cations are much more efficient charge neutralizers. So,
in practice it is the concentration of divalent cations, which is Most PN components are remarkably stable after compound-
the most important cause of destabilisation. There have been ing, at least during the normal shelf lives of PN admixtures,
attempts to quantify the destabilising effect of cations. and in particular the 30-day shelf life most commonly used
Although the relatively simple equations used in colloid sci- in practice. It is important to consider stability at two stages:
ence are more applicable to simple ILE and cannot always be (a) during storage after compounding and (b) during admin-
applied to the more complex AIO admixtures, calculating the istration. There are three possible chemical mechanisms for
critical aggregation number (CAN) from the Schultz-Hardy the degradation of specific PN ingredients (Table 2) primar-
equation [49]. can be a useful indicator and has been used for ily involving vitamins. Thus, it is often the addition of vita-
stability predictions of paediatric PN regimens [52]. mins that subsequently limits the shelf life of PN admixtures
The USP <729> provides pharmaceutical specifications [57–62].
describing stability methods and acceptance criteria defined
as the “percentage of fat residing in globules larger than
5 μm (PFAT5) for a given ILE is not to exceed 0.05%”. It is itamin C (Ascorbic Acid) Oxidative
V
claimed that PFAT5 can also applied to final PN admixtures Degradation
[53] and that PFAT5 has been validated for both the ILE
from the manufacturer and as a total nutrient admixture Ascorbic acid is the least stable ingredient in any PN admix-
(TNA) from the compounder in both animal models and ture and some loss during compounding, storage and admin-
human subjects [54]. Nevertheless, although the principle of istration is inevitable. There are two important factors to note
PFAT5 is sound, as with the CAN approach, there are con- from the degradation pathway for ascorbic acid in Fig. 3.
cerns that the USP monograph cannot be applied accurately First, the initial reaction is reversible; this is important
to all AIO admixtures and that the recommended light obscu- because dehydro-ascorbic is equally biologically functional.
ration techniques will not pick up the smaller lipid droplets Second, the degradation involves oxygen which can origi-
which may have an important role in indicating instability. A nate from:
recent study by Zhao B et al. [55]. that assessed the stability
of MCT/LCT-based PN admixtures by measuring mean 1. Air in infusion solutions and additives—glucose, electro-
droplet diameter (MDD), PFAT5, pH, and osmolality, lytes, water for reconstituting vitamins, (but not amino
reported that all TNA met USP <729> but there were some acid infusions or ILE, both of which are usually protected
significant differences between MDDs and PFAT5s. by a nitrogen gas overlay).
To date, the USP standards have not been officially accepted 2. Air in the bag after compounding, if not removed prior to
in the UK or Europe but PFAT5 is used by some manufactur- sealing
ers, as part of routine stability testing for PN admixtures [56]. 3. Air which dissolves in the infusions during the filling pro-
Other testing laboratories prefer a combination of assessments cess especially as solutions pass through the filling lines
methods based on visual, microscopic and particle size analy- 4. Oxygen permeating through the bag wall during storage.
sis (e.g. laser diffraction, light obscuration) together with their
extensive historical laboratory comparative data to determine Oxygen reacts with ascorbic acid rapidly, catalysed by cop-
and predict AIO PN stability. per ions [63, 64]. Within an hour or two, the oxygen will
The ASPEN consensus recommendations for a stable have reacted to reduce ascorbic acid to dehydroascorbic acid
AIO PN regimen [1, 33], provide a useful ‘rule of thumb’
and can be summarised as follows: Table 2 Chemical mechanisms for PN degradation
Reaction Most important candidate(s)
Glucose >10% (excluding PPN) 1 Oxidation Vitamin C (ascorbic acid)
Amino Acids >4% 2 Reduction Vitamin B1 (thiamine)
Lipid >2% 3 Photodegradation Vitamin A (retinol)
Ca/Mg <20 mEq (10 mmol)/L Vitamin E (tocopherol)
[64]. This in turn is further oxidized and/or hydrolysed to per day [64]. In an EVA bag, the maximum shelf life must
keto-gulonic acid, so the amount of ascorbic acid degraded therefore be only 3–5 days, because of the high oxygen per-
depends almost entirely on the amount of oxygen present in meability of the plastic. This phenomenon can be minimised
the PN admixture after compounding. by using multi-layered bags, which are virtually imperme-
It can be expected that the quantity of ascorbic acid able to oxygen. A comparison of ascorbate (AA + DHAA)
degraded after compounding a typical 2–3 L adult formula- degradation in single layer EVA versus multi-layered bags
tion will amount to 40–60 mg [63]. The amount the patient is illustrated in Fig. 4. Note how degradation is initially
receives depends on the quantity of oxygen in the PN bag, rapid, but then the rate of losses level off to almost zero,
and on the type of bag used. Degradation will continue as after a few hours. This is accounted for by the initial reac-
oxygen permeates through the semi-permeable wall of PVC tion with dissolved oxygen already in the PN admixture.
or EVA PN bags, accounting for a further loss of 10–15 mg Once all the oxygen has reacted, no further degradation of
ascorbic acid takes place. Thus, in multi-layered bags,
ASCORBIC ACID which are now commonly used in UK and some other coun-
tries, the shelf life of PN admixtures can be extended, com-
monly up to 30 days, provided the initial compounding is
O2 undertaken efficiently, to minimise aeration during filling,
and any residual air is removed before sealing the bag
[63–65].
DEHYDRO-ASCORBIC ACID
Unfortunately, the plastic films used to fabricate MCB’s
are also semi-permeable to oxygen. Consequently, following
removal of the outer wrap, mixing of the main ingredients
and the addition of multi-vitamins, degradation of ascorbic
acid will occur as described above, such that shelf lives
2, 3 - DIKETO - GULONIC ACID should be restricted to 48–72 h, including infusion time. The
shelf lives of these products can be further extended to at
least 60 days, usually in a high GMP industrial facility, by
re-packaging the MCB (after mixing and adding vitamins),
in a gas-impermeable overwrap. Any remaining air between
THREONIC ACID + OXALIC ACID the MCB and its overwrap is replaced by nitrogen gas before
sealing the overwrap under vacuum. An oxygen scavenger is
Fig. 3 Ascorbic acid degradation pathway also commonly included.
Fig. 4 Degradation of 100

ascorbate in PN mixture
during storage
80
In multilayered bag
% Ascorbic Acid Remaining
60
40
In EVA bag
20
0 5 10 15 20 25 30
Days Storage @ 5°C
Vitamin B1 (Thiamine) Reduction to extend this in multi-layered bags, and/or by adding vita-
Thiamine is degraded by a reduction reaction with sodium min C, as ranitidine degradation is by light-induced oxida-
metabisulphite [33]. Historically, some amino acid infusions tion [70–73].
contained sodium metabisulphite as a reducing agent to pre-
vent oxidation of amino acids during manufacture and stor-
age. In the absence of metabisulphite, thiamine is stable for Heparin
at least 28 days in PN mixtures [66].
Heparin is commonly added to PN regimens for neonates,
but great care is necessary to avoid destabilizing the ILE
Vitamin A (Retinol) Photodegradation in AIO admixtures, or when lipid-free PN admixtures mix
with ILE via a Y-set. Standard heparin interacts with the
The most light-sensitive ingredient of any PN admixture is emulsifying agent in ILE, in the presence of calcium ions,
retinol (vitamin A) [28, 67]. Many factors can influence the to form calcium-heparin bridges [74]. The emulsion rap-
rate of light induced retinol degradation during PN adminis- idly destabilizes and cracks within a few minutes. This
tration, including the time of day, the position with respect to risk can be avoided by using low molecular weight hepa-
light from the window, volume in bag, infusion rate, ILE in rin [52].
the admixture and the presence/absence of a light protecting
cover over the PN bag [28, 67].
But note the following important points: Insulin
• Since degradation is caused by exposure to ultraviolet Insulin infusions may be required for poorly controlled dia-
light (below 350 nm wavelength), only daylight degrades betic patients or for those patients developing insulin resis-
retinol [67] tance. Addition of insulin to PN regimens has also been
• Artificial light contains very little UV emission advocated to promote anabolism but this can lead to further
• Photodegradation will occur both in the bag and in the metabolic disturbances. Moreover, if added to the PN admix-
administration set as the solution is infused, if the system ture, insulin can partially adher to the plastic container and
is not protected [65]. giving set, limiting its bioavailability. Addition is therefore
discouraged [33, 35].
Various other medications such as hydrocortisone or albu-
min have been demonstrated to have only limited stability
Drug Additions to PN Mixtures and short shelf lives [33] Overall, limited or inconclusive sta-
bility, bioavailability and the potential for introducing con-
It is generally recommended that drugs should NOT be tamination make the addition of all non-nutrient medications
added to PN admixtures unless absolutely necessary. undesirable and generally not recommended
According to ASPEN [33] a decision to make drug additions
should be supported by data on the physicochemical compat-
ibility and stability of the medication and of the final admix- DA Recommendations for Compounding
F
ture, under conditions of typical use. In addition, clinical During the Covid 19 Pandemic and Other
data on the expected therapeutic advantages of incorporating Particles [75]
the drug into the PN admixture should be available. Evidence
is available which identifies the compatibility and stability of Personnel who compound sterile drugs such as PN are
specific drugs in particular PN admixtures [68, 69]. The most required to use PPE to reduce the risk of microbes and other
commonly added drugs are, the histamine type 2 receptor particles present on human skin, hair and clothing contami-
antagonists, heparin, insulin: nating the product they are preparing. Where PPE are in
short supply, the FDA recommends that compounding prac-
tices can be modified as follows
H2 Antagonists
• Use other PPE, if obtainable, that confer equal protection
Cimetidine is stable in PN regimens, and shelf lives of up to • Preserve the existing supply of PPE by
28 days have been indicated in certain mixtures [52]. In con- –– Limiting the number of personnel conducting aseptic
trast, ranitidine is far less stable. Half-lives of only a few activities
days are indicated in many regimens, although it is possible –– Reducing compounding activities
Mitigation strategies to reduce the risk of contamination systems for premature babies and neonates and the regu-
relating to compounding without standard PPE, include latory agencies, MHRA and EMA have now made this a
requirement for PN manufacturers [81, 82].
• Increase the frequency of cleaning compounding areas In practice it has long been a standard recommen-
and gloves dation in UK for all PN systems to be protected from
• Increase the frequency of environmental monitoring light [29, 35, 76].
• Use standard PPE beyond the designated shelf life, if 2. In-line filters during PN administration reduce the poten-
stored appropriately tial for patient harm due to particulates, microprecipi-
• If no other PPE are available: tates, microorganisms, and air emboli. The most recent
–– Reuse masks during the same shift but do not share advice from ASPEN [83] and ESPEN [84] for inclusion
between personnel of a filter in a PN administration system follows the
–– Reuse masks on subsequent days, only if stored cor- much earlier UK recommendations from BPNG [85, 86].
rectly and free from defects It is now generally recommended to use a 1.2 micron
–– Use an appropriate agent to disinfect masks in-line filter for administration of all PN regimens,
–– If sterile gloves are unavailable, non sterile gloves may whether AIO or ‘2 in 1’ PN (without lipid) or ILE
be disinfected and used, after checking material and when separately infused [83].
manufacturers recommendations Single use filters should be placed as close to the cath-
–– Foot covers should not be reused eter hub for AIO admixtures or below the Y-site where the
amino acid/dextrose admixture and ILE co-infuse [83]
and should be changed according to the manufacturer’s
guidelines, typically every 24 h. Due to the potential for
PN Administration After Compounding contamination and subsequent release of endotoxin, fil-
ters should not be connected to the PN system in advance
PN administration errors that occur at the point of patient but should be primed with fluid immediately before initi-
contact are less likely to be intercepted and more likely to ating the infusion.
cause harm. Two relatively simple precautions to be taken When an occluded filter triggers pump alarms, the PN
are: infusion should be stopped and the PN pharmacist should
review the PN formulation to determine if incompatibility
1. To protect the PN system from oxygen and light issues are the cause of the problem and to recommend
2. To filter the PN before reaching the patient. appropriate action.
1. It has been well known since the pioneering work with ractical Tips for Maintaining Stability
P
AIO in Montpelier, France [13] that some components of During PN Administration
PN admixtures are susceptible to oxidation and light cata-
lysed degradation. Photooxidation is defined as a “a • Use an in-line 1.2 μm filter for all PN [83]
chemical reaction occurring as a result of absorption of • Avoid exposure to direct sunlight [76, 81, 82]
light in the presence of oxygen”. The presence (or • Protect the bag content with a light excluding cover [76]
absence) of oxygen is therefore key to the stability of • If possible, light protect the giving set; not protecting the
nutrients in aqueous solution. This phenomenon has been set will lead to some nutrient losses [76]
well demonstrated in our laboratories over the past • Administration at night or well away from a window will
30–35 years [67] and the point is made in the introduction reduce losses substantially [76].
to the UK NHS advisory paper on PN Stability published • The ILE in AIO admixtures may offer some protection to
in 2016 [11] As indicated earlier, vitamins, and ILEs vitamin degradation but will itself be subjected to peroxi-
appear to be the most susceptible to photooxidation when dation [76].
exposed to intense sunlight, including the ultraviolet
range in the presence of air, but ambient light can also
have significant effects [76, 77].
Cressex and colleagues [78, 79] most recently demon- rocedures to Follow Before PN
P
strated that premature neonates, and the critically ill are Administration
most susceptible to light induced oxidative stress. In con-
sequence the most recent guidance from ESPEN [79] and Various Check Lists have been published for final inspection
ASPEN [80] make recommendations to light protect PN of a PN admixture [11, 33, 35].
Key points include: 6. Venek K, et al. A.S.P.E.N. Position paper: recommendations for
changes in commercially available parenteral multivitamin and
multi–trace element products. Nutr Clin Pract. 2012;27:440–91.
• Compare label to prescription 7. Bronsky J, Campoy C, Braegger C, et al. ESPGHAN/ESPEN/
• Compare calculated weight to actual weight ESPR/CSPEN guidelines on pediatric parenteral nutrition: vita-
• Visually check for: mins. Clin Nutr. 2018;37(6, Part B):2366–78.
8. Domellöf M, Szitanyi P, Simchowitz V, et al. ESPGHAN/ESPEN/
–– Colour changes
ESPR/CSPEN guidelines on pediatric parenteral nutrition: iron and
–– Precipitates trace minerals. Clin Nutr. 2018;37(6, Part B):2354–9.
–– Leaks 9. Blaauw R, Osland E, Sriram K, et al. Parenteral provision of micro-
–– Phase separation nutrients to adult patients: an expert consensus paper. J Parenter
Enteral Nutr. 2019;43(Suppl 1):S5–S23.
• Establish an expiry date
10. Hardy G, et al. Parenteral provision of micronutrients to pediat-
• IF IN DOUBT ‘THROW IT OUT’ ric patients: an expert consensus paper. J Parenter Enteral Nutr.
2020;44(Suppl 2):S5–S23.
11. Anon. NHS Pharmaceutical Quality Control Committee. A standard
protocol for deriving and assessment of stability. Part 4- parenteral
nutrition. 2016. www.medicinesresources.nhs.uk/en/Communities/
Parenteral Nutrition Education and Training NHS/UKQAInfoZone.
12. Dudrick SJ, et al. Long term total parenteral nutrition with
PN errors caused by insufficient competency and poor profi- growth development and positive nitrogen balance. Surgery.
1968;64:134–42.
ciency with automatic compounding devices (ACD) are
13. Solassol C, Joyeux H, Etco L, Pujol H, Romieu C. New techniques
areas of concern. A lack of competency-based educational for long term intravenous feeding: an artificial gut in 75 patients.
curriculum in schools of pharmacy or pharmacy technician Ann Surg. 1974;179:519–22.
training programmes in preparation of sterile products and 14. Hardy G. Ten years TPN with 3 litre bags. Pharm J. 1987:H526–8.
15. Furst P. New parenteral substrates in clinical nutrition. Eur J Clin
admixtures, may contribute to PN errors [33].
Nutr. 1994;48:607–16.
PN compounding and administration errors often stem 16. Hardy G, Kleck S, Chourdakis M, Majid H. Towards an interna-
from failure to adhere to the verification steps of PN which tional metrology for clinical nutrition. JPEN J Parenter Enteral
parallel the “five rights” of medication safety: Right patient, Nutr. 2019;43:445.
17. Richelle M, Deckelbaum RJ, Vanwyenberg V, Carpentier
Right drug, Right dose, Right route and Right time. For PN
Y. Lipoprotein metabolism during and after a 6-h infusion of MCT/
these rights must include; confirmation of Patient identity, LCT vs LCT emulsion in man. Clin Nutr. 1997;16:119–23.
visual inspections, verification of PN label, documentation to 18. McMahon MM, et al. Parenteral nutrition in adults in clinical man-
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19. Martindale RG, et al. Lipids in parenteral nutrition. J Parenter
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Nutr. 2019;43:48–470.
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21. Gura K. Aluminium contamination in PN products. Curr Opin Clin
use and effectiveness of double checks and procedures for Nutr Metab Care. 2014;17:551–7.
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23. Pluhator-Murton MM, Fedorak RN, Audette RJ, Marriage BJ,
Yatscoff RW, Gramlich LM. Trace element contamination of total
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Designing Parenteral and Enteral
Regimens
Nicola Vernon, Beth Rye, and Jeremy M.D. Nightingale
Key Points changes or adaptation of the gastrointestinal tract

1. Enteral nutrition (EN) feeding alone is used when there occurs.
is a functional and accessible gastrointestinal tract. 10. In addition to a patient’s nutrient requirements, it is also
2. Parenteral nutrition (PN) is used when there is a non- important, when designing a EN and PN regimen, to
functioning or short gut, inaccessible, inadequate, or consider a patient’s personal wishes and quality of life.
unsafe EN route.
3. A patient’s nutrient (including fluid) requirements start
with understanding their current anatomy and
physiology. Introduction
4. Assessing the macronutrient requirements starts with
calculating the total energy needed, then determining the Wide ranges of enteral nutrition (EN) and parenteral nutri-
protein component and then dividing the remaining tion (PN) regimens are required for different types of patients
energy between carbohydrate and lipid. with intestinal failure. The patients range from the premature
5. The total volume of water and amount of electrolytes newborn infants with necrotizing enterocolitis to adults with
(sodium, potassium, calcium, magnesium, phosphate a short bowel, and from those requiring short-term nutri-
and chloride) needed is determined by firstly calculating tional support in hospital to long-term support at home. The
their baseline requirements, with additions made for any regimens must be of proven efficacy and based on an under-
gastrointestinal losses, for example from vomiting, standing of nutrient requirements in the different groups of
stool, stoma or fistulas. patients.
6. After macronutrient, fluid and electrolyte needs have In general, the gut is used for EN if it is accessible and
been assessed the vitamin and mineral requirements are functional. These requirements are usually less complex
calculated. than those for PN, as the components given are essentially
7. Both EN and PN requirements involve also considering the requirements based upon current/desired growth or
a patient’s; oral intake, degree of gastro-intestinal weight. The nutritional and fluid requirements for patients
absorption and losses (e.g., from stoma/fistula). needing PN are very variable, largely because these patients
8. The initial requirements provide guidance for the pri- continue to eat and absorb some nutrition from their gastro-
mary EN and PN regimen, with it being essential to intestinal (GI) tract. In addition, they may have large fluid
undertake careful monitoring until a stable regimen has losses from one or more stomas or fistulas. It is relatively
been established. unusual for a patient to depend totally upon parenteral nutri-
9. Over-time, the requirements and subsequent EN/PN tion for their nutritional requirements, unless they have a
regimen may change as the clinical needs of a patient bowel obstruction, a gastric/duodenal stoma/fistula or severe
dysmotility.
This chapter considers how requirements vary with
N. Vernon (*) · J. M.D. Nightingale
clinical state in both adults and children, including neo-
e-mail: [email protected]; [email protected] nates. The nutrient requirements of growing children vary
with age, but recommendations at any specified age are
B. Rye
The Hillingdon Hospitals NHS Foundation Trust, Uxbridge, UK based on extrapolations from other age groups. Enteral
e-mail: [email protected] feeds come from the manufacturers already compounded

560 N. Vernon et al.
with all the components, including vitamins, minerals and Table 1 Assessment prior to starting nutritional support
trace elements added, while parenteral feeding bags are 1. Underlying illness and co-morbidities
generally compounded specifically for an individual 2. Gastrointestinal anatomy (e.g. length of small bowel, fistula(s)
patient (bespoke), where most of the components need to etc)
3. Fluid status (e.g. gut losses, oral/intravenous intake, urine output
be specified. Although increasingly patients are being etc)
given ready-made (“off the shelf”) multi- chamber PN 4. Nutritional status (Body mass index (BMI), percentage weight
bags, that are especially useful if there is a problem with loss, mid arm muscle circumference) and current oral/enteral intake
compounding and during a pandemic. Greatest emphasis 5. Outcome targets
will be given to the design of a PN regimen, which is cov- 6. Growth in children
ered before an enteral regimen. It will show how patients
are established, then stabilised on a regimen and how this Table 2 How to work out an adult parenteral regimen
is adjusted with time. 1 Calculate total energy using appropriate kcal per kg body weight;
will need to factor in age, BMI and clinical condition. Add additional
physical activity level as appropriate
Parenteral Nutrition Regimens 2 Calculate amino acid requirement by firstly calculating the
protein requirement; 0.8–2 g/kg/day, then divide by 6.25 g to
calculate nitrogen. Add repletion if appropriate (0.1 gN per kg
After an assessment has been performed (Table 1), there weight lost)
need to be clear objectives for when PN is begun (e.g. treat 3 Calculate amino acid energy: gN × 27
dehydration/undernutrition, reduce diarrhoea, reduce 4 Calculate maximum amount of fat allowed (1.5 g fat/kg)a
obstructive symptoms, improve nutritional status for surgery 5 Calculate carbohydrate energy as: Total energy − (fat
energy + amino acid energy)
etc) and criteria for stopping (e.g. oral intake resumed, surgi-
6 Calculate fat: carbohydrate calorie ratio and ensure it is about
cal resolution, adaptation has occurred, unethical etc). It is 40:60
important that when patients commence PN, that they are 7 Check safety of derived glucose, amino acid and lipid infusion
managed by a multidisciplinary nutrition support team con- rates
sisting at least of a clinician, dietitian, specialist nurse and 8 Calculate/estimate volumes of water, sodium, potassium,
magnesium, calcium and phosphate
pharmacist [1].
a
Many nutrition units divide the non-amino acid energy by 2 to give a
fat: CHO energy ratio of 50:50. The exact ratio then is varied so that all
the contents of a commercial lipid container are used in the feeding bag
The Overall PN Regimen
PN requirements are based upon a careful assessment, which This is not the case for patients with a jejunostomy whose
if the patient is eating will involve an estimate of how much nutritional/fluid requirements change little with time [2].
total fluid/nutrition is being absorbed and lost in secretions.
Whilst the initial regimen will be relatively standardised for
the hospital, the regimen and subsequent prescription at Initial Stabilisation of PN Regimen in Hospital
home will be designed around not only the patient’s nutri-
tional needs but also their wishes and preferences (e.g. nights The formulation of a PN regimen is a stepwise approach
off feed, duration/timing of feed, frequency of lipid, desired aiming to optimise a patients nutritional and hydration sta-
weight, frequency of deliveries etc.), to allow an adequate tus. The stepwise reasoning behind the design attempts to
quality of life. provide enough macronutrients to maintain or improve nutri-
tional status, enough nitrogen to optimise tissue nitrogen
deposition, alongside the fluid, electrolyte, and micronutri-
Anatomical Considerations ent (vitamin/mineral) needs of the patient (Table 2). This is
whilst dealing with the constraints such as volume restric-
If the gut is short (includes an entero-cutaneous fistula that tions for PN stability and/or maximum safe doses of macro-
drains all gut contents) but has normal function, then the nutrients (for example by compromising on the less critical
long-term type of nutritional/fluid support can be predicted carbohydrate: fat ratio), and/or maximum and safe doses of
from a knowledge of the small intestinal length in circuit and the infusion of electrolytes.
the presence or absence of a colon in continuity. With time
(up to 3 years), patients with a colon in continuity are likely Energy: Adults
to have a degree of anatomical (villus hypertrophy) and func- Energy is administered in parenteral admixtures containing
tional adaptation (slowing transit and improvement in some macronutrients with different energy densities: carbohy-
biochemical pathways) so that less PN support is needed. drates (CHO) (~3.75 kcal/g glucose), fats (9.4 kcal/g), and
Designing Parenteral and Enteral Regimens 561
amino acids (~27 kcal/g nitrogen). To know the quantity of Table 5 Combined diet induced thermogenesis and physical activity
each of these to provide in a PN (or EN regimen), it is firstly level (PAL) [8]
important to ascertain what a patients total energy expendi- Description PAL
ture (TEE) and thus overall energy requirements are. In bed and immobile 1.00–1.10
In bed and/or sitting out 1.10–1.20
Whilst total energy intake (EI), can be readily calculated
Limited mobility 1.2–1.25
from the intake of individual macronutrients with known Sedentary 1.25–1.40
energy densities, TEE over a prolonged period of time, can
Reprinted with permission © BDA 2018; Available from Todorovic V
only be accurately and directly calculated by continuous & Mafrici B (2018) A Pocket Guide to Clinical Nutrition, Parenteral &
24-h calorimetry or tracer techniques such as the gold stan- Enteral Nutrition Group, BDA, Sherwood Universal
dard method of doubly labelled water [3]. As this is often not
realistic in clinical practice, more often, TEE is calculated by mia, liver function test abnormalities and high rates of infec-
adding together the perceived components of TEE (Table 3). tion. With often requirements being adjusted to promote
In sick patients a period of negative energy balance, particu- weight gain in those under nourished (BMI <18 kg/m2) and
larly over a prolonged period of time, depletes the body of to avoid over feeding in obesity (BMI >30 kg/m2) (Table 4).
glycogen, fat and protein. This negative energy balance can Particularly in the obese population, regular anthropometry
be corrected by administering more energy than TEE. In is important to monitor changes in body composition and
general, about 0.2 g of tissue are accreted for every kcal prevent rapid muscle loss.
deposited under anabolic conditions. Once the overall energy requirements (TEE) have been
Previously predictive equations were used to estimate calculated, this total is split between the two main energy
basal metabolic rate (BMR) such as Harris and Benedict sources in parenteral nutrition: carbohydrate and lipid.
1919 [4], Schofield 1985 [5] and Henry 2005 [6], with addi- Whilst the ratio of glucose to lipid starts at 50:50 (or 60:40)
tional factors for metabolic stress, DIT and physical activity at first, this ratio is not critical and varies between centres.
added as appropriate [7] to subsequently estimate the Within the first month the glucose to lipid ratio is reduced to
TEE. However, the latest recommendations for energy calcu- approximately 70–85% from glucose and 15–30% from
lations are based on firstly using energy values per kilogram lipid, and particularly if the patient is for long term HPN
of bodyweight or per kilogram of fat free mass, which vary [12]. However, if a central line catheter tip becomes high (in
dependent on a patients age, disease state and body mass SVC or brachiocephalic vein) and replacement is not an
index, to estimate REE [8] (Table 4). Onto this calculation immediate option the feed may be adjusted to have a much
for estimating REE, is then added a combined factor for DIT lower osmolality (to reduce the risk of venous thrombosis)
and physical activity, also known as a PAL (Table 5), as by relying on a high lipid, low glucose content.
appropriate. Whilst these calculations for estimating TEE for Other clinical factors to consider when calculating a
patients vary dependent on age, disease state and BMI, the patient’s estimated energy requirements are:
TEE commonly falls within the range 20–35 kcal/kg/day [9,
10, 12], and rarely more than 40 kcal/kg/day [13]. • Basal Metabolic Rate (BMR): BMR is classically mea-
Care should be taken not to provide excess energy as sured in relaxed, motionless subjects after an overnight
occurred in the 1970/80 s and which resulted in hyperglycae- fast in thermoneutral ambient conditions. Its most impor-
tant determinant is the size of the lean body mass.
Table 3 Components of total energy expenditure Equations that estimate BMR from body weight and
1 Resting energy expenditure (REE) (which is basal metabolic rate height are popular and have been established from mea-
(BMR) ± metabolic stress) surements of BMR in large numbers of healthy volun-
2 Diet induced thermogenesis (DIT) teers. These equations include the Roberston-Reid [14],
3 Physical activity Fleish [15] and Harris-Benedict [4] equations, which have
been found to overestimate BMR of healthy volunteers by
Table 4 Guidelines for estimating resting energy expenditure [8–11] a mean of 0%, +2.5% and + 4.1% respectively [16].
BMI <18.5 kg/m2 25–30 kcal/kg
However, these equations do not necessarily apply to
BMI 18.5–30 kg/ 20–25 kcal/kg patients with disease (e.g. sepsis which frequently accom-
m2 panies intestinal failure (IF)), undernutrition, or distur-
BMI >30 kg/m2 Mifflin St-Jeor (MSJ) Equation: bances in hydration (e.g. oedema).
Men: • Stress factor: sepsis increases BMR by 5–40% [17, 18],
10 × weight (kg) + 6.25 × height (cm) × (age)
+5 fever raises BMR by approximately 13% per °C rise in
Women: body temperature [7]. Intestinal irradiation, chemother-
10 × weight (kg) + 6.25 × height apy, bowel infarction and major surgery also raise BMR
(cm) × (age) − 161 (0–30%).
• Physical activity: intestinal failure (IF) patients, who are Glucose-only regimens are often discouraged initially
bed-bound or mechanically ventilated and minimally active, because they are often associated with higher volumes and
have an estimated physical activity component of about osmolalities, result in higher rates of carbon dioxide produc-
10% of BMR. In contrast, ambulant adult IF patients receiv- tion (a possible clinical disadvantage in pulmonary disease),
ing cyclic nocturnal PN at home have been reported to have and they are more likely to produce hyperosmolar complica-
a physical activity component of about 30% of BMR [19]. tions and essential fatty acid deficiency, than those that con-
Similar, if not higher, values occur in children. tain fat.
• Growth/repletion: additional energy is required for tis-
sue repletion or for normal growth in children (about Lipid: Adults
5 kcal/g of tissue deposited [20]). A positive energy bal- Adult fat infusions are increased cautiously to a dose that
ance (EI > TEE) of about 500 kcal/day in adults can does not usually exceed 1.5 g fat/kg/day or 0.15 g fat/kg/h
achieve slow weight gain, but faster repletion can be and aims to provide no more than 50% of the non-nitrogen
achieved with higher intakes. energy needed. During cyclic PN, gross lipaemia at 6 h after
• Diet-induced thermogenesis: enteral or parenteral feed- ending the infusion indicates the need to reduce the dose of
ing induces a rise in energy expenditure that is p roportional lipid administered since continuation may lead to impaired
to the EI (DIT approximates to 10% of the metabolizable reticuloendothelial and immune function and impaired gas
EI) [19–21]. diffusion across the lung. During continuous lipid infusions,
• Malabsorption: in patients with intestinal failure enteral plasma triglycerides are typically kept below 400 mg/dL.
tube feeding may be poorly tolerated and the absorption is 20% lipid emulsions may be preferable to 10% lipid emul-
poor (50% or more of the energy may not be absorbed), so sions because of their lower phospholipid:triglyceride ratio,
that nutrients may have to be given in increased amounts which is associated with less inhibition by phospholipid
and often continuously. Oral and enteral intake is taken lysosomes of the clearance of infused triglycerides from
into account with an estimate of a malabsorption factor. In plasma.
patients with a short bowel and jejunostomy at 100 cm The infusion of a minimum of 0.5 g fat/kg/day will pre-
from the duodeno-jejunal flexure approximately 40% of vent essential fatty acid (EFA) deficiency, which can develop
the oral diet is absorbed and at 50 cm only 20% [22]. rapidly on continuous glucose-amino acid infusions in the
absence of lipid. Conversion of infused fatty acids to longer
polyunsaturated fatty acids (PUFA), which are necessary for
Carbohydrate: Adults brain development, is slow in infants. Since PUFA are not
Fructose, xylitol, sorbitol and glycerol all have their poten- available for intravenous use, they are given enterally if
tial merits as carbohydrates in PN but glucose (e.g. dextrose tolerated.
monohydrate at 3.4 kcal/g) is both popular and most widely During the preparation of fat emulsions for intravenous
available. Calorimetric studies by King et al. [23]. have use, soya-bean oil or coconut oil are fractionated yielding
shown that infusing dextrose (as the sole non-protein energy long-chain triglycerides (LCT) (14–24 carbon atoms) or
source) at approximately 7 g/kg/day will produce a non- medium-chain triglycerides (MCT) (6–12 carbon atoms)
protein respiratory quotient (npRQ) of approximately 1.0 in [24], emulsified by addition of phosphatidyl-choline and ren-
patients with mild metabolic stress. At this point, fat oxida- dered isosmolar to plasma by the addition of glycerol. While
tion gives way completely to oxidation of glucose. With there are many advantages of giving lipid, it is not consid-
more rapid glucose infusions, up to about 30% of the extra ered appropriate to give it with no glucose, partly because
glucose infused will be diverted into synthesis of new fat, a some tissues have a particular preference or need for glucose
process that dissipates a large amount of the extra energy (leucocytes, repairing tissues, brain), and partly because lean
infused. In severely stressed patients with intestinal failure tissue is more rapidly accreted in the presence of glucose. In
(e.g. peritonitis, post-radiotherapy enteritis) net fat oxidation addition, large doses of parenteral lipids can have detrimen-
(npRQ <1) is likely to persist despite glucose infusions [24]. tal effects.
As a result, such high rates of glucose infusion should nor- Most patients are provided with lipid, in particular in
mally be avoided. those patients with little enteral intake. Long-term intra-
Glucose requirements can be set at 3–6 g/kg/day [12]; venous lipid provision is kept below 1 g/kg/day (i.e.
being aware that excess glucose provision can cause prob- 500 mL 20% intralipid provides 1000 kcal, approxi-
lems particularly with causing hyperglycaemia or abnormal mately 100 g lipid) as above this chronic cholestasis is
liver function tests. Glucose oxidation rate can be calculated common [25]. A 20% soya-based lipid emulsion given
(4–7 mg × kg × 60 × 24/1000 × 4) to give an indication of the once weekly is adequate to prevent essential fatty acid
maximum amount of glucose that can be utilized per 24 h. deficiency. If a patient is having no lipid and has a dry
However, it is possible to exceed these requirements in mal- skin they can apply 10 mL sunflower or safflower oil to
nourished patients requiring weight gain. their skin daily [26, 27].
Medium-Chain Triglycerides Table 6 Approximate recommended intakes of intravenous amino

acids [8, 9, 30]
Compared to LCTs, MCTs are more soluble in phospholipid,
and are present in higher concentrations on the surface of fat Nitrogen (g/
Metabolic stress Example kg/day)a
droplets, which makes them more accessible to tissue lipases.
Nil Healed extensive intestinal 0.128–0.16
Their greater tissue availability is complemented by their resection
ability to cross the hepatocyte mito-chondrial membrane Mild Mild Crohn’s disease in small 0.192
independently of carnitine [27]. Therefore, MCT are cleared intestinal remnant
more rapidly from plasma, and are oxidized more rapidly Moderate Crohn’s fistula with abscess 0.24
than LCT. They are also alleged to cause less depression of Severe Intestinal failure associated with 0.32
acute pancreatitis or severe
immune function [28] and to be more effective in sparing infection
protein in the catabolic patient. Their energy density In obese patients: BMI >30 kg/m2: use 75% of the value estimated
(8.3 kcal/g) is only slightly lower than that of LCT from actual weight
(9.4 kcal/g). Since MCT do not contain essential n3- and n6- BMI >50 kg/m2: use 65% of the value estimated from actual weight
fatty acids (EFAs), commercial preparations are only avail- a
One gram of nitrogen is equivalent to approximately 7.33 g of intrave-
able as a 50:50 MCT/LCT admixtures. Their use might be nous amino acids or 6.25 g of oral protein. Give extra 0.1 g N per kg of
body weight lost. One mole of amino acid (typically ~110 g) contains
considered in the following situations: one mole of water (18 g) derived from the hydrolysis of protein
• Patients with PN-associated liver dysfunction; Balderman & Mafrici B (2018) A Pocket Guide to Clinical Nutrition, Parenteral &
et al. [29] found that PN-associated rises in transami- Enteral Nutrition Group, BDA, Sherwood Universal
nases, liver size and liver density occurred less frequently
with MCT/LCT infusions than with LCT infusions alone. the quoted total energy in a PN regimen (unlike with enteral
• Patients at risk of infusional hyperlipidaemia; the half-life nutrition where the total energy quoted includes the nitrogen
of infused MCT is only about half that of LCT. The faster energy).
clearance of MCT droplets may be due to their smaller
size and less inhibition of lipoprotein lipase (LPL) by fatty Specific Amino Acids
acids released during their hydrolysis, and their metabo- Most commercial parenteral nutrition solutions lack gluta-
lism by different biochemical pathways (see above). mine because of concerns about its instability (spontaneous
degradation to ammonia and pyroglutamic acid). However,
free glutamine can be added to PN solutions shortly before
Nitrogen: Adults use. The alternative is to use a stable dipeptide (e.g. alanyl-
RIV for total amino acids (AA) have been largely based on l-glutamine). Glutamine is a non-essential amino acid that
nitrogen (N) balances, and RIV for specific amino acids on acts as a carbon and nitrogen carrier, e.g. between skeletal
additional measurements of circulating and tissue concentra- muscle, which produces glutamine, and the small intestine,
tions. The doses of amino acids, which yield approximately which utilizes it. Glutamine is an important oxidative fuel
27 kcal/g nitrogen, required to meet patient requirements for the enterocyte, an essential precursor for nucleotide
[30] can be calculated (Table 6). Many patients with intesti- synthesis [34], which is necessary during rapid cell division
nal failure will be nutritionally depleted through malabsorp- (especially epithelial and immune cells) and a regulator of
tion or protein-losing enteropathy, and they may require acid base balance. In rats, glutamine-enriched PN has been
extra nitrogen (up to 0.1 g nitrogen/kg/day) to replete the reported to reduce intestinal villus damage after
protein losses. The nitrogen is more likely to be retained in 5-fluorouracil (5-FU) administration [35], minimize intes-
depleted patients than non-depleted patients in energy bal- tinal disuse-atrophy [36] and restore mucosal integrity
ance. Furthermore, approximately 1–2 mg nitrogen is associated with experimental endotoxaemia [37]. In man,
retained per kcal of energy administered in excess of energy although intravenous glutamine supplementation may
expenditure in non-stressed patients, and possibly more in improve postoperative nitrogen balance, [38] beneficial
depleted patients. In metabolically stressed patients, nitrogen effects on mucosal growth and absorption are not proven
losses may exceed 20 g/day, and positive balances are diffi- [39, 40] or are limited to case studies [41]. However, PN
cult to achieve, even with increased energy and nitrogen regimens enriched with glutamine have been reported to
intake [31]. Large nitrogen losses are documented in sepsis, improve nitrogen balance and reduce hospital stay in
major trauma and burns. An unstressed patient with normal patients undergoing bone marrow transplantation and major
organ function will require 0.14 g–0.2 g nitrogen/kg/day colonic surgery [42, 43]. Other amino acids, which have
[32]. If a patient has a low muscle mass and requires more putative benefits, but which have not always been present in
nitrogen 0.3 g–0.6 nitrogen/kg/day may be used [33]. PN solutions include arginine, which may be an important
It has been customary in some countries, including the immuno-nutrient, and taurine, which may act as an oxidant
UK, not to include nitrogen energy (usually 200–300 kcal) in scavenger during persistent inflammation.
nergy and Nitrogen: Children

E stoma, or fistulae. A clinical guide to the additional quantities
Pre-term infants when starting PN, are often started on of electrolytes that need to be replaced can be established from
6–10 mg dextrose/kg/min, whilst monitoring glucose toler- the composition of different intestinal effluents (chapter
ance, which usually improves with post-natal age. Newborn “Normal Intestinal Anatomy and Physiology”), with patients
infants are at risk of developing tissue carnitine deficiency, with an end-jejunostomy having the highest losses of water,
and infants of low gestational age are at an even greater risk sodium, and divalent cations. Overall, in patients with intesti-
[44]. MCT may be used in such patients because they enter nal failure, it is important to replace these losses, especially
the mitochondrion in a carnitine-independent fashion, where where there are large fluid outputs.
they are oxidized to ketone bodies. Hyperketonaemia, which For the initial regimen, baseline fluid and electrolyte
may have detrimental effects, is prevented by concomitant requirements are calculated (Tables 7 and 8), with the stan-
administration of LCT and/or glucose. MCT have a lower dard ranges initially assuming normal organ function and no
affinity for plasma albumin. This property, together with intestinal losses. Depending on the clinical situation, intesti-
their faster clearance from plasma, makes them less prone to nal anatomy and subsequent gastrointestinal losses of the
displace bilirubin from its binding sites on albumin. This patient, additional fluid, sodium, potassium, and magnesium
minimizes the danger of brain damage by free bilirubin, may be required. Table 9 provides some indication of the
which crosses the blood–brain barrier. In newborn infants an amount of electrolytes lost in different gastrointestinal secre-
initial, continuous, separate, infusion of less than 1 g fat/kg/ tions, to guide the increased amount required. However,
day is slowly increased to a maximum of 3 g fat/kg/day. when using these requirements as a baseline, it is also impor-
Higher infusion rates are more likely to have adverse conse- tant to consider the clinical situation of the patient. Examples
quences including impaired pulmonary gas exchange, and of this include; whilst each litre of most effluents contains
possibly reduced host defense against bacteraemia (a com- about 100 mmol of sodium, acute disease may reduce the
mon accompaniment of necrotizing enterocolitis) [45]. capacity of the kidneys to excrete a sodium and water load,
An infant tolerating 7 mg/kg/min of intravenous dextrose predisposing to dilutional hyponatraemia and refeeding
can be started cautiously on a paediatric amino acid solution oedema. Potassium and magnesium depletion will aggravate
(PAA) increasing to a maximum of 0.34 g N (approximately renal water handling, while protein-losing enteropathy will
2.5 g AA/kg/day) while monitoring serum ammonia and urea produce further sodium retention through hyperaldosteron-
levels. Modern PAA contain an amino acid mixture that aims ism. PN regimens should also consider potassium losses
to establish a circulating amino acid profile that is similar to from gastrointestinal effluents, renal losses due to diuretics
that of healthy breast-fed term infants (or to that of umbilical or amphotericin [49], glucose-induced entry of the ion into
cord-blood in pre-term infants) [46]. However, this cannot cells, and deposition into lean tissue such as muscle (approx-
always be achieved because some amino acids are unstable, imately 3 mEq of K+ per gram nitrogen deposited) [50].
too acidic, or potentially toxic. Furthermore, several solutions Furthermore, it is also important to consider, when calcu-
contain a variety of ‘non-essential’ amino acids that may lating electrolyte requirements that renal calcium reabsorption
become conditionally essential during the metabolic demands is lower during PN induced diuresis [51] and may also be
of refeeding. The following are examples: arginine, because influenced by poor vitamin D status resulting from malabsorp-
its synthesis may not meet the demands of the urea cycle, and
because of possible immune-enhancing properties; cysteine,
Table 7 Estimation of fluid requirements before GI losses considered
because of absence of cystathionase in fetal liver; and taurine [48]
[47], because low circulating concentrations are observed in
18–60 years old 35 mL/kg body weight
infants receiving long-term PN. The low taurine concentra- >60 years old 30 mL/kg body weight
tions may result from the loss of taurine-conjugated bile salts Pyrexia Add 2–2.5 mL/kg for each °C body temperature
in patients without a functioning terminal ileum or due to an is above 37 °C
inadequate supply of its precursor (cysteine) in PN admix-
tures. Therefore, it is recommended that these amino acids are Table 8 Estimation of electrolyte requirements before GI losses con-
included in neonatal PN solutions. sidered [8]
Sodium 1–1.5 mmol/kg
luid and Electrolytes: Adults
F Potassium 1–1.5 mmol/kg
Typical daily intakes of water, sodium, and potassium in adult Magnesium 0.1–0.2 mmol/kg
patients without abnormal gastrointestinal fluid losses are Calcium 0.1–0.15 mmol/kg
about 2.5–3.0 L, 90 mmol and 80 mmol respectively. However, Phosphate 0.5–0.7 mmol/kg or
10 mmol/1000 Kcal
changes in the underlying condition of the patient, particularly
Chloride 1–1.5 mmol/kg
large variations in the loss of gastrointestinal effluents, will
affect these requirements. Patients with intestinal failure may & Mafrici B (2018) A Pocket Guide to Clinical Nutrition, Parenteral &
have variable losses of fluids and electrolytes from stool, Enteral Nutrition Group, BDA, Sherwood Universal
tion, which is associated with low intestinal levels of calcium- Consequentially, the fluid and electrolyte requirements may
binding proteins [52]. It has long been known that the plasma need to be recalculated and subsequent adjustments to the
phosphate concentration can drop precipitously during refeed- content of the PN regimen undertaken.
ing, especially with glucose (no fat) regimens, due to intracel-
lular shifts, which partly result in the formation of intracellular icronutrients: Vitamins and Trace Elements
M
high energy phosphate bonds. Lastly it is important to con- The reference intake value (RIV) for vitamins have been
sider that chronic intestinal losses of divalent cations are wors- largely based on studies of oral intake, with additional incre-
ened by the presence of fat in the diet [53], and are not reversed ments for disease and repletion of stores. The recommenda-
by octreotide [54] or omeprazole [55]. tions are also based on measurements of vitamin status and
As medical and dietary therapy is maximised, (e.g. for on losses during preparation, storage and administration of
high output jejunostomy—restricting oral hypotonic fluid PN admixtures (e.g. photo-degradation of vitamin A, oxida-
restriction, sipping an oral glucose-saline solution and taking tion of vitamin C), thus the RIV of vitamins for PN is often
anti-diarrhea and anti-secretory drugs) and/or adaptation of higher than that for EN (Tables 10 (adult) and 11
the GI tract occurs over time, losses will reduce. (children)).
Table 9 Approximate daily volume and composition of intestinal Secretions produced in response to food (from chapter “Normal Intestinal
Anatomy and Physiology”)
Volume (L) pH Na+ (mmol/L) K+ (mmol/L) Cl− (mmol/L) HCO3− (mmol/L) Mg2+ (mmol/L) Ca2+ (mmol/L)
Saliva 0.5 7 45 20 44 60 0.7 1.3
Gastric juice 2.0 2 10 10 130 0 0.5 2.0
Pancreatic juice 0.6 8 140 10 30 0 0.2 0.3
Hepatic bile 0.9 7 145 5 100 28 0.6 2.5
Small bowel secretion 1.8a 7 138 6 141 <5 <0.1 2.5
Serum 7.4 140 4 100 24 1.0 2.4
Jejunostomy fluid 6 100 15 – – 4.2 16.1
a
This fluid is released and absorbed on the mucosa and rarely needs to be taken into account in calculating fluid losses, estimates of its electrolyte
composition are unreliable
Table 10 Adult recommended vitamin intakes in enteral and parenteral regimensa

Enteral adult Parenteral adult
(b) dose/day (c) dose/day Comments
Vitamin A μg (retinol 700 3300 IU Increased losses in steatorrhoea, high losses in nephrotic syndrome, low storage in
equivalents) liver disease; enteral requirement in IF patients typically 3000–15,000 μg/day [56]
Vitamin D 0–10 5 Increased losses in steatorrhoea, routine PN supplementation may induce
(cholecalciferol) μg hypercalcaemia and osteomalacia [56]; adult recommendations assume adequate
sunlight exposure; IF patients need typically 4000 μg/day by enteral route
Vitamin E (alpha- >4000 10,000–50,000 Requirements depend on iv or enteral intake of PUFA, selenium supplementation
tocopherol) μga decreases requirements; enteral requirements of IF patients typically 34,000 μg/day [56]
Vitamin K μgd 1 μg/kg/day 10 mg Increased losses in steatorrhoea, increased requirements in neonatal period and
menadione/week during broad spectrum antibiotic treatment
Vitamin B1 (thiamine) 900 (males) 1200–5000 Increased requirements during high carbohydrate intake
μg 800 (females)
Vitamin B2 1300 (males) 3600 Contribution by colonic bacteria unquantified, accelerated flavoprotein breakdown
(riboflavine) μg 1100 (females) in catabolic patients interferes with assessment of requirements
Niacin μg 6600 μg (NE) 40,000 Low intakes of tryptophan, pyridoxine or riboflavine may increase requirements
per 1000 kcal
Vitamin B6 1400 (males) 4000 Malabsorbed in diseased/bypassed small intestine, requirements related to total
(pyridoxine) μg 1200 (females) amino acid metabolism (co-factor in transaminases, decarboxylases, etc)
or 15 μg/g
protein
Vitamin B12 1.5 3 Malabsorbed in ileal resection or bypass, utilised by small intestinal bacteria which
(cobalamin) μg reduce its bioavailability
Folic acid μg 200 400 Sulfasalazine reduces absorption, alcoholism increases requirements
Vitamin C (ascorbic 40,000 100,000 Enteral administration further increases risk of oxalate stones in SBS—colon
acid) μg patients. Critically-ill patients probably need 500,000 μg/day iv
Panthotenic acid μgd 3000–7000 15,000
Biotin μgd 10–200 60 Bioavailability of biotin synthesised by colonic bacteria unknown
a Amounts not adjusted for absorption or excess loss of nutrient
b
Amounts based on oral Reference Nutrient intakes (d or safe intake) [57]
c
Refers to patients without excess gastrointestinal loss [56, 58, 59]
Table 11 Child recommended vitamin intakes in enteral and parenteral regimensa

Enteral Enteral Parenteral Parenteral
dose/day Dose/day
Preterm (b, c) Term (d) Preterm (e) Term (e)
dose/kg/day dose/day dose/kg/day dose/kg/day Comments
Vitamin A μg 99–248 350 500 700 Preterm infant invariably depleted at birth. PN-related
(retinol equivalents) toxicity reported in infants at doses above 1300 μg/day
Vitamin D Up to 5.0 8.5 4 10 Concentration in preterm formulas should not exceed
(cholecalciferol) μg 3 μg/100 kcal
Vitamin E (alpha- At least 660 400 μg/g 2800 7000 Preterm formulas should contain at least 0.9 mg/g
tocopherol)a μg PUFA PUFA. Large iv doses induced liver failure in preterm
infants
Vitamin K μgf Nil 10 80 200 Phytoquinolone recommended. Synthetic water-soluble
preparation causes dose dependent toxicity. Preterm
infants need 0.5–1.0 mg im at birth, then 2–3 μg/kg
weekly till breast-fed
Vitamin B1 22–413 200 350 1200 Supplementation of preterm breast milk (20 μg/100 kcal)
(thiamine) μg only if milk is heat-treated
Vitamin B2 66–990 400 150 1400 Renal clearance of excess iv dose reduced in preterm
(riboflavine) μg infant
Niacin μg 90–800 3000 6800 17,000 Preterm formulas should contain at least 800 μg/100 kcal
Vitamin B6 39–413 200 180 1.0 Preterm formulas should contain at least 15 μg/g protein
(pyridoxine) μg and/or 300 μg/100 kcal
Vitamin B12 At least 0.17 0.3 0.3 1000 Marked elevation of serum B12 reported in preterm infants
(cobalamin) μg receiving 600 μg/kg/day iv
Folic acid μg At least 66 50 56 140 Red cell folate levels adequate in preterm infants
receiving 75 μg/kg/day iv
Vitamin C (ascorbic 8300–66,000 25,000 25,000 80,000 Preterm infants need lower doses than term infants to
acid) μg maintain normal plasma ascorbic acid levels (>34 μmol/L)
Panthotenic acid μgf At least 330 1700 2000 5000 Preterm formulas should contain at least 300 μg/100 kcal
a
Amounts not adjusted for absorption or excess loss of nutrient
b
Data from ESPGAN 1987 [60]
C
Data from Lucas 1991 [61]
d
Amounts based on oral Reference Nutrient intakes (f or safe intake) [62]
e
Data from Greene et al. 1988 [63]
The RIV and subsequent parenteral doses of trace ele- The vitamins and trace elements for PN come as commer-
ments have been largely based on those for oral intake, mul- cially ready-made preparations (Tables 14 and 15) which
tiplied by a factor for absorption, which varies from <0.1 to generally provide amounts in excess of basal requirements as
1.0, depending on the trace element. Further adjustments are they are intended for patients who are nutritionally depleted.
made to consider losses in GI effluents and measurements of Depending on the vitamin and trace element status of the
trace element status. For many trace elements, RIV is often patient and enteral absorption, these preparations can be
much lower in PN than EN (Tables 12 (adult) and 13 (chil- given daily or on alternate days. Additional supplementation
dren)). This is because only proportions of trace elements are of vitamins and trace elements, particularly iron, vitamin D,
absorbed via the GI tract. Prolonged excess administration of and selenium, may be needed in addition to PN if serum lev-
trace elements can lead to toxicity because the regulatory els remain low upon monitoring.
role of the gut is bypassed (e.g. the gut is the only major site
regulating iron status within the body). Toxicity may also
occur because of reduced excretion of trace elements in urine djustment of PN Regimen During Hospital
A
(e.g. when there is renal impairment) or in bile (e.g. of man- Stay and the Final Script for HPN
ganese when there is liver impairment).
Vitamins and trace elements are included in PN regimens, Often during the hospital stabilisation period, sepsis is
especially if there is no enteral nutrition or poor GI absorp- treated, and a stoma/fistula output becomes more estab-
tion. However, where ready-made multi-chamber PN bags lished, as does the patients oral intake. Fluid balance usually
are used, the infusion of the vitamins and trace elements dominates the clinical picture and a stable regimen, particu-
must be undertaken separately, or an assessment made on if larly regarding establishing the regimens water and electro-
there is adequate access and absorption via the enteral route. lytes. Fluid balance, weight, clinical symptoms/sign of
Table 12 Adult recommended mineral and trace element intakes in enteral and parenteral regimensa
Enteral
adult
(b) Parenteral
dose/ adult (c)
day dose/day Comments
Sodium (Na) 70 50–100 Healthy gut absorbs >95%, IF patients may require more than 200 mmol/day. Intestinal losses increase
mmol during high enteral intake and decrease during ORS administration
Chloride (Cl) 70 50–100 Healthy gut absorbs >90%, IF patients may need more than 200 mmol/day
mmol
Potassium 90 50–100 Suspend K administration if oliguria develops
(K) mmol
Calcium (Ca) 17.5 6–10 Healthy gut absorbs up to 40%, IF patients may need up to 120 mmol/day [56] patients with a
mmol functioning colon have lower Ca requirements [64]
Phosphorus 17.5 20–40 Healthy gut absorbs 50–60%, IF patients need up to 40 mmol/day
(P) mmol
Magnesium 12.3 6–12 Healthy gut absorbs up to 75%, for clinical hypomagnesaemia give 17 mmol Mg iv over 30 min before
(Mg) mmol starting TPN: steatorrhoea, nephrotoxic drugs, alcohol increase requirements [65]
Zinc (Zn) 142 38–62 Oral phytate, Ca, Zn reduce absorption, IF patients require 1200 μg (18 μmol) per litre of intestinal
μmol effluent, renal losses of Zn increased during amino acid infusions
Copper (Cu) 19 4.7–7.8 Oral phytates, Vitamin C, Cd, Zn reduce absorption, diarrhoeal losses not proportional to effluent
μmol volume, increase Cu intake in diarrhoea, reduce intake in liver dysfunction
Chromium 0.48 0.19–0.29 Glucose loading increases urinary clearance
(Cr) μmold
Selenium (Se) 0.95 0.51–1.01 High losses in pus + fistula fluids
μmol
Manganese 25 1.1–1.8 Absorption: adults <4%, neonates up to 50%, >90% excreted in bile
(Mn) μmold
Molybdenum 0.52– Excreted mostly in urine, significant increased losses in short bowel syndrome; 300 μg (3 μmol)/day iv
(Mo) μmold 4.17 recommended in SBS patients [66]
Iodine (I) 1 PN addition of 1 μg (0.008 μmol)/kg/day recommended only in depleted patients
μmol
a
b
Amounts based on oral Reference Nutrient intakes (d or safe intake) [57]
c
Refers to patients without excess gastrointestinal losses [56, 58, 59]
dehydration (thirst/dry mouth)/over hydration (oedema, onitoring and Adjusting the HPN Regimen
M
raised JVP) are assessed daily and blood tests (renal and liver in Outpatients
function) undertaken as needed (usually 2 or more times a
week). A urine output of greater than 1000 mL/24 h with a During the multi-disciplinary clinic (MDT) visit, a brief clin-
random urine sodium of 20 mmol/L or more is desirable. The ical examination assessing hydration (postural blood pres-
energy given depends upon the oral intake, estimated absorp- sure), nutritional status and underlying condition is
tion (which can be better predicted if a bowel length has been performed. Weight, mid arm muscle circumference, triceps
measured either at surgery or more commonly radiologi- skinfold thickness is measured so BMI and mid arm muscle
cally) [71], blood glucose and weight/muscle mass targets mass can be calculated, along with handgrip dynamometry
(which should increase in hospital). The regimen is adjusted and an oral intake diet history. Blood tests including renal,
until these are all within desirable ranges and weight/muscle liver function, along with mineral (especially magnesium),
mass is on the appropriate trajectory. trace elements and vitamins (mainly fat-soluble ones) [10]
The HPN prescription is formulated towards the end of are taken and a random urine for sodium concentration is
the patient’s hospital admission when they are clinically sta- collected. Over time intestinal adaptation in patients with a
ble and when they are consuming a similar amount of food retained colon may reduce the parenteral requirement for
and drink each day. Depending upon their nutritional and fluid, energy, nitrogen, and electrolytes. In addition, it is
fluid status they are reviewed in outpatients 1–8 weeks after common for a patient’s oral intake to improve at home, and
discharge and subsequently every 3–6 months. this may result in less PN being needed.
Table 13 Child recommended mineral and trace element intakes in enteral and parenteral regimensa
Enteral Enteral Parenteral Parenteral term
preterm (b, c) term (d) preterm (e, f) (f, g) dose/kg/
dose/kg/day dose/day dose/kg/day day Comments
Sodium (Na) 1.3–3 9 3–5 2–4 Beware of hyponatraemia due to high insensible water
mmol loss, hypotonic diarrhoea, immature renal tubular Na
reabsorption
Chloride (Cl) 1.4–3.2 9 3–5 2–3 Doses of Cl above 6 mmol/kg/day may cause
mmol hyperchloraemic acidosis
Potassium (K) 2–5 20 1–2 2–3 Beware of non-oliguric hyperkalaemia due to immature
mmol distal tubular secretion of K
Calcium (Ca) 1.9–5.7 13.1 1.5–2.2 0.2–1.2 During low fluid intakes Ca and PO4 in PN should be in a
mmol 1:1 molar ratio and should not exceed 15 mmol/l [63]
Phosphorus (P) 1.8–4.8 12.9 1.5–2.2 1–2
mmol
Magnesium 0.3–0.8 2.3 0.3–0.4 0.12–0.5 Danger of hypermagnesaemia in renal insufficiency
(Mg) mmol
Zinc (Zn) μmol 9.3–27.9 61 6.1 3.8 PN intakes refer to stable infant [67]; 2–3 times more Zn
may be required during diarrhoea
Copper (Cu) 1.6–3.1 3.1 0.32 0.32 PN intakes refer to stable infant [67]; do not administer iv
μmol Cu in cholestasis
Chromium (Cr) 0.004 0.004 Do not supplement preterm enteral formulas routinely
μmolh
Selenium (Se) 0.13 0.025 0.025 Do not supplement preterm enteral formulas routinely
μmol
Manganese 0.04–0.24 0.3 0.018 0.018 1 μg (0.018 μmol)/kg/day induces positive Mn balance in
(Mn) μmolh infants without diarrhoea [67]; withhold iv Mn in
cholestasis; monitor Mn status by serum levels [56] and
MRI [68]
Molybdenum 0.015–0.05 0.003 0.003 Do not add Mo routinely to enteral formulas or short term
(Mo) μmolh PN regimens [67]
Iodine (I) μmol 0.09–0.58 0.39 0.008 0.008 Infants absorb extra iodine from topical disinfectants
a
b
Data from ESPGAN, 1987 [60]
c
Data from Lucas, 1991 [61]
d
Amounts based on oral Reference Nutrient intakes (hor safe intake) [62]
e
Data from Yu, 1992 [69]
f
Data from Greene et al, 1988 [63]
g
Data from Poole 1983 [70]
Table 14 Sources of parenteral micronutrients Table 15 Sources of parenteral vitamins

Trace Addaven Nutryelt Tracutil Fat soluble vitamin Vitlipid adult Cernevit
element (μmol/10 mL) (μmol/10 mL) (μmol/10 mL) Vitamin A (μg) 990 1000
Zinc 77 153 50 Vitamin E (μg) 9.1 10.2
Copper 6 4.7 12 Vitamin K (μg) 150 –
Selenium 1.0 0.9 0.3 Vitamin D (μg) 5 5
Iron 20 18 35 Water soluble vitamin
Manganese 1 1 10 Vitamin B1 (μg) 3.1 3.5
Chromium 0.2 0.19 0.2 4.9 4.1
Vitamin B2 (μg)
Molybdenum 0.2 0.21 0.1
Vitamin B6 (μg) 4.9 5.5
Iodine 1.0 1.0 1.0
Niacin (μg) 40 46
Fluoride 50 50 30
Folic acid (μg) 400 414
Vitamin B 12 (μg) 5.0 6.0
Biotin (μg) 60 69
Vitamin C (μg) 11 125
actors with HPN That May Result in Adjusting

F Enteral Nutrition Regimens
the Feeding Regimen
The calculations for energy requirements are the same as for
Poor Sleep parenteral nutrition, however the nitrogen supplied is quoted
Patients are often kept awake at night by the pump noise and/ in grams of protein. Examples of typical commercial enteral
or its bright lights and they may get up 2–3 times during the feeds are shown in Table 16. Whilst the composition of the
night to pass urine. These problems can be reduced by hav- commercial enteral feeds is set and unable to be manipu-
ing nights free from feed, keeping the feed volume as low as lated, occasionally more sodium chloride (to bring the total
is possible to maintain hydration and running the feed sodium concentration to 100 mmol/L) is added to the feed, in
through as fast as is safe. Whilst one of the main aims is to patients with high output stomas or fistulae while trying to
give the feed on as few nights as possible, this can usually be keep the osmolality near to 280–300 mOsm/kg.
easily done in patients with a colon in continuity but not in Although early minimal enteral feeding (MEF) (e.g.
patients with a jejunostomy who rapidly become salt and 200 mL/day in adults) does not contribute significantly to
water depleted and need fluid daily. Some patients prefer to nutrient requirements, it may help to reduce PN-associated
feed during the day and may have a backpack containing a intestinal atrophy and minimise trans-intestinal bacterial
pump and the feeding bag. translocation. The addition of low-dose enteral feeding to
intravenously fed rats has been reported to increase nitrogen
Cramps retention, reduce bacterial translocation [73] and reduce
Many complain of cramps during the feed [72]. This may be PN-associated increases in macromolecular lactose permea-
due to a low sodium concentration feed that is given quickly bility [74]. MEF increases neonatal gut motility and pro-
or due to sodium depletion. In the long-term these can be motes the release of gut trophic hormones, such as gastrin
corrected by increasing the sodium content in the feed, but in and enteroglucagon. Enteral feeding has been reported to
the short-term immediate relief can be obtained by taking reverse PN-induced enterocyte atrophy in human volunteers
oral table salt. Magnesium depletion may also contribute. [75] and to preserve intestinal mucosal integrity in PN-fed
Thirst
While thirst is most commonly due to water and sodium Table 16 Composition of typical enteral feeds per 100 g
depletion, it can also be due to high concentrations of sodium Elemental
in the feed. A low random urinary sodium gives an indication (ca
Polymeric (ca Monomeric (ca 0.75 kcal/
of the cause.
1 kcal/mL)a 1 kcal/mL)b mL)
Energy (Kcal) 440 440 364
aint/Nausea When Feed Stops
F Fat:CHO:Protein 38:49:13 38:49:13 17:71:12
This can be due to reactive hypoglycaemia and may be energies (kcal)
avoided if the feed is slowed gradually over the last hour of CHO (g) 60 59 70
feeding; also known as ramping the feed. (maltodextrin) (maltodextrin)
Lactose 0.17 0 0
Protein 13.8 (whey 13.8 (peptides, 10.0 (as
nwell After Feeds Containing Lipid
U protein) 86% of amino
Many patients complain of malaise, joint pains and/or nau- MW <1000) acids)
sea after a lipid feed. It can be given less frequently (e.g. Gluten Nil Nil Nil
once a week) or occasionally it is omitted altogether. Glutamine (g) Nil Nil 0.09
Fat (g) 18 (arachis oil) 18 (sunflower + 6.64
Alternatively, sometimes changing to a different lipid prepa-
MCT oils) (arachis oil)
ration helps. LCT:MCT 100:1 17:83 100:1
Fibre Nil Nil Nil
requent Feeding Bag Deliveries (Feed Bag
F Osmolality 269 389 684
Stability) (mOsm/kg)
If a bag has good stability, it may be delivered every 2 or a
IF patients with normal transit time and good pancreatic function may
more weeks. If not, then it may be weekly. Stability is more absorb LCT
b
Moderate osmolality, peptide content, and MCT supplementation are
likely to be a problem if there is lipid in the feed or if the feed desirable properties in IF patients, fibre supplementation should be
is of a very large volume (e.g. 4 l or more). considered
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Nursing Care of Patients Receiving
Home Parenteral Support
Cathy Cawley and Mia Small

1. The aim of nursing care of patients receiving home paren-
teral support (HPS) is for the patient to understand their The loss of a major organ’s function challenges the integrity
condition, treatment and potential complications and so of the whole person. Although the primary changes may be
feel in control and able to enjoy an acceptable quality of physical they have an impact on how the person thinks and
life (QOL). feels and this can impact upon future enjoyment of life.
2. An intravenous catheter with the minimum number of Some patients with intestinal failure (IF) experience only
lumens to meet the vascular access needs of the patient a short illness before complete recovery whereas others such
should be used so as to reduce the risk of catheter-related as those with an entero-cutaneous fistula may have longer
complications. periods of illness, possibly being left with a stoma an open
3. A peripherally inserted central catheter (PICC), tunnelled wound, or in some cases both. A few are left permanently
cuffed Hickman™ type catheter or totally implanted port affected requiring long-term enteral and/or parenteral sup-
can be used for home parenteral support (HPS). port. All patients require the same level of attention to their
4. The choice of device should be made between the clinical needs. Even those who appear to have responded well to
team and the patient/carer and take into account an assess- treatment and achieved excellent clinical outcomes may be
ment of the patient’s veins (ultrasound/venography). The left with disabling fears resulting from their experiences.
catheter/vein ratio should be 45% or less. Hospital admissions can be prolonged and the external
5. Catheter manipulations should be kept to a minimum, and world shrinks to that around the bedside, with the healthcare
an aseptic non-touch technique (ANTT) should be used team, particularly nurses who usually spend most time with
for all procedures. Key elements of the technique include the patient, becoming the focus of social contact. Interactions
hand decontamination, not touching key parts, ensuring take place while the nurse is giving personal care and treat-
that sterile items do not come into contact with non sterile ment. As progress is commonly very slow and the care
ones, and effective disinfection of the needle free connec- required exacting, for example changing a fistula appliance,
tor/catheter hub. nursing such patients can be physically and emotionally
6. Patient discharge on HPS requires a collaborative multi- demanding.
disciplinary approach which covers; Support systems to maintain the well-being of nurses,
• Funding enabling them cope with the stress resulting from the care of
• Delivery of the prescribed parenteral support patients with IF need to be built into departmental organiza-
• The ancillary items required to administer it tion. This can be achieved through strong leadership from an
• Who is going to care for the CVC expert clinical nurse, staff development programs, an open
• Ongoing support and information about how to obtain environment where feelings can be shared and the clinical
advice quickly. governance systems provide a framework for safe, up to date
evidence based, low risk practice during hospital care, reha-
C. Cawley bilitation and ongoing treatment at home. Obtaining and
Salford Care Organisation, Part of Northern Care Alliance (NCA), maintaining physiological stability often takes priority over
Salford, UK other aspects of care because the physiological consequences
M. Small (*) of intestinal failure can threaten survival and impair other
Nutrition and Intestinal Failure, St Mark’s Hospital, functions, such as the ability to think clearly, understand and
Harrow, Middlesex, UK
learn.

574 C. Cawley and M. Small
This chapter aims to outline the nursing care of patients The role of the nurse is to help the patient identify where
receiving HPS. It is recognised that the set up and continua- equipment will be stored in the home, alongside facilitating
tion of HPS at home will vary from country to country. their understanding of the medical devices they now require,
Examples from the process in England where there is a for example their central venous catheter, stoma/fistula appli-
national framework agreement for the supply of HPS ser- ances or enteral tubes.
vices are given for reference. Where specific products are
mentioned, this is for information only and should not be
seen as an endorsement. The chapter will cover the patients’ Central Venous Catheter
understanding of intestinal failure, equipment used, the pro-
cedures to connect and disconnect the HPS, and common Reliable venous access is required for home parenteral sup-
problems or complications. port. To reduce irritation to the vein it is given via a central
venous catheter (CVC)—CVC or “line”—that has been
inserted into a large vein with good blood flow. In most peo-
he Patients’ Understanding of Intestinal
T ple this will be the superior vena cava. Occasionally, if this
Failure vein is not suitable/accessible the inferior vena cava is used.
To reduce the risk of thrombosis the catheter tip should be at
Some of the features of intestinal failure which may include the vena cava/right atrial junction [1]. Although popular in
pain, nausea, diarrhoea, the effects of fistulas, difficult sto- some countries, the use of an arterio-venous fistula for paren-
mas, electrolyte imbalance and undernutrition can under- teral support is not widely used.
mine the patients’ dignity and sense of self-worth. There Ensuring the catheter is accessible to the patient and in a
may be frequent, prolonged hospital admissions and numer- position where it will not be visible when clothing is worn is
ous operations, each one being more difficult to face as the of equal importance to selecting a device suitable for long-
patients’ experience of perioperative problems increase. term use. The choice between a PICC, Hickman™ type cath-
During acute illness feelings of helplessness are common eter with an external segment and a totally implanted port
and realistic. There is little the patient can control and events should be made following discussions with the patient,
appear as an assault on the body and mind challenging the although choice of device may be limited to what is available
patients’ belief in themselves as autonomous adults. For at the hospital and who holds the budget for vascular access
example, an inability to control the bowel and possibly see- devices. Factors affecting the choice of catheter used include
ing, and smelling, faeces draining from an abdominal wound how long it is needed, the condition of the veins, and lifestyle
may evoke primitive feelings about bowel function and being considerations. As patients with IF may require lifelong vas-
controlled by others in early life. Open wounds are often in a cular access it is imperative that measures are taken to pre-
position where the patient can look into the body and see serve the viability of the patient’s veins—peripheral and
physical evidence of degeneration. central, and it is suggested that a validated assessment guide
For the patient who develops chronic IF there is the such as the UK Vessel Health and Preservation (VHP)
daunting task of learning how to manage the condition at Framework is used [2]. In addition, vein lumen size should
home, of becoming re-integrated into the family and soci- be measured using an ultrasound as the size of catheter
ety, and adapting expectations of daily life to one which within the vein can result in a reduction in flow and increased
may be different from that of other people and from their rate of catheter related thrombosis [3, 4]. To reduce the risk
premorbid life. Until discharge the patient may not have got of thrombosis a catheter vein ratio of 45% or less [3–5] is
dressed and the transition from being in a hospital gown to recommended. While these studies have been on PICCs the
putting on clothes should not be underestimated. The same principle can be applied to Hickman™ type catheters
patient has entered an unfamiliar arena where jargon and and totally implanted ports.
medical abbreviations are widely, used and the nurse is Catheters can have one, two or three lumens. To reduce
well placed to provide information in a simple to under- the incidence of catheter associated complications—most
stand format. It is important that the patient understand notably infection—the minimum number of lumen to meet
their new anatomy, how it has altered, and the length of the patient’s vascular access requirements should be selected
residual bowel they have. [6–8]. Figure 1 shows a single and double lumen catheter.
The patient being discharged on HPS will need to use, The design of a triple lumen catheter is the same as a dou-
and find space for, numerous pieces of medical equipment. ble lumen but with an extra lumen.
Nursing Care of Patients Receiving Home Parenteral Support 575
Fig. 1 Single and double lumen catheter
eripherally Inserted Central

P
Catheter
Peripherally inserted central catheters (PICC) are inserted

via one of the veins in the upper arm with the tip lying in the
superior vena cava. See Fig. 2. Single, double and triple
lumen PICC are available.
Due to their ease of insertion and removal PICC are often
chosen for individuals who only require home parenteral
support for a few months. They can however remain in place
for years. The device with the minimum number of lumen to
meet the patient’s vascular access requirements should be
selected, and it must be appreciated that the double and tri-
ple lumen PICC will be a larger Fr gauge than single lumen Fig. 2 Peripherally inserted central catheter (PICC)
devices so as to accommodate the multiple lumen
(1 Fr = 1/3). This can increase the risk of catheter related Table 1 Types of adhesive and mechanical securement
thrombosis [9]. In the UK PICC are inserted directly into Securement
the vein however, some overseas centres tunnel the PICC type Examples
with the intention of reducing the risk of infection and Adhesive Gauze and surgical tape
thrombosis [10]. While their study established that the tun- Steri-strips and semi-permeable transparent dressing
nelling technique was successful, they conclude that the Combination dressing and securement, for example
SorbaView® SHIELD
extent to which tunnelling a PICC reduces complications
Manufactured sutureless device, for example
warrants further study. Statlock®, or Griplok®
PICCs need to be secured and covered with a sterile dress- Tissue adhesive
ing. Careful consideration needs to be given to the method Mechanical Subcutaneous metal skin anchor - SecurAcath®
used as inadequate securement could lead to a number of
complications for example; outward PICC migration, infec-
tion, vessel trauma from the catheter being able to move in Adhesive securement devices need (Fig. 3) to be changed
and out of the vein (“pistoning”), and medical adhesive- weekly, or at any time they become loose or soiled. To reduce
related skin injury (MARSI) [11–13]. Broadly speaking skin damage the manufacturers advice about removal should
methods can be classed as adhesive or mechanical. See be followed (e.g. some must be removed with alcohol con-
Table 1. taining products).
Fig. 3 Commonly used

adhesive securement devices
Statlock ® Griplok®
Fig. 4 Mechanical
securement
device—SecurAcath®
SecurAcath® has been the subject of a National Institute Tunnelled Cuffed Hickman™ Type Catheter
of Clinical Excellence (NICE) Medical Technology
Assessment [12, 13]. They concluded that there was evi- This type of device is the one most commonly used for HPS
dence to support the use of the device in reducing uninten- as they can remain in place for many years (Fig. 5). It is
tional catheter migration especially when the PICC would be named after Dr Robert Hickman who led the group of sur-
in-situ for more than 15 days (Fig. 4). geons that developed it [14]. The catheter is tunneled under
Cyanoacrylate glue has been used successfully by a num- the skin to exit the body on the chest wall. It is held in place
ber of centres to stabilise a PICC, however a review of the underneath the skin by a small cuff made from a felt-like
evidence supports its use primarily as a means to reduce post material called Dacron™ that the body forms scar tissue
insertion site bleeding and extra-luminal catheter contamina- around. The term Hickman is a trademark and refers to a tun-
tion [11]. neled catheter of a particular size made by one company;
a The catheter in situ
b The skin tunnel and cuff
Fig. 5 Hickman™ type catheter. (a) The catheter in situ. (b) The skin tunnel and cuff
however it tends to be used to refer to any make or size of Totally Implanted Port (“Port-a-cath™”)
tunneled cuffed catheter. Nutrition teams often use a
Broviac™ catheter, which is narrower (6.6Fr) than a A totally implanted port is a small metal reservoir filled with
Hickman™ (9.6 Fr). The smaller size is believed to reduce a self-sealing silicone disc. The port is inserted under the
the risk and incidence of thrombosis as there is a better cath- skin on the chest wall. The port has an attached catheter
eter : vessel ratio with the smaller sized device taking up less which is inserted into the superior vena cava via the subcla-
vessel space than the larger [3–5]. Single, double and triple vian or internal jugular vein. Totally implanted ports are
lumen devices are available. often called “ports” or “Port-a-Cath™ which was the name
Hickman™ type catheters need to be secured until the of the first manufactured device (Fig. 7a).
cuff becomes embedded (Fig. 6). This is achieved by either The implanted port is accessed by inserting a removable
suturing around the line or using a removable stitch fixation infusion set with a non-coring (Huber) needle through the
device which can either be sutured in place or attached with skin and silicone disc (Fig. 7b). Using a hypodermic needle
an adhesive securement device. One make of Hickman™ will remove small sections of the silicone disc on removal
catheter has two suture rings bonded onto the catheter which thereby reducing the lifespan of the device. The needle needs
allows sutures to be placed. to be long enough to go through the silicone septum and
The sutures/devices only need to be in place until the cuff reach the back of the port. Failure to reach the back of the
has become embedded—typically 3–6 weeks. port can result in sluggish flow or occlusion.
Fig. 6 Hickman™ catheter

securement methods
Fig. 7 Totally implanted a Front view

port. (a) Front view. (b)
Lateral view with the needle
in the port
b Lateral view with the needle in the port

Fig. 8 Portacator® port

location device
At the end of the infusion the infusion set can be removed stabilizing the port and isolating the silicone septum
leaving the patient with no visible device during infusion [15]. See Fig. 8.
free periods. The infusion set can be left in situ for up to 7
days, however, there is no definitive data to support this [7,
15]. Further study is needed to determine how long it is safe Valved Catheters
to leave an infusion set in-situ and if this guidance would
vary depending on the nature of the infusate, for example Valved catheters have a pressure sensitive bi-directional
parenteral nutrition or chemotherapy. valve at either the distal or proximal end of the catheter. The
Using an implanted port for home parenteral support valve is believed to reduce the risk of blood backflow and
relies on successful insertion of an infusion set with Huber subsequent catheter occlusion. As the valve prevents air from
needle. As such their use is not suitable for patients with a entering the catheter they do not have a clamp. The pressure
needle phobia. sensitive valve is closed unless a syringe or giving set is
Fluctuation in weight and how mobile the port is attached and fluid injected. The valve will also open if the
within the skin pocket can make insertion difficult, plunger on an attached syringe is pulled back thereby allow-
which can lead to missed infusions and/or the possibility ing blood sampling. Some patients prefer valved catheters as
of insertion in the subcutaneous tissue. Multiple attempts the absence of the clamp makes the catheter more discreet
at insertion can not only be painful, but increase the risk and comfortable (Fig. 9).
of infection particularly if the same needle is used for There is mixed evidence surrounding the benefit of a
successive attempts Using a port location device valved device vs. a non-valved one, a summary of which can
(Portacator®, PFM Medical), can help overcome this by be found in Table 2.
Fig. 9 Common valved catheters
Table 2 Comparison of valved vs. non valved catheters Table 3 Central venous catheter selection
PICC Tunneled Port Catheter
PASV less PASV easier to More catheter type Advantages Disadvantages
occlusions than aspirate than non malfunction valved vs PICC • Easy to insert at • Require addition of extension set
Groshong, n = 100 valved, n = 54, non valved p < 0.05 bedside to be able to self access
p = 0.06 [16] p = 0.004 [17] [18] • Non invasive • Requires constant use of
Solo vs PASV vs PASV easier to Increased ball valve easy removal at dressing and securement device
unvalved, n = 180, aspirate vs non effect → risk of the bedside
no difference [19] valved, n = 73, thrombosis n = 356 • Waterproof • Visible if short sleeved clothing
p = 0.02 [20] p < 0.01 [21] covers available to worn
n = 35 no difference in allow bathing and • Increased risk of thrombosis
infective or mechanical swimming • Not all PICC can be repaired
comps [22] Hickman™ • Longevity. Can • Requires surgical cut down to
type remain in place for remove
many years
• Infected devices
Power Injectable Catheters can often be
salvaged
Power injectable catheters are designed to withstand power • Not visible under
injection of CT contrast. They are available in PICC, clothes
• Can be repaired
Hickman™ type catheters and totally implanted ports. To
• Minimal scarring
distinguish them from non-power injectable devices they are left on removal
usually purple and/or have purple hubs. This could poten- • Waterproof
tially lead to wrong route administration as the purple has covers and
been adopted by most enteral tube and syringe manufactur- dressings available
to allow bathing
ers. Due to them being made from stronger polyurethane and swimminga
there is concern that their use is associated with a higher risk (continued)
of catheter related thrombosis than in non-power injectable
devices [9].
There are many considerations in selecting a central cath-
eter for an individual patient (Table 3).
Table 3 (continued) the catheter. The individual specification of devices varies in

Catheter several ways;
type Advantages Disadvantages
Totally • Not visible when • Shorter lifespan than Hickman™ • Connection surface (flat or slightly recessed)
implanted not being accessed type device due to the eventual • Dead space
port failure of the silicone septum to
seal after needle removal
• Fluid pathway
• No need for a • Need to insert needle to access, • Frequency of change
covering dressing so not suitable for anyone with • Intricacy of valve mechanism
when not in use needle phobia • Amount of fluid displacement on insertion or removal of
• No restriction • Removal either under local or a syringe
with bathing and general anaesthetic
swimming • Noticeable scarring on
–– Positive connector—a small amount of infusion fluid
removal is forced into the catheter end
• Salvage of infected devices –– Negative connector—a small amount of blood moves
difficult due to surface area of the back into the catheter end
port chamber and silicone disc, –– Neutral connector—no movement of fluid in either
and the inability to target
antibiotic therapy to all of the direction
puncture sites a needle has been • Clamping sequence
inserted –– Positive connector—apply clamp after removing
Valved • More discreet as • Risk of air entry if valve fails syringe
do not need a
clamp –– Negative connector—apply clamp before removing
• Valve might help syringe
reduce risk of –– Neutral connector—apply clamp before removing
occlusion syringe
Power • Allow power • Increased risk of thrombosis • Ease of application/access
injectable injection of CT • Potential for wrong route
contrast administration as purple is
commonly used to denote The extent to which these features may, or may not, influence
enteral devices and syringes catheter related complications such as infection and occlu-
a
Several waterproof options for patients with Hickman™ are now avail- sion has yet to be determined [7, 23]. For the patient being
able; Independence Activity Pouch (Independence Direct), Cath Dry™ discharged on HPS the two most important considerations
pouch and Secuderm® dressing (Vygon UK). Within England, the
are the connection surface and how easy it is for it to be
Independence Activity Pouch and Cath Dry™ pouch are available via
NHS Prescription, while Secuderm® can be supplied via the national effectively disinfected, and the ease of application and
framework access. Some connectors have a smaller profile and as such
can be difficult for some individuals to apply, connectors
with an irregular surface may not always be adequately dis-
infected, while some connectors require more force to
Needle Free Connector depress the valve with a syringe. Logistically, which connec-
tor is used in the home will depend on what is available
A Needle Free Connector (NFC) is a removable device locally. Under the national HPN framework for England any
which permits the connection of administration sets and make of connector can be requested which means that the
syringes to the hub of an intravenous catheter without the use individual needs of the patient can be met. Manufacturer’s
of needles. When in situ they create a closed system which guidance should be followed regarding the frequency of
prevents air entry and minimises bacterial ingress (Fig. 10). change as this can vary.
Their use in patients on HPS is recommended to help reduce It is important that the patient knows the name of the con-
bacterial contamination of the catheter [7]. nector they have, and that there are different brands avail-
There are many different connectors available, but they all able, so that if they are admitted to a hospital that uses a
work in a similar way. The connector has an internal 2-way different brand they understand that this is an acceptable dif-
valve which is depressed when a syringe or intravenous giv- ference. This is particularly relevant on discharge so that the
ing set is applied allowing fluid to flow into the catheter. patient knows to remove the connector used in hospital and
Depressing the valve also permits blood to be drawn from apply the one they are supplied with at home.
Fig. 10 Commonly used Needle Free Connectors
Fig. 11 Port protector cap
Port Protector Cap have been followed by other prospective studies [26, 27], in-
vitro evaluation [28] and abstract presentations also showing
A port protector cap is a single use protective cover, similar to a reduction in infection rates As the success of passive disin-
a bottle cap in design, containing a 70% isopropyl alcohol foam fection relies on full contact of the alcohol impregnated
disc (Fig. 11). When applied to a needle free connector during sponge with the surface of the needle free connector know-
infusion free periods it provides continuous passive disinfec- ing which brand of port protector and needle free connector
tion plus a physical barrier to cross contamination. There are a was evaluated is essential. It is also important to note that to
number of different caps available but they all work in the same date there have not been any comparative studies evaluating
way by providing direct contact with the surface of a needle each available protector on each available needle free con-
free connector with 70% isopropyl alcohol. nector. Muslim patients need to be reassured that there are no
Initial studies have shown promising results in reducing restrictions on them using any medical devices containing
catheter related bloodstream infection [24, 25], and these alcohol [29].
In-Line Filters Table 4 Pump parameters

Parameter Comments
Although intravenous solutions may appear clear to the Pump weight and size • Noise level increases with increase
in flow rate
naked eye, they contain particles of 1–25 μm, which can
• Pump weight needs to factor in
induce sterile inflammation and cause granulomas elsewhere weight of parenteral support bags
such as lungs and brain [30]. The particles consist of glass, Battery • Can the patient receive their full
cotton fibres, precipitated proteins, microcrystalline drug infusion on a single battery charge?
particles, degenerative products of interactions between flu- Giving set • How easy is it to grip and insert?
ids and glass, plastic and even rubber stoppers. Some arise • Is the giving set kink resistant so as
to reduce occlusion alarms?
from glass ampoules [31] and some from syringes them-
• How easy is it to place in the
selves [32]. Consequently, the use of in line filtration is com- pump?
mon practice for patients on home parenteral support, and Backpack • How easy is it to secure the pump
the importance of using a 1.2 μm filter is reiterated in an and infusion fluid?
American Society for Parenteral and Enteral (ASPEN) • What carrying options, handle(s),
wheels, carrying straps are available
Position Paper [33]. As well as filtering out particulate mat-
Programming the • How easy is it to programme?
ter, in line filters can also filter some harmful bacteria. It is pump and alarms • Are keys intuitive to use and easy to
for this attribute that The European Society of Enteral and depress?
Parenteral Nutrition (European Society of Clinical Nutrition • Are pump alarms easy to understand
and Metabolism) (ESPEN) recommend their use [7]. and correct?
In line filters are integrated into all ambulatory pump giv- Adapted with permission from LITRE (Looking into the Requirements
for Equipment) [36]
ing sets primarily to filter out air as the giving set does not
have a drip chamber. A separate in line filter should be used
if patients are using a static pump. If patients are receiving
any long term IV medication the use of a filter straw or nee- Central Venous Catheter Care
dle to draw these up and reconstitute will provide additional
protection against particulate matter. Reducing the risk and incidence of central venous catheter
related infection is paramount in the care of patients receiv-
ing parenteral support. To reduce the risk of infection it is
Infusion Pumps important to understand how infection occurs, and where
infection comes from. There are a number of ways in which
Infusion pumps and accessories used for home parenteral infection can occur. The skin surrounding the exit site is the
support have evolved over the years, with advances in the size major source of local infections, whereas the catheter hub is
and weight of the pump, battery life, running noise and back- the major source of blood stream infections [37].
pack design. In England ambulatory pumps are now standard Local infections can occur if the skin becomes over colo-
practice for all patients which is in stark contrast to 20+ years nized by micro-organisms. This could be from the environ-
ago when only 7% of patients had them [34]. The freedom ment (for example if the area is not kept covered with a
of movement with an ambulatory pump has been associated sterile dressing), from the hands during dressing changes if
with an increased quality of life [35]. Pump selection will they have not been adequately washed, from using contami-
depend on what is available locally, but if there is a choice nated (unclean) equipment, or contact with body fluids, for
then consideration should be made including the parameters example stoma or fistula content.
listed in Table 4. One pump may be more suitable for a patient Catheter hub contamination can occur from the hands,
than another, especially with respect to ease of inserting the from any contact with non-sterile equipment, from using
giving set into the bag of parenteral support, inserting the giv- contaminated equipment, or contact with body fluids, for
ing set into the pump, and programming the pump. example stoma or fistula content.
many Key-Parts/Sites count as numerous, which can lead to

confusion and debate between health care professionals as to
which technique is the correct one to use. It is important to
remember that the principles are the same for each approach,
so both are acceptable for central venous catheter care for
home parenteral support. The most important thing is that the
key principles—“A” “N” “T” “T” are followed as described
below.
A: Always Wash Hands Effectively
Hands are the most common vehicle by which micro-

Fig. 12 General principles of ANTT® organisms are transmitted; therefore effective hand hygiene
is essential to remove them and reduce the risk of infection.
Hand hygiene is a general term that covers both handwash-
Aseptic Technique ing and hand decontamination. This can be achieved by
using an antibacterial hand wash solution, or a combination
The risk and incidence of local and systemic infection can be of non-antibacterial hand wash solution followed by antimi-
significantly reduced if there are strictly adhered to proce- crobial hand rub.
dures for the care of the catheter and administration of paren- There are two types of micro-organisms present on the
teral support. The aim of these procedures is to reduce both skin which effective hand hygiene will address;
skin colonization and catheter hub contamination.
This can be achieved by using an aseptic technique. • transient skin flora
Asepsis is the absence of bacteria, viruses, and other micro- –– These micro-organisms are acquired on the skin
organisms [8]. An aseptic technique therefore aims to pre- through contact with other people, objects, or the envi-
vent bacteria, viruses, and other micro-organisms being ronment. These can be easily removed by
introduced onto the skin, or into the catheter and subse- handwashing.
quently the bloodstream. An aseptic technique is used widely • resident skin flora
in healthcare—essentially for all clinical procedures from –– These are micro-organisms, which have adapted to the
basic wound care to surgery. There are numerous ways of natural condition of the skin. They live in deep skin
effectively performing an aseptic technique, consequently crevices, hair follicles, sweat glands, and moist areas,
there are differences between hospitals in the way it has been such as beneath rings. These are harder to remove.
taught and performed, which will inevitably result in differ- The hand washing procedure involves three stages—prepa-
ences in how patients and carers are trained. ration, washing and rinsing, and drying [8].
The acknowledged differences with how aseptic tech-
nique has been taught and undertaken led to the development Preparation
of a technique known as Aseptic Non Touch Technique® Forearms should ideally be free of any clothing which could
(ANTT®). This was introduced with the aim of improving impede effective hand washing or potential contamination of
the efficacy of and standardizing the technique [38–40]. equipment, and rings and bracelets should be removed. If
ANTT® has been adopted by many hospitals within the UK jewellery cannot be removed, the washing (and drying) of
and internationally. It is a theory and practice framework items into the handwashing technique should be incorpo-
using standardized principles and terminology [41]. The rated. In particular, rings should be rotated to allow washing
general principles of ANTT® can be found in Fig. 12. of the skin underneath them. The largest concentration of
micro-organisms is found under the fingernails; therefore,
nails should not be so long as to interfere with the handwash-
Standard vs. Surgical-ANTT® ing process. There have been numerous reports linking the
use of artificial nails with an increased risk of line infections
The ANTT framework describes two types of technique, [42–45]. Consequently, their use is not recommended. This
Standard-ANTT® or Surgical-ANTT®, based on the com- may prove restrictive for some patients, and also difficult to
plexity of the procedure and the number of Key-Sites and enforce. Patients/carers should be made aware of the risk so
Key-Parts. What isn’t clear from these definitions is how they can make an informed decision. Although not men-
tioned in the literature, bitten nails could also be an infection Skin Care
risk due to the ridges and open areas present on the fingers. Damaged or sore skin can make washing hands uncomfort-
Nailbrushes are also not recommended as they will harbour able, and increases the risk of infection; therefore it is impor-
micro-organisms, and could also damage the skin, making it tant to keep your skin healthy. In order to protect the skin
more susceptible to infection warm, not hot water, should be used to wash the hands. Water
The hands should be moistened with running water before that is too hot or too cold can crack the skin and allow micro-
applying the liquid soap. This ensures complete coverage of organisms to enter.
the hands with soap, and also reduces the drying effect of the The regular use of hand lotion can help prevent chapped
soap on the skin. It is important to use running water rather hands—in particular the cuticles—which can increase the
than standing water, for example water in a bowl or basin, as risk micro-organisms entering the skin. Even skin that does
hands could become re-contaminated. The temperature of not look dry to the naked eye may have small cracks in it.
the water does not matter as it does not affect how many Hand lotion should be applied at the end of each procedure
micro-organisms are physically removed and having the to help keep hands well moisturized. Assessing efficacy of
temperature too hot can lead to skin irritation. hand washing using UV disclosing lotion is common in hos-
pital settings and it seems reasonable to include in patient/
Washing and Rinsing carer teaching.
Hands must be washed thoroughly to ensure micro-
organisms are removed, but should not damage the skin, as
this will increase the risk of infection. The procedure N: Never Contaminate Key-Parts/Sites
should take a minimum of 20 s. Liquid soap is advised
rather than bar soap as this can easily become contami- Key-Part
nated. Micro-organisms will remain on areas of the hand A Key-Part refers to the part, or parts, of a piece of equip-
not exposed to soap and water therefore, the handwashing ment which if contaminated with micro-organisms could
technique needs to consider all aspects of the hands and introduce infection. For example, touching, exposure to the
wrists. Hands and wrists should be rinsed thoroughly environment, or using non-sterile equipment all have the
before drying so as to remove all soap debris, as this will potential for the transmission of micro-organisms. When try-
contain micro-organisms and residual soap could lead to ing to identify the Key-Parts/Sites for any procedure ask the
skin irritation. following question “Could touching this with unwashed
hands lead to infection?” If the answer is yes, then it is defi-
Drying nitely a Key-Part. The number of Key-Parts will vary depend-
Hands should be dried with good disposable quality paper ing on the procedure being undertaken and also the equipment
towels. Paper towels are advised to be used as they are dis- used. Figure 13 demonstrates the difference in the number of
posable. Cloth towels can rapidly become damp and can Key-Parts when accessing a Needle Free Connector with a
quickly become contaminated [8]. Some patients may want a prefilled syringe vs. a manually drawn up syringe.
more environmentally friendly option than using disposable
paper towels. In this instance, the use of muslin cloths or cot- Key-Site
ton face flannels could be substituted. They would need to be Key-Sites are open wounds or breaks in skin integrity (such
used once only and bulk washed on their own in the washing as where the catheter exits the body) which that need to be
machine at 60 °C. protected from contamination with micro-organisms. See
The use of a clean paper towel/muslin cloth/cotton face Fig. 14.
flannel to switch off the tap, carry the rucksack or manouevre Key-Parts and Key-Sites are protected during an aseptic
the drip stand should also be employed to protect the newly procedure by using a non-touch technique, which as the
cleaned hand from re-contamination. name suggests, means not directly touching them with any-
thing that is not sterile, or allowing them to come into contact
Hand Decontamination with any non-sterile items.
In addition to handwashing, hands can be effectively decon- In addition, the Key-Parts and Key-Sites are protected by
taminated by applying alcohol hand rub. The hand rub will creating an aseptic field. An aseptic field is an area created to
rapidly destroy any micro-organisms on the skin surface. maintain asepsis during a clinical procedure. This is achieved
Alcohol hand rub should be applied to clean, dry hands, and by using a sterile towel or sterile packaging, either to place
the hands rubbed together, following the steps in the hand- equipment or Key-Parts on. The aseptic field needs to be
washing technique, until they are completely dry. large enough to protect the Key-Parts. See Fig. 15.
Fig. 13 Key-Parts when accessing a Needle Free Connector (NFC) with a prefilled syringe vs. a manually drawn up syringe
T: Touch Non Key-Parts/Sites with Confidence the care of the catheter and administration of home paren-
teral support.
Non Key-Parts/Sites can be touched with confidence as there As more knowledge is gained around the control of infec-
is no risk of transmitting micro-organisms by doing so. tion it is possible that new products may be introduced and/
Essentially, non-Key-Parts are any part of the equipment or changes made to how the procedures are undertaken.
which is not a Key-Part. When trying to identify the non There may also be temporary changes, for example, during a
Key-Parts/Sites for any procedure ask the following question national pandemic.
“Could touching this with unwashed hands lead to infec-
tion?” If the answer is no, then it is a non-Key-Part. Using Gloves
the example outlined in Fig. 14 of Key-Parts when accessing Gloves are worn to reduce the risk of infection during the
a Needle Free Connector(NFC) with a prefilled syringe vs. a aseptic procedures. The wearing of gloves is not a substitute
manually drawn up syringe, Fig. 16 illustrates the non for handwashing, but in addition to it [8]. Microscopic punc-
Key-Parts. tures can develop in the gloves, which are not visible to the
naked eye, and if the hands have not been thoroughly washed
this could result in contamination with micro-organisms and
T: Take Effective Infection Control Precautions subsequent infection.
It has been standard practice for many years to use sterile
Infection control precautions include the use of personal pro- gloves for any procedures involving central venous catheters,
tective equipment (PPE), and the appropriate preparation however, as a non-touch technique is used clean non-sterile
and use of any equipment (sterile or unsterile), used during gloves may be safely used [8, 46]. If recommending the use
Fig. 14 Key-Sites in central venous catheter care
of clean non-sterile gloves it is important to consider how

they are stored prior to use and assess the potential for cross
contamination. Assessment criteria should include ease of
removing gloves from the box, and if it is possible to do this
without contaminating the glove fingers. Patients should be
advised not to replace any surplus gloves that are removed
along with the ones they will be using as this could result in
contamination.
Trolley/Procedure Tray
Selecting equipment for patients on parenteral support to use
at home will depend on what is available locally, but it isn’t
always necessary to replicate what the patient has been used
to seeing in hospital. An example of this is what is used to
place the sterile items on in order to undertake the proce-
dures. In hospital this will either be a trolley or a procedure
tray(s), however, any flat surface that can be effectively
cleaned and disinfected is suitable. Patients should be
encouraged to think of what will work for them in their home
environment, especially if space is limited. Whatever surface
is used it needs to be cleaned and then disinfected. Cleaning
Fig. 15 Creating an aseptic field

Fig. 16 Non-Key-Parts when accessing a Needle Free Connector (NFC) with a prefilled syringe vs. a manually drawn up syringe
with soap and water or a detergent wipe will remove any dust emphasis needs to be placed on that the membrane of the
which contains micro-organisms, and visible dirt. Once this sterile end connector is the Key-Part and where the disinfec-
has dried the surface needs to be disinfected with either a tion should concentrate. As the length of the catheter and
disinfection wipe or spray. A lot of emphasis is often placed clamp are non Key-Parts it is not necessary to disinfect them.
on this activity, especially whether or not it is acceptable to Repeatedly exposing the catheter material to 70% Isopropyl
use a back and forth motion or to only wipe in one direction. Alcohol (one of the ingredients of the disinfection wipes)
The topic can cause a difference of opinion between nurses could lead to it becoming brittle over time. If it gives patients/
and often reflects the way they were first taught how to do an carers peace of mind to disinfect the clamp this is fine, but it
aseptic technique. The crucial thing is that the entire surface should to be disinfected after the membrane of the needle
comes into contact with the products being used. free connector. See Fig. 18.
Due to the importance associated with this part of any
eedle Free Connector
N procedure where the line is accessed it seems reasonable
The membrane of the needle free connector needs to be to assess the patient/carer’s efficacy in disinfecting the
effectively disinfected prior to connecting a syringe or giving needle free connector membrane. This can be achieved
set to it, to avoid the transfer of micro-organisms into the by using dummy lines and connectors and UV disclosing
line. This is probably the most important step in any proce- lotion. The membrane is covered in UV disclosing lotion
dure during which the line is accessed. See Fig. 17. which is invisible to the naked eye. Following disinfec-
A single use sterile wipe impregnated with Chlorhexidine tion the patient/carer can be shown how much of the dis-
2% and 70% Isopropyl Alcohol should be used for a mini- closing lotion they have removed by using a UV black
mum of 15 s using pressure and friction in a twisting action light detector. This assessment would also be applicable
as if juicing an orange [8, 47]. This is often referred to as for reassessing established home parenteral support
“scrub the hub”. The connector should then be allowed to dry patients who have developed catheter related bloodstream
for 30 s before accessing [8]. When teaching patients/carers infection.
Fig. 17 Commonly used NFC showing the wipeable membrane
Fig. 18 Order of disinfection—membrane then clamp
Sterile Dressing [48]. When appraising the literature it is important to note

To protect the skin surrounding where the line exits the body the following;
from contamination that could lead to a local infection, the
site needs to be covered with a sterile dressing (Fig. 19). • Catheter type
Dressings should be vapour permeable, which means they –– Direct venous access, PICC or tunneled Hickman™
prevent the build-up of moisture under the dressing, as this • Dressing details including the Moisture Vapour Transmis-
could increase the risk of infection [8]. Transparent dressings sion Rate (MVTR)
allow the exit site to be continually inspected, not just at –– The higher the MVTR greater the ability of the dress-
dressing changes, however, a dressing with an absorbent pad ing to allow skin moisture to evaporate
is recommended if there is any discharge from the exit site. It • What type of infection
is still unclear however, if there is a difference in infection –– Local and/or systemic?
rates between different dressing and securement devices
Fig. 19 Examples of sterile exit site dressings
Fig. 20 Biopatch® dressing
An important consideration for the patient/carer is the ease Sometimes it may be clinically indicated to use an chlorhexi-
of dressing application. There are some “1 hand” dressings dine impregnated dressing, for example Ethicon Biopatch®
available which as the name suggests can be applied with 1 or 3M™ Tegaderm™ CHG [8, 48, 49]. While these dress-
as opposed to both hands. ings do not treat infection, they may be helpful in reducing
Dressings should be changed every 7 days, or at any time the risk of infection in individuals who have had a history of
they become loose or soiled [7, 8]. The dressing only needs line site infections. The active ingredient is slowly released
to be large enough to cover the exit site and a few cm of sur- into the skin over a period of days. They should be changed
rounding skin, however, not all suitable dressings are avail- every 7 days, or at any time it becomes saturated with fluid.
able this small, so a larger dressings may need to be used. See Fig. 20.
Fig. 21 Securing the catheter hub
Securing the Catheter Hub cluded there was still disparity in definition and standardisa-
tion [50]. As any procedure should be based on the
Even if the catheter hub is protected with a port protector, for evidence-based elements of central venous catheter care the
example Curos™, during infusion free periods, keeping it reason behind such variation is hard to comprehend. Aware
secured away from a stoma or fistula site is an important, but of differences in catheter care NHS England requested a
sometimes, overlooked, infection control precaution. This is standardised set of procedures so as to reduce any confusion
particularly relevant with Hickman™ type catheters. The for patients, service users and health care professionals. The
hub can be secured with surgical tape or a special dressing, unified protocol was developed by the IF units at St Marks
for example Griplok® that can stay on the skin for a number and Salford Royal Hospitals and was supported by the
of days. See Fig. 21. National Nurses Nutrition Group (NNNG), British
It has been common practice to recommend the catheter Association for Parenteral and Enteral Nutrition (BAPEN),
hub is wrapped in gauze when not in use. There are a number and the patient support group Patients on Intravenous and
of proposed benefits to this namely; acting as a deterrent to Naso-gastric Nutrition Treatment (PINNT). The unified pro-
non-qualified staff accessing the catheter, patient comfort, tocol outlines key principles during connection, disconnec-
and reducing the risk of infection. There is no evidence to tion and changing the dressing [51]. See Appendix 1 at the
suggest that wrapping the catheter end in gauze is an effec- end of this chapter.
tive infection control strategy, as gauze has an open weave
design which will not repel micro-organisms, and if wet
could actually increase the risk of infection. If wrapping is Catheter Related Complications
done to reduce discomfort from the catheter hub and clamp
from digging into the skin then this is acceptable. For cathe- Catheter related complications can impact on morbidity and
ter safety any wrapping needs to be easy to remove without mortality therefore prompt identification and initiation of
the use of scissors. appropriate treatment is vital.
IFA Unified Protocol: Standardised

B Catheter Related Infection
Parenteral Support Catheter Guidelines
Catheter related infection is an umbrella term covering both
Despite the popularity of ANNT® a Royal College of Nursing systemic infection and local infection [8]. Local infections
investigation on the understanding of aseptic technique con- can be categorized according to the amount of skin affected
Table 5 Localised catheter related infections

Type of infection Signs and symptoms Suggested treatment
Exit site infection Erythema and/or induration within Targeted oral antibiotic therapy. IV antibiotics may be
2 cm of the catheter exit site in the required if absorption is severely limited. Once resolved the
absence of systemic infection [37]. A use of a Chlorhexidine Gluconate dressing is recommended
purulent discharge may also be present [8, 48, 49]
Tunnel infection Tenderness, erythema and/or As the infection is more widespread targeted IV antibiotic
induration >2 cm from the exit site therapy is required, although removal may be required if the
along the subcutaneous tunnel in the infection does not respond to treatment Once resolved the
absence of systemic infection [37]. A use of a Chlorhexidine Gluconate dressing is recommended
purulent discharge may also be [8, 48, 49]
present
Descending tunnel infection (suggested Tenderness, erythema and/or As the infection is more widespread targeted IV antibiotic
definition in the absence of any formal induration >2 cm from the catheter therapy is required, although removal may be required if the
definition) vein insertion site along the infection does not respond to treatment Once resolved the
subcutaneous tunnel in the absence of use of a Chlorhexidine Gluconate dressing is recommended
systemic infection. A purulent [8, 48, 49]
discharge may also be present
Complete tunnel infection (suggested Tenderness, erythema and/or As the infection is more widespread targeted IV antibiotic
definition in the absence of any formal induration along the entire length of therapy is required, although removal may be required if the
definition) the subcutaneous tunnel in the absence infection does not respond to treatment Once resolved the
of systemic infection. A purulent use of a Chlorhexidine Gluconate dressing is recommended
discharge may also be present [8, 48, 49]
Cuff infection (suggested definition in Tenderness, erythema and/or Targeted IV antibiotic therapy as the infection is likely to be
the absence of any formal definition) induration localised over the cuff of a deeper than in an exit site infection. The catheter may need
tunneled catheter in the absence of an to be removed or it may spontaneously fall out if the
exit site, tunnel or systemic infection. infection disrupts the tissue anchoring the cuff in place
A purulent discharge may also be
present
Port pocket infection Purulent fluid in the subcutaneous Targeted IV antibiotics
pocket of a totally implanted port in
the absence of a systemic infection
[37]
and type of device they can occur with [37]. The definitions areas of skin making maintaining skin integrity an important
have not been revised since 2002, and do not distinguish an nursing consideration.
isolated cuff infection, or that a tunnel infection can be The risk of MARSI increases with inappropriate adhesive
ascending (from exit site up the skin tunnel), descending selection, application, or removal. The skin damage may not
(from insertion site down the skin tunnel), or complete be immediately noticeable. MARSI can take the form of red-
(affecting the entire tunnel). Localised infections along with ness, skin tears, or blisters and be painful and very itchy. It is
signs and symptoms and suggested treatment are shown in often mistaken for an allergy to the dressing or an infection.
Table 5. Secondary infection can occur if MARSI results in breaks in
the skin as bacteria are able to enter.
It is thought that MARSI is largely avoidable. Things
edical Adhesive Related Skin Injury
M which can help minimize the risk of developing MARSI
(“MARSI”) include using medical adhesive remover when removing the
dressing and protecting the skin with a silicone barrier wipe
While not an infection, Medical Adhesive Related Skin prior to dressing application [53].
Injury (MARSI) can be mistaken for one, and could lead to Other strategies include alternating the size of dressing
infection if not appropriately treated. MARSI refers to skin used and/or using dressings with an absorbent pad. This
damage from prolonged and/or frequent contact with medi- helps by not having the same area of skin constantly in con-
cal adhesive. If left untreated it can lead to infection and loss tact with the medical adhesive. Alternatively, a dressing with
of skin integrity [52]. Patients on home parenteral support a low tack adhesive can be used.
may use a number of products with different types of medi- Care should be taken not to stretch a dressing when
cal adhesive; for example dressings, securement devices, applying it as this can cause microscopic skin tears as the
surgical tape and stoma appliances. The adhesive products skin contracts once the dressing is in place (Fig. 22). In addi-
will need to be repeatedly applied and removed to the same tion, dressings should be removed as per manufacturer’s
of CRBSI often say they think they have a “line infection”

which to health care professionals not used to caring for
patients with long term CVC suggests a local skin infection
rather than a systemic infection. This misunderstanding
could lead to ineffective treatment, or even no treatment,
being initiated. Providing patients with pre printed pro-
forma letters for common complications can aid in them
accessing appropriate treatment if they attend the emer-
gency department.
Not everyone with CRBSI present with the same symp-
toms, and it is important to help the patient recognize symp-
toms which may be subtle, for example, general malaise or
thinking they have a cold, or overt such as a temperature of
38 °C or more and rigors. It is also important to note that a
temperature of less than 36 °C or less can indicate systemic
infection, which may not seem obvious to patients. Patients
should be advised that while symptoms are often experi-
enced during an infusion or post flushing the catheter, they
can also occur during infusion free periods.
To be able to benchmark outcome measures it is sug-
gested that IF centres aim for an inpatient catheter related
bloodstream rate of less than 3/1000 catheter days and an
outpatient one of less than 1/1000 catheter days [55]. To
date, there has been no recommendation to report infection
rates per type of device. As the risk of catheter related infec-
tion varies between PICC, Hickman™ type and implanted
ports it seems reasonable to suggest reporting individual
device infection rates in addition to the overall rate. The
Fig. 22 Removing medical adhesive from the skin
identification and treatment of CRBSI is covered in chapter
“Prevention, Diagnosis and Management of Catheter-
guidelines. For example, some dressings need to be removed Related Blood Stream Infections”.
using alcohol-based products, or by being stretched outward
to remove the contact with the adhesive, as opposed to lifting
them off. When lifting off a dressing the surrounding skin Catheter Occlusion
should be supported, and the dressing peeled back slowly
and as close to the skin as possible. This has been termed the Reduction in central venous catheter patency can result in
“low and slow” method [54]. missed infusions and if not resolved will require insertion
of a new device. Central venous catheter occlusion may be
thrombotic or non-thrombotic in nature. Thrombotic
ystemic Infection: Catheter Related Blood
S occlusions arise from the formation of a thrombus either
Stream Infection within, surrounding, or at the line tip. They can also arise
from backflow into the catheter during infusion free peri-
Of all of the potential complications of home parenteral ods, or failing to adequately flush the catheter post blood
support, catheter related bloodstream infection (CRBSI) is sampling [56].
arguably the one which patients fear the most. Patients/car- Non-thrombotic occlusions can occur from particulate
ers need to be aware of how systemic infection can occur, debris or lipid particles [57]. There are also numerous
alongside how it can present and the implications of not mechanical causes of occlusion and it is important to exclude
seeking urgent medical attention. Information needs to be any of these before considering pharmaceutical intervention.
given in simple language the patient understands without See Table 6.
causing undue anxiety, however does need to include some Occlusion can be complete where it is not possible to
medical terms, such as bloodstream infection or sepsis, so instill or aspirate anything, partial where there is resistance
that patients are able to accurately convey their concerns to on instillation, or a persistent withdrawal occlusion (PWO)
healthcare professionals. Patients with signs and symptoms where fluids may be infused but it is not possible to withdraw
Table 6 Mechanical causes and interventions of occluded central venous catheters

Possible cause Intervention
Kinked/clamped 1. Straighten line
line 2. Ensure line clamp is open
3. Examine reinforcement sleeve for indentations & massage line between thumb and index finger to remove any kinks
Faulty Needle Free Remove connector and reassess patency by flushing with 0.9% sodium chloride for injection directly via line hub
Connector
Faulty pre filled Try flushing with a new prefilled 0.9% sodium chloride for injection syringe in case the seal on the one used previously
syringe wasn’t completely released
Obstruction within 1. Direct observation inside the catheter hub to check no obvious obstruction, for example a sponge from Curos™ Port
line hub Protector
2. If connection between hub & line is obscured consider manual extraction of debris. Manual extraction of debris should
not be attempted in catheters with proximal valves, for example PASV™ or Solo™ valves as this could damage the valve
Constriction of Remove any potentially constricting sutures/dressings. (re-suture if catheter in-situ <3 weeks)
sutures/dressing
Catheter tip against 1. Change patients position (supine/upright or vice-versa)
vessel wall 2. Try the Valsalva manoeuvre and reassess patency
Catheter tip 1. Check notes and/or CXR for initial tip placement
migration or 2. Perform repeat CXR to assess current tip position
malposition 3. Measure external length of catheter (PICC) and compare against length on insertion
“Pinch-off” 1. Check patient’s notes for verification of venous access route
syndrome 2. Assess if the occlusion is intermittent or positional (relieved by rolling shoulder forward or raising arm on ipsilateral
(subclavian vein side). If the occlusion is relieved by rolling the shoulder or raising the arm the CVC will need to be removed and replaced
catheters only) as there is no treatment for pinch-off syndrome
Implanted ports: 1. Insert new Huber™ needle and reassess patency
needle 2. Consider inserting longer needle if the back of the port is not felt
displacement
Displacement/ 1. If the metal spike from the catheter repair segment has dislodged then the segment may no longer be in alignment with
misalignment of the native catheter. This will restrict flow
catheter repair 2. If a patient has a repaired catheter consider removing the repair segment and performing a new repair
segment
blood [58]. Simple strategies to resolve a PWO include eter rupture. Gaining a history of the occlusion will help
changing the patient’s position (e.g. raising their arms above guide treatment options, for example;
their heads or asking them to cough). While thrombus, lipid
and precipitate (protein or drug deposits) can all cause PWO, • Was it sudden onset?
the commonest cause is a fibrin sheath formed around the • Has the catheter been getting sluggish over a period of
catheter [59, 60]. time?
A fibrin sheath is a collection of fibrin and platelets that • Has the catheter been used for blood sampling and not
can be demonstrated in 40% of all catheters with radiological flushed afterward?
screening after radio-opaque dye has been injected down the • Have they noticed any blood leaking from the needle free
catheter [61]. It starts from where the catheter enters the vein connector?
and spreads towards the tip. It does not generally cause a • Is the catheter used for any medication?
problem until it surrounds the catheter tip when it may clas- • Does their parenteral support regimen include lipid con-
sically act as a one-way valve such that a solution can be taining bags?
infused down the catheter but not withdrawn.
It is also important to rule out catheter related thrombosis as
a cause.
Treatment of Catheter Occlusion Possible signs of thrombosis include;
Simple strategies should be tried first, such as asking the • Ipsilateral swelling of the arm, neck, head or face
patient to raise their arms and cough, and massaging out any • distended collatoral circulation over chest wall
kinks within the clamping reinforcement area. Having atrau- • Jaw and shoulder pain
matic clamps to hand is essential to be able to clamp the • Headaches and/or a feeling of head fullness
catheter should any attempt to restore patency results in cath- • Localised pain and or numbness [62]
atheter Related Thrombosis Is

C standard practice at St Mark’s Hospital UK for more than 20
Covered in Chapter “Central Vein years.
Thrombosis” If these methods do not restore patency then instilla-
tion of an appropriate pharmaceutical agent can be con-
Any attempts to unblock CVC should only be attempted by sidered. During instillation the catheter needs to be
healthcare professionals who are experienced with the man- monitored catheter closely for signs of “ballooning” or
agement of such devices and have demonstrated competency traumatic fracture, and it is essential to have atraumatic
in the procedures and management of any potential compli- clamps close to hand in case of catheter rupture. If the
cations for example catheter rupture. instillation of the selected pharmaceutical agent actually
As part of the initial assessment of a blocked catheter to resolves the occlusion, the patient should be observed for
determine the nature of the occlusion it is recommended that at least 30 min. Although uncommon, patients may
the catheter hub is directly observed to identify if the open- develop systemic sepsis following restoration of patency
ing between the catheter hub and catheter has become and so should be advised of this potential risk, and the
obstructed with any debris or foreign body, for example a need to seek urgent medical treatment if they become
sponge from a port protector. There should be a clear pin unwell. If the pharmaceutical agent is being left in situ for
prick opening visible when the inside of the catheter hub is a set time period it is advisable that the patient return for
viewed. Any visible debris can be removed by using a green removal of the drug and reassessment of patency by an
(21G) safety needle. The technique should not be attempted experienced healthcare professional as opposed to the
on catheters with a proximal valve, for example PASV™ or patient doing this themselves at home.
Solo™. While this may seem an unorthodox method, it must The evidence supporting the use of different pharma-
be appreciated that only the external catheter hub is being ceutical agents is mixed with studies using different doses,
manipulated. In some cases this method is the only interven- mode of instillation (bolus or infusion) and different dwell
tion required to restore patency. In a case series of 39 (30 times. The type of occlusion (full, partial or complete) is
total, 9 partial) occlusions hub clearout with a green (21G) not always mentioned, or the catheter type (PICC, tun-
needle was used successfully in 5 (17%) episodes of total neled or implanted port), number of lumens (single, dou-
occlusion. In 2(7%) episodes this was the only method used. ble or triple), catheter material (silicone or polyurethane)
Of the 9 partial occlusions, hub clear out alone was used on valved or non-valved devices and size of syringe used. All
7 (78%) occasions [63]. of these variables could impact on the results. A review of
Before instilling a pharmaceutical agent it is also sug- thrombolytic treatment of catheter occlusion concluded
gested that manipulation with 0.9% Sodium Chloride for that further randomized comparative studies were needed
Injection is attempted. During this method a 10 mL Luer to determine the most effective management for catheter
lock syringe with 5 mL 9% Sodium Chloride for Injection is occlusion [64]. Table 7 outlines commonly used pharma-
attached directly to the catheter hub. A gentle back and forth ceutical agents for unblocking central venous catheters.
motion on the syringe plunger is then employed to see if this From this it can be appreciated that there is the most evi-
will dissolve the obstruction. The plunger should only be dence supporting thrombotic occlusions, and very scant
depressed up to the level of resistance, as forcing the plunger evidence for occlusions resulting from lipid or drug
all of the way in could result in catheter rupture. If this pro- deposits. There may be restrictions on use in some coun-
cess is successful debris from the catheter will become visi- tries, for example Urokinase is not licensed for use in the
ble in the syringe. Patience is required as it can take up to United States [64] and Hydrochloric Acid [71] which was
30 min plus to dissolve all of the intraluminal debris. used to dissolve drug precipitate is no longer available in
Although this method is not cited in the literature, it has been the UK.
Table 7 Commonly used pharmaceutical agents for unblocking central venous catheters
Urokinase Alteplase (t-PA) Ethanol Sodium hydroxide
n = 19. 5000 units Urokinase, 5–10 n = 25. t-PA 6 occlusions failed n = 5. 3 mL Ethanol 70%, 1 h n = 13 totally implanted port.
minutes dwell time followed by to clear with 10,000 units dwell time, patency restored in Partially occluded. 10 mL 0.1
attempted aspiration, repeated every Urokinase 4 h dwell time, 5 of 4/5 (80%) cases [67] Sodium Hydroxide solution at a
5–10 min for a maximum of these successfully cleared with rate of 1 mL per hour followed
30–60 min or successful clearance. 2 mg/2 mL t-PA 4 h dwell time by a 2 h lock. Increase in patency
Successful restoration in 6 of 19 [66] determined by formal assessment
(32%) cases [65] of gravity flow rate pre and post
intervention. All 13 cases
demonstrated an improvement in
flow rate [68]
n = 19. 6 h Urokinase 40,000 units COOL 1 trial. n = 995. Single n = 9. 70% Ethanol up to 3 mL,
per hour. Patency restored in 15/19 lumen 26%, double lumen 39%, patency restored in 7/12 (58%)
(79%) cases [69] triple lumen 6% and totally cases. 0.1 Hydrochloric acid up
implanted ports 29%. 2 mg t-PA, to 3 mL bolus with second dose
dwell time 30–120 min. Single if unsuccessful left for up to 1 h.
dose-restoration of patency in Patency restored in 2/3 (67%)
52% devices at 30 min and 78% cases [71]
devices at 120 min. Second
dose—restoration of patency in
84% devices at 30 min and 87%
at 120 min. Restoration of
patency 86% single lumen
devices, 93% double lumen
devices, 90% triple lumen
devices and 79% totally
implanted ports [70]
PASSPORT 1 trial. n = 200. Bolus
with 12,500–50,000 units Urokinase,
or catheter infusion with 100,000–
250,000 units of Urokinase. The
cumulative success rate for
thrombolysis was 90.5% after first
intervention, 97% after second
intervention, and 99% after three [72]
PASSPORT 2 trial. n = 117. 53%
withdrawal occlusion, 47% total
occlusion, Withdrawal occlusion
patency restored in 80% cases, total
occlusion patency restored in 88%
cases. Success dose dependent, 83%
success with 5000 units Urokinase,
92% with 25,000 units Urokinase
[73]
Syringe Techniques with some back and forth motion this suggests that the occlu-
sion does not affect the entire catheter and instillation of any
Applying a specific syringe technique, on its own or in com- pharmaceutical agent will be possible.
bination, with 0.9% Sodium Chloride for Injection or phar-
maceutical agent, can aid in the restoration of patency. A
Luer lock, rather than a Luer slip, syringe must always be Negative Pressure Technique
used so as to prevent the syringe being expelled during the
unblocking procedure. A 10 mL syringe should be used to This is achieved by using 3 way tap, although it can be
avoid catheter damage, however only part filling this can be undertaken without. The aim is to create a vacuum within the
beneficial as it makes it easier to assess the level of blockage. catheter which will then automatically draw whatever fluid is
The amount of “give” within the catheter can be determined being used to restore patency, i.e. 0.9% Sodium Chloride for
by pressing the syringe plunger with the thumb. If there is Injection, Urokinase, Alteplase or Ethanol [74]. Figure 23
total resistance this suggests that the occlusion affects most illustrates the negative pressure technique using a 3 way tap
of the catheter, whereas if it is possible to depress the plunger or with a single syringe.
Fig. 23 Negative pressure technique for restoring patency

Fig. 24 Percussive POP

technique
Percussive POP Technique the end of an infusion to clear any residue adhering to the
inner surface of the catheter [8]. The catheter also needs to be
The percussive POP technique generates shock waves flushed prior to commencing an infusion, and in between any
through the CVC thereby loosening the obstruction and medication. Using effective techniques to flush and minimise
allowing it to be extracted, rather than introduced, into the the risk of blood backflow into the device should be incorpo-
patient. There is limited evidence to support this technique, rated into catheter care guidelines. Two established measures
however two in-vivo evaluations demonstrated no catheter are the use of push pause flushing and positive pressure
damage and/or adverse patient outcomes [63, 75]. The first clamping.
study reported a 94% success rate in 50 catheters with no
complications, and the second had a 93% success rate in 39
catheters also with no complications. A further in-vitro eval- Push Pause Flushing
uation [76] in 30 PICC had a 86% success rate and no cath-
eter damage. As an in-vitro assessment permits the entire Flushing with a stop start—“push-pause”—motion causes
catheter length to be occluded with blood this gives valuable turbulence of flow, thus preventing the build-up of blood
information regarding the safety associated with this method. and/or infusion deposits within the catheter, which could
In addition, the POP technique is simple and inexpensive. lead to occlusion [77]. A review of the literature found that
See Fig. 24. pulsatile (push pause) flushing is most efficient when under-
taken briskly with only a 0.4 s pause between each push [78].
See Fig. 25.
Maintaining Patency Syringe size is important when flushing a CVC due to the
pressure that is generated. Syringes of 10 mL or greater
To maintain patency it important that any infusion fluid is not should be used as smaller syringes generate more pressure
allowed to sit within the catheter. The catheter should be which could rupture the CVC [46].
flushed promptly with 0.9% Sodium Chloride for Injection at
Fig. 25 Push pause flushing
Positive Pressure Clamping the catheter and this may limit the amount of blood that
refluxes back up the catheter [46]. For valved catheters with
Maintaining a positive pressure within the catheter lumen no integral clamp, positive pressure can be achieved by keep-
may reduce the risk of occlusion resulting from blood backing the thumb on the syringe plunger while removing the
flow into the catheter tip. Clamping the catheter while inject- syringe. See Fig. 26.
ing the last few millilitres of fluid seals a column of fluid in
Fig. 26 Positive pressure a Non-valved catheter

clamping in non-valved and
valved catheters. (a)
Non-valved catheter. (b)
Valved catheter
b Valved catheter
ositive Pressure and Anti-reflux Needle

P positive pressure valves it is recommended that individual
Free Connectors manufacturers safety and efficacy data, alongside any restric-
tions of use, for example valved catheters, is reviewed.
Positive pressure can also be obtained with the use of An anti-reflux connector, for example TKO® valve bonded
either a positive pressure Needle Free Connector, or an onto a needle free connector, may also help reduce blood
anti-reflux Needle Free Connector. Positive pressure con- backflow. The TKO® 3 way pressure sensitive valve is closed
nectors, for example CLC2000® (ICU Medical), will expel unless a syringe or giving set is attached and fluid injected.
a small amount of flushing solution from the catheter tip The valve will also open if the plunger on an attached syringe
thereby preventing or minimising the amount of blood is pulled back thereby allowing blood sampling. Jasinsky
backflow. To achieve this they require a different clamping and Wurster demonstrated a statistically significant reduc-
sequence than standard needle free connectors (NFC). The tion in occlusion rates, from 30% to 12.5% of catheters
syringe should be removed before the line is clamped—as (p < 0.01) over a 3 month period when using a TKO® valve
opposed to after. bonded to a Nexus needle free connector [80]. In the UK the
There is conflicting data on their ability to reduce occlu- TKO® valve is bonded to a Vygon Bionector. The TKO®
sion when compared to other types of connector [79]. This valve should not be used with catheters which already have a
may be due to the variation in design making it hard to draw valve, for example Groshong™, PASV™ and Solo™. See
definitive conclusions. If considering the introduction of Fig. 27.
Fig. 27 Example of a
positive pressure valve and
anti-reflux connector
Catheter Damage and Repair pounding and delivery of the parenteral support, ancillaries,
equipment and specialist nursing support if clinically indi-
The ability to be able to repair damaged devices is of clinical cated. Key documents from this framework are included as
benefit as it can mitigate the need to change the catheter. examples, as it is recognised service specifications will vary
There are a number of ways a catheter can become damaged, according to what is available locally.
for example; Discharge planning needs to consider the following
criteria;
• Flushing against resistance
• Use of small syringes (<10 mL) • Is the patient suitable for homecare?
• Power injection of contrast material in non-power inject- • Who will fund, prescribe and provide the parenteral
able devices support?
• Use of scissors/sharp objects near CVC • What are the specific nutrient and/or fluid requirements?
• Repeatedly clamping in the same place • Who will fund and provide the necessary ancillaries and
• Getting catheter caught in a door equipment?
• Contact with pets • Who will care for the catheter and administer the paren-
teral support?
Prevention strategies include; • Ongoing support arrangements for patients once
• Routine movement of clamp along reinforcement area discharged
• Securing end of the CVC to prevent contact with sharp
objects
Is the Patient Suitable for Homecare?
It is possible to repair Hickman™ CVC with manufacturer
specific repair kits. There are different ones available for This assessment needs to consider where the patient intends
single and double lumen catheters, and whether a single to reside on discharge, practical issues such as mobility and
lumen pigtail or both lumens are affected. There needs to be dexterity alongside identifying any potential safeguarding
sufficient undamaged native line available—approximately concerns, psychological well-being, and the patients’ social
5 cm from the exit site—as the damaged section will be support network. The English National Framework Patient
removed to allow a new catheter segment with clamp and Needs Assessment form can be found in Appendix 2 at the
hub to be applied. While a formal repair kit with new cathe- end of this chapter. A pre-discharge home assessment is rec-
ter segment and hub is available for Groshong™ catheters, ommended to ensure the basic requirements—electricity and
replacement hubs are also available, meaning that a repair running water—are in place. While some patients may want
can also be more simply achieved by removing the damaged a separate room to undertake their procedures, this isn’t clin-
section and inserting a new Groshong™ hub. ically necessary, and the nurse is well placed to guide the
Catheter repair kits should be available and staff familiar patient in identifying where equipment and ancillaries will
with their application. A skillful repair to a damaged/split line be stored, and also where the procedures will take place.
prevents the trauma and risk of a fresh insertion and can main- The challenge arises if it is felt that a patient is not suit-
tain the integrity of a line for several years. Catheter repair has able for homecare, for example safety concerns regarding the
not been associated with an increase of infection [81–83]. line, as there is no easily identifiable and sustainable alter-
nate way for the infusions to be administered.
Discharge Planning
ho Will Fund, Prescribe and Provide
W
Discharging a patient on home parenteral support is complex the Parenteral Support?
and will inevitably vary from country to country depending
on funding arrangements, availability of equipment, and pro- Funding streams will vary from country to country. It is rec-
vision of any specialist nursing support. Within England ommended that one staff member is allocated the task of
there is a national framework agreement which covers com- securing funding so as to act as a central point of contact
with the relevant commissioning body. It is important to from a different source than disinfection wipes or needle free
identify who will be prescribing and providing the parenteral connectors.
support, when the first delivery will be made, how frequent When selecting ancillaries there should be consideration
subsequent deliveries will be, and what time of day these of whether or not the patient and/or carer is able to use them,
will occur. Upon discharge there should be a supply of suf- and not just replicate what has been used in hospital. For
ficient Parenteral Support to ensure uninterrupted therapy example, some dressings require both hands to apply which
The Parenteral Support may be provided by a commercial may prove challenging, so “1 hand” dressings which have a
homecare company, hospital pharmacy or community phar- rigid frame to keep the dressing material wrinkle free during
macy depending on what is available locally. application may be easier to use. This may seem trivial, how-
Within England funding is automatically secured by an ever it could mean the difference between a patient being
online high cost management system known as Blueteq. able to undertake their own dressing change or needing to
Only hospitals who have been approved to provide a home rely on someone else to do this. Other considerations include
parenteral support service have access to this, and approval is the use of gloves with textured finger tips to aid with insert-
automatic as long as all of the clinical criteria set out are met. ing the pump giving set into the bag of parenteral support, or
selecting a larger profile needle free connector which is eas-
ier to manipulate.
hat Are the Specific Nutrient and/or Fluid
W All ancillaries and equipment must meet local medical
Requirements? device related regulations, for example CE/UKCA marking,
and it must be determined that the patient and/or carer are not
When formulating a home parenteral support prescription allergic to any of the materials contained within them.
consideration the needs to be made regarding the practicali- The patient will need to identify suitable storage for
ties of the regimen being administered at home. For example, ancillaries and equipment and this needs to be discussed
while it may be possible to gain stability on a 4 L bag, will with them prior to discharge, so as to prepare them for the
the patient be able to lift and carry this around? Although the volume of items which need to be stored. Ancillaries need
infusion becomes more manageable as more fluid is infused, to be stored off the floor in a clean and dry environment.
sometimes it may be necessary to have two infusions of a Some patients may opt to buy plastic storage units with
manageable size, for example a 3 L bag followed by a litre drawers, but a chest of drawers or cupboard is equally suit-
bag. able. Fridges may be stored in an outside garage or shed but
How long a patient infuses for can impact on their daily they may need to be moved inside during the winter months
routine so this needs to be considered when sending a patient as fridges can only work normally if the temperature of the
home on parenteral support. Infusion rates in hospital are room in which they are situated is warmer than the tem-
usually dictated by the shift pattern of nursing staff, but at perature inside the fridge. If the patients’ regimen includes
home the self-caring patient can have more flexibility. Things the use of sharps then they need to be supplied with an
to consider when determining flow rates include the hourly approved sharps container which needs to be stored out of
content of glucose and certain electrolytes, for example reach of children or pets. The patient needs to be aware of
potassium and magnesium. Patients/carers should be how to dispose of filled containers and receive
informed of the maximal hourly infusion rate they can use, replacements.
but some may choose to infuse over a longer period so as to
not have to wake early to disconnect.
The infusion mode—same volume throughout, or vari- ho Will Care for the Catheter
W
able—also needs to be considered. A variable rate is achieved and Administer the Parenteral Support?
by programming the infusion pump to taper run the infusion
at a slower rate at the beginning and end of the infusion. This Where possible the patient should be trained to care for their
can be useful in preventing rebound hypoglycaemia [84]. catheter and administer the parenteral support. Not only does
this promote autonomy it also reduces the number of people
accessing the catheter. Assessment to determine if a patient
ho Will Fund and Provide the Necessary
W will be able to self-care includes visual acuity, manual dex-
Ancillaries and Equipment? terity and strength. Deficiency in any of these might impact
upon the patient’s ability to undertake the procedures them-
It is easier if the ancillaries and equipment can be provided selves, but thinking creatively may help resolve the issue(s).
by the same provider as the Parenteral Support, but it is For example, patients often struggle to insert the giving set
appreciated that this may not be possible in all countries. spike into the parenteral support. As well as using gloves
Ancillaries and equipment may need to be provided by a with textured fingers, having the bag of parenteral support
number of providers depending on the classification of the laid on a flat surface as opposed to hanging on a drip stand
product, for example dressings may need to be provided might enable the patient to successfully insert the giving set.
Patients with manual dexterity issues may benefit from hav- • Whether the catheter is valved or non-valved
ing prefilled 0.9% Sodium Chloride for Injection syringes as • If the patient is receiving additional medications via the
opposed to manually drawing up flush solution. Even if catheter
patients cannot undertake all of the required procedures they • Number of lumen the catheter has
may be able to undertake some, for example they may be • If the patient is receiving one infusion at a time or 21
able to disconnect and change their dressing, but not be able
to connect an infusion. There are common elements to all procedures, for exam-
If a patient is unable to undertake their own procedures ple hand decontamination and putting on sterile gloves. In
then alternative arrangements need to be made. It may be pos- addition, all procedures start and end with a social handwash,
sible to identify a family member/carer who is able and will- and can be broadly broken down into the following stages;
ing to be trained. Due to the severity of potential complications,
most notably sepsis, both parties need to be happy with this • Create an aseptic field with equipment needed to under-
arrangement. Logistics, such as availability for all connection take procedure
and disconnection visits, also needs to be determined. • Create an aseptic field around the catheter
Nursing support will need to be secured for patients • Undertake procedure
unable to undertake their own procedures and have no iden-
tifiable family member/carer who can learn. This can prove
challenging as not all community based nursing services will Creating a Suitable Environment
have experience of central venous catheter management and
administration of parenteral support. While community Patients do not need to make any alterations to their home,
based IV therapy services may exist their remit is usually for but there are some basic “housekeeping” principles to bear in
short term IV medication administration, and doesn’t extend mind when deciding on where the procedures will be
to long term infusion therapies. Within England, the National undertaken;
HPN Framework also includes specialist nursing support.
These nurses have to be able to demonstrate competency in 1. Where will the procedures take place?
the understanding of gastrointestinal function, parenteral The patient needs to think about how easy it will be for
support, care of central venous catheters, and recognition of themselves, their carer and/or the nurses to get from
common catheter related complications. These competencies where they will wash their hands to where the procedures
can be found in Appendix 3. While they may seem excessive will take place. Doors should be left open if possible and
it serves to illustrate the complexity of care a patient on home clean hands protected with a clean paper towel/muslin
parenteral support requires. cloth to minimize the hands becoming contaminated from
manoevering the drip stand/back pack. If training is hap-
pening in hospital, this should be identified at the outset,
Patient/Carer Training so that the patient feels confident to undertake their pro-
cedures in a new setting when discharged.
Just as with the nurse competencies there is an English national 2. Is there anything within the chosen area that could be an
framework patient competency document outlining what the infection risk?
patient/carer needs to learn. Broadly speaking these cover; There should be no vacuuming during the procedures, or
fans in operation, as these will generate dust, and dust
• Understanding how their gastrointestinal function has contains micro-organisms. It is advisable that any win-
changed, dows are closed and pets kept in a separate room while
• How to safely access the catheter and administer the pre- the procedures are in progress.
scribed parenteral support
• Care for the skin around the catheter In addition to the practical procedures training also needs to
• Troubleshooting common catheter and infusion related consider troubleshooting and lifestyle considerations such as
complications bathing and showering. The full version of the patient train-
ing competencies can be found in Appendix 4.
The full patient/carer competency document can be found in
Appendix 4. 1
The UK has seen a move from all patients being able to have a com-
The specific steps needed to undertake these procedures pounded regimen to using Multi Chamber Bags with additional IV flu-
will vary depending upon a number of things; ids where clinically possible. This has been due to capacity constraints
and product shortages, and has resulted in different ways of administer-
ing parenteral support, including separate vitamin/mineral infusions,
• The type of catheter, PICC, tunneled Hickman™ type, or use of double/triple spike giving sets which allow multiple concurrent
implanted port infusions (stability permitting), and double lumen extension sets.
Table 8 Catheter and infusion related problems associated with a central venous catheter include the catheter
Problem Detail being viewed as the intrusion of a foreign body which can
Local infection Can identify signs and symptoms of become the focus for neglect, self-harm and abuse. There are
• Exit site infection reports of patients deliberately damaging their catheter and
• Tunnel infection of injecting faecal matter through it. Patients have described
• Cuff infection (Hickman™ type catheter only)
being tethered to the pump during infusions with associated
• Port pocket infection (implanted port only)
• Can identify the correct action to take restriction in their daily activities. Rather than being seen
Bloodstream • Can identify signs and symptoms of a positively as a lifeline, patients may describe the catheter
infection bloodstream infection and the correct action to tethering them like an umbilical cord to the hospital and
take healthcare professionals. The catheter has also been associ-
Blocked catheter • Can identify signs of a blocked catheter ated with disruption in gender identity. This is presumably
• Knows simple first aid measures, for example
massaging under the clamp, changing the needle
due to having something hanging from the body, however it
free connector may also be experienced by patients with totally implanted
• Can identify the correct action to take ports if the size and shape of the port are clearly visible on
Catheter fracture • Can identify catheter fracture the chest wall [85]. For some, having nutrition and/or hydra-
• Knows to apply atraumatic clamp above the tion in liquid form parenteral support may be seen as a return
damaged area
to early childhood where they were reliant on liquid
• Can identify the correct action to take
Catheter related • Can describe signs and symptoms of nutrition.
thrombosis thrombosis (all catheters) Being aware of the possible psychological issues patients
• Can describe signs and symptoms of may experience will hopefully facilitate conversation
thrombophlebitis (PICC) between the nurse and patient, and identify possible mea-
• Can identify the correct action to take sures to alleviate some of these. Examples include suggest-
Fluid overload • Can describe signs and symptoms of fluid
overload
ing an implanted port, positioning the exit site of a Hickman™
• Can identify the correct action to take type catheter in a less visible position such as on the side of
Dehydration • Can describe signs and symptoms of the body below the armpit and discussing infusion times and
dehydration and when additional IV fluids are how they can be best fitted in around their day.
required
Catheter • Knows function of cuff (Hickman™ type
malposition catheter) and approximate location within skin
tunnel ngoing Support Arrangements for Patients
O
• Knows external length of PICC (If applicable) Once Discharged
• Understands the implication of catheter
malposition and correct action to take Patients need to know of ad hoc and scheduled support
arrangements once they are discharged. It is important to
manage patients expectations regarding this, particularly
Troubleshooting regarding the frequency of scheduled follow up. Before
being discharged on Home Parenteral Support patients will
Correct and early recognition of catheter and infusion related have had a lengthy inpatient stay during which they would
problems is essential in patients receiving home parenteral have been reviewed regularly by the multidisciplinary team,
support. Patients/carers need to be able to identify the com- individually, and as a team. They may also have developed
plications listed below and the correct action to take friendships with other patients. This stops on discharge
(Table 8). which some patients might find daunting.
Once discharged patients need to know who and how to
contact should they have any questions, or think they have
Body Image developed a line or Parenteral Support related problem. This
must include out of normal working hours, weekends and
It is easy to appreciate how a patient with a stoma or fistula public holiday arrangements. Encourage patients to enter
may experience issues with body image, however the impact any relevant phone numbers into their mobile phone before
from a central venous catheter is probably underestimated. they are discharged, as paper copies may be lost among the
While patients may be grateful that there is an effective treat- volume of paper information they will receive on discharge.
ment for their medical condition this doesn’t necessarily It must be appreciated that patients may initially feel
mean that the presence of a central venous catheter isn’t overwhelmed on discharge when the reality of how Intestinal
associated with psychological issues [85]. Negative feelings Failure has changed their pre admission life becomes truly
Table 9 BIFA recommendations for haematological and biochemical In addition to the haematological and biochemical moni-
monitoring of HPN (Home Parenteral Nutrition) [86]
toring, outpatient review should also cover appropriateness
British Intestinal Failure Alliance (BIFA) Guidance. Haematological of current parenteral support regimen, weight, anthropome-
and biochemical monitoring of adult patients receiving Home
Parenteral Nutrition
try, review of the central venous catheter, any issues with
1. All haematological and biochemical monitoring of HPN (home deliveries of parenteral support and necessary ancillaries,
parenteral nutrition) patients should be individualised and may and quality of life.
change with their clinical condition. The point at which patients
become stable post discharge will vary
2. Routine blood tests, including standard electrolytes, chloride,
bicarbonate (as a measure of acid-base balance), calcium,
Summary
magnesium, phosphate, renal and liver function tests, glucose, full
blood count, ferritin and CRP should be performed monthly for the Patients receiving home parenteral support have a lot to incor-
first 3 months after discharge. If stable this may then be 3–4 monthly porate into their daily lives including the administration of
3. When discharged patients should have their prothrombin time,
parenteral support, maintenance of their central venous cath-
cholesterol and triglyceride, HbA1c, vitamin D & B12 and folate
concentrations checked. These should then be monitored at least eter and stoma/fistula management. In addition they may also
6-monthly have debilitating symptoms such as nausea/vomiting and
4. Patients who are to receive long-term HPN should have baseline chronic pain. Nurses are well placed to help patients integrate
vitamins A&E, zinc, copper, manganese and selenium concentrations back into the community and live as full a life as possible.
checked and then monitored 6-monthly
5. If the CRP is significantly raised (>20 mg/l) iron can be measured
with transferrin and transferrin saturation to assist interpretation of Acknowledgments formally of
iron status. In this situation care must be taken in the interpretation Suzanne Wood
of zinc, copper, selenium and vitamins A, D and E in view of their Kingston Hospital, Surrey, UK
inflammatory response St Mark’s Hospital, Harrow, UK
6. When measuring zinc, copper, manganese or selenium use a trace
element-free collection tube
7. If the triglyceride concentration is elevated a fasting concentration
should be repeated ppendix 1. British Intestinal Failure Alliance
A
8. Urine sodium concentration is useful for assessing sodium balance (BIFA) Guidance
in patients with a short bowel and a 24-h urinary oxalate collection
for assessing risk of renal stone formation in patients with a short
bowel and colon in continuity tandardised Parenteral Support Catheter
S
Guidelines
apparent. The initial joy of being home may be replaced by onnecting a Parenteral Support (PS) Infusion
C
anxiety over how to incorporate parenteral support and or Key Principles of Care and Management of Central Venous
stoma/fistula management into their daily life. Patients Catheters.
should be made aware of patient support groups, for example
PINNT (Patients on Intravenous and Nasogastric Tube • Identify the key parts.
Therapy, www.pinnt.com) who can provide support, educa- • Ensure no touching of any key parts during the
tion and practical advice about living with parenteral sup- procedure.
port. Encouraging an activity, within physical capacity, • Apply alcohol hand rub directly to hands during the pro-
which gives pleasure and expresses individuality, may help cedure if touching any non-sterile contents and/or if there
to provide continuity with their past life and serve as hope is any risk of contamination.
that not all aspects of their pre intestinal failure life are over.
It needs to be recognized that patients will have different Social Handwash
goals for example one patient may view going on an overseas Step 1—Gather & Check Equipment
holiday to be a major achievement, whereas others may view
getting dressed and going out for coffee to be of equal • Bag of parenteral support (PS) (Check PS prescription,
achievement. integrity of bag & expiry date)
Patients should be regularly reviewed in a specialized • Trolley/tray
multidisciplinary outpatient clinic with staff experienced in • Detergent wipes (or paper towel, soap and water)
intestinal failure and parenteral support [7]. Frequency and • 2% CHG & 70% IPA disinfectant wipes • Sterile dressing-
nature of this follow up will depend on how stable the patient pack or dressing towels
is with regard to their prescribed regimen. BIFA (British • Gloves of choice (as recommended by HPN Centre)
Intestinal Failure Alliance) statement regarding haematolog- • 10mL pre-filled syringe(s) 0.9% sodium chloride for
ical and biochemical monitoring are listed in Table 9 [86]. injection
• Alcohol hand rub • Apply alcohol hand rub directly to hands during the pro-
• Sterile intravenous giving set cedure if touching any non-sterile contents and/or if there
• Surgical tape is any risk of contamination.
• Infusion pump, stand/rucksack
Social Handwash
Step 2—Aseptic Handwash Step 1—Gather & Check Equipment
Step 3—Prepare Equipment
• Trolley/tray
• Clean & disinfect trolley/tray surface • Detergent wipes (or paper towel, soap and water)
• Attach strips of tape to the edge of the trolley/tray • 2% CHG & 70% IPA disinfectant wipes
• Open sterile dressing pack/towel onto trolley/tray surface • Sterile dressing-pack or dressing towels
to create an aseptic field • Gloves of choice (as recommended by HPN Centre)
• Open equipment needed onto aseptic field • 10mL pre-filled syringe(s) 0.9% sodium chloride for
• Using gloves (as recommended by HPN Centre) spike injection
bag of PS and prime giving set • Alcohol hand rub
• Port protector (as recommended by HPN Centre)
Step 4—Prepare Patient & Catheter • Surgical tape
• Open sterile towel & place under catheter. Tape in place. Step 2—Aseptic Handwash
• Remove any outer dressing covering the catheter (if used) Step 3—Prepare Equipment
& port protector (if used)
• Clean & disinfect trolley/tray surface
Step 5—Access Catheter • Attach strips of tape to the edge of the trolley/tray
• Open sterile dressing pack/towel onto trolley/tray surface
• Put on gloves to create an aseptic field
• Disinfect needle-free device (The order of these first 2 • Open equipment needed onto aseptic field
steps can be interchanged depending on HPN Centre
recommendation) Step 4—Prepare Patient & Catheter
• Prime pre-filled syringe(s)
• Attach syringe to needle-free device and flush catheter • Switch off pump and close clamp on giving set
using push pause flushing and positive pressure clamping • Open sterile towel & place under catheter. Tape in
technique (as recommended by HPN Centre) place.
• Attach giving set • Remove outer dressing (if present) to release catheter and
clamp catheter (if present and recommended by HPN
Step 6—Start infusion & Secure Catheter centre)
• Ensure giving set & catheter clamps are released Step 5—Access Catheter
• Start infusion at prescribed rate
• Remove gloves • Put on gloves
• Secure catheter (as recommended by HPN Centre) • Disconnect giving set from needle-free device (The order
of these first 2 steps can be interchanged depending on
Step 7—Clear away HPN Centre recommendation)
• Disinfect needle free device
• Complete any documentation • Prime pre-filled syringe(s)
• Attach syringe(s) to needle-free device and flush catheter
Social Handwash using push pause flushing and positive pressure clamping
technique (as recommended by HPN Centre)
isconnecting a Parenteral Support (PS) Infusion
D • Attach port protector (as recommended by HPN centre)
Key Principles of Care and Management of Central Venous
Catheters. Step 6—Secure catheter
• Identify the key parts. • Remove gloves

• Ensure no touching of any key parts during the procedure. • Secure catheter (as recommended by HPN Centre)
Step 7—Clear away • Disinfect skin with single-use 2% CHG & 70% IPA
• Complete any documentation sponge applicator(s)
• Apply dressing(s) &/or suture-less securement device as
Social Handwash per manufacturer’s recommendation
hanging the Parenteral Support (PS) Catheter

C Step 6—Secure Catheter
Dressing
Key Principles of Care and Management of Central Venous • Remove gloves
Catheters • Secure catheter (as recommended by HPN Centre)
• Identify the key parts. Step 7—Clear away

• Ensure no touching of any key parts during the procedure.
• Apply alcohol hand rub directly to hands during the pro- • Complete any documentation
cedure if touching any non-sterile contents and/or if there
is any risk of contamination. Social Handwash
• This procedure should not be incorporated into any other
procedure in which the catheter hub is manipulated so
keeping the risk of cross contamination to a minimum. Glossary of Terms
• Dressings need to be changed every 7 days, if they are
soiled or have become loose. A fabric island type dressing Alcohol hand rub
is recommended if there is discharge from the exit site. An alcohol containing product (gel or foam) designed to
reduce the number of micro-organisms on the hands. It
Social Handwash should be applied to clean, dry hands, and the hands rubbed
Step 1—Gather & Check Expiry Dates of Equipment together, following the steps in the aseptic hand washing
technique, until they are completely dry.
• Trolley/tray • Detergent wipes (or paper towel, soap and
water) Aseptic hand wash
• 2% CHG & 70% IPA disinfectant wipes A thorough hand wash procedure concentrating particularly
• Sterile dressing-pack or dressing towel on the areas of the hands where resident bacteria can be
• Gloves of choice (as recommended by HPN Centre) found. To be effective the hand wash solution must come into
• Single use 2% CHG & 70% IPA sponge applicator(s) contact with all of the surfaces of the hands and wrists. While
• Sterile dressing(s) of choice there are many different hand washing techniques cited in
• Alcohol hand rub the literature (with 6–13 steps) the principles are the same, to
• Suture-less securement device (if required) make sure all surfaces of the hands (including the wrists), are
adequately washed, rinsed and dried, especially those areas
Step 2—Aseptic Handwash which may be missed such as finger tips, thumbs and between
Step 3—Prepare Equipment the fingers.
• Clean & disinfect trolley/tray surface CVC

• Open sterile pack/towel and create an aseptic field A vascular access device whose tip lies in the lower third of
• Open equipment needed onto aseptic field the superior vena cava or the upper third of the inferior vena
cava (ideally at the vena cava / right atrial junction). They
Step 4—Prepare Patient & Catheter can either be centrally inserted via the subclavian, internal
jugular or femoral veins or peripherally inserted via the bra-
• Remove existing dressing(s) &/or suture-less securement chiocephalic veins. The femoral route, which may have a
device higher risk of infection, is chosen when the upper veins can-
• Attach anchoring strip (if present) from suture-less not be accessed.
securement device
Disinfectant wipes
Step 5—Access Catheter Single use wipes containing 2% chlorhexidine and 70% iso-
propyl alcohol (2% CHG & 70% IPA). The combination of
• Put on gloves of choice (as recommended by HPN both disinfectants is thought to be more effective than when
Centre) either is used alone.
Key-Part(s) organisms to and from the wearer’s hand. The wearing of

Things which if touched directly or indirectly could result in gloves is not a substitute for hand washing.
the introduction of micro-organisms. They include the cath-
eter hub, the end of the giving set, syringe tip and the skin Sterile towel
surrounding the exit site. This can be either supplied separately or within a dressing
pack. The towel is used to create the aseptic field onto which
Needle Free Connector (NFC) the sterile items are placed. A second sterile towel is used to
A device which permits the connection of administration lie under the patient’s catheter thereby creating an aseptic
sets, and syringes to the hub of a vascular access device with- field when accessing the catheter.
out the use of needles. They were introduced to reduce the
incidence of needle stick injuries. They should be disinfected
using pressure and friction for a minimum of 15 s prior to, ppendix 2. Patient Needs Assessment Form
A
and after, each time they are accessed. for HPN, NHS England 2019® (Used
with Permission)
Parenteral Support (PS)
A term which covers both parenteral nutrition and parenteral The purpose of this document is to assess if the patient is
fluids. suitable for homecare and HPN. It should be used in con-
junction with discharge planning documents used in the
Port Protector Cap Purchasing Authority. It can also be used once the patient is
A disposable single use disinfection cap that contains 70% at home if there are any changes in the patient’s circum-
Isopropyl Alcohol (IPA). The port protector twists onto the stances and/or to periodically assess a patient’s suitability to
end of a needle free connector to passively disinfect and pro- undertake training for care of their central venous catheter.
tect from cross contamination during infusion free periods.
Date of Assessment: Assessment conducted by:
Positive pressure clamping technique Patient Name DOB NHS
The catheter is clamped while flushing with the last mL of Number
Preferred name Employment/Education
solution so as to seal a column of fluid within the catheter. Status
This may reduce the backflow of blood and thereby the risk Permanent address: Secondary address: (students,
of occlusion. initial discharge address (if
different from permanent),
children living at 2 addresses
Push-Pause flushing technique
including temporary foster
Flushing with a stop/start motion causes turbulence of fluid care placement
within the catheter that may help reduce the build-up of any General Concerns and Comments
deposits and reduce the risk of occlusion. Underlying illness leading to
intestinal failure
Does the patient have any
2% chlorhexidine gluconate (CHG) & 70% isopropyl
co-morbidities that may result
alcohol (IPA) sponge applicator them being unsafe at home?
These are single use sponges contain 2% CHG and 70% IPA What is the patient or carers’
are designed to disinfect the skin around the exit site. By understanding of the risks and
using gentle, repeated back and forth strokes for 30 s this benefits of having a central
venous catheter (CVC)? Are there
provides an effective reduction on bacterial load on the skin. any concerns that the patient may
be unsafe with a CVC?
Social hand wash What medications is the patient
Also known as a routine hand wash. A general hand wash to on?
remove transient microbes picked up on the hands during Psychological wellbeing with
regards to HPN. Are there any
daily activities. concerns here such as self-harm,
neglect or abuse?
Sterile gloves Is there family support for the
These have traditionally been advised as best practice for the patient going home on HPN? Are
there any concerns? Include
administration of parenteral support however non sterile details of any hospice/respite
gloves can be used. Sterile gloves had been thought to reduce facility referrals or details.
the risk of infection by reducing the transfer of micro-
Are there any safeguarding Specific training assessment

issues? Include Social Worker questions
details and any safeguarding These questions are aimed at
plans. determining an individual’s physical
Home environment—use RPS ability to undertake HPN
standard document for assessment procedures
Physical Comments Can they use a smartphone/
Mobility: electronic tablet? Yes/No
Are there any concerns regarding Unscrew/screw on a lid such as on a
mobility toothpaste tube?
Yes/No Yes/No
If yes Open a packet, such as a plaster/
Physio assessment/OT packet of crisps
Yes/No Yes/No
Date: Can they lift a weight equivalent to
Dexterity: a bag of PN such as 4 litres of milk?
Is dexterity limited Yes/No
Yes/No Can they raise it as high as a drip
Can patient perform activities of stand?
daily living? Yes/No
(Washing, dressing etc.?) Recommendations for
Yes/No administration of HPN and care
of CVC
If issues
Train to become independent
OT assessment
Yes/No
Yes/No
Re-assess once at home
Vision:
Yes/No
Does the patient have any visual
impairments Yes/No Family member* to train
If yes—what modifications are Yes/No
needed before discharge? Joint care (patient / family
Hearing: member*/nurse) Yes/No
Does the patient have hearing Full nursing support
impairments? Yes/No Yes/No
If yes—what modifications are Transition training (paed-adult
needed before discharge? services)
Other health concerns: Yes/No
Yes/No *It is recommended that any family
Stoma care, wound care, palliative member taking on the responsibility
support, medication, diabetes, is 18 years of age or older
respiratory conditions, drug / For patients assessed as being
alcohol intake etc.) able to train to independence
If yes—please list what extra Does patient understand the remit
services are required of the nursing service and that NHS
The following 3 questions need to Patient Carer(s) England expects patients to
be completed for both the patient self-care unless assessed as being
and carer(s) who would be unable to learn?
undertaking administration of Yes/No
parenteral support and care of General Comments:
central venous catheter Action plan Date
Communication: (Reading and achieved
spoken) Signature of healthcare professional undertaking Date
Reading barriers assessment:
Yes/No
Language barriers This record should be made available to the Contractor
Yes/No and the record kept in the patients notes at the Purchasing
If yes—how will this be addressed
Authority
before discharge
Cognition:
Does the patient have a clear
understanding of procedures and
protocol? Yes/No
ppendix 3. Home Parenteral Nutrition

A d. Cleans and disinfects general aseptic field
Nurse Competencies NHS England 2019® (for example, plastic tray/trolley) correctly
e. Correctly opens sterile items onto aseptic
(used with permission) field
f. Can identify key parts and non-key parts
ome Parenteral Nutrition Nurse
H g. Understands the concept of key part and
Competencies key site management
h. Disinfects needle free connector for
minimum of 15 seconds with pressure and
Aim: The nurse administering home parenteral nutrition
friction, and allows to dry for 30 seconds
(whether from a homecare company or an NHS nurse under- 3. To safely disconnect and flush catheter
taking this work) will need to acquire the knowledge and a. Deals appropriately with pump and
skills listed below. catheter at end of infusion
All nursing staff need to be aware of the following British b. Prepares syringe with flushing solution
correctly
Intestinal Failure Alliance (BIFA) documents;
c. Understands the rationale behind pulsatile
flushing and can demonstrate flushing a
• Guidance Standardised Parenteral Support Catheter catheter with push-pause technique
Guidelines, https://www.bapen.org.uk/pdfs/bifa/stan- d. Understands the rationale behind positive
dardised-parenteral-support-catheter-guidelines.pdf pressure clamping and can demonstrate
effectively when disconnecting a syringe
• Intestinal Failure Alliance (BIFA) Recommendations for (open ended catheter)
Catheter Related Blood Stream Infections (CRBSI) Diag- e. Understands the rationale behind
nosis https://www.bapen.org.uk/pdfs/bifa/recommenda- maintaining positive pressure and can
tions-for-crbsi-diagnosis.pdf demonstrate effectively when disconnecting
• British Intestinal Failure Alliance (BIFA) Recommenda- a syringe from a valved catheter
f. Care of unused lumens (if applicable)
tion Management of Catheter Related Blood Stream
g. Prepares and instills antimicrobial lock
Infections (CRBSIs) https://www.bapen.org.uk/pdfs/bifa/ correctly (where applicable). Knows the
recommendations-on-management-of-crbsi.pdf active ingredient(s) within the prescribed
lock, indications for use and possible side
effects
h. Removal and safe disposal of Huber
Learning outcome Achieved Signature needle (port only)
(date)
i. Knows purpose of a port protector and
1. Intestinal failure mode of action. Applies 70% isopropyl
a. Understands principles of normal alcohol port protector correctly and knows
intestinal function frequency of change
b. Can describe how gut function has j. Secures catheter as per hospital protocol
changed in someone with intestinal failure and can explain to the patient the rationale
c. Understands common drug therapy used behind such securement
in patients with intestinal failure. 4. Administration of any additional
d. Knows how to minimize effect of GI prescribed medications (if applicable)
changes on fluid balance in someone with a. Prepares and administers any additional
intestinal failure prescribed medications correctly. Knows the
e. Has an understanding of the paediatric indications for use for these, any
specific nursing considerations (where contraindications and possible side effects
applicable) b. Knows how to safely dispose of used
2. Vascular access devices used for home ampoules/vials/sharps
parenteral nutrition c. Knows what to do in case of needlestick
a. Can identify the following devices; injury
tunneled catheter, PICC, implanted port 5. Addition(s) to IV fluid (if applicable)
b. Can identify commonly used tunneled a. Completes all patient identity checks with
catheters, for example Vygon, Bard and the prescription
Cook b. Can identify additive port on IV fluid
c. Can identify commonly used valved container
devices, for example Groshong, PASV and c. Prepares any prescribed additions
Solo and knows the position of the valve correctly as per manufacturer’s instructions
2. To understand principles of asepsis using appropriate aseptic technique
a. Washes and dries hands effectively
b. Applies hand rub correctly
c. Applies gloves correctly
d. Adds any prescribed additions to the IV c. Knows how to ramp up and ramp down
fluid container correctly using a safety infusion on each of the pumps on the
needle, and is aware of the correct order of framework and when this would be indicated
any additions, using appropriate aseptic 8. Care of exit site
technique a. Can describe appearance of a healthy exit/
e. Ensures any additions have been dispersed implanted port site
adequately within the IV fluid container b. Assesses exit/implanted port site at each
f. Primes giving set correctly (primary catheter manipulation
infusion) c. Knows when to clean exit site
g. Primes any additional administration set d. Knows what to clean exit site with and
for simultaneous secondary infusion, for method of cleaning. Can suggest alternative
example Y-site or Octopus double lumen cleaning solutions in cases of proven allergy
extension set. e. Suitable dressings to use and correct
h. Knows how to use Micrel double spike method of application and removal. Can
giving set and administration tubing (if used) suggest alternative suitable dressings in
i. Knows how to safely dispose of used cases of proven allergy
ampoules/vials/sharps f. Knows frequency of sutureless securement
6. To safely set up PN or IV fluids device change
a. Checks solution correctly g. Can change commonly used sutureless
b. Can identify if a bag is not safe to securement devices and the necessary
administer, ie cracking, creaming, particles measures to reduce catheter dislodgement
c. Primes giving set (single, or double spike h. Knows when and how to remove exit site
if used) correctly either manually or via sutures from all types of devices including
pump. (Note: for manually primed giving how to remove an external stitch fixator
sets NHS Improvement have recommended i. Can identify possible medical adhesive
that once primed the giving set is placed into related skin injury (MARSI) and how to
the pump before being connected to the treat this
catheter so as to reduce the risk of accidental j. Can identify any skin impairment from a
free flow) SecurAcath device (if used)
d. Checks patency of line before connecting 9. How and when to change needle free
infusion (as per hospital protocol) connector
e. Has received training on all pumps on the a. Knows how often the following needle
HPN framework free connectors should be routinely changed
f. Deals with pump alarms appropriately Vygon Bionector
g. Protects bag from light (where applicable) Fanin Clave/Microclave
h. Insertion of Huber needle (port only). Can Fanin Neutron
identify if needle has been inserted correctly Carefusion Smartsite
and is the correct length ICU Medical CLC2000
i. Knows how to use Portacator (port Vygon Bionector TKO
location device) and when it would be b. Knows any additional times connector
recommended should be changed
j. Can deal appropriately with blood c. Can change connector during
backflow in giving set disconnection procedure
k. Protects giving set/line connection during d. Can change connector during connection
infusion (if applicable and as per hospital procedure
protocols) e. Knows the difference between specific
l. Knows what to do or advise if the PN bag clamping sequence needed for use with a
is damaged/leaking/contaminated or the positive pressure needle free connector, and
delivery is delayed/missing. (note: paeds do how this differs from the clamping sequence
not always have a buffer bag) required for neutral and negative connectors
m. Knows how to use a gravity giving set f. Knows any incompatible connector/device
and when this would be indicated combinations, for example if anti reflux
n. For insulin dependent patients. Can connector (TKO) can be used with a valved
measure blood glucose and administer CVC
insulin prior to connecting parenteral 10. To detect possible infection
nutrition. (Only in cases where patient/carer a. Can identity signs of possible bloodstream
is unable to do) infection
7. Calculates infusion rates correctly c. Can identify signs of possible exit site/
a. Knows maximum hourly infusion rate for tunnel infection
prescribed parenteral support d. Can identify signs of possible cuff
b. Knows maximum hourly infusion rate for infection
additional IV fluids e. Can identify overgranulation tissue at exit
site
f. Can identify signs of possible port pocket f. Can identify action to take and point of
infection (port only) contact for the above
g. Can identify action to take and point of 16. Can recognize signs of possible
contact for above thrombophlebitis and thrombosis
11. To detect possible hypoglycaemia a. Can describe and recognize signs of
a. Can identify the signs of possible thrombophlebitis in patients with a PICC
hypoglycaemia. b. Can describe possible signs and symptoms
b. Can identify measures taken to prevent of a central venous catheter related
hypoglycaemia. thrombosis
c. Knows the at risk periods of c. Can identify action to take and point of
hypoglycaemia. contact for the above
d. Can identify action to take and point of 17. Correct storage of PN, IV fluids and
contact for further advice. any other prescribed IV medication
12. To prevent air embolism a. Can describe how to correctly store PN
a. Knows how air can enter bloodstream and b. Can read expiry date correctly
infusion c. Understands about stock rotation
b. Can describe signs and symptoms of d. Understands importance of cleaning
suspected air embolism fridge
c. Can describe position patient should be e. Can describe how to correctly store any
placed in if air embolism is suspected IV fluids
d. Knows when and how to clamp catheter f. Can describe how to safely dispose of any
e. Can identity what an approved unused prescribed PN/IV fluids or other
replacement catheter clamp looks like and prescribed medication
can apply to a non valved catheter 18. Can identify signs of fluid overload
f. Knows how to deal with “air in line” a. Can recognize signs and causes of
during infusion possible fluid overload
g. Knows what to do in case of catheter b. Can identify action to take and point of
falling out contact.
13. To act appropriately with a blocked 19. Can identify signs of dehydration
catheter a. Can recognize signs and causes of
a. Can identify common reasons catheters possible dehydration
can become blocked b. Is aware of the sodium content of the
b. Knows signs of catheter blockage following commonly prescribed prn fluids
c. Can identify and perform simple “first 1 L 0.9% sodium chloride
aid” measures to try and restore patency 1 L 4% dextrose & 0.18% sodium
d. Can identify action to take and point of chloride
contact and when it would be clinically appropriate
14. To act appropriately with catheter to administer them
fracture c. Can identify action to take and point of
a. Knows how catheters can become contact
fractured 20. Can take blood from central venous
b. Can identify signs of catheter fracture catheter
c. Knows what to do in case of catheter a. Knows when a discard volume is
fracture necessary and why
d. Can identify when a catheter has been b. Knows how much discard volume to take
repaired and can assess the integrity of the with different vascular access devices
repair c. Can identity measures to facilitate blood
e. Can identify point of contact for the above return in cases where blood cannot be easily
15. Can identify possible catheter aspirated
malposition d. Flushes catheter following blood sampling
a. Knows the approximate external length of 21. Safe disposal of healthcare waste
catheter (Cuffed and PICCs) a. Can describe how to safely dispose on
b. Knows function of cuff and how to locate healthcare waste associated with the
approximate location within skin tunnel administration of PN/IV fluids and any other
c. Can identify an exposed cuff prescribed IV medication
d. Understands function of SecurAcath 22. Lifestyle issues
engineered securement device(if used) and a. Knows how to advise patient on how to
how to identify it is correctly placed safely care for external surface of the line
e. Knows where a catheter tip should be and and clamp
understands the implication of catheter b. Knows how to advise patient on how
malposition protect line during showering/bathing (as per
hospital protocols)
c. Can advise patient re process to follow if c. Applies gloves (if recommended)correctly

they want to go on holiday d. Cleans and disinfects trolley/tray correctly
23. Care of venting gastrostomy tube (if e. Correctly opens sterile items onto aseptic
applicable) field
a. Understands function of venting f. Can identify key parts and non-key parts
gastrostomy tube g. Understands the concept of key part and
b. Can access tube with appropriate enteral key site management
syringe h. Disinfects needle free connector for
c. Can aspirate and flush tube as per hospital minimum of 15 seconds with pressure and
protocol friction, and allows to dry for 30 seconds
d. Understands rationale behind, and can 3. To safely disconnect and flush catheter
demonstrate, rotating and advancing tubes a. Deals appropriately with pump and
e. Can undertake routine balloon care catheter at end of infusion
(balloon tubes only) b. Prepares syringe with flushing solution
f. Knows advice to give and point of contact correctly
if tube falls out. c. Flushes catheter with push-pause
24. Knows about and informs patients technique
about the patient support group PINNT d. Uses positive pressure clamping technique
a. Knows about and informs patient about when disconnecting syringe (open ended
the PINNT Verify tag catheters)
b. Knows about and informs patient about e. Uses positive pressure when disconnecting
the PINNT restaurant card syringe (valved catheters)
c. Knows about and informs patient about f. Care of unused lumens (if applicable)
the Patient Safety poster g. Prepares and instills antimicrobial lock
correctly (if applicable)
Date training completed h. Removal and safe disposal of Huber
Signature Print Name needle (port only)
i. Applies 70% isopropyl alcohol port
protector correctly (if recommended)
j. Secures catheter as per hospital protocol
ppendix 4. Home Parenteral Nutrition
A 4. Administration of any additional
Patient Competencies, NHS 2019® (used prescribed bolus medications via central
with permission) venous catheter (if applicable)
a. Prepares and administers any additional
prescribed bolus medications correctly
ome Parenteral Nutrition Patient
H b. Knows how to safely dispose of used
Competencies ampoules/vials/sharps
c. Knows what to do in case of needlestick
Name ___________________________________________ injury (if applicable)
_______________________________ 5. Addition(s) to IV fluids (if applicable)
Aim: The patient/carer* will acquire the knowledge and a. Can identify additive port on IV fluid
container
skills necessary to safely and effectively administer paren- b. Prepares any prescribed additions
teral support (nutrition and or intravenous fluids) and care for correctly as per manufacturer’s instructions
the central venous catheter. *It is recommended that any using an appropriate aseptic technique
family members undertaking administration of parenteral c. Adds any prescribed additions, using an
appropriate aseptic technique to the IV fluid
support and care of central venous catheters are 18 years of
container correctly using a safety needle and
age or above. is aware of the correct order of any additions
d. Ensures any additions have been dispersed
Learning outcome Achieved Signature adequately within the IV fluid container
(date) e. Primes giving set correctly
1. To understand why parenteral support f. Primes any additional administration set
is required for simultaneous secondary infusion, for
a. Principles of normal intestinal function example Y-site or Octopus double lumen
b. How gut function has changed extension set
c. How to minimize effect of GI changes g. Knows how to use Micrel double spike
d. How and when to administer additional giving set and administration tubing (if used)
IV fluids h. Knows how to safely dispose of used
2. To understand principles of asepsis ampoules/vials/sharps
a. Washes and dries hands effectively 6. To safely set up parenteral support (PN
b. Applies hand rub correctly or IV fluids)
a. Checks solution(s) correctly c. Can identify signs of possible exit site/

b. Can identify if a bag(s) not safe to tunnel infection
administer, ie cracking, creaming d. Can identify signs of possible cuff
c. Primes giving set (single, or double spike infection
if used) correctly either manually or via e. Can identify signs of possible port pocket
pump. (Note: for manually primed giving infection (port only)
sets NHS Improvement have recommended f. Can identify action to take and point of
that once primed the giving set is placed into contact for above
the pump before being connected to the 11. To prevent air embolism
catheter so as to reduce the risk of accidental a. Knows how air can enter bloodstream and
free flow) infusion
d. Checks patency of catheter before b. Knows when and how to clamp catheter
connecting infusion (as per hospital c. Knows how to deal with “air in line”
protocol) during infusion
e. Uses pump correctly d. Knows what to do in case of catheter
f. Deals with pump alarms appropriately falling out
g. Protects bag from light (where applicable) e. Can identify point of contact
h. Insertion of Huber needle (implanted port 11. To act appropriately with blocked
only). Can identify if needle has been central venous catheter
inserted correctly and is the correct length a. Knows signs of central venous catheter
i. Knows how to use Portactor (port locating blockage
device) if recommended (port only) b. Can identify simple “first aid” measures
j. Can deal appropriately with blood c. Can identify action to take and point of
backflow in giving set contact
k. Protects giving set/catheter connection 12. To act appropriately with central
during infusion (if applicable as per hospital venous catheter fracture
protocol)
a. Knows how catheters can become
l. Knows how to use a gravity giving set and fractured
when this would be indicated
b. Can identify signs of catheter fracture
7. Calculates infusion rates correctly
c. Knows what to do in case of catheter
a. Knows maximum hourly infusion rate for fracture
prescribed parenteral support
d. Can identify point of contact
b. Knows maximum hourly infusion rate for
13. Can identify possible catheter
additional IV fluids
malposition
c. Knows how to ramp up and ramp down
a. Knows function of cuff (tunneled catheter)
infusion (where applicable)
and approximate location within skin tunnel
8. How and when to dress exit site
b. Knows external length of PICC (if
a. Knows frequency of dressing change and applicable)
cleaning of exit site
c. Understands function of SecurAcath
b. Knows how to remove dressing to device (if used)
minimize skin impairment (+/- medical
d. Understands implication of catheter
adhesive remover)
malposition
c. Knows what to clean exit site with and
e. Can identify action to take and point of
method of cleaning
contact
d. Knows how to apply silicone skin
14. Can recognize signs of possible
protection (if recommended)
thrombosis
e. Suitable dressings to use
a. Can describe possible signs and symptoms
f. Knows frequency of sutureless securement of a central venous catheter related
device change (PICC only) thrombosis
9. How and when to change needle free b. Can identify action to take and point of
connector contact
a. Knows name of connector used an how c. Can describe possible signs and symptoms
often this should be routinely changed of thrombophlebitis (PICC only)
b. Knows any additional times connector d. Can identify action to take and point of
should be changed contact
c. Can change connector during 15. Correct storage of PN, IV fluids and
disconnection procedure any other prescribed IV medication
d. Can change connector during connection a. Can describe how to correctly store
procedure parenteral support
10. To detect possible infection b. Can read expiry date correctly
a. Can identity signs of possible bloodstream c. Understands about stock rotation
infection
d. Understands importance of cleaning References

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Care of Intestinal Stoma
and Enterocutaneous Fistula(s)
Louise Williams and Gordon L. Carlson

1. Good nursing care of intestinal fistulas and stomas is
essential to the effective management of patients with Patients with acute intestinal failure complicated by the pres-
intestinal failure. ence of an intestinal stoma or enterocutaneous fistula should
2. A stoma should be presited (marked) on flat skin away be managed by a multidisciplinary team. Suboptimal care of
from bony prominences, skin creases or where clothing stomas and/or fistulas may result in adverse physical and
may grip, at a site agreed by the patient. psychological consequences [1] and may prejudice nutri-
3. An understanding of the relevant intestinal anatomy may tional support, surgical treatment or spontaneous fistula
be helpful in predicting the short and long-term behav- closure.
iour of an enterocutaneous fistula (ECF) or stoma. This chapter outlines the fundamental principles of man-
4. Effective skin care involves avoiding contact between agement of patients with intestinal stomas and enterocutane-
stoma and fistula effluent and the skin, especially in the ous fistulas in patients with intestinal failure. Distal enteral
case of more proximal stomas and fistulas, from which feeding which may be complete or trophic is increasingly
the effluent is highly corrosive. being performed into a distal unobstructed segment of bowel
5. A well-fitting adhesive appliance will protect the skin, (stoma or fistula) and is discussed in chapter “Distal Feeding
remove unpleasant odours, reduce risk of cross-infection, and Hydration”.
allow assessment of fluid losses, preserve dignity and
allow the patient mobility and rest.
6. Fistula and stoma appliances which incorporate negative Definitions
pressure and drainage devices should be considered in
higher output fistulas and stomas, in order to facilitate Intestinal Stoma
skin care.
7. In cases where there is uncontrollable and unmanageable An intestinal stoma is a surgically created opening in the
leakage from a fistula, early surgery to produce a tempo- abdominal wall related to a portion of the gastrointestinal
rary proximal loop jejunostomy may greatly facilitate tract. Its purpose is to provide a pathway for digested mate-
nursing care and improve patient wellbeing. rial to leave the body when the normal pathway is obstructed
8. Accurate recording of fluid balance (and notably fistula or its function otherwise impaired [2]. An intestinal stoma
or stoma output) is essential for the effective management may involve the stomach (a gastrostomy), part of the small
of patients with high output fistulas. intestine (duodenostomy, jejunostomy, ileostomy) or a part
9. Measurement and a photographic record of an ECF of the large intestine (colostomy). Some stomas may even
should be kept. involve two separate segments of the gastrointestinal tract
(for example an ileocolostomy). A stoma is termed an end
stoma (in which the bowel at the site selected is divided and
L. Williams (*) brought up to the skin) or a loop/defunctioning stoma when
Department of Colorectal & Stoma Care, Queen’s Medical Centre,
the bowel is not divided but simply opened (Fig. 1). A
Nottingham University Hospitals NHS Trust, Nottingham, UK
e-mail: [email protected] defunctioning stoma is usually intended for a few months
often to defunction an anastomosis distal to it (e.g. in low
G. L. Carlson
Surgery, Salford Royal NHS Foundation Trust, Salford, UK anterior resection or the rectum or ileoanal pouch). In each
e-mail: [email protected] case, the bowel is ideally brought out through the rectus

620 L. Williams and G. L. Carlson
a b
Fig. 1 Types of stoma (a) A colostomy, (b) A Brooke ileostomy, (c) A loop colostomy, (d) a loop ileostomy
Care of Intestinal Stoma and Enterocutaneous Fistula(s) 621
abdominis muscle to minimize the chance of a parastomal attachments, the number of openings, the orientation with
hernia developing [3] and then sutured to the skin after an respect to the long axis of the intestinal tract and the presence
approximately 2.5 cm circular area of skin has been removed. of an associated abscess cavity. When more than one organ
Large bowel stomas (colostomies) are generally sutured system is involved, fistulas are described as complex. For
flush with the skin, whereas small bowel stomas (ileostomy, example, a fistula arising from the side of the terminal ileum
jejunostomy, duodenostomy) usually have an everted 2.5– and passing directly to the skin of the abdomen would be
3.0 cm spout. This modification, devised by Brooke, enables described as a simple lateral ileal fistula (Fig. 2a). A similar
the corrosive effluent to be kept away from the skin and track passing from the side of ileum into an abscess cavity,
appliances to be kept on with relative ease [4]. and the bladder then to the skin is described as a complex
lateral ileovesicocutaneous fistula (Fig. 2b). Fistulas that
arise perpendicular to the long axis of the gut are referred to
Enterocutaneous Fistula as end fistulas and may arise following complete anasto-
motic dehiscence or rectal stump blow out after Hartmann’s
An enterocutaneous fistula is an abnormal communication procedure. They classically develop from the duodenal
between the gastrointestinal tract and the skin. stump after a Polya gastrectomy. An enteric fistula occurring
Enterocutaneous fistulas may develop as result of complica- in the setting of an open abdomen creating a communication
tions of surgery or as a result of intrinsic disease of the gas- between the GI tract and the external atmosphere may be
trointestinal tract (e.g. in Crohn’s disease, malignancy or referred to as an enteroatmospheric fistula (EAF). Intestinal
diverticular disease of the colon). Enterocutaneous fistulas fistulas are most commonly caused by an anastomotic or
(Fig. 2) are classified according to the site of origin and suture line leakage, trauma, inflammatory bowel disease,
Fig. 2 Classification of a Fistula

intestinal fistulas, showing (a)
a simple lateral ileocutaneous
fistula track and (b) a Skin
complex track involving skin
and bladder with intervening
abscess cavities
lleum
Abscess
cavities
External
fistula
tracts
Internal
fistula tracts
Skin Terminal
ileum
Urinary
bladder
malignant disease, diverticular disease of the colon, or as a Jejunostomy

consequence of radiotherapy [5].
The output from a jejunostomy increases dramatically
after food/fluid is taken orally and may reach more than
The “Normal” Stoma 6 L if less than a metre of jejunum remains. Patients with a
jejunostomy are likely to require continued intravenous
It is usual for a stoma to be oedematous after surgery and to fluid and electrolyte therapy in order to prevent metabolic
shrink over the first 1–2 postoperative weeks. This usually complications. It should be stressed that excessive thirst
results in a requirement for a smaller template. due to dehydration should be treated with oral fluid restric-
tion (typically to <1500 mL/day) and the loss replaced
intravenously. Allowing such patients unrestricted access
Choosing the Stoma Site to oral fluids results in a vicious cycle in which excessive
fluid intake results in increasing fluid output from the
The Stoma Care Nurse should discuss the planned surgery stoma and greater thirst. It is important to remember that
with the patient, using diagrams to explain what a stoma is, each litre of jejunostomy effluent contains approximately
how it will affect their life, how it is managed and how to 100 mmol of sodium and 20–40 mmol of potassium and
manage problems. The ideal site for the stoma is selected these electrolytes must be replaced. Maintenance electro-
after careful evaluation of the patient. A flat area of normal lyte fluids are available for intravenous replacement in
skin contour, below the belt or waistline (except for a trans- these circumstances.
verse colostomy) is chosen away from bony prominences In patients with a newly-created jejunostomy, careful
(iliac crest or costal margin), surgical scars/skin folds/creases attention to monitoring of fluid and electrolyte balance
and unobscured by pendulous breasts. The optimal site should be undertaken. Although daily plasma measurements
avoids places where clothing grips the abdomen or where the are of value, homeostatic mechanisms result in failure of
bag would be conspicuous or easily damaged. The site cho- plasma measurements to detect dehydration or electrolyte
sen is marked with indelible ink and should be just medial to depletion until late in their evolution. A more useful and
the linea semilunaris. The patient is asked to sit, bend, stand more acceptable means of monitoring the patient’s fluid and
and walk to check the suitability of position (it may be useful electrolyte status is to weigh the patient and perform mea-
to apply a bag if difficulties are evident or if the patient surement of urinary sodium concentration at least twice-
requests). A reserve site may also be chosen as type of stoma weekly. The finding of a urinary sodium of less than
brought out during surgery may change, some surgeons may 20 mmol/L in such patients implies sodium depletion and a
ask for patient to be sited on both sides. need for further assessment (chapter “Management of a
High Output Stoma, Jejunotomy or Uncomplicated
Enterocutaneous Fistula”).
Colostomy
A colostomy generally begins to act 2–5 days after surgery. Diet with a Stoma
Flatus, followed by watery faeces, will first become apparent
but with the introduction of oral fluids and diet the effluent Patients with stomas can be reassured that they will not have
will become solid. The volume of output will be influenced to make major modifications to their diet. Some foods, how-
by the diet, the presence of coexisting intestinal disease and ever, may cause discomfort or even intestinal obstruction,
the precise location of the stoma with respect to the colon. In malodorous flatulence or diarrhoea and may be best avoided,
general, a colostomy output varies between 200 and although patients will ultimately determine their dietary
600 mL/24 h. preferences on an individual basis.
Nuts and fibrous foods such as dried fruits (e.g. raisins
and sultanas) and ‘pithy’ fruit (e.g. orange) may cause dis-
Ileostomy comfort or even obstruction in patients with an ileostomy.
Other foods that may be partly digested include celery, coco-
An ileostomy generally starts to work within 24 h. During nut, coleslaw (raw cabbage), sweet-corn, orange, mushroom,
the first week, an output of about 1.2 L of watery stool is nuts, peas, popcorn, pineapple, relishes (e.g. chutney), seeds
expected and this falls for the second week to about 600 mL and skins (e.g. apples/pears). Foods that may cause flatu-
daily of porridge-like stool. The output initially rises as food lence/malodour are generally avoided (asparagus, baked
is taken. A normal ileostomy may reduce its output over the beans, cabbage, broccoli, brussel sprouts, fish, cauliflower,
following few months. eggs, beer, carbonated beverages, onions and parsnips).
Reduction of Odour fluid and salt intake needs to be ensured as patients with a
stoma may be at increased risk of dehydration.
Deodorizing drops can be put into a stoma bag if there is
perceived to be a major problem of malodour. Neutralizing
sprays can also be used. If there is a malodorous wound it Psychological Care
may be redressed with a charcoal- or metronidazole-based
dressing. Some foods may cause flatulence (e.g. brassicas Psychological care is an integral part of the management
such as sprouts) and the diet can be restricted if desired. of patients with stomas and fistulas. This is especially
important in the patient who presents with a fistula after
repeated failed surgical procedures. In such cases there
Training of Patient/Carer may be complete loss of confidence in the carers and a
state of profound depression and withdrawal. Interestingly,
The patient and/or their carer must learn how to empty the few, if any, clinical psychologists have specific experience
stoma bag and change and dispose of a one- or two-piece in the problems faced by such patients and are unable to
appliance. They need to know how to look after the peristo- relate to the unique problems associated with complex and
mal skin and cope with leakage, flatus or malodour. They repeated surgery, multiple fistulas and stomas and pro-
also need to identify a reliable source of supply of stoma care longed hospitalization. In general, trained members of
products. nursing staff have proven to be the most effective source of
psychological support. The patient should be given suffi-
cient information at all times to be aware and actively
Irrigation engaged in their treatment plan. This may include explana-
tions of investigative procedures, surgical options, intended
Some patients try to regulate their colostomy output by irri- outcomes and any possible complications. It is necessary
gation, enabling ‘continence’. It is undertaken every 24–48 h, to repeat these discussions several times so that uncer-
cleansing the colon. One litre of warm water is inserted tainty can be avoided. Family members should also be
slowly via a cone on the end of soft tubing sited 5–10 cm into included whenever this is thought to be appropriate. The
the stoma. Some patients prefer to use a pump to administer availability of the spouse or partner is of vital importance
the water at a slow pace, their stoma nurse can provide this and their support is invaluable in offsetting the initial feel-
for them from one of the stoma care company’s and trained ings of shame and mutilation felt by many patients [8].
them how to use it. After a period of time a long drainable Education should be given to the relatives so that the shar-
pouch is connected over the stoma allowing faeces and water ing relationship is allowed to continue, and the family
to drain into the toilet. The procedure is time-consuming and needs to behave normally and demonstrate continued
some patients prefer to do the procedure at night when the acceptance of the patient, promoting positive attitudes and
bathroom is not in constant use [6]. Irrigation is not suitable dispelling possible feelings of rejection or revulsion [9].
for an ileostomy. The new body image can be difficult to accept but if there
is time for the consideration of change then mental adjust-
ment will be easier. However, sudden developments, as in
Activities the occurrence of a fistulae or emergency surgery requiring
a stoma can give rise to rejection, denial and the problems
A patient may cover their stoma with a minibag for swim- of withdrawal. Other factors influencing body image are
ming or sexual intercourse. A bag is usually changed after the visibility of the change and its encroachment on life-
swimming. Participation in most sports is possible though style [8]. Encouragement and allowing ample opportuni-
heavy contact sports (e.g. rugby) should be undertaken with ties to talk will be much needed for both parties and they
caution and a shield can be provided to wear over the stoma should be encouraged to voice concerns and fears.
to protect it, weight-lifting may make a stoma more likely to Reassurance regarding the progress or possible outcomes
prolapse. When flying, it is helpful and reassuring for the will be constantly required and the nurse must answer hon-
patient to carry spare stoma bags in both the aeroplane hold estly but never offer false or premature reassurance [9].
and in the hand luggage. A journey of any length requires an
appropriate supply of spare products in case there is a need
to change the appliance whilst travelling [7]. They are Problem Stomas: Leakage
advised to do short trips first to gain confidence. The insur-
ance company will need to be informed that the patient has a There are many reasons for leakage (Table 1). While the
stoma in case of any complications. During the flight a good stoma site and complications relating to it may be respon-
Table 1 Reasons for stomal leakage

1. Badly sited stoma on bony prominence, skin creases, dips or
scars
2. Stoma shrinkage, retraction, prolapse, or peristomal herniation
3. Poor technique (can be due to poor vision or manual
dexterity)
4. Weight change (gain or loss)
5. Pancaking
6. Peristomal skin allergy or granulation tissue
sible, a poor technique is often the cause. This may be due

to poor vision or manual dexterity, an overfull appliance,
one that has been left on for too long or alternatively changed
too frequently. An uneven skin surface due to sitting in one
position for a long time or changing weight (increase,
decrease or pregnancy) may affect the way an appliance fits,
thus making it liable to leak. Pancaking of solid stool at the
top of a stoma can cause leakage. It can be helped by putting
baby oil onto the inside top of the appliance, covering the
filter or an adhesive bar can be placed on the outside of
Fig. 3 Superficial necrosis and healthy tissue is seen underneath the
stoma to form a bridge. This prevents both pancaking and
covering
also the stoma bag sticking to the stoma. Peristomal skin
irritation can be due to allergy to plaster or the appliance
adhesive and a change of these may help. The hairs around
an appliance may need to be shaved. Fungal infections fre-
quently occur on moist, warm peristomal skin. Granulation
at the stoma edge is harmless but can cause bleeding or pre-
vent bag application. This responds to cautery with a silver
nitrate pencil.
The Complicated Stoma
Specific medical and nursing care may be required to man-

age the stoma when complications occur. The principal gen-
eral complication associated with creation of a stoma relates
to fluid and electrolyte balance in patients with a high output Fig. 4 Stenosis of the stoma following superficial necrosis
proximal stoma (chapter “Management of a High Output
Stoma, Jejunotomy or Uncomplicated Enterocutaneous
Fistula”). Local complications associated with stoma forma- ileostomy), bleeding, retraction, necrosis and peristomal
tion may be apparent early or late in the postoperative period. infection. Infection is surprisingly uncommon in the absence
Complications of stomas are common and 20–30% of of an element of necrosis at the mucocutaneous junction.
patients will require further surgery within 5 years for a These complications may require further surgery. Necrosis
problem with the stoma. of the stoma (Fig. 3) may be managed conservatively, pro-
vided that the patient is systemically well, has no signs of
spreading peritonitis and viable mucosa is identifiable out-
Early side the patients’ abdominal wall. This can usually be easily
ascertained by gently inserting an endoscope into the stoma
In the first days after surgery, local complications relating to or even using a lubricated test-tube and shining a torch along
the blood supply of the stoma and its attachment to the skin it for illumination. When conservative management is suc-
are common. These include obstruction from torsion or cessful, the stoma generally heals with stenosis (Fig. 4) and
oedema of the stoma (especially in the presence of a loop may require subsequent refashioning.
Late
Local complications that develop in the weeks or months

after fashioning a stoma, generally relate to stoma care itself,
the development of a parastomal hernia or intestinal disease.
Skin Damage
Intestinal effluent is a digestive juice and can rapidly diges-

tive the peristomal skin. Skin excoriation will begin to occur
within half an hour of exposure to jejunostomy/ileostomy
fluid and protective powder or barrier spray should be applied
to the area to help healing and to protect the skin. Ulceration
around a stoma may be due to a poorly fitting stoma appli-
ance but in patients with inflammatory bowel disease, pyo-
derma gangrenosum (Fig. 5) should be suspected, with
typical ‘punched out’ ulcers.
Bowel Damage
Ulceration, excessive granulation tissue and bleeding from

the mucosa, usually of an ileostomy, are common complaints
and may be attributable to a poorly fitting stoma appliance
(Fig. 6). In patients with Crohn’s disease, recrudescence of
disease within the stoma may occur and present with pain,
bleeding and visible ulceration. In severe cases, the associ-
Fig. 6 Granulations and superficial ulceration of an ileostomy, due to a
ated stricturing may lead to intestinal obstruction. A biopsy
poorly fitting stoma appliance
may be required to establish a definitive diagnosis.
the rectal sheath and if the abdominal musculature is very

Herniation weak as often occurs in the elderly. There is some evidence
to suggest that coordinated abdominal wall exercises in the
Parastomal herniation is very common complication of an postoperative period may reduce the frequency and/or sever-
end colostomy particularly if a stoma brought out is lateral to ity of herniation. The Stoma nurse should offer advice and
expertise on the prevention of a parastomal hernia in the
form of exercise and wearing a support belt when participat-
ing in strenuous activates [10]. A parastomal hernia may pre-
dispose to intestinal obstruction and strangulation, is
disfiguring for the patient and may make it difficult to fit an
appliance.
Parastomal hernias are difficult to correct surgically. A
variety of surgical approaches may be adopted, ranging from
local suture repair and mesh repair to laparotomy and trans-
position of the stoma, depending upon the size of the hernia
and the age and condition of the patient. The long-term
results of repair are poor, however, with up to 50% of patients
reporting a recurrence of their hernia. In general, surgical
repair of a parastomal hernia is avoided unless the hernia
prevents the fitting of a stoma appliance or is narrow-necked
Fig. 5 Pyoderma gangrenosum around an ileostomy and symptomatic.
Prolapse refashioning of the stoma [12]. It must be remembered that

refashioning an ilesotomy may involve a considerable
Prolapse of a stoma is generally associated with the develop- amount of bowel being resected (>5 cm) and this can be very
ment of a parastomal hernia and is characterized by an ‘ele- important if the patient has intestinal failure.
phant’s trunk-like’ everted protrusion of the stoma. This may Stoma retraction occurs when insufficient bowel has been
prevent satisfactory fitting of an appliance and is especially mobilized to allow the mucosa to be sutured to the skin edge
common in patients with a transverse loop colostomy, which without tension. In the absence of impaired vascularity (as
should therefore be avoided if at all possible. Surgery may be opposed to stenosis) the bowel does not become necrotic but
required to refashion the stoma, especially if prolapse inter- the opening of the stoma lies in a depression. This leads to
feres with stoma care. leakage under the flange, which may then lift off. Persistent
Emergency surgery may be avoided in some cases by leakage, which cannot be compensated for by the use of an
techniques to reduce oedema of prolapsed stomas, for exam- appropriate appliance, is an indication for surgical refashion-
ple by application of granulated sugar, which may facilitate ing of the stoma.
reduction of prolapse [11] (Fig. 7). Elective refashioning will
usually be required however.
Enterocutaneous Fistula Management
Stenosis and Retraction The key principles in the management of a patient with an
enterocutaneous fistula is the adequate treatment of abdomi-
These complications both result from defective surgical nal sepsis, which is the most common cause of death [13]
technique. Stenosis results from circumferential fibrosis at (chapter “Acute Surgical Intestinal Failure. Sepsis and
the mucocutaneous junction, most commonly as a secondary Enterocutaneous Fistula(s)”). When possible, abdominal
consequence of ischaemia and necrosis. If it is too painful to sepsis is managed by percutaneous drainage, but in some
perform a digital examination of the stoma to assess the cases, notably those in which sepsis has arisen due to anasto-
depth of mucosa stricture then patient may need referring motic dehiscence, a laparotomy will usually be required for
onto a surgeon for dilatation under general anesthetic or drainage of abscesses and creation of a proximal defunction-
ing stoma to divert the faecal stream.
Once abdominal sepsis has been treated, attention is
given to skin care, nutritional and metabolic support. Many
fistulas will heal spontaneously but they will not if there is
continuity between the gut mucosa and the skin, disease at
the site of the fistula (for example Crohn’s disease), distal
obstruction and/or an intervening undrained abscess cavity
[5]. In such cases enteral nutritional support with a low resi-
due diet is appropriate for low output (<200 mL/day) fistu-
las in the distal ileum or colon, whereas patients with high
output (>500 mL/day) fistulas, which are typically found in
the proximal small bowel will usually require parenteral
nutrition. It is the authors’ preference to restrict such patients
to sips of fluid only (some units say “nil by mouth”) if con-
trast radiology suggests that a fistula is likely to close spon-
taneously. It should be noted that spontaneous closure will
not occur when there is exposed bowel mucosa at the fistula
opening. Such fistulas eventually mature and behave much
like stomas. Where closure is unlikely (as above) and bowel
content is not leaking into the abdominal cavity, prevention
of oral intake is unnecessary and such patients can be
allowed relatively unrestricted access to fluids and diet, pro-
vided fluid intake is not excessive and does not make local
management of the fistula impossible. The same principles
apply to the management of the high output fistula as the
high output stoma (e.g. restriction of oral fluid intake and
Fig. 7 Prolapsed stoma the use of oral glucose–electrolyte solutions, drugs that
reduce motility and intestinal or secretions) (chapter with an intestinal stoma or fistula are the selection of appro-
“Management of a High Output Stoma, Jejunotomy or priate equipment and the adoption of suitable management
Uncomplicated Enterocutaneous Fistula”). techniques.
The Stoma nurse should determine the type and size of
appliance and initially the frequency of bag emptying and
Management of the Patient changing. The aim is to keep the equipment and procedures
with an Enterocutaneous Fistula (or simple and allow for the patient to choose their preferences.
Complicated Stoma) Complex ritualistic procedures must be avoided.
Skin Care Stoma/Fistula Appliances

A well-fitting adhesive appliance will protect the skin,
Care of the skin around a stoma or fistula is perhaps the most remove unpleasant odours, reduce risk of cross-infection,
important component of nursing care. The principal objec- allow assessment of fluid losses, preserve dignity and allow
tive is to keep the effluent away from the skin. The more the patient mobility and rest [1]. There are many types of
proximal in the gut a fistula, the more likely its output is to stoma and fistula appliances available and the manufacturers
discharge corrosive fluid with activated pancreatic enzymes also produce accessories to treat damaged skin, produce an
that can cause painful skin destruction (Fig. 8). even body contour (thus allowing better fitting of a stoma
Management of the peristomal skin should be pro-active, appliance) and deodorize offensive exudates. Immediately
with the goal being prevention by identifying and managing postoperatively a clear, unvented, drainable standard bag on
the causes effectively, thus preventing skin breakdown occur- which the aperture is cut to fit the stoma is used so that the
ring [14]. An initial assessment of the stoma/fistula and sur- viability of the stoma can be monitored and stool/air output
rounding skin should first be made noting approximate can be observed. As the stomal output becomes regular and
measurements, skin condition/degree of excoriation, descrip- predictable a one- or two-piece bag can be used. The former
tion of output and any associated nursing implications (e.g. attaches directly to the skin and may be closed or drainable.
pain). Skin contours are noted for creases where leakage A closed bag is often appropriate for a colostomy, which is
could occur. It is often helpful to photograph the wounds at typically changed 2–3 times a day. A drainable appliance is
this time. This information, together with accurate measure- appropriate for ileostomies/jejunostomies or for colostomies
ments of stoma output, allows the stomatherapist to select with a fluid output. Flatus valves (vent/charcoal filter), to
the most appropriate appliance thus enabling collection of allow escape of gases, are now present in most appliances.
the effluent and controlling the problems of leakage and Two-piece appliances have a flange that can stay on the skin
odour. The patient, in turn, gains comfort, confidence and for 3–4 days and are fitted with either a drainable or closed
independence. Key aspects of management of the patient bag. Drainable bags should be changed every 24–72 h. Stoma
products have changed dramatically over the years and a
large selection are now available. Bags for use over an estab-
lished stoma can have a pre-cut aperture if patient prefers
this and come in all different sizes as colors. Most bags hold
about 200–300 mL of fluid. Extensive wound areas require a
large ‘wound manager’ (Fig. 9). These can be adapted to the
size and shape of any wound and are drained continuously.
Planned stomas that are of routine size are more easily
catered for, but stomas that have become flush or have
retracted, can be successfully managed with the use of con-
vex flanges incorporated within the bags.
Adhesive Flanges
An appliance usually sticks to the skin by a cohesive seal.
Clean, warm, dry skin is needed. If the skin is itchy, a barrier
spray or wipe can be used and helps both with itching and
adhesion.
Filling Pastes/Wafers/Dressings
Fig. 8 Extensive skin damage resulting from a high output entero- There are many hydrocolloid pastes that can be used to fill
atmospheric fistula with inadequate skin protection defects in a wound. Wafers may be used to help adherence of
a wipe and rolled up and closed securely. Odour powders/

deodorant sprays may be used at this time. The bag is subse-
quently changed as required. In hot conditions this may need
to be undertaken more frequently as the backing can ‘melt’
or due to the patient’s skin sweating and the appliance may
therefore leak.
itting an Appliance Over a Complex Fistula

F
The area should be cleaned with warm water and dried thor-
oughly with soft wipes and a hairdryer can be used on a cool
setting. Shaving of body hair may be necessary to optimise
adhesion and prevent discomfort. Excoriated skin should
have Stomahesive Protective ostomy powder applied spar-
ingly. It is often helpful in caring for large fistula wounds to
make a template of the area with a piece of clear plastic
material that usually comes in the packaging with the appli-
ance. This assists with cutting the base of the bag and is use-
ful in observing the healing process, as smaller templates
will be required probably weekly. Crevices or creases of
intact skin can be filled with Stoma paste or pieces of
Moldable seals to even the site (Fig. 10). It may be necessary
Fig. 9 Fistula appliance attached to a high output collection bag hold
2L to cover this area with a protective sheet cut to fit, but the
base of the wound manager alone is usually quite adequate.
The immediate edge around the stoma/fistula should be filled
the appliance and may act as barriers between the bag/skin. with soft paste to help adhere and prevent leakage of the
The flanges of a stoma bag can safely cover wounds if effluent between the surfaces. The readily prepared appli-
needed. ance should now be applied, firmly moulding it to the surface
Absorbent dressings with associated barrier creams are
inadequate for outputs of more than 20 mL/day.
Appropriate well-fitting/constructed stoma appliances cut
to fit the area and so cover exposed skin enable successful
management [15].
Techniques
itting an Appliance Over a Stoma

F
The appliance is peeled from the skin gently by easing the
skin away and barrier remover spray or wipes can be used to
assist this. The surrounding skin is then cleaned using soft
wipes and warm water and the area dried well with a dry
wipe. Tap water alone is adequate for this purpose. However,
if desired, an unperfumed, gentle soap could be used. Direct
contact with the intestinal mucosa should be avoided. An
appliance of the correct size is selected and cut to size. The
backing is peeled off and applied gently to the abdomen over
the stoma area.
An ileostomy bag is usually emptied 5–6 times/24 h (total
volume is about 500–800 mL/24 h) and most patients do this
once during the night. If the patient has a high stoma output
the flange/bag/dressing change is undertaken when the out-
put is likely to be lowest or when help is available. Following
drainage of the bag, the end of the appliance is cleaned with Figs. 10–12 Applying a bag to an intestinal fistula
Figs. 10–12 (continued)
and ensuring that no creases occur during the procedure require a short-term treatment of low suction until the area
(Figs. 11 and 12). The patient should be encouraged to rest shrinks to manageable dimensions. This is applied via a cath-
for approximately 30 min to promote adhesion of the eter incorporated within the bag, through which low-grade
appliance. continuous suction can be applied. This treatment should not
The technique used should be fully documented with a be prolonged because negative pressure at the cutaneous sur-
photographic care plan so that other team members can face of a fistula where there is no exposed mucosa may pre-
maintain the prescribed care. The area should be regularly vent spontaneous fistula closure and the treatment may also
inspected and any evidence of pain, burning of the skin, leak- restricts mobilization [16]. However, the application of nega-
age, odour or detachment of the appliance should be investi- tive pressure where a fistula cannot, in any event, heal spon-
gated and treated appropriately, appliances should not be taneously (for example where there is already
patched if leaking appliance will need replacing to prevent enteroatmospheric fistulation) may greatly facilitate nursing
sore skin occurring. The plan of nursing care should be eval- care.
uated regularly and changes made as required. The patient In some cases, the configuration of the fistula may make
with extensive fistula formation may not be able to partici- adequate skin and fistula care almost impossible to
pate in any practical aspects of the skin care until their gen- achieve—for example where a fistula sits at the base of a
eral condition is improved or surgery to treat the underlying deep and/or irregular cavity on a skin crease. Persistent
problem is undertaken. However, wherever possible the leakage and excoriation may result in ulceration, pain,
patient should be encouraged to begin to participate in caring inability to eat and drink (in order to avoid leakage) and
for their stoma and so in turn gain independence, autonomy psychological distress and be associated with poor mobility
and sense of well-being. The plan to teach and involve the and demoralization. These circumstances may represent an
patient with their care should begin following discussion indication for early surgery, if only to explore the (usually
between the stomatherapist, nurses and, most importantly, relatively untouched) left upper quadrant of the abdomen, in
the patient. order to establish a proximal stoma to defunction the fistula.
Some fistulas lie in large irregular cavities, which make A well-spouted proximal loop jejunostomy may have sig-
them exceptionally difficult to manage. Such fistulas may nificant implications for fluid and electrolyte balance and
nutritional support, but patients invariably find them easier nurses will maintain continuity of care, and supportive coun-
to tolerate (as a temporary measure) than an uncontrollable selling will still be required. Certain problems only become
fistula. evident on discharge from hospital, especially relating to dif-
The ultimate goal of stoma and fistula management is for ficulties in personal or sexual relationships. These may
the patient to be able to care for themselves. This may not require expert help from marriage guidance or psychosexual
always be possible, however. Depending upon the patient’s counsellors though the nurse can help assess the situation
individual circumstances, close relatives may need to under- and make arrangements for referral if appropriate.
take patient care or the patient may request they be at least
made aware of the needs that may be required. Practical
skills should be demonstrated to the patient with careful References
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10. North J, Osborne W. ASCN UK guidelines: parastomal hernias. Br
High output fistulas/stomas (over 500 mL/24 h) may require J Nurs. 2017;26(22):1262–3, (S6-S13).
frequent drainage and this can disturb sleep, thus adding to 11. Theofanis G, Saedon M, Kho S, Mulita F, Germanos S, Leung
stress. To prevent this, a secondary drainage container allow- E. Avoiding emergency stoma surgery with the use of sugar. Br J
ing continuous gravity drainage of stoma bags into a high Nurs. 2017;26(22):1262–3, (S24-S26).
12. Association of Stoma Care Nurses UK. National clinical guide-
output drainage bag with thick piping that can hold up to 2 L lines. Edinburgh: Association of Stoma Care Nurses UK; 2019.
(Fig. 9) can be used. 13. Soeters PB, Ebeid AM, Fischer JE. Review of 404 patients with
gastrointestinal fistulas. Impact of parenteral nutrition. Ann Surg.
1979;190:189–202.
14. Metcalf C. Managing moisture associated skin damage in stoma
Discharge care. Br J Nurs. 2018;27(22):S4–6.
15. Gross E, Irving M. Protection of the skin around intestinal fistulas.
Patients need to be independent with their stoma care to Br J Surg. 1977;64:258–63.
ensure safe discharge from hospital, in the absence then there 16. Blower AL, Irving MH. Enterocutaneous fistulas. Surgery.
1992;12:27–31.
will need to be adequate support in place at home [17]. When 17. Burch J. Promoting enhanced recovery after colorectal surgery. Br
the patient is discharged the stomatherapist and the district J Nurs. 2013;22(5):S4–9. Stoma care supplement.
Management of a High Output Stoma,
Jejunotomy or Uncomplicated
Enterocutaneous Fistula

1. A high output stoma (HOS) or fistula is when the output
causes the patient to become water, sodium and magne- Most of the classical work published about patients with a
sium depleted. short residual length of intestine related to those with jeju-
2. A HOS tends to occur when the output is more than 1.5– num in continuity with colon [1–3]. A number of patients
2.0 L/24 h though this varies according to the amount of with a jejunostomy are being managed, mainly because the
food/drink taken orally. colon is often removed during the surgical treatment of
3. Management starts with excluding causes other than a Crohn’s disease or it is temporarily out of circuit in the man-
short bowel (especially intermittent or partial obstruc- agement of ischaemia or a fistula/obstruction. These patients
tion). It is helpful to have a measurement of residual have immediate and serious problems because of large intes-
small bowel length (at surgery, or by a contrast radiologi- tinal losses of water, sodium and magnesium. The residual
cal examination). The stoma and output should be bowel length may not have been measured and such patients
inspected are often categorized as having ileostomy diarrhoea. The
4. The patient is rehydrated both to relieve excessive thirst management of patients with a jejunostomy, ileostomy diar-
and correct electrolyte abnormalities. rhoea or a high-output enterocutaneous fistula is the same.
5. Oral hypotonic fluids (tea, coffee, fruit juice, alcohol or This chapter outlines the medical problems caused by the
water etc.) are restricted to a litre or less per 24 h. 1–2 L large volumes of fluid lost from the stoma or fistula and,
of a glucose/saline solution (sodium concentration using data from balance studies, discusses treatments.
90–120 mmol/L) (cold, taken through a straw) is sipped Information about stoma care is found in chapter “Care of
throughout the day +/− magnesium supplements. Intestinal Stoma and Enterocutaneous Fistula(s)”.
6. Oral medication to slow transit (loperamide often in high
dose or codeine phosphate) is taken before food/drink.
For those with a net secretory output (greater than total How Common Is a HOS?
oral intake) a proton pump inhibitor (omeprazole) may be
taken to reduce the volume of gastric acid produced. A normal ileostomy may function within the first day of sur-
7. If hydration cannot be maintained with oral measures gery depending upon whether an ileus occurs (often due to
subcutaneous saline (usually 1 L with magnesium) given opiates and excessive intravenous saline). The stomal output
1–4 times/week may be given before parenteral fluids. from an ileostomy may reduce over several months as adap-
8. In addition to renal function, the urinary sodium concen- tation occurs and the normal output when established is 600–
tration and serum magnesium level must be monitored. 1200 mL/24 h. Patients with a jejunostomy (less than 200 cm
9. Consideration should be given to surgically bringing any small bowel remaining) do not generally show any improve-
small or large bowel that is in situ but out of circuit, back ment in absorption with time [4].
into continuity. A high output stoma (HOS) (often called ileostomy diar-
rhoea) is when the output is enough to cause “dehydration”
(water and sodium depletion). In general this occurs with an
output of greater than 1.5–2.0 L/24 h. However this depends
on the oral intake. A 2 L output for someone taking in 4.0 L
J. M.D. Nightingale (*) will cause no problems but if only an intake of 0.5 L it will
result in dehydration [5].

In one study a HOS occurred early in 16% patients (within Table 1 Reasons for a high output stoma
3 weeks of a stoma being formed) and late (more than Early (<3 weeks of formation)
3 weeks) in 4% in whom this was a persistent problem [6]. • Abdominal sepsis/ileus/ischaemia (low albumin)
Other studies show similar rates 16–31% following surgery • Drug-related
– Prokinetic drugs (e.g. metoclopramide)
[7–9]. Problems are more common in patients with a loop
– Low cortisol
ileostomy or after an ileal resection. There are rarely any
– Opiate withdrawal (e.g. codeine phosphate)
problems of HOS when more than half the colon remains in • Enteritis (Cl difficile)
continuity and there is more than 50 cm functioning small Late (chronic more than 3 weeks)
bowel present [6]. • Short bowel—jejunostomy <200 cm
Evidence that many patients with an ileostomy are salt • Intermittent/partial obstruction (strictures)
and water depleted comes from the observation that plasma • Other less common causes:
renin and aldosterone levels are high in ileostomy patients – Recurrent disease
– Internal fistula
[10, 11] and 13% have a urine sodium concentration of less
– Small bowel diverticula
than 10 mmol/L [12]. Unrecognised, chronic dehydration in – Coeliac disease
these patients can lead to end stage renal failure. Diuretics – Thyrotoxicosis
given to patients with an ileostomy (especially if they have
had problems of HOS) may precipitate renal failure and gen-
erally should be avoided. Care must be taken with renal dial-
ysis if needed to not remove additional fluid (indeed more
may need to be given).
Presentation of Patients with a Jejunostomy
The problem of fluid loss from a jejunostomy is apparent

immediately after the surgery that removes the bowel. The
fasting stomal output may be less than a L/24 h but it will rise
when food and drink are consumed to as much as 8 or more
litres a day. This results in dehydration, sodium depletion
and hypomagnesaemia. These patients are dependent on
their treatment; if they miss a day of treatment, they rapidly
become unwell from dehydration.
Patients with a jejunostomy do have problems of protein–
energy undernutrition but these develop slowly over several Fig. 1 Narrow stoma causing intermittent high output and renal fail-
ure. Resolved after stoma was refashioned
weeks and are usually attended to at the same time as the
fluid balance problems. As jejunal length gets shorter fluid
balance problems (less than 200 cm jejunum) occur before early HOS are medication related; this can be because of a
nutritional ones (less than 100 cm jejunum). The fluid/nutri- prokinetic drug (e.g. metoclopramide) or the sudden, usu-
tional problems should be predicted and treated before the ally accidental, withdrawal of a medication (e.g. opiates or
patient becomes dehydrated or undernourished. cortisol). Clostridium difficile can affect the small bowel
and cause a HOS [9]. A chronically HOS is most commonly
due to a short bowel (jejunostomy). However intermittent/
auses of a High Output Other Than a Short
C partial obstruction due to small bowel strictures is common
Bowel (with associated bacterial overgrowth); a stenosis is most
commonly at the stoma [8] (Fig. 1). Dilation of a stricture
Causes of a HOS other than a short bowel (jejunostomy and a low fibre/residue diet (Table 2) may prevent the
<200 cm) should be sought. This is a common group who obstructive episodes and the occurrence of a HOS. Recurrent
may have a normal length of small intestine (Table 1). An disease (including ischaemia), internal fistula, small bowel
early HOS is most commonly due to sepsis (a raised WBC diverticula, coeliac disease and thyrotoxicosis can all con-
on day 1 is a clue [9] and may be why an early HOS is more tribute and if treated the HOS may resolve. If the HOS is
common in diabetics [7]. The other common causes of an due to strictures and there is a low serum albumin it may be
Management of a High Output Stoma, Jejunotomy or Uncomplicated Enterocutaneous Fistula 633
Table 2 Low fibre/low residue diet as the time taken for the food residue to be passed in the stool
Avoid may be 2–3 days.
Vegetables/fruit
Nuts
Wholemeal products
Investigator-Selected Diet
Eat
Meat/Fish/Eggs
Dairy For each 24-h period, the investigator specifies the exact
White Rice/Pasta/Bread composition and amount and the time at which food and
Potato without skin drink are to be consumed by the patient. This is an experi-
Jelly mental ideal but patients with a short bowel are fastidious
NB: Good teeth/dentures, chew well (often not done well at times of eaters who often feel full very quickly, and such a study is
stress) difficult to perform in practice. Studies have been done, how-
ever, in which the proportion and total amount of macronu-
that a section of chronically/critically ischaemic bowel trients and fluid are fixed [15]. A 2-day collection is adequate
remains in situ and the problem will only resolve with a sur- for patients with a jejunostomy, but if the colon has been
gical resection. retained a run-in period of at least 2 days is needed, so that
remnants of other meals will have been passed in the stool.
alance Studies for Patients with a Short

B
Bowel: Jejunostomy Patient-Selected Diet
Balance studies have provided the most useful information Patients select a diet freely on the first study day and eat and
about the problems and the management of patients with a drink whatever is normal for them. They keep an accurate
jejunostomy. They are easier to perform in patients with a record of the food and drink, the amount and the time at
jejunostomy than in patients with a short bowel and a pre- which it is consumed. On all subsequent study days they
served colon as a 1–3-day run-in period is not required, and consume exactly the same food and drink in the same
the stomal bag allows for easier collection. amounts and at exactly the same times as on the first day. All
Patients with a short bowel may not feel hungry, and those studies by Nightingale et al. use this method for 2 paired
with a jejunostomy are often just in positive water and control days and 2 further paired test days when a therapy is
sodium balance, so cannot abruptly stop treatments that are given [16].
maintaining their equilibrium. Patients who suddenly stop The way in which stool, ileostomy or jejunostomy output
taking codeine phosphate when they have been taking it for is analysed is important. When jejunostomy output is centri-
several months or years are likely to develop the symptoms fuged, three layers are seen: fat at the top, fluid in the middle
and signs of opiate withdrawal, which include diarrhoea, and solid at the bottom (Fig. 2). In general, the higher the
manifested as a rise in stomal output. Balance studies are output the larger the middle fluid layer; if the output is low
rarely done in the ideal experimental setting with the patient (less than 1 L daily) then it may not be possible to see a fluid
taking no medications. layer, and the fatty layer and the solid component merge
There are three possible ways to study intestinal balance together. While it is simpler to aspirate the fluid layer, filter
in patients with a short bowel. With each, a duplicate oral it, and assay for electrolytes; this can only be done when
intake is made and assayed. there is a large liquid output and when the patient is taking
little or no solid food. Not all studies state whether the whole
stomal output is analysed or whether it is just the fluid layer.
Test Meal All studies by Newton, McIntyre, Rodrigues and Nightingale
assayed the whole stomal sample. This involved diluting sto-
A standardized meal containing a non-absorbable marker mal samples with concentrated hydrochloric acid before
(e.g. polyethylene glycol) is given and the stool or stomal flame emission photometry for sodium and potassium mea-
output is collected for a fixed period while nothing else is surements or ashing a sample in a 550 °C furnace for 15 h
taken orally. Rodrigues et al. showed that over 90% of a non- before dissolving in nitric acid and using atomic absorption
absorbable marker in a liquid test meal was recovered from spectrophotometry to measure magnesium and calcium con-
jejunostomy fluid in the 6 h after the meal [13, 14]. This centrations. Energy content can be determined by freeze-
technique is not appropriate for patients with a retained colon drying a sample then performing bomb calorimetry.
Fig. 3 Diagram to show sodium movement into the jejunal lumen

when hypotonic fluid is drunk (upper gastrointestinal secretions not
shown)
remaining, so are lost through the stoma. So in most normal

subjects, about 6 L of chyme pass the duodeno-jejunal flex-
ure each day and the meal is still just diluted by intestinal
secretions 100 cm distal from the duodeno-jejunal flexure
[17, 18]. When the small bowel length is less than this, more
emerges from the stoma than is taken in by mouth. Even in
the fasting state there is an obligatory loss of intestinal secre-
tions produced with the migrating myoelectric complex
(MMC) [19].
ypo- and Hyper-Tonic Fluid Ingestion

H
and Thirst
Jejunal mucosa is ‘leaky’ and rapid sodium fluxes occur

across it. If water or any solution with a sodium concentra-
Fig. 2 Centrifuged ileostomy output. Net absorber (150 cm jejunum) tion of less than 90 mmol/L is drunk there is a net efflux of
on left and net secretor (60 cm jejunum) on right. Note the different size sodium from the plasma into the bowel lumen [20] until a
of the middle fluid layer (arrowed). The top layer is fatty and bottom is luminal sodium concentration of 90–100 mmol/L is reached.
precipitate/solids In a patient with a jejunostomy this fluid is then lost in the
stomal output (100 mmol/L sodium) (Fig. 3). Hypertonic
easons for a High Output
R fluid (e.g. an elemental diet) will cause a net secretion of
from a Jejunostomy/High Fistula water (and sodium) into the lumen till the osmolality nears
300 mOsm/kg. Patients, who are water and sodium depleted,
There are four potential physiological reasons for a HOS in are often very thirsty and so may drink an increasing amount
patients with a short bowel and jejunostomy: loss of the nor- of hypotonic fluid (often containing no sodium) and the
mal daily secretions produced in response to food, hypo- or effect is to increase the stomal output and increase the
hyper-tonic fluid/food ingestion, gastric acid hypersecretion, sodium losses and so further increasing the thirst [12,
and rapid gastrointestinal transit. An excessive thirst may 20–23].
exacerbate the situation.
Gastric Acid Hypersecretion

Loss of Normal Daily Intestinal Secretions
There is some evidence to suggest, at least in the short term,
The most important reason for a large volume of stomal out- that loss of intestinal phase negative feedback inhibition results
put is that the normal daily intestinal secretions produced in in hypergastrinaemia [24, 25] and gastric acid hypersecretion,
response to food and drink (about 4 L/day made up of 0.5 mL which may all contribute to the high output from a jejunos-
saliva. 2 L gastric juice and 1.5 L pancreaticobiliary secre- tomy. In man, gastric acid hypersecretion has only been dem-
tions) cannot be reabsorbed in the short length of bowel onstrated in the immediate postoperative period in patients
Fig. 4 Gastric emptying of

a b
liquid and solid in a normal
subject (a) and in a patient (b)
with a jejunostomy 30 cm
from the duodeno-jejunal
flexure 15 min after starting to
eat a meal of a pancake and
orange juice
with a retained colon [26]. It is unclear whether this phenome- 600

non persists beyond the first weeks, but a low pH (<6) in the
500
fresh stomal effluent when it exceeds 1 L daily is suggestive.
Sodium (mmol)
400
Parenteral nutrition
300 and saline
Rapid Gastrointestinal Transit
Parenteral fluid
200
Oral supplements
Rapid gastric emptying of liquid occurs and may increase the
100
stomal output [27] (Fig. 4). The gastric emptying rate is fast-
est in those with the shortest lengths of residual jejunum. 0
Small bowel transit time for liquid and solid is also very 0 1 2
3 4 5 6 7 8 9
Weight (kg)
rapid [28]. Both of these effects may be mainly due to low r=0.95, p<0.0001
serum levels of peptide YY [25] and, to a lesser extent, low
levels of GLP-2 [28]. Fig. 5 Wet weight and sodium content of jejunostomy output for 15
patients with less than 200 cm remaining jejunum. (r = 0.96, p < 0.0001).
The mean sodium concentration was 88 mmol/L (range 60–118 mmol)
[29]
he Problem of High-Volume Jejunostomy
T
Output
one of two groups, either net ‘secretors’ or net ‘absorbers’,
Water and Sodium Losses according to intestinal water and sodium balance. This balance
depends upon the degree of dilution of food and drink by diges-
Balance studies in patients with a jejunostomy, using a tive juices and the net absorption that has occurred [5] (Fig. 6).
patient-selected diet, showed that the daily weight of stomal ‘Absorbers’ tend to have more than 100 cm of residual
output was about 6–8 kg/d in those on parenteral nutrition jejunum and can absorb more water and sodium from their
with added saline and about 2 kg/d among those receiving diet (which may have been modified to have an increased
oral supplements. The intestinal output is mostly water amount of sodium) than they take orally. Their daily jejunos-
(mean 92%, range 85–96%) and there is a good correlation tomy output is usually about 2 kg or less in 24 h, thus they
between stomal output weight and its sodium content (Fig. 5) can be managed with oral sodium and water supplements
[29]. The mean jejunostomy sodium concentration is and parenteral fluids are not needed.
88 mmol/L, being lower in patients with a shorter remaining ‘Secretors’ tend to have less than 100 cm of residual jeju-
length of jejunum and higher in those with a greater length. num and lose more water and sodium from their stoma than
The sodium concentration in the terminal ileum may be they take by mouth. Usual daily stomal output may be
nearer to that of plasma (140 mmol/L). 4–8 kg. These patients cannot convert from negative to posi-
tive water and sodium balance by taking a modified diet or
ype of Patient with a Jejunostomy (Based Upon
T sodium supplements and they need long-term parenteral
Water and Sodium Balance) supplements [5]. These requirements change very little with
Classification of patients with a jejunostomy is based upon bal- time [30]. The jejunostomy output from a net ‘secretor’
ance studies using a patient-selected diet. The weight and increases during the daytime in response to food and
sodium content of the diet is compared to the weight and sodium decreases at night, thus any drug therapy that aims to reduce
content of the stomal output. The patients can be divided into the output must be given prior to food (Fig. 7).
a Fluid balance b Sodium balance

mmol/24 hrs
-3
kg/24 hrs
400 *
-2 * *
Fluid
absorption * *
-1
Sodium
200
*
0 absorption *
*
-1 0 *
-2
Fluid
secretion
-3 -200
Sodium
-4 secretion
-5 -400
0 20 40 60 80 100 120 140 160 0 20 40 60 80 100 120 140 160
Jejunal length (cm) Jejunal length (cm)
r=0.75, p<0.006 r=0.59, p<0.05
c mmol/24 hrs Potassium balance d

100 Energy balance
kcal/24 hrs
* * 3000
80
* *
60 2500
* *
2000
40 * *
Potassium
absorption 20 1500
* *
0 1000 *
-20 500
Potassium -40 0
secretion
-60 -500
0 20 40 60 80 100 120 140 160 0 20 40 60 80 100 120 140 160
Jejunal length (cm) Jejunal length (cm)
r=0.77, p<0.001 r=0.56, p<0.05
e Magnesium balance
30
mmol/24 hrs
25
20
6 long-term parenteral nutrition and saline
15 3 long-term parenteral saline and oral nutrients
6 oral supplements (nutrients and/or glucose-saline
* solution)
10
5
Mean oral magnesium intake was (range 3-70) mmol/day.
0 Patients taking oral magnesium supplements.
-5
*
0 20 40 60 80 100 120 140 160
r=0.56, p<0.05 Jejunal length (cm)
Fig. 6 Balance studies using the patient-selected diet performed for plements [5]. (a) Total weight, (b) sodium, (c) potassium (d) energy and
2 days on 15 patients with a jejunostomy who were all maintaining (e) magnesium. Note that positive intestinal fluid and sodium balance is
fluid, electrolyte and nutritional status. Six needed long-term intrave- achieved at 100 cm jejunum, potassium at 50 cm, and there was no rela-
nous nutrition, 3 required long-term intravenous fluids but maintained tionship with magnesium balance
their nutrition with an oral diet, and 6 took oral fluid and nutrient sup-
1.5 ual jejunal length (Fig. 6e). Hypomagnesaemis is estimated

Weight to occur in 78% of patient with a jejunostomy [29]. While it
(kg)
may cause fatigue, depression, irritability, muscle weakness,
1.0 tremor, tetany if there is associated hypocalcaemia, and, if
Jejunostomy output
Oral intake very severe, convulsions; it is often asymptomatic even at
very low serum levels (e.g. 0.2 mmol/L). The reasons for
0.5
hypomagnesaemia include secondary hyperaldosteronism
[33, 34], removal of ileum/colon which are key areas in the
0.0 gut for absorption, free fatty acid malabsorption (so com-
plexing with Ca and Mg) (especially if taking a high fat diet)
8 10 12 14 16 18 20 22 24 2 4 6 8
Time (hours)
[35, 36] and taking proton pump inhibitor drugs [37]. In the
long-term hypomagnesaemia will lead to a loss of bone den-
Fig. 7 Oral intake (kg) and stomal output measured every 2 h in a sity with a risk of fractures, and chondrocalcinosis [38].
patient who has 30 cm of residual jejunum and shows net secretion [5]
Nutrient Malabsorption
A clinician, unlike a research worker, is unlikely to be
able to perform accurate balance studies, in which case the In the long term, parenteral nutrition with additional fluids is
classification can be predicted from knowledge of the resid- always needed if a patient absorbs less than one-third of the
ual jejunal length. The change from a net secretory state to a oral energy intake [5, 12] and is usually needed when less
net absorptive state in terms of intestinal water and sodium than 75 cm of jejunum remain. In some young people with
balance occurs at a jejunal length of about 100 cm. high-energy requirements, parenteral nutrition may be
needed even when absorption is 35–60%.
Potassium Deficiency
Social Problems of a HOS
The effluent from a jejunostomy or ileostomy contains rela-
tively little potassium (about 15 mmol/L) [5, 11, 31]. Values Patients with a HOS may have problems with the stoma bags
are higher in patients with a colostomy as the colon secretes becoming detached and so leaking (especially at night), the
potassium. Potassium problems are unusual and the potas- skin care may be difficult and thus very sore, the frequent
sium intake rarely needs to be greater than normal. Net loss emptying of the stomal bag means there will be a need to find
through the stoma occurs only when less than 50 cm of jeju- a toilet quickly, this can limit going out. The treatment for a
num remains [5] (Fig. 6c). HOS cannot be abruptly stopped otherwise dehydration
Low serum potassium levels do not usually reflect gut results. The patient may always feel thirsty yet have to avoid
losses, but may occur when a patient is sodium depleted and quenching their thirst with hypotonic fluid. They may suffer
thus has secondary hyperaldosteronism. The high aldoste- from muscle cramps (helped by taking table salt).
rone levels cause renal conservation of sodium at the expense
of potassium, which is excreted in the urine in greater
amounts than normal [10, 11, 31]. Management of HOS
Hypomagnesaemia causes dysfunction of many of the
potassium transport systems (e.g. the Na+/K+-ATPase pump) As stated the management starts with excluding causes of a
and increases renal excretion of potassium; thus hypomagne- HOS other than a short bowel and appropriately treating
saemia can cause a hypokalaemia, which is resistant to them. A history of colicky abdominal pain, loud bowel
potassium treatment [32]. sounds (borborygmi); a stoma ceasing to work for a time is
Before hypokalaemia can be corrected in patients with a suggestive of an obstructive cause. The HOS occurs during
high-output stoma, sodium and water depletion must be cor- recovery from the obstruction and at this time the patient
rected and the serum magnesium brought into the normal range. may have no symptoms other than those of dehydration.
Such patients often present for medical care episodically
(every few months or even years). Radiological contrast
Magnesium Deficiency examinations do not always show the stricture(s) and a trial
of a low fibre/residue diet can be used both as a treatment and
Patients with a jejunostomy are often in precarious magne- as a diagnostic test. If there are strictures bacterial over-
sium balance, and the balance does not correlate with resid- growth may be occurring and a trial of oral antibiotics (e.g.
Fig. 8 Stomal output (colour/

volume) on normal diet,
jejunal length and type of
nutritional/fluid support
50 cm 100 cm 200 cm
4L/24 hr 2L/24 hr <2L/24 hr
PN IVF or Oral Oral
co-amoxyclav or rifaximin) may be tried and if successful Table 3 Jejunostomy length and the type of nutritional/fluid support
given in rotation (e.g. changing every 6 weeks). If pancreatic needed
malabsorption is thought to contribute to a HOS then a trial Jejunum (cm) Nutrition Fluid
of pancreatic enzyme replacement may be tried. A stomal 0–50 Parenteral Saline
elastase measurement is unlikely to be reliable due to dilu- 51–100 Parenterala Saline
tion by secretions and oral fluid intake. Other medical condi- 101–150 Oral/Enteral OGS
151–200 None OGS
tions may need treatment if found (e.g. low fibre diet, steroids
OGS oral (or enteral) glucose/saline solution
for Addison’s, antibiotics for Clostridium, gluten free diet if a
At 85–100 cm may need parenteral saline only
Coeliac etc).
mass Urinary electrolytes are usually more useful than serum

Clinical Assessment measurements because the normal physiological homeo-
static mechanisms preserve serum electrolyte concentrations
The initial assessment of water and sodium deficiency until the late stages of depletion. A low random urinary
involves asking the patient about feeling dry, thirsty, lethar- sodium concentration (<10 mmol/L) is the best indicator of
gic, faint or having muscle weakness and cramps. The physi- maximal sodium conservation and therefore sodium defi-
cal examination includes looking for dry mucous membranes, ciency, even if serum estimations are normal. When inter-
reduced skin turgor, rapid weight loss (negative fluid bal- preting a urinary sodium result it is important to check that
ance), a postural blood pressure fall (>10 mmHg), oliguria the patient is not receiving diuretics or intravenous/subcuta-
(less than 800 mL/24 h) and an assessment of the patient’s neous saline or has renal impairment/tubular damage (e.g.
nutritional status (this is usually good unless the bowel is less from resolving acute kidney injury) when the result may be
than 100 cm). In general, patients who have a stomal output falsely normal. In addition a urinary sodium concentration
of more than 1.5 L daily when eating are likely to require can be low if the patient has hypovolaemia due to a low cir-
water and sodium supplements. The stomal should be culating volume secondary to a low plasma oncotic pressure
inspected and the stoma effluent colour, consistency and (e.g. due to a low serum albumin).
24 h volume should be noted (a yellow/green colour in an
established stoma suggests a short length of remaining owel Length Measurement
B
bowel) (Fig. 8). A finger should be inserted gently into the Predictions about the outcome can be made if the residual
stoma to determine if there is a stenosis. However an obstruc- length of small intestine from the duodenojejunal flexure has
tion at the stoma may not be felt if it is a functional obstruc- been measured at surgery or radiologically from a small
tion, due to oedema or the thickness of the abdominal wall, bowel meal film using an opisometer (Table 3) [39, 40].
and a trial of a wide bore catheter placed into the stoma may However estimates can be made from CT/MRI enterography
be tried to determine if the output reduces. providing the total small bowel length is less than 200 cm. A
If dehydration is severe, serum creatinine and urea will radiological examination will also show the quality of the
rise. The creatinine may be low if there is reduced muscle bowel detecting recurrent disease/obstruction [39]. Despite
this the remaining small bowel length is often unknown. The oral treatment to reduce a HOS and its consequences
Estimates made from the length of bowel resected are unreli- of dehydration starts with restricting oral hypotonic fluids
able as the normal small intestinal length is so variable and giving a glucose saline solution (or in mild cases extra
(chapter “Normal Intestinal Anatomy and Physiology”). oral salt) to sip. If this alone is not successful then oral medi-
Citrulline is an amino acid produced by functioning small cations to reduce gut motility and/or secretions may be tried.
bowel mucosa, fasting levels do correlate with residual small
bowel length. Although clinically used to assess the progress
of small bowel function after a small bowel transplant or Restrict Oral Fluids
when the colon is brought into continuity, it has not been
widely adopted as a marker of functioning small bowel [41]. Jejunal mucosa is ‘leaky’ and rapid sodium fluxes occur
across it. If water or any solution with a sodium concentra-
tion of less than 90 mmol/L is drunk there is a net efflux of
Treatment sodium from the plasma into the bowel lumen [19] until a
luminal sodium concentration of 90–100 mmol/L is reached
Total jejunal loss of sodium increases in a linear relationship (Fig. 3). In a patient with a jejunostomy this fluid is then lost
with volume (at a concentration of about 90 mmol/L) so the in the stomal output. It is a common mistake for patients to
clinician can predict with reasonable accuracy that an effluent be encouraged to drink oral hypotonic solutions to quench
volume of 3 L contains 270 mmol of sodium (Fig. 5). The their thirst, but this literally washes sodium out of the body
concentration of sodium in the output remains constant what- [11, 19–21]. Thus patients must never be advised to “drink as
ever treatment is given. While there is a small obligatory sto- much as possible” either to quench their thirst or keep up
mal loss when fasting, the greatest increase in stomal output with their stomal output as this will increase stomal sodium
is after food or drink (Fig. 7). Consideration should be given losses, worsen dehydration and increase thirst.
to attempting to reduce stomal output, even in patients with a Treatment for the high output from a jejunostomy, ileos-
jejunostomy requiring parenteral nutrition, as this may well tomy or high fistula starts with the patient restricting the total
reduce the amount or frequency of intravenous fluid replace- amount of oral hypotonic fluid (water, tea, coffee, fruit juices,
ment and the social difficulties in managing the stoma. alcohol or dilute salt solutions) to 0.5–1.0 L/24 h (Fig. 4). To
A patient presenting with a HOS and renal failure will make up the rest of the fluid requirement the patient is encour-
need urgent rehydration and in most cases the progression to aged to drink a glucose–saline rehydration solution. Many
irreversible or chronic renal failure can be prevented. The patients at home with a marginally high stomal output (1–1.5 L)
replacement fluid needs to contain 100–150 mmol sodium/L will be helped by a combination of mild oral fluid restriction
e.g. intravenous normal saline, 2–4 L/day. During this time (less than 1.5 L per day) and the addition of salt to their diet.
the patient may be kept “nil by mouth” to reduce the stomal Patients are often advised to take liquids and solids at dif-
output. In general dialysis is avoided as the removal of any ferent times (no liquid for half an hour before and after food),
more fluid can worsen the renal failure which may become however there is no published evidence that this reduces sto-
permanent. Great care must be taken not to give too much mal output or increases absorption of macro- or micronutri-
fluid as this will readily cause oedema, partly due to the high ents [42].
circulating aldosterone levels [10, 11, 12, 31]. Cramps can be
rapidly helped by oral or intravenous sodium chloride, and/
or by magnesium supplementation. Drink Oral Glucose–Saline Solution
Once renal failure has been corrected and thirst relieved,
usually over 2–3 days, an attempt is made to reduce stomal Patients with stomal losses of less than 1200 mL daily can usu-
output, even in patients with a jejunostomy requiring paren- ally maintain sodium balance by adding extra salt to the limit of
teral nutrition, as this may well reduce the amount or fre- palatability at the table and when cooking. When stoma losses
quency of intravenous fluid replacement and the social are in the range 1200–2000 mL, or sometimes more, it is pos-
difficulties in managing the stoma. sible for a patient to maintain sodium balance by taking a glu-
Sometimes, admitting patients with a chronic HOS, giv- cose–saline solution or salt capsules [22]. In hot weather,
ing intravenous saline and keeping them ‘nil by mouth’ will patients with a stoma are more likely to have problems of dehy-
demonstrate to them that their output is mostly driven by dration because of water and sodium loss in sweat.
their oral intake. Intravenous fluids are gradually withdrawn As the sodium content of jejunostomy (or ileostomy)
over 2–3 days while food and oral fluids are reintroduced. effluent is relatively constant at about 90 mmol/L and as
These patients are dependent upon their treatment regimen there is coupled absorption of sodium and glucose in the
and if missed/stopped for a day may result in dehydration jejunum [43–45], patients are advised to sip a glucose–saline
and a hospital admission for rehydration. solution with a sodium concentration of at least 90 mmol/L
Table 4 Oral rehydration solutions as single strength Dioralyte® or commercial preparations

Modified WHO used to treat infective or traveler’s diarrhoea or in sport’s
Cholera solution drinks sports are not adequate.
Dioralyte® strength Sodium chloride capsules (500 mg each) are effective when
“St Mark’s Sodium citrate taken in large amounts (14/24 h), but can cause some patients
Solution”b Single Doublea solution
to feel sick and even vomit [22]. If an enteral feed is given,
Volume (L) 1 1 1 1
Na+ (mmol) 90 60 120 120 sodium chloride needs to be added to make the total sodium
K+ (mmol) 0 20 40 0 concentration of the feed 100 mmol/L while keeping the osmo-
Cl− (mmol) 90 60 120 0 lality near to 300 mOsm/kg. A hyperosmolar solution/feed
Citrate (mmol) 0 10 20 120 (e.g. of amino acids) will cause increase stomal water losses.
Glucose (mmol) 80 90 180 80 Even patients with a jejunostomy receiving long term par-
A stronger solution that can be used is is sodium chloride 7 g enteral support should restrict their intake of oral hypotonic
(120 mmol), glucose (8 g) (44 mmol) and tap water 1 L fluid and sip a glucose saline solution to prevent stomal fluid
a
10 sachets
b
Sodium chloride 3.5 g (60 mmol), sodium bicarbonate 2.5 g (30 mmol) losses.
or sodium citrate 2.9 g (30 mmol), glucose 20 g (110 mmol) and 1 L tap
water
Subcutaneous or Parenteral Fluids
throughout the day. The first World Health Organization
(WHO) cholera solution had a sodium concentration of Some patients cannot be maintained (hydration, sodium and/
90 mmol/L [46] and is still commonly used (without the or magnesium) with an oral regimen (usually if jejunal length
potassium chloride) (sometimes referred to as the St Mark’s is less than 100 cm) and regular subcutaneous or parenteral
solution) (Table 4). Patients can prepare this solution at home saline supplements are needed. Subcutaneous saline can be
using simple measuring scoops. There is no evidence that the slow to run (e.g. a litre usually containing 4–8 mmol magne-
sodium bicarbonate adds to the effectiveness of this solution sium sulphate that takes 10–12 h to infuse), it may cause
[45] and it may be more palatable if sodium bicarbonate is swelling of a limb; however it is relatively simple and quick
replaced by sodium citrate. Indeed a pure sodium citrate to start with few risks of infection. It is most appropriate if
solution (sodium concentration 120 mmol/L) was successful the additional fluid is only needed 1–4 days a week. If more
[47]. If the sodium concentration is increased further (e.g. to frequent or a higher volume is needed (due to thirst/dehydra-
136 mmol/L), absorption of sodium and water is improved tion) then intravenous normal saline, 2–4 L/day, often with
[48]. Although taste perception changes in patients who are added magnesium sulphate (4–14 mmol/L) may be given.
depleted in salt and water, they may find this solution, which Patients with less than 100 cm jejunum remaining may
tastes like ‘sweet seawater’, too salty to drink. Double need oral or parenteral nutritional supplements, but a few
strength Dioralyte ® is often given (Table 4). It does contain need, no nutritional supplements, only 1 or 2 L of parenteral
potassium and so serum potassium measurements may need saline daily, usually with added magnesium sulphate.
to be made more frequently than 3 monthly, especially if
renal impairment occurs.
A glucose-polymer (55 g Maxijul®) may be substituted rug Therapy to reduce the High-Volume
D
for glucose to increase the energy intake by a mean of Output from a Jejunostomy
115 kcal/d [22]. The glucose-polymer (or even a rice-based
solution) can be especially useful in diabetic patients as it If restricting oral fluids and giving a glucose– saline solution
causes less extreme changes in blood glucose than a glucose- to drink are not adequate treatment, drugs may be needed.
based solution. The intestinal output, especially in net ‘secretors’ rises after
The patient should be encouraged to sip a total of 1 L or meals (Fig. 7), and it is therefore important to give the drugs
more of one of these solutions in small quantities at intervals before food. Drugs used to reduce jejunostomy output act to
throughout the day. They should make up the majority of the reduce either intestinal motility or secretions.
oral fluid intake. As compliance is often a major problem,
patients need to understand the need for the solution and can ntimotility (Antidiarrhoeal) Drugs
A
make it more palatable by chilling, and/or flavouring with Opiate drugs such as tincture of opium (laudanum) or
fruit juice and drinking it through a straw. Compliance with codeine phosphate have been used for many years to treat
the regimen is vital as if one day of fluid restriction/glucose diarrhoea but are sedative and, in the long term, addictive.
saline solution consumption is omitted the patient may be Synthetic drugs were manufactured with the aim that they
admitted to hospital dehydrated. It is important to note that should be free of opiate-like activity upon the central ner-
solutions with a sodium content of less than 90 mmol/L such vous system. Diphenoxylate (Lomotil®) was the first to be
used in clinical practice but has largely been replaced by lop- peutic range 0.24–1.2 mg/mL). Loperamide toxicity should
eramide (Imodium®) which has no central nervous system be considered in any patient with fainting episodes not
effects. Loperamide is a synthetic piperidine opioid made in accounted for by dehydration or other drugs and if there is
1969 (for diarrhoea), it acts on μ receptor in myenteric plexus QT prolongation or a serious ventricular arrhythmia includ-
to inhibit gut motility and reduce gastrointestinal secretions. ing torsades de pointes or cardiac arrest has occurred [58].
It also increases the tone of the anal sphincter. It has peak
levels within 4–5 h, a half life of 7–15 h and circulates in the Antisecretory Drugs
enterohepatic circulation with 30–40% excreted in faeces Food and drink are diluted by digestive juices, thus the vol-
(1% in urine). It is 97% protein bound. ume of stomal effluent can be reduced in ‘secretors’ by drugs
Loperamide is preferred to codeine phosphate as it does that reduce the secretions from the stomach, liver and pan-
not sedate and is not addictive. Codeine phosphate increases creas. Drugs that reduce gastric acid secretion, such as the H2
the output of stomal fat [49, 50]; loperamide does not [50, antagonists or proton pump inhibitors or the somatostatin
51] although it reduces the post-prandial pancreatico-biliary analogue octreotide, are most commonly used.
secretion of trypsin and bilirubin in patients with a short
bowel and preserved colon [52]. H2 Antagonists/Proton Pump Inhibitors
Loperamide and codeine phosphate reduce intestinal Cimetidine (400 mg orally or intravenously four times a day)
motility and thus decrease water and sodium output from an reduced the output from a jejunostomy/ileostomy when the
ileostomy by about 20–30% [49–51, 53, 54]. Oral loper- daily output exceeded 2 L daily [59, 60]. This beneficial
amide, 4 mg taken four times a day, was more effective in effect is likely to be due to the reduction in normal daily
reducing the weight and sodium content of ileostomy fluid gastric acid secretion or to a reduction in gastric acid
than codeine phosphate 60 mg taken four times a day [50], hypersecretion.
but the effect of both together may be greater [55]. These Omeprazole, 40 mg orally once a day, reduced the stomal
drugs are effective in most patients with a jejunostomy [13], output by a mean of 0.7 kg/24 h in 7 patients with a net secre-
particularly net ‘absorbers’. A combination of both of these tory output [61] (Fig. 9a). Omeprazole, 40 mg given intrave-
drugs, taken before food, a glucose–saline solution and other nously twice a day, reduced the jejunostomy output in
fluid restriction can liberate some patients from dependence patients whose output exceeded 2.6 kg/24 h.48 Omeprazole
on parenteral saline supplements [55]. is readily absorbed in the duodenum and upper small bowel,
Loperamide circulates through the entero-hepatic circula- but if less than 50 cm of jejunum remains it may need to be
tion, but this is severely disrupted in these patients, and small given intravenously. Giving omeprazole orally dissolved in
bowel transit may be rapid. Thus high doses of loperamide bicarbonate may improve absorption enough for it to be suc-
(e.g. 12–24 mg) at a time) may be needed, as in patients who cessful. Omeprazole has little beneficial effect in patients
have had a vagotomy and pyloroplasty [56]. One case series who are net absorbers.
suggested even higher doses (40 mg five times a day, 30 mg Oral omeprazole, 40 mg once daily, gave an equivalent
three times a day and 100 mg four times a day) were effec- reduction in stomal output to oral ranitidine, 300 mg twice
tive [57]. daily, in one patient [5, 61]. Intravenous omeprazole, 40 mg
In 2017 the UK Medicines and Healthcare products twice daily, was more effective than intravenous ranitidine
Regulatory Agency (MHRA) issued an alert about serious 150 mg twice daily, probably because the dose of ranitidine
cardiovascular events (QT prolongation, torsades de pointes, was too low [62]. Oral omeprazole, 40 mg once daily, was
and cardiac arrest/deaths) associated with high or very high shown in two patients to be equivalent to intravenous octreo-
doses of loperamide when used as a drug of abuse or for self- tide 50 μg twice daily [5, 61].
treatment of opioid withdrawal. The British Intestinal Failure Omeprazole, ranitidine and cimetidine reduce jejunos-
Alliance (BIFA) advice about this included performing an tomy output in those with the highest outputs (net ‘secre-
ECG in all patients with a high output stoma/fistula before tors’) while often having no effect on net ‘absorbers’. They
starting high dose loperamide (more than 4 mg four times a may need to be given intravenously if less than 50 cm of jeju-
day) and the QT interval being measured. It was suggested num remains. They do not change the absorption of energy,
that the ECG should be repeated after starting the high dose carbohydrate, lipid, nitrogen and divalent cations [61, 62]
and then every 3 years if the patient remained on high dose and do not reduce jejunostomy output sufficiently to prevent
loperamide therapy. If the QT interval was prolonged cardiac the need for parenteral fluid and electrolyte replacement.
co-morbidities should be considered, drugs known to pro- Other PPI drugs have not been reported to reduce jejunos-
long the QT interval are rationalised and metabolic causes tomy output but are likely to be as effective. The PPIs have
(e.g. hypomagnesaemia) treated. The total daily dose of lop- been associated with Cl difficile infection, abnormal liver
eramide should be below 80 mg, however if this is exceeded function tests, hypomagnesaemia, osteopenia/osteoporosis
serum loperamide levels should be measured (normal thera- and increased risk of fractures (hip, wrist and spine), myo-
cardial infarction (possibly by suppressing NO production) in intestinal output have occurred in net ‘secretors’, (Fig. 9)
and renal impairment [63]. When used (e.g. omeprazole and many patients have been able to reduce the volume of
40–80 mg daily) the dose can be titrated such that fresh sto- parenteral supplements needed [71, 72]. Although some
mal fluid has a pH greater than 5. patients have achieved positive intestinal fluid balance,
they have rarely been able to stop parenteral fluids com-
Somatostatin and Octreotide pletely [71, 72]. All studies have shown a reduction in
Somatostatin and octreotide reduce salivary, gastric and sodium output which parallels that of the intestinal output
pancreatico-biliary secretions, slow small bowel transit, and [13, 28, 66–72]. Stomal output has been reported as reduced
may delay gastric emptying; for these reasons they may be [70] in 2 and increased [28] in 2 jejunostomy patients clas-
expected to reduce the intestinal output from a jejunostomy sified as net ‘absorbers’. However, in one study in which all
in both net ‘secretors’ and ‘absorbers’. Somatostatin has a patients had mild ileostomy diarrhoea (0.8–1.3 kg/24 h)
serum half-life of 3 min so is given by continuous infusion, and were thus net absorbers, the output reduced by only
whereas that of octreotide is 90 min so it is usually given as 0.3 kg/24 h [67]. Octreotide, 20–100 μg/24 h, has been used
regular (two or three times daily) subcutaneous injections successfully to reduce ileostomy diarrhoea in 2 children
before food. aged 3 months and 5 years [73]. In 3 patients, an intrave-
nous dose of 50 μg octreotide twice a day was as effective
Somatostatin in reducing the intestinal output as 100 μg three times a day
Four patients with more than 100 cm of small intestine [69]. Magnesium balance has not been changed by octreo-
remaining (one also had some residual colon) were given a tide [68, 70].
continuous infusion of somatostatin, 4 μg/min for 24 h. The effect of octreotide is maintained in the long term
Mean daily intestinal output reduced from 1.9 kg to 1.2 kg, [66, 68–70, 72]. After a year’s continuous therapy with 50 μg
however magnesium, nitrogen and fat absorption were intravenous octreotide twice daily, the reduction in stomal
unchanged [64]. output was the same as at the start of treatment [69, 72].
Somatostatin and octreotide both reduce the output from
Octreotide a high fistula and appear to accelerate the rate of spontaneous
Effect of octreotide upon water, sodium and magnesium closure [74, 75].
balance. A case report in 1984 first demonstrated that 50 μg
of octreotide given subcutaneously twice a day allowed a Effect of Octreotide Upon Nutrient Absorption Although
patient with ileostomy diarrhoea to stop intravenous fluids octreotide reduces stimulated gastric acid and pancreatic
[65]. Several studies in adults have shown octreotide to enzyme secretion and reduces the splanchnic uptake of
reduce ileostomy diarrhoea and large-volume jejunostomy amino acids [76], it does not significantly change total energy
outputs (Table 5) [13, 28, 66–72]. The greatest reductions [69, 71, 72] or nitrogen absorption [66, 68, 70–72]. As
Table 5 Octreotide to treat high-volume ileostomy or jejunostomy output

Stomal output (l or kg/24 h)
Author Number Dose Days Control Octreotide
Ileostomy diarrhoea
Cooper et al. [66] 1986 5 25 μg/h infusion 3 5.3 4.2
Kusuhara et al. [67]* 1992 12 100 μg t.d.s. 5 1.0 0.7
High-output jejunostomy
Shaffer et al. [68] 1988 6(?) 50–150 μg/24 h s.c. 3 4.0 2.4
Rodrigues et al. [13] 1989** 4(4) 50 μg s.c. 6h 0.9/6 h† 0.4/6 h†
Nightingale et al. [28, 69] 1989 6(6) 50 μg b.d. i.v. 2 5.0 2.8
2(0) 100 μg t.d.s.
Ladefoged et al. [70] 1989 6(4) 25 μg/h infusion 2 – 1.1 less
5(4) 50 μg b.d. s.c. 2 – 1.4 less
Lemann et al. [71] 1993 7(7) 100 μg t.d.s. s.c. 10 h 1.6/10 h† 1.0/10 h†
O’Keefe et al. [72] 1994 10(10) 100 μg t.d.s. s.c. 3 8.1† 4.8†
*Defunctioning ileostomy above ‘ileoanal anastomosis’
() number of net ‘secretors’
s.c. subcutaneous, i.v. intravenous, b.d. twice daily, t.d.s. three times a day
All had normal meals except ** in which a liquid meal was given
Median results except †, where means are presented
Fig. 9 Mean daily stomal a

output from 2 day collections.
b
Effect of (a) omeprazole
(40 mg orally once a day),
and (b) octreotide (50 μg
given intravenously twice a
day) except 〇 when 100 μg
given subcutaneously three
times a day into net
‘absorbers’ upon jejunostomy
output. The dotted line shows
the effect of intravenous
omeprazole given to one
patient with 30 cm jejunum
after there was no response to
an oral dose
pancreatico-biliary secretion is reduced, it would be expected

Octreotide at a dose of 50 μg twice daily given subcutane-
that fat absorption would be reduced [66]. However, it is usu-
ously or intravenously reduces intestinal water and sodium
ally unchanged [69–72].
losses in most patients with a jejunostomy, and in some with
ileostomy diarrhoea or a high small intestinal fistula. This
effect is greatest in patients with the highest net ‘secretory’
Problems of Octreotide Therapy A subcutaneous injection
output and is maintained long-term without tolerance devel-
of octreotide may be painful, especially in the very thin,
oping. The reduction in output may reduce, but rarely avoids,
while an intravenous injection may cause flushing, nausea
the need for parenteral fluids. Some patients use these prepa-
and headache [69]. Blood glucose generally remains within
rations, particularly octreotide, before meals to diminish the
the normal range [70]. Patients with a jejunostomy have a
social inconvenience of a profuse jejunostomy output after
very high prevalence of gallstones (45%) [29], and long-term
food. In these patients octreotide does not affect the absorp-
octreotide therapy may further increase this [77]. Although
tion of magnesium or nutrients.
hypoglycaemia may occur [73], there is no evidence that
octreotide causes diabetes or hypothyroidism after prolonged
ong Acting Somatostatin Analogues Long acting octreo-
L
usage. Increasing the consistency of the small bowel con-
tide 20 mg [79] and lanreotide 120 mg [80] have both been
tents could increase the risk of developing small bowel
used to treat HOS with deep subcutaneous/intramuscular
obstruction if there are adhesions [72].
injections every 4 weeks.
Mechanism of Action of Octreotide Octreotide increases

Mineralocorticoids
total intestinal transit time [13, 66, 71, 72]. This probably
The distal ileum, with its tight intracellular junctions, can
reflects an increase in small bowel transit time as the rate
concentrate the intraluminal contents. This ability develops
of gastric emptying remains normal [66, 71]. This slowing
from 2 to 16 weeks after the formation of an ileostomy [81,
of transit may be the mechanism whereby some net
82]. This capacity for sodium absorption may partly relate to
‘absorbers’ respond to octreotide therapy. In net ‘secre-
high aldosterone levels [10, 30] and can be induced by min-
tors’, the reduction in jejunostomy output was similar to
eralocorticoids (e.g. 2 mg oral fludrocortisone or 2 mg intra-
that achieved with omeprazole, hence the suggestion that,
venous d-aldosterone) [83–85] or high-dose hydrocortisone
in these patients, octreotide acts mainly by reducing the
[86]. Although intraluminal hydrocortisone does increase
volume of gastric acid secreted in response to food [78]. A
jejunal water, sodium and glucose absorption in normal sub-
reduction in pancreaticobiliary secretion may explain why
jects [87], mineralocorticoids do not usually reduce ileos-
fat malabsorption increases in some patients [66], and it
tomy output. However, studies have only been performed in
may be this that increases the intestinal output in some net
patients with a relatively normal ileostomy output. Studies of
‘absorbers’ [78].
patients with a high-output ileostomy or jejunostomy are
awaited, but it would not be surprising if these were disap- sium loss; correction of these conditions may help to treat
pointing, as high circulating aldosterone levels may have magnesium depletion. In addition, a diet relatively low in fat
already maximized sodium absorption. reduces stool or stomal magnesium losses [35] (chapter
“Dietary Treatment of Patients with a Short Bowel”).
Desmopressin Serum magnesium levels can usually be improved by oral
Desmopressin, an analogue of antidiuretic hormone, has no supplements, however the data about the magnesium absorp-
effect upon ileal fluid or electrolyte loss in man [88]. tion from different preparations are often derived from nor-
mal volunteer studies and studies of patients with a short
Cholylsarcosine bowel and retained colon. Tablet dissolution and magnesium
A synthetic bile acid resistant to bacterial deconjugation and availability may be very different in patients with a jejunos-
dehydroxylation, cholylsarcosine (4 g taken three times a tomy than in normal subjects and patients with a short bowel
day), was given to 3 patients with a jejunostomy and resulted and retained colon.
in an improvement in fat (18%, 37% and 51%) and calcium Many oral magnesium salts, which are generally poorly
absorption but did not affect the volume of stomal output absorbed, have been given as a treatment and include magne-
[89, 90]. sium sulphate, chloride, hydroxide, acetate, carbonate, glu-
conate, lactate, citrate, aspartate, pyroglutamate, oxide and
Clonidine diglycinate [99, 100]. In clinical practice in the UK magne-
Clonidine is an α2-adrenergic agonist that prolongs gastroin- sium oxide, glycerophosphate or aspartate are most com-
testinal transit and has been used to treat chronic diarrhoea. monly given. Magnesium oxide may be given to a total of
A 0.3 mg clonidine patch (as has been used in hypertension 12–24 mmol daily. Oral magnesium treatment, such as three
[91]) to 8 jejunostomy patients receiving parenteral nutrition gelatine capsules each of 4 mmol (160 mg of MgO), is usu-
resulted in a reduction in stomal output of 0.44 kg/day ally given at night when intestinal transit is assumed to be
(39 mmol sodium) without affecting energy, fat or xylose slowest and hence there is more time for absorption. This
absorption [92]. It is rarely used but may be a treatment for regimen increases magnesium absorption and does not
those who are not responding to other conventional appear to increase stomal output.
treatments. A topical magnesium chloride spray may help those with
magnesium depletion who do not adequately absorb magne-
eptide Hormones (Including Growth Factors)
P sium preparations from their gut [101] and may offer a mode
(Chapter “Pro-Adaptive Hormones of correcting serum levels and helping symptoms that may
in the Rehabilitation of Adult Patients be related to hypomagnesaemia. Proton pump inhibitor drugs
with a Short Bowel”) can reduce serum magnesium levels and a trial of stopping
Patients with a jejunostomy have low circulating levels of these may be beneficial [37].
PYY (slows transit) and GLP-2 [24, 27]. GLP-2 agonists If oral magnesium supplements do not bring the
(e.g. teduglutide, apraglutide and glepaglutide), which magnesium level into the normal range, oral

stimulates small bowel mucosal growth and increases 1α-hydroxycholecalciferol in a gradually increasing dose
absorption of salt, water and nutrients, may be used as a (every 2–4 weeks) of 1–9 μg daily has been shown to improve
treatment (though are expensive and in the UK can only magnesium balance in patients with a retained colon [102,
prescribed by specialist IF/HPN centres) [93]. While in 103]. This action occurs by increasing both intestinal and
studies teduglutide may reduce parenteral requirements by renal magnesium absorption [103]. As hypomagnesaemia
20% and may occasionally allow a patient to stop paren- will have caused both a failure of parathormone release and
teral nutrition [94–96]. A GLP-1 agonist (liraglutide) which a resistance to its action, 1α-hydroxycholecalciferol cannot
primarily slows upper gastrointestinal transit has been used be made in the kidney in adequate amounts. Thus it is impor-
with some success [97]. There may be a future role for tant that the 1α preparation is given.
using combinations of peptide hormone analogues. While Magnesium can occasionally be given as: a subcutaneous
peptide YY analogues have been manufactured they have injection of 4 mmol magnesium sulphate every 2 or more
not been used clinically [98].
Table 6 Summary for hypomagnesaemia treatment
Correct dehydration
Magnesium Supplements Oral magnesium (oxide, glycerophosphate, aspartate)
Topical magnesium chloride spray
There are many therapeutic ways of improving hypomagne- 1-alpha calciferol
saemia (Table 6). Dehydration and sodium depletion cause Reduce lipid in diet
secondary hyperaldosteronism, which leads to renal magne- Stop PPI
days, but this can cause skin ulceration; an intramuscular diet increased the loss of the divalent cations Mg and Ca
injection of 10 mmol/L, but this is painful; or a regular [35], but this was not the case in another [106]. There is no
intravenous infusion of 4–8 mmol, usually in a litre of saline advantage in giving a diet of small molecules (e.g. an ele-
over 1–2 h, though this can cause a flushing sensation. mental diet); this causes a feed to be hyperosmolar [106] and
Occasionally a subcutaneous infusion [104] 4–8 mmol of usually contains little sodium, so potentially increasing the
magnesium sulphate is infused subcutaneously in a litre of losses of water and sodium from the stoma. A peptide diet
saline over 10–12 h 1–3 times a week. Initially there was a still has the problem of a relatively high osmolality and thus
worry that this caused hardening of the subcutaneous tissues can increase stomal output [106]. Little advantage comes
but was not supported by longer term experience. from taking a diet of water-soluble medium-chain triglycer-
ides in place of normal fat [107]. The addition of glutamine,
15 g, to a litre of rehydration solution in patients with a jeju-
Nutrient Absorption nostomy resulted in no additional benefit in terms of water or
sodium absorption [108]. The fibre content of the diet plays
Need for Enteral or Parenteral Nutrition only a minor role in determining jejunal output [49].
Thus jejunostomy patients need a large total oral energy
Most patients with less than 75 cm of jejunum remaining intake of a polymeric, iso-osmolar (300 mOsm/kg) diet that
need long-term parenteral nutrition; most in the range is relatively high in fat with added salt (sodium concentration
75–100 cm need parenteral saline (sometimes with added 100 mmol/L). The volume of the stomal output may become
magnesium) but manage to maintain nutritional status with so high with a normal diet or with extra feeding that it is a
an enteral regimen even though they may only absorb about major social disability. If this is the case, parenteral feeding
50–60% of their oral energy intake. may be needed to enable oral intake to be reduced.
All patients wish to eat food so as to feel normal and to The ideal nutrient solution with an osmolality of
maintain social relationships. In patients maintained on par- 300 mOsm/kg and a sodium concentration of at least
enteral nutrition, an oral intake is detrimental as it increases 100 mmol/litre has yet to be marketed. A low fibre diet is
jejunostomy losses (Fig. 7). Patients taking an oral regimen advised if intermittent/partial obstructions is thought to be
need to consume more energy than a normal person to com- occurring and often is first used as these patients have a high
pensate for malabsorption. Most patients can achieve this by probability of having adhesions and an area of bowel nar-
eating more high-energy food. Oral sip-feeds may be given rowing. Liquid diets must be near ro iso-osmolar. A hyperos-
in addition to food, preferably taken between meals and at molar feed (e.g. amino acids) will cause water secretion into
bedtime. By these means, a patient may increase energy the gut and also if little/no sodium in the feed then sodium
intake by at least 1000 kcal/d. If oral sip-feeds during the day excretion will occur.
fail to achieve weight gain or maintain nutrition, a nasogas-
tric or gastrostomy tube may be inserted and a feed given at
night so that the short residual length of intestine is used at a Monitoring
time when it is usually inactive. There are rarely any prob-
lems inserting a percutaneous endoscopic gastrostomy Accurate daily measurements of body weight, fluid balance
(PEG) in patients with Crohn’s disease provided that there is (especially stomal effluent) and postural blood pressure are
no distal obstruction [105]. important. Serum electrolyte (creatinine, potassium and
Once weight is regained, the daily energy requirement magnesium) and urinary sodium estimation may be done
may decrease so that a nocturnal feed can be reduced or every 1–3 days initially but once or twice weekly when the
stopped and sip-feeds during the day may become adequate. patient is stable in hospital. The aims are to maintain hydra-
Only if these measures fail and the patient continues to lose tion and body weight and a daily urine volume of at least
weight, or fails to regain lost weight, is parenteral nutrition 800 mL with a sodium concentration greater than
given. 20 mmol/L. At home, if stable, measurements of weight,
urine sodium concentration and serum magnesium are done
every 3 months [109].
Oral/Enteral Nutrition/Food
Patients with a jejunostomy absorb a constant proportion of Predicting Drug Absorption

the nitrogen, energy and fat from their diet [14, 36, 104].
Increasing fat in the diet raises fat excretion but does not usu- Many drugs are incompletely absorbed by patients with a
ally increase stomal output, nor make the output offensive short bowel and may be needed in much higher amounts than
[14, 36, 106]. One study showed that increasing fat in the usual (e.g. thyroxine, warfarin and digoxin [110] or may
need to be given intravenously. An attempt to predict the Future Treatments

absorption of a medication in patients with a short bowel can
be made by using the time to peak levels and the biopharma- The ideal nutrient solution with an osmolality of 300 mOsm/
ceutical classification of drugs (see chapter drugs and short kg and a sodium concentration of 100–140 mmol/L has yet
bowel). A drug with a short time to peak plasma levels is to be marketed. A feed of high viscosity (possibly containing
likely to be absorbed in the upper gut and so be absorbed in non-absorbable carbohydrate) that delays gastric emptying
patients with a short bowel; this will not be the case if there so allowing more time for absorption may be developed.
is a long time to peak plasma levels. The biopharmaceutical As the awareness of the physiological changes in patients
classification of drugs is based upon drug aqueous solubility with a jejunostomy becomes better defined, treatments, espe-
and intestinal permeability [111, 112]. A drug with high sol- cially with peptide hormones, may be more physiologically
ubility and high permeability (class 1) is likely to be well administered. For example a combination of peptide hor-
absorbed in a short length of gut but this will not be the case mone analogues (e.g. GLP2 and PYY) may be given at or
for one with poor solubility and permeability. just after a meal.
Changes in Jejunostomy Output with Time References
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106. McIntyre PB, Fitchew M, Lennard-Jones JE. Patients with end permanent parenteral nutrition dependency: an experience of
a jejunostomy do not need a special diet. Gastroenterology. 38 adults with short bowel syndrome. Ann Surg. 2012;256(5):739–
1986;91:25–33. 44; discussion 744–5.
107. Jeppesen PB, Mortensen PB. The influence of a preserved colon 117. Yannam GR, Sudan DL, Grant W, Botha J, Langnas A, Thompson
on the absorption of medium-chain fat in patients with small JS. Intestinal lengthening in adult patients with short bowel syn-
bowel resection. Gut. 1998;43:478–83. drome. J Gastrointest Surg. 2010;14(12):1931–6.
Dietary Treatment of Patients
with a Short Bowel
Morag Pearson and Jeremy M.D. Nightingale
Key Points nutrition (PN), so reducing associated complications and

1. A patient with a short bowel taking an oral diet requires a improving the quality of life.
malabsorption factor to be taken into account. Adaptive Short bowel is categorised according to residual anatomy
hyperphagia will help compensate for this. [1, 2]:
2. Adhesions are common and so the diet may need to be
low in fibre to reduce the chance of obstruction. Jejunostomy: following jejuno-ileal resection, colectomy
3. Jejunostomy patients, whose intestine does not adapt and formation of a jejunostomy, patients will immediately
with time, need a high energy iso-osmolar (high lipid) become dehydrated due to large stomal water and sodium
oral/enteral intake with added sodium (and cation supple- losses, which are greatest after food and drink consump-
ments). They should restrict oral hypotonic fluids and tion, and rapidly develop malnutrition.
take an oral rehydration solution. Jejunum-colon: following a jejuno-ileal resection with
4. Jejunum-colon patients, whose absorption (adaptation) jejuno-colic anastomosis, patients appear well apart from
may improve for up to 2 years after the anastomosis, need diarrhoea/steatorrhoea, but in the following months may
a high carbohydrate diet (for colonic fermentation), with lose weight and become severely undernourished.
no excess lipid (worsens diarrhoea), that is low in oxalate Jejunum-ileum: following a predominantly jejunal resec-
with calcium supplementation (to prevent calcium oxa- tion leaving more than 10 cm of terminal ileum in conti-
late renal stones). nuity with colon, patients rarely develop nutritional
5. d-lactic acidosis may occur in jejunum-colon patients. It problems, but if undernutrition or severe diarrhoea arise,
causes confusion, a high anion gap acidosis and may be then they are treated as per jejunum-colon guidance so
helped by antibiotics ideally targeted at specific faecal will not be discussed separately in this chapter.
microbes.
Patients with short bowel and taking an oral diet only may
have difficulty maintaining nutritional status, fluid and elec-
trolyte balance. This is due to malabsorption and fluid losses
Introduction which may result in malnutrition and/or dehydration if there
is not adequate nutritional support and fluid replacement.
Intestinal rehabilitation aims to optimise residual intestinal In the immediate postoperative period, many patients may
function through medical, pharmacological, dietary and sur- require PN, but its long-term use has been associated with
gical strategies and to provide the nutrition, fluid and electro- life-threatening metabolic, hepatic and catheter related com-
lytes required to maintain health (with a normal body weight) plications [3, 4] and a reduced quality of life [5, 6]. Over
and growth in children. It also aims to promote nutritional time, intestinal absorption in those with a colon in continuity
autonomy and enable a reduction or weaning of parenteral may improve with adaptation of the residual bowel, a pro-
cess that is stimulated by intraluminal nutrients and gastroin-
testinal (especially pancreatico-biliary) secretions. When the
M. Pearson (*) gut is functional, patients are encouraged to eat, with advice
Advanced Specialist Dietitian (Intestinal Failure), (Retired),
Formerly St Mark’s Hospital, Harrow, Middlesex, UK on modifying oral intake to reduce stoma or stool losses.
When the gut has the potential to absorb water, electrolytes
J. M.D. Nightingale
St Mark’s Hospital, Harrow, Middlesex, UK and nutrients then nutritional intake should be optimised
e-mail: [email protected] through dietary counselling, use of oral rehydration solution,

652 M. Pearson and J. M.D. Nightingale
anti-secretory and anti-motility medications, overnight found that jejunal length was inversely correlated with
enteral nutrition (EN), distal feeding or other rehabilitative energy absorption (r = 0.64, p < 0.02) [9]. Patients who
strategies such as surgical restoration of continuity or intesti-
required PN had <80 cm jejunum and absorbed <35% of
notrophic hormones. In this way some patients may be able their oral energy intake (mean 8646 kJ (2066 kcal)/day),
to reduce or withdraw their need for parenteral support [2]. whereas those stable on diet had >100 cm jejunum and
Dietary aspects of intestinal rehabilitation include under-absorbed 58% of their oral energy intake (mean 12,782 kJ
standing the anatomical and physiological changes that (3055 kcal)/day, suggesting an increased oral intake to com-
affect nutrient, fluid and electrolyte absorption; assessing pensate for malabsorption. Jejunal length was also inversely
and monitoring patients, promoting adaptation (including correlated with net intestinal fluid (r = 0.75, p < 0.01) and
hyperphagia) and dietary strategies to optimise absorption, sodium losses (r = 0.59, p < 0.05), such that patients could be
reduce stoma/stool losses and short bowel related classified as either net ‘secretors’ or ‘absorbers’ depending
complications. The practical aspects of dietary care should on the relative weight of their oral intake and stomal output
be integrated within the multidisciplinary team management. and corresponding sodium content. ‘Secretors’ had less than
This chapter focuses on the dietary aspects of intestinal reha-100 cm residual jejunum and lost more water and sodium
bilitation, especially the dietary treatment to maximise from their stoma than they took by mouth (daily jejunostomy
absorption of nutrients, fluid and electrolytes and reduce output 2–8 kg, containing 154–551 mmol sodium). They
short bowel related complications. It outlines most of the key could not convert from negative to positive water and sodium
studies on which dietetic advice is based and it gives a full balance by taking more orally and so required long-term par-
practical dietetic account about d-lactic acidosis and calcium enteral supplements. Their stoma output increased during the
oxalate renal stones. day in response to food and decreased at night, highlighting
the need to take anti-motility medication prior to food. The
‘absorbers’ had more than 100 cm of residual jejunum and
Remaining Bowel Length and Energy/Fluid absorbed more water and sodium from their diet than they
Absorption took orally (daily jejunostomy output 1–3 kg containing
149–368 mmol sodium). They were able to avoid parenteral
Balance studies, performed in short bowel patients eating support by taking a high salt diet with an oral rehydration
their usual diet, provide an objective measure of nutrient solution to maintain fluid and sodium balance.
absorption and thus residual intestinal absorptive capacity Jeppesen et al. [10] investigated energy and wet weight
[7] (Table 1). They involve the 24-h collection of duplicate absorption by 48-h balance studies in 44 non-HPN patients
oral food and fluid intake plus all stoma/stool and urinary with intestinal insufficiency (<200 cm small bowel or malab-
losses, each of which are homogenized and frozen or freeze- sorption exceeding 2 MJ/day) and 45 HPN patients with
dried for analysis. Fluid (wet weight) absorption is calcu- intestinal failure. Non-HPN patients had a higher median
lated from the difference between the weight of oral intake energy intake (11.69 MJ (2794 kcal)/day) compared with
and faecal losses, whilst energy content is analysed by bomb HPN patients (7.56 MJ (1807 kcal)/day), (p < 0.001), corre-
calorimetry and absorption calculated from the difference sponding respectively to 178% and 134% of basal metabolic
between dietary intake and stool losses. rate (BMR) as calculated by Harris-Benedict and a twofold
Rodrigues et al. [8] measured energy absorption from a higher energy absorption (7.92 MJ (1893 kcal)/day) com-
polymeric test drink, following an overnight fast, in 12 short pared with HPN patients (3.96 MJ (946 kcal)/day),
bowel patients including seven with jejunostomies stable on (p < 0.001), corresponding respectively to 130% and 71% of
an oral diet/enteral feed (median 110 cm small bowel) and BMR (p < 0.001). Intestinal wet weight absorption was
five (three jejunostomies, one jejunocolic anastomosis to threefold higher in non-HPN patients (2.48 kg/day) com-
colostomy, one ileo-rectal anastomosis) on home parenteral pared with HPN patients (0.84 kg/day), p < 0.001). Non-
nutrition (HPN) (median 50 cm small bowel) who remained HPN patients, who absorbed less than half of their intake,
nil by mouth during the 6-h collection of intestinal output. avoided HPN through hyperphagia with energy intakes of
Median energy absorption was 67% (range 59–78%) in 10–24 MJ (2390–5736 kcal)/day, equivalent to 200–400% of
patients stable on diet compared with 27% (range 2–63%), BMR. Non-HPN patients who maintained intestinal auton-
(p < 0.01) in those dependent on PN. Energy absorption cor- omy, tended to have an energy absorption that exceeded 84%
related with residual jejunal length (r = 0.73, p < 0.01), wet of BMR and wet weight absorption of more than 1.4 kg/day,
weight (r = −0.83, p < 0.001) and dry weight (r = −0.99, whereas those dependent on HPN absorbed less of either or
p < 0.001) of the stoma/stool output. both.
Balance studies in 15 patients (six PN, three intravenous Whilst balance techniques remain the optimal way to
fluid (IVF) and six diet/oral nutrient supplements (ONS)) quantify intestinal insufficiency or failure in individual
with <150 cm jejunum to stoma, who ate their usual diet also patients [10], very few centres have the facilities to under-
Dietary Treatment of Patients with a Short Bowel 653
Table 1 Studies of energy, fluid and sodium absorption in patients with a short bowel
Diet composition
Mean daily energy
(MJ) (kcal) (range)
Mean residual Mean Mean daily wet Mean daily % Mean daily Mean daily
small bowel residual weight (kg) (range) energy stoma or stool stoma or stool
length (cm) colon Mean daily sodium absorption wet weight (kg) sodium output
Reference Subjects (range) (range) Method (mmol) (range) (range) (range) (mmol) (range)
Rodrigues 7 Oral Median 110 – Balance 300 mL polymeric Median 67% Median 0.4 Median 53
et al. 1989 7 jejunostomy (60–140) 6h drink containing (59–78) (0.3–0.6) (31–80)
[8] (1ONS, 2NG, 337 kcal and
1NGE, 3 IVF) 10.5 mmol Na
5 HPN Median 50 50% colon Balance 300 mL polymeric Median 27% Median 0.7 Median 77
3 jejunostomy (20–100) (n = 1); 6h drink containing (2–63) (0.3–1.5) (29–144)
1 JCA Rectum 337 kcal and
1 JRA (n = 1)) 10.5 mmol Na
Nightingale 6 Oral 105–140 – Balance Usual diet 12.78MJ 58% 1.9 (1.2–3.5) 200 (148–368)
et al. 1990 6 jejunostomy 1 day (3043kcal)
[9] (8.13–20.03)
3.5 kg (2.7–5.2)
361 mmol Na
(157–800)
3 IVF 95–140 – Balance Usual diet 9.72MJ 46% 2.9 (1.5–3.7) 294 (154–392)
3 jejunostomy 1 day (2322kcal)
(6.6–13.98)
2.2 kg (2–2.4)
151 mmol Na
(140–172)
6 HPN 25–70 Rectum Balance Usual diet 35% 5.4 (3.0–7.8) 431 (256–551)
5 jejunostomy, (n = 1) 1 day 8.65MJ (2066kcal)
1JRA (3.75–14.43)
2.7 kg (1.3–4.6)
195 mmol Na
(100–335)
Jeppesen 44 Oral 57% Balance Usual diet 11.69MJa 71% (58–78) 1.25 (0.7–1.8) 105 (19–159) %
et al. 2000 21 180 (165–195) (57–100) 2 days (2794kcal) % Fluid Na absorption
[10] jejuno- (n = 23) (9.28–13.56) absorption 63% 30% (−13 to
ileostomy 3.6kga (3.01–4.4) (55–80) 89)
23 JCA 140 (89–158) 135 mmol Naa
(104–180)
45 HPN 100 (49–140) 64% Balance Usual diet 7.56 MJa 49% (40–76) 2.2 (1.2–3.0) 129 (69–218)
27 90 (45–131) (28–100) 2 days (1807 kcal) % Fluid % Na
jejuno- (n = 18) (5.7–9.38) absorption absorption
ileostomy 2.8 kga (2.2–3.7) 31% (0–51) −16% (−67 to
18 JCA 134 mmol Naa 46)
(67–159)
HPN home parenteral nutrition, IVF intravenous fluids, ONS oral nutritional supplement, NG nasogastric, NGE nasogastric electrolytes, JCA
jejunum-colon, JRA jejuno-rectal anastomosis, cm centimetre, n number, kcal kilocalorie, kg kilogram, mmol millimole, Na sodium, kJ kilojoule,
MJ megajoule, % percentage
a
Median
take these meticulous metabolic studies, so clinicians use to avoid long-term PN is 60–115 cm in jejunostomy and
knowledge of type and length of residual bowel to predict 30–65 cm in jejunum-colon patients [12–15] (Table 2). In the
long-term nutritional support requirements [11]. Large latter group, conservation of colon is beneficial because it
cohort studies in short bowel patients with <200 cm healthy absorbs water, sodium, calcium, some nutrients, maintains a
jejunum report that the minimum small bowel length required normal rate of gastric emptying of liquids and may stimulate
Table 2 Guide to predicting long-term nutritional support/fluid variable and unique to each patient [2] (chapter “Intestinal
requirements from residual bowel length in short bowel patients
Adaptation”).
[12–15]
Jejunal length Jejunum-
(cm) colon Jejunostomy
0–50 PN PN ± PS; restrict hypotonic fluids Residual Anatomy
51–100 ONa PN ± PSb; ORS
101–150 ONa ON (added salt); if stoma losses In jejunum-colon patients, no definite structural intestinal
>1.5 L, ORS adaptation has been demonstrated, [18, 19], but functional
151–200 ON ON (added salt) ± ORS adaptation with slowing of gastric emptying and small bowel
cm centimetre, PN parenteral nutrition, PS parenteral saline (±magne- transit may occur [20], probably due to high PYY [21] and
sium), ON oral nutrition (± oral or enteral nutritional support), ORS oral
GLP-2 [22] concentrations. There is increased jejunal
(or enteral) rehydration solution in combination with hypotonic fluid
restriction absorption of macronutrients, water, sodium and calcium
a
If colon length reduced, may require added salt ± ORS with time [23–26] that allows a gradual reduction in paren-
b
At 85–100 cm may need parenteral fluid/electrolytes only teral requirements with an increased chance of the patient
being able to reduce or stop PN [1, 12–15]. Although most
intestinal hyperplasia [13]. Preservation of more than 50% of adaptation is thought to occur within the first 2–3 years post-
colon in patients with less than 100 cm small bowel reduced resection [15, 27], improved intestinal absorption with
parenteral sodium and energy requirements by half, com- reduced dependence on PN has been observed many years
pared with those without colon [16] and is equivalent to later [13, 28, 29] and late adaptation has been enhanced by
about 50 cm of small intestine in terms of the need for paren- intestinotrophic therapies [30], highlighting the importance
teral supplements [13], which explains the importance of of ongoing monitoring and optimisation of dietary and phar-
restoration of colonic continuity where ever possible. maceutical management.
However, long-term nutritional support needs may be In contrast, there is no evidence of structural [31] or func-
affected by both the integrity and degree of adaptation within tional [13, 32] adaptation at any time in jejunostomy patients,
the remaining bowel as well as patient specific factors, so likely due to low plasma concentrations of PYY [21] and
each patient should be assessed and monitored on an indi- GLP-2 [33] and leading to rapid gastric emptying and small
vidual basis. bowel transit with reduced absorption. Thus, their parenteral
nutrition and fluid needs are unlikely to change with time [1].
Integrity of Remaining Bowel

Enteral Nutrients
If the remaining small bowel is affected by active Crohn’s
disease [16], radiation enteritis [16] or radiological proven Luminal stimulation with enteral nutrients is required to
lesions [14, 15], then its absorptive capacity may be reduced maintain the structure of the intestinal mucosa [17]. Lack of
and longer than predicted lengths of small bowel may be enteral nutrition induces mucosal atrophy and decreases
required to achieve independence from PN [2]. digestive enzyme and nutrient transporter activity in animals
and humans, even when adequate calories are provided via
PN [17]. PN-induced mucosal atrophy is reversed by reintro-
Adaptation of Residual Bowel duction of enteral nutrition [34, 35], so it is important that
food or EN are reintroduced as soon as possible after resec-
Post-resection intestinal adaptation is a spontaneous process tion, even in those likely to require long-term PN. Animal
that attempts to increase nutrient and fluid absorption from studies suggest that post-resection adaptation is enhanced by
the remaining bowel through intestinal mucosa hyperplasia nutrient complexity, fats particularly long-chain triglycer-
to increase the absorptive area (structural adaptation) and/or ides (LCTs) and short-chain fatty acids (SCFAs), but the
by slowing of gastrointestinal transit to increase nutrient and optimum diet to stimulate human intestinal adaptation is not
fluid absorption (functional adaptation) [11, 17]. It is pro- yet known [17]. SCFAs are trophic [36] and make a signifi-
moted by intraluminal nutrients and pancreatico-biliary cant contribution to energy balance in jejunum-colon patients
secretions, the development of hyperphagia, modified gas- [37]. However, in six jejunum-colon patients, 2-week dietary
trointestinal hormonal secretion (glucagon-like peptide-1 supplementation with 4 g daily of pectin, a starch that acts a
(GLP-1), glucagon-like peptide-2 (GLP-2) and plasma pep- substrate for bacterial SCFA production, increased colonic
tide YY (PYY)), alteration of the gut microbiota and accu- levels of SCFAs but failed to demonstrate improvements in
mulation of faecal d/l-lactate in some patients and is highly macronutrient or fluid absorption [38].
Hyperphagia Nutritional Assessment and Monitoring
Many patients compensate for significantly reduced energy Short bowel syndrome (SBS) is a complex condition that
absorption by spontaneously increasing their oral intake in a requires a multidisciplinary evaluation to determine the most
behavioural adaptation known as hyperphagia. In a study of appropriate therapy. Patients may rapidly become dehy-
90 patients with <200 cm small bowel, with or without drated, electrolyte depleted and malnourished, so require a
colonic resection (39 oral diet; 51 HPN), 14 of whom were comprehensive nutrition assessment at baseline (chapter
studied in early (<6 months) and late (>6 months) periods “Assessment of Nutritional and Fluid Status”), which should
after digestive continuity, 81% had hyperphagia (a spontane- be repeated regularly to assess the effectiveness of nutrition
ous oral intake >1.5 times resting energy expenditure), which intervention [43], particularly during HPN weaning when
was independently and negatively related to fat absorption close monitoring is required (chapter “Monitoring of
(p < 0.01) and body mass index (p < 0.001) but not braked by Parenteral Nutrition at Home”).
the presence of PN. There was an increase in hyperphagia
over time highlighting the importance of promoting oral
intake in patients receiving long-term PN to maximize resid- Nutritional Status
ual absorptive capacity [39].
The assessment of nutritional status should include weight,
body mass index (BMI) and percentage weight loss over
Intestinal Growth Factors 3–6 months. If the patient is dehydrated or overhydrated then
their weight may be several kilograms below or above their
Growth hormone (GH) receptors are located throughout the actual weight and this should be taken in to account when
intestine and GH induces growth and proliferation in many assessing nutritional status and calculating requirements [43].
different tissues plus the production of the intestinotrophic Rapid changes in body weight are likely to reflect the signifi-
hormone, insulin-like growth factor-1 [40]. In addition to cant fluid shifts that may be experienced by these patients, so it
regulating gastrointestinal motility, the hormones GLP-1, is best practice to measure mid arm circumference and triceps
GLP-2 and PYY exert a trophic effect on the mucosa by skinfold thickness (TST) to calculate mid arm muscle circum-
enhancing intestinal villus and crypt cell growth [2]. These ference (MAMC) in order to monitor changes in body compo-
intestinal growth factors have the potential to hasten or sition in response to nutrition support [43] (chapter “Assessment
exceed the normal intestinal adaptation response, leading to of Nutritional and Fluid Status”). Handgrip is also valuable in
investigation of the efficacy of GH, its recombinant somato- determining functional capacity. MAMC and handgrip should
tropin and the GLP-2 analogue, teduglutide, in maximizing be repeated monthly in hospital [43] and at least annually in
absorption from the remnant bowel, decreasing intestinal stable outpatients to detect any changes in nutritional status to
losses and reducing the requirement for parenteral nutrition inform amendments in nutritional support.
or fluids [41] (chapter “Pro-Adaptive Hormones in the
Rehabilitation of ADULT patients with a Short Bowel”).
Micronutrient Status
Patient Specific Factors Short bowel patients are at high risk of developing micronu-
trient deficiencies due to fat malabsorption and high stoma/
Patient specific factors that may delay adaptation and/or fistula losses or diarrhoea/steatorrhoea. A serum micronutri-
influence long-term PN requirements include the ability to ent screen, which depending on laboratory availability, may
restore oral feeding or develop a post-resection adaptive include folate, iron, ferritin, selenium, zinc, copper, vitamins
hyperphagia and to adapt dietary intake to decrease intestinal B12, A, D and E, should be performed in conjunction with
losses; reduced oral or enteral intake due to symptoms such the assessment of clinical signs and symptoms of deficiency
as nausea, vomiting, bloating or pain, food aversion, aging, at the onset of HPN and then at least once per year [4, 44]
chronic narcotic use, psychological factors, underlying (chapter “Monitoring of Parenteral Nutrition at Home”),
comorbidities and social factors [11, 28]. Occasionally PN although frequency may vary with changes in clinical status
may be required if increasing the oral or enteral nutrient or micronutrient prescription during PN weaning [45].
intake causes a socially unacceptably high stomal output, Whilst laboratory tests play an important role in determining
severe diarrhoea or fails to meet nutritional needs when individual requirements, it is unclear to what extent serum
energy requirements are high and absorption is 30–60% concentrations reflect tissue status and true requirements,
[42]. especially during acute illness [46]. Serum concentrations
lack diagnostic sensitivity as they are maintained within the [42]. Magnesium should be monitored daily during the
reference range until severe deficiency or excess develops refeeding risk period until stable when it may be reduced to
[46]. Most plasma micronutrients fall as part of the systemic twice per week and post-discharge at each outpatient review.
inflammatory response (with the exception of copper, which
rises in association with caeruloplasmin synthesis [47]), due
to redistribution between tissues and blood, making them Clinical Assessment
unreliable measures of nutritional status when C-reactive
protein (CRP) >10 mg/L [45]. In the absence of functional or Information about underlying illness, co-morbidities and
intracellular measurements, it may be helpful to review serial anatomy, residual bowel length and quality (from surgical
measurements in relation to CRP changes [48], in the context records and bowel mapping studies using radiology, endo-
of clinical features and potential risk factors for deficiency scopic or colonoscopic imaging), enable predictions to be
[46]. Micronutrient concentrations may also be affected by made about absorption, long term fluid/nutrition support
other factors for example recent intake (folate) [49], lipid needs, including the potential for PN weaning and are crucial
levels (vitamin E) [50], hypoalbuminaemia (zinc) [45], oes- to the provision of appropriate advice on diet and fluid intake.
trogens (copper) [47] as well as specimen contamination or In addition to hydration, clinical assessment should
analytical problems. review mobility, signs and symptoms of weight loss, muscle
wasting, micronutrient and essential fatty acid deficiencies,
intestinal function (nausea, vomiting, bloating, stoma/fistula
Fluid and Electrolyte Status losses, bowel frequency/stool type and losses from naso-
enteric or venting gastrostomy/enterostomy catheters or
Fluid and sodium deficiency result in loss of extracellular abdominal drains), temperature, inflammatory markers and
fluid volume leading to thirst, hypotension and pre-renal fail- signs of sepsis, inflammation or acute disease which may
ure. Hydration status may be assessed from clinical appear- increase nutritional requirements, urinalysis to monitor for
ance, fluid balance charts, routine haematology and ketones and glucose and review of medication including over
biochemistry including random urinary sodium. Dehydration the counter or herbal preparations which may cause side
is indicated by a low urine output (<1 L/24 h), rapid weight effects such as nausea, taste changes, increased intestinal
loss (1 kg in 24 h indicates fluid depletion by 1 L) and in the losses or abnormal electrolytes [43].
absence of renal disease by a raised urea and creatinine [1].
However, creatinine may be low in patients with reduced
muscle mass and urea may be low if protein/nitrogen intake Nutritional Intake
is reduced so making dehydration difficult to identify [51].
Because of the influence of the renin-angiotensin mecha- The relative contributions from parenteral, enteral or dietary
nism, the plasma sodium concentration remains normal until intake are assessed in conjunction with factors affecting oral
body stores are severely depleted [52], so a random urinary intake, an estimate of likely dietary absorption and review of
sodium provides a better indicator of sodium status optimisation in relation to short bowel management to
(<20 mmol/L indicates maximal renal conservation in inform decisions about the most appropriate form of long-
response to sodium depletion). Physical signs of depletion term nutrition support, scope for dietary optimisation and PN
become apparent before major changes in blood chemistry, weaning.
providing important warning signs and include thirst, dry Oral nutritional intake may be assessed from a detailed
mouth, loss of appetite, nausea, lethargy, muscle cramps, food diary or diet history to establish the type and amounts
sunken dark-ringed eyes, reduced skin tone, rapid low vol- of food consumed, eating patterns, food and fluid prefer-
ume pulse and dizziness on standing due to postural hypo- ences, cooking methods, any previous trials of dietary modi-
tension (confirmed by a lying to standing decrease in blood fication or nutrition support, including route, rate, formula
pressure >20 mmHg systolic and >10 mmHg diastolic) [53]. and outcome [43] as well as appetite, degree of adaptive
Inpatient hydration status should be reviewed daily (weight, hyperphagia and clinical (e.g. dentition, nausea, vomiting,
clinical symptoms, fluid charts and biochemistry) until stable bloating, stoma/fistula output or leakages, stool frequency,
[4] when biochemistry may be reduced to twice per week incontinence, pain, medication side effects), cultural, behav-
and post-discharge at each outpatient review. ioral, social or psychological factors [54] that may affect
Magnesium depletion is common, especially in patients food intake.
with a high stomal output and a serum value of <0.6 mmol/L Dietary energy and protein intake may be compared with
may give rise to symptoms (fatigue, depression, irritability, requirements estimated from predictive equations, adjusted
muscle cramps and if severe, cardiac arrhythmias and con- for age, sex, weight, disease activity, physical activity and
vulsions; tetany may indicate a concomitant hypocalceamia) requirement for weight gain/loss or lean tissue gain [55]. In
short bowel patients who are malnourished, ideal body kg/day of ideal body weight and 80–100 g protein/day to
weight has been shown to be a better predictor of resting counteract increased losses.
energy expenditure than actual body weight [56]. Estimated Messing et al. 1991 [59] measured macronutrient absorp-
requirements should also be adjusted to compensate for tion during a 3-day balance study in ten short bowel patients
nutrient malabsorption using evidence from balance studies. (one jejunostomy, nine jejunum-colon, mean small bowel
length 75 cm, five receiving HPN) who ate a constant diet
that replicated their usual intake and provided mean
Nutritional Management of Short Bowel 3103 kcal (57.9 kcal/kg) per day) and 23%, 46% and 31% of
energy from protein, carbohydrate and fat respectively. HPN
The nutritional management of short bowel is a dynamic pro- provided a mean 1120 kcal/day and there was no significant
cess that involves overlap or transition between diet, EN and difference in oral intake between parenteral and non-
PN in response to changes in the patient’s condition and intes- parenteral groups. They absorbed 67% of dietary energy and
tinal adaptation [57]. Post-operatively, patients generally 61%, 79% and 52% respectively from protein, carbohydrate
receive PN to maintain fluid, electrolyte and nutritional sta- and fat, with the higher proportion from carbohydrate
tus, until their gastrointestinal function allows re-introduction thought to reflect colonic fermentation. The five patients
of oral or EN. If the patient’s residual bowel length, anatomy, stable on diet maintained their weight by spontaneously
quality and adaptive potential predict the need for long term increasing their energy intake to 2.5 times their estimated
PN, then dietary treatment aims to balance eating for pleasure basal energy expenditure (Harris-Benedict) to compensate
with avoiding high intestinal losses, whereas if there is poten- for malabsorption.
tial to reduce PN dependence, then oral intake is optimised to Crenn et al. 2004 [39] investigated oral intake by dietary
maximise absorption. Nutritional goals include the mainte- questionnaire and macronutrient absorption in a 3-day bal-
nance of a healthy weight (BMI), normal body composition ance study in 90 patients with <200 cm small bowel, with or
(triceps skin fold thickness and mid-arm circumference mea- without colonic resection (39 oral and 51 HPN), 14 of whom
surements used to calculate mid arm muscle circumference), were studied in the early (<6 months) and late (>6 months)
acceptable functional status (activities of daily living, mobil- periods after digestive continuity. Both groups spontane-
ity, handgrip), adequate fluid and electrolyte balance (stable ously ate a high energy diet (oral group: mean 2667 kcal
weight, a daily urinary volume of at least 1000 mL with ran- (45.6 kcal/kg) per day and HPN group: 2507 kcal (48.1 kcal/
dom urine sodium concentration of greater than 20 mmol/L, kg) per day) that provided twice their estimated resting
normal serum creatinine and urea with magnesium energy expenditure (Harris Benedict) and contained similar
>0.6 mmol/L) [42], micronutrients within the normal range proportions of energy from protein (20%), carbohydrate
with no clinical signs of deficiency or toxicity and an accept- (45–47%) and fat (33–35%). During the balance study they
able quality of life. Whilst the ultimate goal is enteral inde- received a constant diet that replicated their usual intake and
pendence, this takes time and may not be achievable, net dietary absorption was higher in the oral diet group (68%
highlighting the importance of regular monitoring and indi- energy, 70% protein, 73% carbohydrate and 61% fat) com-
vidualised management by the multidisciplinary team. pared with the PN group (57% energy, 52% protein, 65%
carbohydrate, 47% fat). In the subgroup, re-establishment of
digestive continuity improved fat and protein absorption in
Macronutrient Absorption the first 6 months by 30% and 37% respectively with a fur-
ther 15% increase in protein absorption after this period. It
Balance studies show that the absorption of dietary macronu- was concluded that macronutrient absorption may be
trients varies with type, length and quality of remaining improved by restoration of colonic continuity and promotion
bowel (Table 3). of spontaneous adaptive hyperphagia as an oral nutritional
Woolf et al. 1987 [58] investigated macronutrient absorp- strategy.
tion during a 10-day balance study in eight stable short bowel Estívariz et al. 2008 [60] investigated the habitual home
patients (five jejunostomy, three jejunum-colon, remaining oral diet (7-day food diary plus dietetic review) and macro-
small bowel length 107 cm to all, one receiving HPN), who nutrient absorption during a 4-day balance study in 19 short
received isocaloric diets (mean 1869 kcal (31.4 kcal/kg) per bowel patients (five jejuno- or jejuno-ileostomies, 14
day), that matched their usual intake with constant protein, jejunum-colon, mean small bowel length 118 cm), who had
carbohydrate, fat (22%, 32% and 46% of energy respec- received HPN but no dietary instruction for 31 months prior
tively) and fluid (2196 mL/day) content. They absorbed 62% to starting a bowel rehabilitation programme. Mean sponta-
of dietary energy and 81%, 61% and 54% respectively from neous energy and protein intakes were respectively 2656 kcal
protein, carbohydrate and fat. It was concluded that short (39 kcal/kg) and 17 g N2 (0.22 g N2/kg) per day, with 15%,
bowel patients should increase their oral intake to 35–40 kcal/ 53% and 31% of energy from protein, carbohydrate and fat.
Table 3 Studies of macronutrient absorption in patients with a short bowel

Diet composition % Daily nutrient absorption
Mean daily
Mean residual energy
small bowel % Mean (kcal) ± SD
length residual (range) Energy Protein CHO Fat
(cm) ± SD colon ±SD % Protein, CHO Mean ± SD Mean ± SD Mean ± SD Mean ± SD
Reference Subjects (range) (range) Method and fat (range) (range) (range) (range)
Woolf 7 Oral, 1 107—all TDR Balance Usual diet 62 ± 3 81 ± 5 61 ± 7 54 ± 4
et al. 1987 HPN jejunumb (n = 3) 10 days 1869 ± 174 kcal (52–76) (71–90) (24–81) (35–71)
[58] 5 (1165–2708)
Jejunostomy 22% protein
3 JCA 32% CHO
46% fat
Messing 4 Oral, 5 75 (0–200) 67 ± 37 Balance Usual diet 67 ± 12a 61 ± 19a 79 ± 15a 52 ± 16a
et al. 1991 HPN 1 (n = 9) 3 days 3103 ± 754 kcala
[59] Jejunostomy 23% protein
9 JCA 46% CHO
31% fat
Crenn 39 Oral 105 ± 37 69 ± 30 Balance Usual diet 68 ± 15 70 ± 17 73 ± 19 61 ± 24
et al. 2004 5 (25–190) (0–100) 3 days 2667 ± 817 kcal (51–91) (37–94) (40–93) (17–97)
[39] Jejunostomy (n = 34) (1425–4854)
34 JCA 20% protein
47% CHO
33% fat
51 HPN 61 ± 47 62 ± 32 Balance Usual diet 57 ± 18 52 ± 21 65 ± 21 47 ± 23
7 (0–200) (0–100) 3 days 2507 ± 844 kcal (15–90) (0–89) (18–100) (0–89)
Jejunostomy (n = 44) (1345–4642)
44 JCA 20% protein
45% CHO
35% fat
Estívaritz 19 HPN 118 ± 25 Left to Balance Usual diet 59 ± 3a 42 ± 5a 76 ± 3a 41 ± 5a
et al. 2008 5 (Duodenum entire 4 days 2656 ± 242 kcala
[60] Jejunostomy −350) (n = 14) 15% protein
14 JCA 53% CHO
31% fat
HPN home parenteral nutrition, JCA jejunum-colon, cm centimetre, SD standard deviation, TDR transverse descending colon plus rectum, n num-
ber, kcal kilocalorie, % percentage, CHO carbohydrate
a
Range not available
b
mean not available
There was no difference in fat and carbohydrate consump- two-thirds of their oral energy and protein intake [8–10, 39,
tion, whether the colon was present or absent. Simple sugars 58–60]. They compensated for significantly reduced energy
comprised 43% of oral carbohydrate intake, whilst oral fluid absorption by spontaneously increasing oral energy intake
intake averaged 2712 mL/day, primarily from water, coffee, to >1.5 times resting energy expenditure through hyperpha-
sodas, fruit juices and sports drinks. During the balance gia [39]. One study found that patients, who absorbed less
study they received a constant diet that replicated their usual than half of their intake, avoided HPN by increasing energy
intake and mean dietary absorption was 59% energy, 42% intake to 200–400% of basal metabolic rate equivalent to
nitrogen, 76% carbohydrate and 41% fat. It was concluded 10–24 MJ (2380–5714 kcal)/day [10]. Thus, short bowel
that patients were consuming types of foods and fluids that patients are recommended to compensate for malabsorp-
were incorrect for their residual intestinal anatomy and function by taking a hyperphagic diet containing 30–60 kcal/kg
tion, which may worsen malabsorption and thus increase and 0.2–0.25 gN2 (1.25–1.5 g protein)/kg/day [57] from
HPN requirements. This highlights the importance of indi- regular meals, snacks, food fortification, ONS or overnight
vidualised nutritional assessment and counselling to facili- EN. However, balance studies demonstrated differences in
tate intestinal rehabilitation. response to dietary manipulation depending on the pres-
Studies of macronutrient absorption include patients ence or absence of colon, leading to the recognition that
with varying lengths of small bowel, with or without colon dietary advice should be tailored to the residual bowel anat-
in continuity, which makes comparisons difficult, but on omy to optimise absorption and minimise complications
average, patients who achieved enteral autonomy, absorbed [4] (Table 4).
Table 4 Dietary recommendations in short bowel patients according drate fermentation could provide unrealised clinical benefits
to intestinal anatomy [57]
in terms of energy balance.
Jejuno-ileal or The effect of colon on energy absorption was also demon-
Jejunostomy or jejunocolic
Dietary content ileostomy anastomosis
strated indirectly in two large cohort reviews, which noted
Energy 30–60 kcal/kg/day 30–60 kcal/kg/day that preservation of at least half the colon was equivalent to
Nitrogen 0.2–0.25 g/kg/day 0.2–0.25 g/kg/day about 50 cm of small intestine in terms of the need for paren-
Protein 1.25–1.5 g/kg/day 1.25–1.5 g/kg/day teral supplements [13], and in patients with <100 cm small
Fat 30–40% of total energy 20–30% of total bowel, it reduced parenteral energy requirements by 50%
energy compared with stoma patients with the same small bowel
Medium-chain No proven benefit up to 50% of total
length [16].
triglycerides (MCT) fat
Carbohydrate 40–50% of total energy a
50–60% of total Nordgaard et al. 1994 [61] investigated the effect of
energy b manipulating carbohydrate and fat intake on nutrient and
Lactose No need to restrict No need to restrict fluid absorption in eight patients with 50–245 cm small
Oxalate Normal Low bowel to colon, who were maintained on isocaloric diets
Sodium chloride Extra required from salty Normal (10.7 MJ (2557 kcal)/day, 20% protein) and randomised to
foods, addition of salt in
cooking or to food on receive either a low carbohydrate, high fat (20:60% of
serving energy) or a high carbohydrate, low fat (60:20%) diet, each
Oral nutritional Polymeric Polymeric or over 4 days. The high carbohydrate low fat diet reduced fae-
supplements or semi-elemental cal energy loss by 2.0 MJ (478 kcal)/day (p < 0.00001) and
enteral nutrition with high MCT
content
significantly increased energy absorption from 49 to 69%
Oral fluid Restriction of hypotonic No restriction (p < 0.001) compared with the low carbohydrate, high fat
fluids with substitution of usually required diet. Faecal excretions of carbohydrates were low and not
oral rehydration solution affected by change in carbohydrate intake whereas faecal fat
kcal kilocalorie, kg kilogram, g gram, % percentage increased from 44 to 75% as dietary fat intake increased.
a
Polysaccharides in preference to mono/disaccharides to keep osmolal- There was no change in the faecal volume between the two
ity low
b
Polysaccharides in preference to mono/disaccharides to reduce the diets, but the amount of water consumed with the high carbo-
extremely rare occurrence of d-lactic acidosis hydrate diet was one litre more than with the high fat diet,
suggesting that the colon is capable of reabsorbing additional
fluid or that the high carbohydrate diet may improve fluid
Dietary Treatment for Patients absorption.
with Jejunum in Continuity A second study in 82 patients with varying lengths of
with a Functioning Colon small bowel in continuity with colon, who consumed their
habitual diet (mean 9.9 MJ (2366 kcal)/day), which was high
Carbohydrate (Table 5) in carbohydrate (55% total energy) found that colonic diges-
tion can supply up to 4.2 MJ (1000 kcal) per day as small
The recognition of the colon, not only as an organ for fluid bowel failure proceeds, highlighting the importance of
and electrolyte absorption, but as a potential energy- encouraging patients with <200 cm to take a high carbohy-
salvaging organ has altered dietary recommendations for drate diet [37]. However, high carbohydrate diets increase
jejunum-colon patients [61]. the volume of food to be eaten (Fig. 1), which may reduce
Energy salvage from bacterial fermentation of unab- energy intake and colonic fermentation produces gases,
sorbed carbohydrate was demonstrated by Royall et al. 1992 which may increase bloating and flatulence [4], so patients
[62], who measured hourly breath hydrogen and blood ace- should be supported to find a balance between maximising
tate concentrations in twelve short bowel patients (seven carbohydrate intake for energy and avoiding unwanted side
with and five without colon) and six normal volunteers after effects.
consumption of a 50 g carbohydrate bread meal following an Pectin is water soluble, non-cellulose fibre, which may
overnight fast. Breath hydrogen levels were significantly prolong gastrointestinal transit time and is fermented by the
higher in jejunum-colon than jejunostomy or normal volun- colonic bacterial flora to produce SCFAs, which may enhance
teers (p < 0.01), indicating capacity for fermentation and energy absorption. Atia et al. 2011 [38] investigated the
blood acetate levels were also significantly higher (p < 0.05), effect of giving a pectin supplement (4 g three times per day
reaching a peak at 4 h suggesting their production from for 2 weeks) on intestinal absorption and transit in six short
colonic fermentation. It was proposed that colonic carbohy- bowel patients with 50 cm small bowel anastomosed to colon
Table 5 Studies of the effect of diet composition on nutrient absorption in patients with a short bowel
Mean residual
small bowel Effect on Effect on water Effect on
length (cm), energy and sodium divalent cation
Reference Subjects (range) Method Diet composition absorption absorption absorption
Jejunostomy
McIntyre 4 Jejunostomy 103 (0–150) RCT, Three diets containing None None None for Ca
et al. 1986 (2 oral, 2 HPN) crossover, equivalent amounts of and Mg
[202] each patient calories, nitrogen,
acted as own electrolytes and minerals,
control but varying fat and fibre
• HF (68–106 g)/
Hfibre (26–29 g)
• LF (42–50 g)/Hfibre
(24–29 g)
• LF (39–46 g)/Nfibre
(14–15 g)
Each over 2–3 days
Nordgaard 6 Jejunostomy 168 (100–250) RCT, Two isocaloric diets based None None –
et al. 1994 (4 oral, 1HPN, crossover on habitual intake (mean % Energy stoma vol
[61] 1HPF) 10. 6 MJ (2533 kcal)/d), absorption HCHO/LF:
20% protein) with varying HCHO/LF: LCHO/HF
CHO and fat LCHO/HF 2691:1959
• HCHO/LF (60% 55: 48% mL/day
CHO, 20% fat) p = 0.21 p = 0.10
• LCHO/HF (20%
CHO, 60% fat)
Each over 4 days (last
3 days test period)
Ovesen 5 Jejunostomy 83 (35–125) RCT, Three isocaloric, – None HF (60%) diet
et al. 1983 (5 HPN) crossover isonitogenous diets with ↑ stoma losses
[199] varying fat, CHO, P/S ratio of Ca, Mg, Cu
• 30% fat, 55% CHO and Zn
• 60% fat, 25% CHO,
P/S 1:1
• 60% fat, 25% CHO,
P/S 1:4
2 days test period)
Jeppesen 6 Jejunostomy 203 (125–300) RCT, Two isocaloric diets based None MCT ↑ stoma –
et al. 1998 3 Ileostomy crossover on habitual intake (mean % Energy vol
[79] (5 oral, 4 HPN) 10.8 MJ (2581 kcal)/d), absorption LCT: MCT/
with varying LCT or LCT/ LCT: MCT/ LCT
MCT content LCT 2177: 2729 g/
• HF (50% LCT) 47:49%, day (p = 0.07)
• HF (25% P = 0.63
MCT + 25% LCT)
3 days test period)
Woolf et al. 5 Jejunostomy 31 (n = 2) RCT, Two isocaloric, None None None for Ca,
1983 [201] 3 Jejunum- 51 (n = 1) crossover, isonitogenous diets, based Mg and Zn
transverse All (n = 5) each patient on habitual intake with
colon (5 oral, 3 acted as own constant fluid and fibre but
HPN) control varying CHO and fat
• HF 60% fat, 20%
CHO
• LF 20% fat: 60%
CHO
4 days test period)
Table 5 (continued)
Mean residual
small bowel Effect on Effect on water Effect on
length (cm), energy and sodium divalent cation
Reference Subjects (range) Method Diet composition absorption absorption absorption
Jejunum-colon
Nordgaard 6 114 (50–245) RCT, Two isocaloric diets based HCHO ↑ % None –
et al. 1994 Jejunum-ileum- crossover on habitual intake (mean energy Faecal vol
[61] colon 10. 7 MJ (2557 kcal)/d), absorption HCHO/LF:
2 20% protein) with varying HCHO/LF: LCHO/HF
Jejunum-colon CHO and fat LCHO/HF 809:766 mL/
(7 oral, 1 HPN) • HCHO/LF (60% 69: 49% day
CHO, 20% fat) (p < 0.001) NS
• LCHO/HF (20%
CHO, 60% fat)
3 days test period)
Andersson 10 Ileal-colon 110 (0–195) Balance Two isocaloric diets with – LF ↓ faecal –
et al. 1974 1 Ileostomy small bowel varying fat, protein and water by 36%
[67] 2 active resected CHO and Na by 11%
Crohn’s • HF: 100 g/d
without (2450 kcal, 16% protein,
resection (13 37% fat, 47% CHO),
oral) over 8–16 days
• LF: 40 g/d
(2420 kcal, 20% protein,
15% fat, 65% CHO)
over 16–24 days
Hessov 7 Ileal-colon 145 (35–195) Balance Two isocaloric diets with – – LF ↑ %
et al. 1983 2 active ileum resected varying fat, protein and absorption of
[68] Crohn’s CHO Ca (−25 to
without • HF: 100 g/d 4%; p < 0.01)
resection (2660 kcal, 16% protein, Zn (5–30%;
(9 oral) 33% fat, 51% CHO), p < 0.01)
3 × 4 day periods Mg (4–20%;
• LF: 40 g/d NS)
(2460 kcal (22%
protein, 15% fat, 63%
CHO) over 4 × 4 day
periods
Jeppesen 10 JCA 143 (50–250) RCT, Two isocaloric diets based MCT ↑% None –
et al. 1998 (8 oral, 2 HPN) crossover on habitual intake (mean energy faecal vol
[79] 9.6 MJ (2294 kcal)/d), absorption LCT: MCT/
with varying LCT or LCT/ LCT: MCT/ LCT
MCT content LCT 981:1114 g/day
• HF 50% LCT 46:58% p = 0.32
• HF 25% p = 0.02
MCT + 25% LCT
3 days test period)
Atia et al. 6 Jejunum- 50.3 ± 36.5 Balance Standard diet (30 kcal/kg, None None –
2011 [38] colon (2 oral, 4 1 g protein/kg, 100 g fat % Energy Faecal wet
HPN) and 16 g mixed fibre per absorption weight
day) pre: post pre: post pectin
• Pre pectin pectin 1582:1689 g/
supplementation 68.3:62.1% day (p = 1)
• Post 2 weeks (p = 0.44)
supplementation with
3 × 4 g pectin/day
3 days test period)
HPN home parenteral nutrition, HPF home parenteral fluid, cm centimetre, n number, RCT randomized controlled trial, HF high fat, LF low fat,
Hfibre high fibre, Nfibre normal fibre, kcal kilocalorie, d day, CHO carbohydrate, HCHO high carbohydrate, LCHO low carbohydrate, P/S poly-
unsaturated/saturated fatty acid ratio, MJ megajoule, LCT long chain fatty acid, MCT medium chain fatty acid, g gramme, kg kilogrammes, ↑
increase, ↓ decrease, vol volume, mL millilitre, Na sodium, Ca calcium, Mg magnesium, Cu copper, Zn zinc, NS not significant
Fig. 1 Two 700 kcal meals.

A high fat fried meal and a
pasta meal. While the pasta
meal is ideal for jejunum-
colon patient it is a much
larger volume so can be hard
to consume
(four HPN). Whilst there was an increase in short chain fatty free diets in the stoma (p = 0.36) or colon (p = 0.19) patients.
acid production (p = 0.02), there was no change in percent- Since foods containing lactose provide a valuable source of
age energy (p = 0.438), carbohydrate (p = 0.56) or fat energy, protein and calcium, they should not be restricted
(p = 0.22) absorption, faecal wet weight (p = 1.00) or urine unless there is a clear association between lactose ingestion
production (p = 1.00). There was a non-significant increase and increased diarrhoea [4].
in gastric emptying and oro-colonic transit time. As the addi-
tion of soluble fibre did not enhance overall intestinal absorp-
tion, supplementation is not recommended in short bowel Fat (Table 5)
[4].
Unlike carbohydrate and protein, long chain fatty acids
(LCFAs) are only absorbed from the small bowel and their
Lactose malabsorption in to colon results in steatorrhoea and a con-
comitant diarrhoea [65], that led to the use of a low-fat diet
Small bowel resection may cause secondary lactose intoler- for symptomatic treatment after ileal resection [66].
ance due to reduced absorptive surface and shortened transit. Balance studies compared the effect of a high fat (100 g/
Arrigoni et al. 1994 [63] randomised 17 patients with day over two to four 4-day periods) versus low fat intake
<150 cm small bowel (six jejunostomy, 11 jejunum-colon) to (40 g/day over 16–24 days) on stool output in 13 patients
receive a 20 g lactose load from milk or yogurt after a 12 h with diarrhoea post-ileal resection (ten ileal-colonic anasto-
fast, then measured faecal weight and carbohydrate excre- mosis, two active Crohn’s disease and one ileostomy), who
tion from lactose and hexose flow rates (stoma) or breath ate a constant energy and protein diet [67]. The low-fat diet
hydrogen excretion (colon) over the next 8 h. There were no reduced mean faecal fat excretion from 23 to 9 g/day with a
clinical signs of intolerance or increase in faecal weight, but marked reduction in faecal water and sodium excretion by
lactose was better absorbed from yogurt than milk (76% ver- 36% and 11% respectively, such that ten patients passed
sus 50%, p < 0.05) in the stoma patients with no significant formed stool. There was a mean weight gain of 1.5 kg despite
difference in colon patients. a lower energy intake during the study (mean 2420 kcal)
In a follow-up study, Marteau et al. 1997 [64] studied a compared with usual intake (mean 3290 kcal). However, it is
single 20 g lactose load in 14 fasted patients with <150 cm not known whether these patients had a true short bowel and
small bowel (six jejunostomy, eight jejunum-colon) and then the reduction in fat was accompanied by an increase in pro-
randomised them to receive their usual diet plus either 20 g/d tein and carbohydrate intake, which may have influenced
lactose or no lactose, each over 3 days, with an interval of colonic absorption.
7 days in between. Lactose absorption from the single load A follow-up study in nine of these patients found that the
was 61% and 53% in the stoma and colon patients respec- low-fat diet increased absorption of magnesium (not signifi-
tively. There were no symptoms of intolerance and no differ- cant), calcium (p < 0.01) and zinc (p < 0.01), although inter-
ences in faecal weight between the lactose rich or lactose pretation is limited by the higher mineral content of the
low-fat diet, which occurred as a consequence of its increased increased fat (MCT + LCT) absorption from 23 to 58%
protein content [68]. (p < 0.001) and increased bomb calorimetric energy absorp-
In their comparison of a low fat (20%), high-carbohydrate tion from 46 to 58% of dietary intake (p = 0.02) correspond-
(60%) versus high-fat (60%) low-carbohydrate (20%) diet in ing to 1.308 MJ (313 kcal)/day, with no significant increase in
eight patients with 50–245 cm small bowel to colon faecal volume. In stoma patients, MCT increased fat absorp-
Nordgaard et al. 1994 [61] found that fecal fat excretion tion from 37 to 46% (p = 0.05), but did not improve overall
increased from 44 to 75% as dietary fat intake increased and energy absorption because there was a concomitant decrease
this accounted for differences in faecal loss of energy. in protein and carbohydrate absorption, possibly related to
Whilst a low-fat diet decreases steatorrhoea/diarrhoea, increased stoma volume (2177 to 2729 g/day; p = 0.07). It
calcium, magnesium and zinc losses and oxalate absorption was postulated that MCTs are water-soluble so may be
[69], it may have the adverse effect of reducing food palat- absorbed from the colon in a similar way to short chain fatty
ability and oral energy intake as it is less energy dense than acids (SCFAs) and may therefore provide an alternative
comparable weights of carbohydrate. In practice, patients energy source for jejunum-colon patients, particularly in
should be supported to find a balance between including fat those struggling with satiety or wind on a high carbohydrate
for energy and avoiding steatorrhoea. Symptomatic patients diet or who are at the borderline of requiring PN [4].
who report pale, oily stools that float and are difficult to MCTs are unsuitable as the sole source of fat as they do
flush, may benefit from reducing intake of high fat foods and not contain essential fatty acids or fat-soluble vitamins, but
changing to lower fat products and cooking methods. The may be used to partially replace LCTs through the inclusion
combination of severe fat malabsorption (>25–50% of of natural food sources like coconut or palm kernel oil, com-
dietary fat intake) [70] and a low-fat diet [71] may increase mercial MCT oil preparations or ONS with a high MCT con-
the risk of essential fatty acid deficiency, so these patients tent. MCT containing products should be introduced slowly
should consume fats that are rich in essential fatty acids [71]. in divided doses to prevent gastrointestinal symptoms like
They should be monitored for clinical signs of deficiency abdominal discomfort, bloating or diarrhoea [75].
(dry flaky skin), which may be prevented or treated by cuta-
neous application of sunflower oil [72] or safflower oil [73].
These patients are also at risk of developing fat soluble vita- anagement or Prevention of Complications
M
min deficiency [71, 74] so require oral supplementation, in Jejunum- Colon Patients
often at above recommended doses to compensate for malab-
sorption, with regular monitoring for clinical signs of defi- d-Lactic Acidosis
ciency and trends in serum concentrations [4, 27].
Although conservation of colon is beneficial, its presence is
associated with the extremely rare occurrence of d-lactic aci-
Medium-Chain Triglycerides (MCTs) (Table 5) dosis (DLA). A systematic review identified 98 original case
reports published between 1977 and 2017 in patients aged
MCTs are rapidly absorbed by passive diffusion from the small 7 months to 86 years [80]. It is associated with the rapid deg-
bowel into the portal system, without the need for cholecysto- radation of large quantities of unabsorbed carbohydrate in
kinin, pancreatic enzymes or bile [75], so may be beneficial in individuals with an altered colonic microbiota that increases
patients with a short bowel. Early case reports noted that the d-lactate production, leading to faecal accumulation,
substitution of long chain fatty acids (LCT) with MCT reduced increased concentrations in blood and urine, metabolic aci-
steatorrhoea and supported weight gain [76–78], whilst colonic dosis and neurological symptoms.
absorption of MCT was reported in animal studies [79]. Lactic acid has two optical isomers, l- and d-lactate,
Jeppesen et al. 1998 [79] investigated colonic absorption which are metabolized to or produced from pyruvate by iso-
of MCT in 19 small bowel resected patients (six jejunostomy mer specific enzymes, l-lactate dehydrogenase (l-LDH) and
and three ileostomies, mean small bowel length 203 cm; ten d-lactate dehydrogenase (d-LDH). Human cells lack d-LDH
jejunum-colon, mean small bowel length 143 cm), who were but do contain l-LDH so the primary isomer formed during
randomised and crossed over between two isocaloric (10 MJ anaerobic glycolysis is l-lactate, although small quantities of
(2390 kcal)) high fat diets containing 50% of energy from d-lactate are produced via the methylglyoxal pathway [81],
LCT or a 50% substitution of LCT with MCT, each over which are metabolized to pyruvate by the enzyme d-2-
3 days. Jejunum-colon patients absorbed MCTs considerably hydroxyacid-dehydrogenase (d-2-HDH) [82, 83] located
better than those with a stoma. In jejunum-colon patients, fae- mainly in liver and kidney or excreted in urine [84] so blood
cal excretion of MCT was negligible suggesting almost com- concentrations normally remain low. However, colonic bac-
plete (>90%) absorption of MCT even when LCT was teria can produce both l- and/or d-lactate depending on the
malabsorbed. The replacement of half LCT with MCT l-LDH and d-LDH content of bacterial species [85] and the
presence of dl-lactate racemase, which converts one lactate DLA did not cause neurological symptoms [87, 97, 103] and
isomer to the other [85]. Both isomers may be degraded to other types of acidosis of comparable or greater severity do
SCFAs [85, 86], absorbed in to the circulation [87] or not cause such symptoms [98]. It has been hypothesized that
excreted in the stool so do not usually accumulate as their noxious substances produced during colonic fermentation
production does not exceed metabolism [88]. like aldehydes, alcohols, mercaptans and amines may act as
In jejunum-colon patients, the bacterial degradation of false neurotransmitters to cause neurological symptoms [88]
large amounts of unabsorbed carbohydrate increases organic or that inhibition of pyruvate dehydrogenase (PDH) by thia-
acid production, which leads to a progressive decrease in mine deficiency [104] or low intraneuronal pH from d-lactate
intraluminal pH, favouring the growth of acid-resistant, lac- accumulation may affect pyruvate metabolism by altering
tate generating bacteria [85, 89] with increased numbers of neurotransmitter production and neurological functioning
the Lactobacillus/Leuconostoc group and reduced numbers [105].
and diversity of Clostridium and Bacteroides [90, 91]. If Acute episodes of DLA are treated with parenteral bicar-
d-lactate producing bacteria become predominant, then deg- bonate to correct acidosis [89, 106], rehydration with lactate
radation of large amounts of carbohydrate, particularly read- free crystalloids [100] to optimize renal excretion of d-
ily fermentable simple sugars, increase d-lactate production, lactate [92], carbohydrate restriction to decrease the sub-
leading to accumulation and raised concentrations in blood strate available for further d-lactate production [106, 107],
and urine [92]. Other contributory factors include the use of non-absorbable broad-spectrum oral antibiotics to reduce
antibiotics [90, 93, 94] or probiotics [95, 96] that alter the d-lactate producing bacteria [1], thiamine repletion to
intestinal flora to promote d-lactate-producing bacteria [80], increase PDH availability for pyruvate metabolism [92] or
a reduction in intestinal bacteria able to convert d-lactate to haemodialysis to clear both isomers in severe d-lactate toxic-
SCFAs [92], decreased metabolism due to inhibition of d-2- ity [108]. Temporary fasting is associated with a rise in
HDH by reduced pH [83] or hyperoxaluria [83] and reduced serum bicarbonate and fall in serum and urine d-lactate lev-
renal excretion due to impaired renal function or hypoperfu- els within 72 h [109] that allows rapid improvement in
sion secondary dehydration [97, 98]. encephalopathy. Malnourished patients may be given short-
The occurrence of DLA is unpredictable and may reflect term PN during fasting, as calories derived primarily from
an imbalance between microbial formation and the individu- carbohydrate or lipid had no significant effect on either acid
al’s ability to metabolise d-lactic acid [85, 97, 98]. Mayeur or d-lactate concentrations [110].
et al. 2013 [99] investigated the microbiota imbalance in 16 However, the prevention of repeated episodes is more
short bowel patients (<150 cm jejunum in continuity with challenging. Simple sugars should be restricted with substi-
colon) who had been stable for 2 years and found two sub- tution of modest amounts of slowly digestible, less easily
types: those who had no detectable lactate (44%) and those fermentable polysaccharides to limit the substrate available
who accumulated d- and l-lactate in faeces (56%). Patients for bacterial fermentation [85, 106, 109]. Serum d-lactate
who did not accumulate lactate or who preferentially accu- concentrations rise through the day to peak after the last eve-
mulated l-lactate had never developed DLA, whereas those ning meal and then fall during the night to their lowest con-
with a high faecal d/l-lactate ratio and low plasma bicarbon- centration just before the first morning meal, so consuming
ate values had an increased risk of developing DLA. It was modest amounts of carbohydrate over 4–6 small meals will
concluded that the d/l faecal lactate ratio may provide a bet- lower peak serum concentrations [111]. Overnight EN
ter index of imbalanced microbiota and higher DLA risk should be used with caution as it will prevent the usual
than d- and l-lactate faecal concentrations per se. decline in serum d-lactate concentrations and thereby
DLA presents with neurological symptoms including increase acidosis risk [111].
impaired alertness, ataxia, gait disturbances, weakness, Maintaining adequate hydration supports renal clearance
slurred speech, deep rapid breathing (Kussmal breathing), of d-lactate, so the usual dietary and pharmacological mea-
confusion, nausea or vomiting, blurred vision, nystagmus, sures to reduce stool output should be emphasized [92]. The
aggressive or inappropriate behavior and stupor that may inhibition of d-2-HDH activity by hyperoxaluria may be
progress to coma [80, 98, 100] and a metabolic acidosis with reduced by consumption of a low oxalate, moderate fat diet
an increased serum anion gap that is confirmed by increased in conjunction with calcium supplements to bind dietary
concentrations of d-lactate in blood and urine, while l- oxalate [92].
lactate is often normal [97, 98]. Recurrent DLA symptoms may be prevented by a rotating
Whilst neurological symptoms are attributed to elevated course of oral antibiotics, although efficacy varies widely.
d-lactate concentrations, there is poor correlation between Alternatively, some patients may take antibiotics when they
the onset or severity of symptoms and plasma concentrations recognize early neurological disturbances to prevent the
[101, 102]. In normal subjects, the infusion of d-lactate to development of encephalopathy [92]. However, antibiotic
produce comparable plasma concentrations to those found in therapy can induce DLA by promoting overgrowth of d-
lactate producing organisms, which may be prevented though metastable solution that is prone to precipitate upon small
selection of appropriately targeted therapy using stool cul- increases in oxalate concentration [128] and higher oxalate
ture antimicrobial sensitivities [93, 94]. Long-term use may concentrations substantially increase the risk of nucleation,
promote antibiotic resistance, so probiotics have been tried growth and aggregation of kidney stones [130].
as an alternative therapeutic option [112]. Depending on the Nephrolithiasis results in renal colic, obstructive uropathy
supplemented strains, there are reports of DLA being induced (which may cause irreversible renal damage), urinary tract
[95, 96] or prevented by probiotics [112–115] or synbiotics infection, (which in the presence of obstruction may cause
[116, 117]. More recently the microbiological analysis of pyonephrosis) and rarely nephrocalcinosis with progressive
stool facilitated the selection of a strain-specific non-d- renal impairment [131].
lactate producing daily probiotic that prevented further epi- The association between hyperoxaluria, ileal resection
sodes of DLA in a 4-year-old boy with short bowel [112]. and increased oxalate absorption was first demonstrated by
There is a need for randomized controlled trials to test strain- Chadwick et al. 1973 [132] who measured urinary excretion
specific effects and to determine the duration and frequency of the isotope 14C oxalate taken with food. Ileal-resected
of probiotic use [118]. If dietary and medical therapies fail, patients absorbed up to five times more oxalate than control
then surgical strategies such as intestinal lengthening [85] or subjects but oxalate excretion returned to normal with a low
colonic resection may be considered whilst promising results oxalate semi-synthetic diet (<4 mg oxalate per 24 h).
from fecal transplantation have been reported [119, 120]. Extensive ileal resection (≥100 cm compared with <50 cm)
was associated with increased urinary oxalate excretion and
there was a direct correlation between fat malabsorption and
Calcium Oxalate Renal Stones urinary oxalate excretion such that increasing dietary fat fur-
ther increased urinary oxalate excretion [133].
In contrast to short bowel patients with a jejunostomy, those Steatorrhoea was associated with increased colonic
with less than 200 cm jejunum in continuity with colon have absorption of dietary oxalate [134–136], especially in the
a 25% increased risk of developing symptomatic calcium distal colon [137]. Calcium and oxalate normally form an
oxalate renal stones, which develop at a median of 30 months insoluble complex that is passed in the stool, but ileal resec-
(range 2–67) post-surgery due to increased colonic oxalate tion results in malabsorption of free fatty acids in to the
absorption leading to hyperoxaluria [13] (chapter colon, where they bind with calcium to release soluble oxa-
“Nephrolithiasis and Nephrocalcinosis”). late for absorption [138]. Both free fatty acids and unab-
Urinary oxalate is derived from the diet, endogenous pro- sorbed bile acids increase colonic permeability to oxalate,
duction (metabolism of glycine, glycolate, hydroxyproline thereby facilitating its absorption [139]. An infusion of che-
and synthesis from glyoxylate) and breakdown of ascorbic nodeoxycholate in to the colon increased oxalate absorption
acid [121]. Normally less than 10% is derived from diet fivefold [140], whilst cholestyramine (a bile-salt binding
[122] but this may increase up to 50% depending on oxalate drug) taken orally reduced oxalate absorption [132, 141].
intake, its bioavailability, the presence of oxalate-binding Colonic oxalate absorption is increased by low dietary cal-
cations and oxalate-degrading bacteria and gastrointestinal cium, hyperparathyroidism and vitamin D administration, all
absorption [123, 124]. Oxalic acid is present in plant foods of which reduce calcium concentration in the colon and thus
including nuts, fruits, vegetables, grains and legumes as sol- the extent to which oxalate is bound to calcium in the gut
uble (sodium or potassium oxalate) or insoluble (calcium or lumen [131, 135, 142–145].
magnesium oxalate) salts that may be absorbed throughout Oxalate absorption may be reduced by the presence of
the gastrointestinal tract by active or passive mechanisms intestinal bacteria able to metabolise oxalate including ‘gen-
[125]. Since oxalate cannot be further metabolised, it is eralist oxalotrophs’ like bifidobacterium and lactobacillus
excreted in urine with a peak 2–4 h after ingestion, suggest- that degrade other carbon sources as well as oxalate and
ing that small intestine is a key absorptive site and that oxa- ‘specialist oxalotrophs’ like Oxalobacter formigenes which
late rich foods can induce transient hyperoxaluria that may is a commensal anaerobe that metabolises only oxalate [146].
not be noticed in 24-h urine samples [126, 127]. Treatment with antibiotics markedly reduces colonisation
In health, urinary supersaturation is affected by solute with Oxalobacter formigenes [147–149]; it is cultured less
concentration, ionic strength, pH value and the presence of frequently from the stools of patients with Crohn’s disease or
promotors (calcium, sodium, oxalate, low urine volume and steatorrhoea [150] and its growth is inhibited by low bile
low urine pH) or inhibitors (citrate, magnesium, phospho- acid concentrations [151], all of which may contribute to
nates and other organic substances) of stone formation, increased oxalate absorption and nephrolithiasis in jejunum-
which may vary during the day depending on fluid intake, colon patients. A study of 37 idiopathic calcium oxalate
dietary intake and body metabolism [128, 129]. Urine is stone formers (excluding enteric hyperoxaluria) found that
often supersaturated with respect to calcium oxalate in a colonisation with oxalobacter formigenes was associated
with a reduced risk of calcium oxalate stone formation and a As there is no definitive information on the oxalate con-
significantly lower urinary oxalate excretion compared with tent of foods or their effect on urinary excretion and oxalate
non-colonised patients whilst on a controlled diet [152]. rich meals may cause a transient rise in renal oxalate load
The concentration of lithogenic substances in urine is that is amplified by increased intestinal absorption [123,
determined by the excretion rate of calcium and oxalate and 168], it is reasonable to advise jejunum-colon patients to
independently by the excretion of water [131]. Jejunum- reduce hyperoxaluria by avoiding foods that are high in oxa-
colon patients who experience bowel frequency may become late [124, 154] including spinach, rhubarb, beetroot, whole-
dehydrated with a reduced urinary volume, which increases meal bread, bran-containing cereals, black tea, chocolate,
calcium and oxalate concentrations and makes nucleation cocoa, nuts, beans, soybeans and soy products. If individual
more likely to occur. patients require more specific dietary advice, then dietitians
should select food analyses based on reliable methods and
revention of Calcium-Oxalate Stones
P use averages for the food concerned [124, 169]. Regular
from Enteric Hyperoxaluria dietary counselling at clinic visits significantly reduced uri-
The incidence of calcium-oxalate stones may be reduced by nary oxalate by 55.5% in 137 patients with urolithiasis risk,
restriction of dietary oxalate and fat in conjunction with managed initially with only dietary intervention [170].
adequate oral calcium to reduce oxalate absorption and main- Whilst fat restriction is theoretically helpful, it may not be
tenance of hydration to achieve adequate urine volume. desirable for nutritional reasons, so patients should be sup-
ported to moderate their fat intake to reduce steatorrhoea and
eduction of Dietary Oxalate and Fat
R thus limit hyperoxaluria. Substitution with MCTs may be
The restriction of dietary oxalate and fat intake in metabolic helpful in reducing oxalate absorption [138].
studies of enteric hyperoxaluria [69, 132, 134, 153] reduced
urinary oxalate excretion but this has never been confirmed dequate Dietary Calcium
A
by randomised controlled trial [131, 154]. Holmes et al. Studies in patients with ileal disease or resection and jejuno-
2016 [155] cited that loading studies in normal subjects con- ileal bypass found that the degree of hyperoxaluria corre-
suming controlled oxalate and calcium diets found that lated directly with severity of steatorrhoea and inversely with
increasing oral oxalate from 100 to 750 mg/day increased dietary calcium content [135, 138]. High calcium diets [135]
urinary oxalate by 2 mg per 100 mg of oxalate consumed and oral calcium supplements [143–145] reduced oxalate
[123, 156]. Calcium-oxalate stone formers with hyperoxal- absorption and urinary oxalate excretion, although this has
uria had a 36% reduction in urinary oxalate excretion when never been confirmed by randomised controlled trial [131,
they consumed a low oxalate (80–100 mg/day) and normal 154].
calcium (1000 mg/day) diet [157]. A loading study in twelve healthy volunteers consuming a
Both clinical investigation and dietary advice have been controlled oxalate diet (250 mg oxalate/day) found that
hampered by inadequate or inaccurate data on the oxalate reducing calcium from 1002 to 391 mg increased urinary
content of foods and variations in its bioavailability and gas- oxalate excretion by a mean of 28.2% [123]. Another study
trointestinal absorption [123]. Differences in oxalate values in eight healthy volunteers consuming a controlled diet
for a single food may reflect the analytical technique, with (2500 kcal, 83 g protein, 63 mg oxalate) found oxalate
methods utilising colorimetric [158, 159] or enzymatic [160] absorption depended linearly on calcium intake with mean
assays reported to be less specific or reproducible than high oxalate absorption decreasing from 17 to 2.6% as calcium
performance capillary electrophoresis and ion chromatogra- intake increased from 200 to 1200 mg/day. Within this range,
phy [161, 162]. an increase in calcium supply by 70 mg decreased oxalate
Accuracy is further limited by variation in amount of oxa- absorption by 1% and vice versa. Calcium addition beyond
late synthesized by the plant due to cultivar, growing condi- 1200 mg/day reduced oxalate absorption only one-tenth as
tions and time of harvest [163]. The amount of oxalate effectively [171].
absorbed from a food is affected by its salt form (oxalate The American Urological Association guidelines [154]
absorption is proportional to the amount of soluble oxalate note that large prospective epidemiological studies found an
[164]), food processing and cooking methods (boiling vege- increased risk of stone formation with lower calcium diets
tables reduced oxalate content by 30% due to loss of soluble [172–174] whilst higher calcium diets were associated with
oxalate [165]) and meal composition (simultaneous con- reduced oxalate excretion [175]. When the recommended
sumption of calcium and magnesium reduced oxalate absorp- daily quantity of dietary calcium was consumed, calcium
tion by formation of insoluble salts [124, 166]), oxalate stone risk was not significantly affected despite a
gastrointestinal transit time, the presence of oxalate degrad- relatively high dietary oxalate intake [176]. However, sup-
ing bacteria in the large bowel [161, 162] and inherited plemental calcium was associated with an increased risk of
capacity to absorb oxalate [167]. stone formation in older women [172], but not younger
women and men [174]. The discrepancy between risks asso- reversed when probiotic treatment was stopped; the use of
ciated with dietary calcium and supplemental calcium may different probiotic preparations containing multiple bacterial
be due to the timing of calcium supplement intake and/or strains that varied in their administration with meals and
overzealous supplementation resulting in excessive total cal- variations in the control of dietary factors that might con-
cium [177]. found probiotic-induced effects [193]. Research in this field
A randomized controlled trial in recurrent hypercalciuric is still in its early stages and more work is required to deter-
calcium oxalate stone formers, not known to have enteric mine the exact strain and dose and validate oxalate-targeting
hyperoxaluria or bowel resection, reported a 51% reduction probiotics.
in stone recurrence in men consuming a normal calcium
(1200 mg/day), lower sodium (1200 mg/day) and animal Vitamin C
protein (52 g/day) diet compared with a low calcium diet Ingested vitamin C is partly converted to oxalate and excreted
(400 mg/day) at 5 years [178]. Oxalate consumption was in urine, which may increase the risk of calcium oxalate
thought to be similar in both groups as they were advised to stone formation and a metabolic study in 47 stone formers
restrict intake of oxalate-rich foods. Although urinary cal- found that supplementation with 1- or 2-g vitamin C
cium declined in both groups, urinary oxalate increased in increased mean urinary oxalate by 61% and 41% respec-
the lower calcium group and decreased in the normal cal- tively [194]. In a large epidemiological study, total and sup-
cium group. However, it is not possible to determine the plemental intake of ≥1000 mg/day vitamin C was
independent effect of calcium due to the use of a multicom- significantly associated with a higher risk of incident kidney
ponent diet [154, 179]. stones in men, but not among women [195], but there was no
Consequently jejunum-colon patients should be advised association with dietary vitamin C in any cohort. Whilst it
to consume calcium in line with dietary recommendations may not be generalizable to women, it is prudent to advise
[154, 179] from either dairy or non-dairy sources [180]. If avoidance of vitamin C supplements [154].
dietary intake is inadequate, then calcium supplements in
doses not exceeding 1000–1200 mg daily [154] may be taken
with meals to enhance gastrointestinal binding of oxalate Dietary Treatment for Patients
[135, 144, 145, 181]. with a Jejunostomy
Prevention of Dehydration Macronutrient Absorption

In health, fluid intake is the main determinant of urine vol-
ume and as such a high fluid intake is a critical component of arbohydrate Versus Fat (Table 5)
C
stone prevention. Observational studies found that higher Since protein and carbohydrate are mostly absorbed from the
fluid intake reduces the risk of stone formation [172, 174, first 200 cm of jejunum [196] and fat malabsorption is
182], whilst a randomized controlled trial found reduced increased by ileal resection and bile salt deficiency [197],
stone recurrence rates among recurrent calcium oxalate stone jejunostomy patients were historically advised to take a low
formers randomized to a high fluid intake compared with a fat, high carbohydrate diet to improve absorption [66].
comparable group given no specific recommendations (12% However, reducing fat intake may compromise energy intake
versus 27%, respectively at 5 years) [183]. Although there is and increasing carbohydrate, particularly from simple sug-
no definitive threshold for urine volume and increased risk, ars, may increase intestinal luminal osmolality and thus sto-
stone formers are generally recommended to take a fluid mal fluid losses [198, 199].
intake that will achieve a urine volume of at least 2.5 L daily The potential for a higher fat intake to improve energy
[154, 179]. However, a high fluid intake may increase stool absorption without increasing jejunal losses was first sug-
frequency in jejunum-colon patients, so their hydration and gested by Simko et al. 1980 [200] who measured fat absorp-
urine output should be optimised through dietary and phar- tion from three isocaloric, isonitrogenous liquid formula
macological measures to reduce stool output although some diets (3850 kcal/24 h) with varying proportions of fat and
may require parenteral fluid support. carbohydrate in a patient with a jejunostomy at 137 cm.
Although fat losses increased proportionately with increas-
Probiotics ing intake, the percentage fat absorption remained remark-
Small studies have assessed the use of oral probiotics con- ably constant irrespective of dietary intake. Increasing
taining oxalobacter in primary hyperoxaluria [184–186] or dietary fat from 64 to 200 g/day, with a reciprocal decrease
different combinations of lactobacillus, bifidobacterium, in carbohydrate from 759 to 453 g/day, led to a linear increase
enterococcus and other oxalate degraders [157, 187–192]. in fat absorption from 44 to 133 g/day (r = 0.99) without
They found promising but mixed results, in part due to tran- shortening intestinal transit time, increasing stool weight or
sient reductions in urinary oxalate excretion that were causing undesirable side effects. Continuation of the high fat
diet led to 16 kg weight gain over 12 months and discontinu- provide high fat/high fibre, reduced fat/high fibre or reduced
ation of parenteral fluids and electrolytes. fat/normal fibre intakes, each over 2–3 days. There were no
Woolf et al. 1983 [201] investigated absorption in eight significant differences in energy, nitrogen or fat absorption
patients (five jejunostomy, three jejuno-transverse colon), or weight of stoma effluent between the three diets. The high
who were maintained on isocaloric, isonitrogenous diets fat diet led to a non-significant increase in faecal fat excre-
with constant fluid and fibre content, but randomised and tion, but did not increase jejunostomy effluent or sodium,
crossed over between a high fat, low carbohydrate diet potassium, calcium or magnesium losses. There was no det-
(60:20% energy) or a low fat, high carbohydrate diet riment with a high fibre diet compared with a normal fibre
(20:60% energy), each over 5 days. There were no signifi- diet. It was concluded that a liberal attitude towards fat and
cant differences in total energy, percentage fat or protein fibre intake was acceptable in patients with a high
plus carbohydrate absorption, stool weight or absorption of jejunostomy.
calcium, magnesium and zinc between the two diets. Faecal In their comparison of a high carbohydrate, low fat
fat excretion was three times higher on high fat than low fat (60:20% of energy) versus low carbohydrate, high fat
diet, but there was no difference in the proportion of (20:60%) diet in six patients with 100–250 cm small bowel
ingested fat that was absorbed. As the low-fat diet con- to a jejunostomy maintained on isocaloric diets (10.6 MJ
ferred no benefits in calorie, fluid or divalent cation absorp- (2533 kcal)/day, 20% protein), Nordgaard et al. 1994 [61]
tion, it was concluded that dietary fat should not be found no significant difference in energy excretion between
restricted. However, these results were reported as a mean high carbohydrate (4.8 MJ/day) and high fat diets (5.9 MJ/
of the two anatomical types of short bowel, which may day; p = 0.08) with carbohydrate and fat excretions propor-
limit their application. tional to the amounts ingested. Energy absorption was simi-
Ovesen et al. 1983 [199] evaluated the effect of fat versus lar between the high carbohydrate (55%) and high fat (48%)
carbohydrate as an energy source and the effect of substitut- diets (p = 0.21). However, the high carbohydrate diet
ing saturated with polyunsaturated fat on the absorption of increased stomal effluents by mean 732 mL/day (p = 0.10)
fat, fluid, sodium, potassium, calcium, magnesium, zinc and compared with the high fat diet. Beverage intakes were simi-
copper in five jejunostomy patients (35–125 cm jejunum), lar (3154 versus 2880 mL for high carbohydrate and high fat
stable on HPN. They were randomised to receive three isoca- respectively) but the higher water content of the high carbo-
loric, isonitrogenous diets: one low fat (30% kcal), high hydrate (1420 mL/day) compared with the high fat diet
complex carbohydrate (55% kcal), and two high fat (60% (717 mL/day; p = 0.0003) resulted in a higher fluid intake of
kcal), low carbohydrate (25% kcal) diets with differing poly- about 1000 mL/day, which may have implications for fluid
unsaturated: saturated fatty acid ratios of 1:4 or 1:1, each management.
over 9 days, with collection of excreta on the last two. In a 3-day balance study of macronutrient absorption in
Although the high fat diet increased steatorrhoea, neither the 90 patients with <200 cm small bowel who received a con-
type nor amount of dietary fat had any consistent effect on stant diet that replicated their usual intake (Table 3), Crenn
jejunostomy volume or fat absorption (40–45%), raising the et al. 2004 [39] reported that fat absorption was significantly
possibility of greater net energy absorption from high fat, but related to jejunal length (p < 0.01). In the twelve jejunos-
this could not be confirmed as carbohydrate absorption was tomy patients, the amount of fat absorbed was dependent on
not measured. The sodium and potassium concentration of fat intake (p < 0.001) without an upper threshold, supporting
the jejunostomy fluid stayed constant, suggesting that losses the promotion of a non-limited fat intake for these patients
reflected jejunostomy volume rather than the fat or carbohy- Thus, fat restriction did not improve energy, fluid or mon-
drate content of the diet. However, the high fat diet did ovalent electrolyte absorption in jejunostomy patients [61,
increase stomal losses of calcium, magnesium, zinc and cop- 199, 202]. Since a constant proportion of dietary fat is
per, which in most cases were converted to net absorption by absorbed [39, 61, 199, 202], jejunostomy patients should be
the low fat, high carbohydrate diet. Altering the polyunsatu- encouraged to take a higher fat diet to increase energy
rated/saturated fatty acid ratio had no effect on divalent cat- absorption, reduce dietary osmolality and provide essential
ion losses. It was concluded that patients should be advised fatty acids. Whilst this does raise fat excretion, it does not
to either reduce their fat intake or receive supplementation to usually increase stomal output nor make it more offensive
achieve adequate cation status. [61, 199, 202]. However, a high fat diet may reduce absorp-
McIntyre et al. 1986 [202] measured absorption in four tion of divalent cations such as calcium, magnesium, zinc
patients with a jejunostomy (60–150 cm jejunum), who were and copper [199] and malabsorption increases the risk of
randomised and crossed-over between three diets, which essential fatty acid [70] and fat-soluble vitamin deficiencies
contained equivalent quantities of nitrogen, calories, electro- [71, 74] so these should also be monitored and supplemented
lytes and minerals but varying amounts of fat and fibre to as required [4, 27].
MCTs (Table 5) of water from plasma into the intestinal lumen to restore iso-
In contrast to patients with a retained colon, the 50% substi- osmolality [4, 205]. Hypotonic fluids with a sodium concen-
tution of LCT with MCT in jejunostomy patients [79] tration of <90 mmol/L like water, tea, coffee, squash, milk,
increased fat absorption from 37 to 46% (p = 0.05), but did juice, fizzy and alcoholic beverages dilute intraluminal
not improve overall energy absorption because MCT signifi- sodium concentration leading to secretion of sodium to
cantly decreased absorption of protein from 63 to 51% maintain luminal concentration at 100 mmol/L [206–208].
(p < 0.05); carbohydrate from 71 to 63% (p < 0.05), LCT The loss of this sodium rich fluid in jejunostomy effluent
from 35 to 27% (p < 0.05) and increased stoma volumes results in dehydration and sodium depletion [9]. Patients
from 2177 to 2729 g/day (p = 0.07) and is therefore not often describe an ‘insatiable thirst’ and their natural response
recommended. is to drink more fluid [4], which may mistakenly be rein-
forced by health professionals, but this literally washes
sodium out of the body creating a vicious cycle of chronic
Fluid and Electrolyte Management dehydration and excessive beverage intake [207–211].
Absorption of sodium from the jejunum can only take
Jejunostomy patients lose large volumes of fluid from their place against a small concentration gradient, when the lumi-
stoma, which increase after eating and drinking due to loss of nal concentration is 90–120 mmol/L [206, 210, 212] and
digestive secretions secondary gastric hypersecretion, rapid depends on water movement and the presence of glucose and
gastric emptying and accelerated small bowel transit. Each amino acids to promote absorption by solvent drag [203]. A
1 L of jejunostomy fluid contains approximately 100 mmol/L study of fluid and electrolyte absorption in seven patients
of sodium [9] so sodium losses rise with stoma volume, with <150 cm small bowel to a stoma found that ingestion of
increasing the risk of dehydration and electrolyte distur- 500 mL of water or tea resulted in negative sodium and fluid
bances. Patients with less than 100 cm jejunum to a stoma balance whereas 500 mL of an oral rehydration solution con-
usually have intestinal fluid and sodium losses that exceed taining 90 mmol/L of sodium led to positive sodium and
oral intake, leading to a constant negative balance that fluid balance [208]. Patients with marginally high stoma
requires correction with long term parenteral replacement, losses in the range of 1200–2000 mL can maintain hydration
whilst those with more than 100 cm residual jejunum may by restricting oral hypotonic fluids to 1 L to decrease net
have lower intestinal losses but still lose considerable secretion with substitution of 1 L of an oral rehydration solu-
amounts of fluid and sodium, which require replacement [9]. tion containing 90–120 mmol/L sodium to meet fluid require-
Dietary management with a high salt diet, restriction of oral ments and promote jejunal absorption [1, 208, 211]. They
hypotonic fluids and substitution of an oral rehydration solu- should avoid hyperosmolar fluids [213] and adherence with
tion to decrease stoma losses in conjunction with anti- hypotonic fluid restriction may be encouraged by use of
secretory medication to decrease gastric secretions and smaller cups or glasses, sucking sweets, ice cubes or lollies,
anti-motility medications to slow transit and improve absorp- self-monitoring of intake and strategies that distract from
tion may secure intestinal autonomy in those with intestinal thirst.
insufficiency or reduce parenteral dependency in those with If patients are struggling with severe thirst and marked
intestinal failure. sodium/water depletion, it may be difficult to replace previ-
ous losses with an oral regimen, but equilibrium can be re-
High Salt Diet established by placing them ‘nil by mouth’ whilst giving
Patients with intestinal outputs of <1200 mL/day can usually intravenous normal saline for 48 h [1]. This also helps to
maintain fluid and sodium balance by taking high salt foods, demonstrate that output is being driven by oral intake.
adding salt in cooking or to food after serving, to utilise the Intravenous saline can then be gradually reduced as oral food
coupled absorption of sodium with glucose and amino acids and fluids are reintroduced.
in the jejunum [1, 203].
rink an Oral Rehydration Solution
D
estrict Oral Hypotonic Fluids
R Oral rehydration solutions have been formulated to provide
The jejunal mucosa is very permeable to water and sodium optimal amounts of sodium in combination with glucose to
fluxes, which maintain intra-luminal contents iso-osmolar facilitate absorption [1, 4]. A modification of the World
with plasma at approximately 300 mOsm/L with a sodium Health Organisation’s original cholera solution, which con-
concentration of about 100 mmol/L [9]. Consumption of tains 90 mmol/L sodium, is made from 20 g glucose, 3.5 g
hyperosmolar fluids such as fruit juices, fizzy or energy sodium chloride and 2.5 g sodium bicarbonate made up to
drinks, alcoholic beverages [204] and some ONS supple- 1 L with water [214]. Although taste perception changes in
ments increase intraluminal osmolality, leading to movement patients who are salt and water deplete, some still find this
solution too salty but acceptance can be improved by chill- absorption [58]. Whilst some patients anecdotally report a
ing, sipping through a straw or flavouring with the addition benefit, the advice to restrict fluid intake with meals is not
of a small amount of squash or cordial as part of the fluid recommended as a general rule [4].
used to make up the solution. Patients should be discour-
aged from adding ice or flavouring to each glass as this Fibre
dilutes the sodium concentration, making it less effective Reducing fibre intake may slow transit to allow more time
[215, 216]. Alternate solutions include replacing sodium for absorption, but a randomized crossover study in four
bicarbonate with sodium citrate to increase palatability jejunostomy patients receiving isocaloric diets with variable
[211] or giving Dioralyte®, made at double the normal amounts of fat and fibre, each over 2–3 days found no signifi-
strength (10 sachets made up to 1 L), which contains cant improvement in absorption and a liberal approach to
120 mmol/L sodium and 40 mmol/L potassium and there- fibre intake was recommended [202]. However, rapid transit
fore requires monitoring to prevent hyperkalaemia [217]. does lead to the appearance of undigested foods in stoma
Patients should sip 1 L in small quantities throughout the effluent and patients anecdotally report a reduction in intes-
day, perhaps with medications in order to preserve their tinal output with reduced fibre [217] from bread, pasta,
hypotonic fluid allowance for more pleasurable drinking. It crackers, biscuits or cakes made with white flour, white rice,
should be noted that many sports drinks have suboptimal refined breakfast cereals, small portions of well cooked,
sodium-glucose composition so do not provide an effective mashed or stewed fruit and vegetables with skins, seeds, pips
alternative to oral rehydration solutions [215, 218]. and stalks removed, small portions of pulses if vegetarian
Alternatively, sodium chloride capsules (500 mg) are effec- and avoidance of nuts and dried fruits. A low fibre diet is
tive when taken in large amounts (7 g/day) but can cause recommended to prevent obstructive symptoms in patients
patients to feel sick and even vomit [211]. with strictures or adhesions [217].
It is vital to give individualised and consistent advice to
aid patient understanding, motivation and compliance.
Chronic dehydration may result in renal impairment so Oral Nutritional Support Supplements
patients should be taught to monitor their urine colour in
conjunction with signs and symptoms of dehydration and Protein: Polymeric, Peptide or Elemental?
given management strategies together with health profes-
sional contact details for advice. It is equally important to Patients who find it difficult to maintain adequate nutritional
educate health professionals about oral fluid and electrolyte intake from diet may increase their energy and protein intake
management so that they can give consistent advice and pro- from orak nutritional support (ONS) taken in between meals
vide appropriate rapid intravenous fluid and electrolyte (Table 6). It was postulated that partially digested proteins in
replacement when required. the form of peptides (semi-elemental) or amino acids (ele-
mental) may be more completely absorbed across a reduced
iming of Antimotility Medications
T absorptive surface than whole protein (polymeric) diets.
Loperamide and codeine phosphate reduce intestinal motil- In a randomised controlled study, McIntyre et al. 1986
ity and thus decrease water and sodium output by approxi- [202] compared absorption of energy, nitrogen, fat and elec-
mately 20–30% [1]. Since the intestinal output rises after trolytes from equal volumes of isocaloric, isonitrogenous
meals, it is important that these medications are taken semi-elemental versus polymeric liquid diet in seven patients
30–60 min before food and at bedtime. If they emerge with <150 cm jejunum to a jejunostomy. Each diet was taken
unchanged in the stoma effluent, then capsules can be opened over 12–14 h, either as a sip feed (five patients) or by slow
or tablets crushed and mixed with water, yogurt or put on continuous nasogastric infusion (two patients). Two patients
food [1]. were unable to tolerate full quantities of either diet and their
measurements were conducted using 50% of the recom-
eparation of Food and Fluids
S mended intake. There were no significant differences in
Loss of the ileal and colonic braking mechanisms results in nitrogen, fat or energy absorption and neither diet signifi-
rapid gastric emptying of liquid [20] so taking fluids sepa- cantly reduced stoma effluent weight nor consistently
rately from food may improve absorption. However, a bal- affected sodium, potassium, magnesium or calcium losses,
ance study in eight short bowel patients (five jejunostomy; suggesting that semi-elemental provides no nutritional
three jejunum-colon) who received isocaloric diets with a advantage over polymeric diet.
constant fluid content and were randomized and crossed over Cosnes et al. 1992 [219] investigated the effect of protein
between taking fluid with meals or restricting fluid intake hydrolysis on absorption in six patients with a jejunostomy
from 1 h before to 1 h after meals, each over 5 days, found no (90–150 cm jejunum), who had been stable on polymeric EN
difference in energy, divalent cation, fluid or electrolyte for at least 2 weeks, prior to being randomized and crossed
Table 6 Studies of the effect of ONS/enteral formula protein composition on nutrient absorption in patients with a short bowel
Mean
residual
small
bowel Effect on Effect on
length Effect on Effect on water and divalent
(cm), energy nitrogen sodium cation
Reference Subjects (range) Method Diet composition absorption absorption absorption absorption
Jejunostomy
McIntyre 7 101 RCT, Two liquid diets based on None None None None for Ca
et al. 1986 Jejunostomy (60–150) crossover, body weight and and Mg
[202] (2HPN each standardized to contain
1HPF patient equal amounts of nitrogen,
2NG acted as fluid and sodium (constant
2oral) own 100 mmol/d) in each test
control period
• Polymeric (6 g
Nitrogen, 1060 kcal,
37 g fat (LCT) and
146 g CHO/L)
• Semi-elemental (6.4 g
Nitrogen, 1000 kcal,
10 g fat (LCT: MCT
50:50%) and 183 g
CHO/L)
Each over 12–14 h by sip
feed (5) or NG (2)
Due to poor tolerance, tests
completed on consumption of
half quantities in two patients
Cosnes 6 110 RCT, Three liquid diets None ↑ Nitrogen None None for Ca
et al. 1992 Jejunostomy (90–150) crossover (3325 kcal, 146 g protein, % Energy absorption from and Mg
[219] (6 NG) double 130 g fat, 395–470 g CHO, absorption semi-elemental
blind 2500 mL and 300 mmol Polymeric: compared with
sodium per day) with semi- polymeric
varying protein hydrolysis elemental 14.3:10.9 g/day
• Polymeric (osmolality 56.8: 57% P = 0.012
580 mOsmol/L) (NS)
• Mixed polymeric:
semi-elemental
50:50% (osmolality
610 mOsmol/L)
• Semi-elemental
(osmolality 667
mOsmol/L)
Each over 22 h/d by NG for
3 days (last 2 days test
period). Nil orally except
approximately 1 L water. 5
patients received 1–2 L
ileocolonic infusion of
saline to maintain Na
balance
HPN home parenteral nutrition, HPF home parenteral fluid, NG nasogastric, cm centimetre, RCT randomized controlled trial, mmol millimole, d
day, g gramme, kcal kilocalorie, LCT long chain fatty acid, MCT medium chain fatty acid, CHO carbohydrate, L litre, % percentage, mL millilitre,
mOsm/L milliosmole/litre, NS not significant, Ca calcium, Mg magnesium
over between exclusive polymeric, semi-elemental or a weight or faecal excretions of sodium, potassium, calcium
50:50 mixture of polymeric and semi-elemental. Nitrogen and magnesium. The osmolality of the peptide diet was high
was significantly better absorbed from peptide (14.3 g/day) (667 mOsm/L) but stool output was increased in only one
than whole protein diet (10.9 g/day), (p = 0.012), but there patient. It was concluded that a semi-elemental diet may be
were no differences in absorption of fat or calories, stool beneficial when nitrogen requirements are high.
Since polymeric ONS are more palatable, lower in osmo- may benefit hydration, their lower energy density will com-
lality and have a higher energy density than elemental for- promise energy intake. In practice, patients may be offered a
mulae, they are less likely to increase stoma losses and 1.5 kcal/mL polymeric, fibre free supplement to maximise
therefore recommended in jejunostomy patients who require nutritional intake within a lower volume, but if the higher
nutrition support [4]. osmolality increases intestinal losses, then a 1 kcal/mL sup-
plement with a lower osmolality (approximately 300 mOsm/
kg) or a lower volume, modular energy/protein supplement
Fibre may be offered. ONS should be sipped slowly in between
meals and their low sodium content necessitates their inclu-
Rodrigues et al. 1989 [220] investigated the effect of fibre sion within any hypotonic fluid restriction.
containing ONS on 6-h intestinal transit, energy, water and
sodium absorption in six patients with 30–120 cm jejunum
(four jejunostomy, one jejunum-colon to colostomy, one ole of Education and Individualised Dietary
R
jejunal-rectal anastomosis) who fasted overnight and were Advice
randomized to drink either 300 mL polymeric diet or 300 mL
polymeric diet containing 6 g soy polysaccharide (40% solu- Patient education and motivation are important factors in
ble fibre). Soy polysaccharide decreased percentage energy determining the success of the PN weaning [223]. A lack of
absorption from 20 to 6% in the four patients measured. It understanding may lead to sub-optimal management with
delayed transit time in three of four patients from 66 to potential clinical consequences [224] and a study in short
166 min (postulated to be due to a delay in gastric emptying, bowel patients on HPN, who had not received dietary educa-
although this was not measured), but increased 6-h wet tion, found dietary patterns that were likely to worsen diar-
weight (895 to 917 g) and sodium output (89 to 136 mmol) rhoea, cause malnutrition (or prevent repletion) and increase
in four of five patients. Thus, fibre enriched ONS are not parenteral fluid and nutrient requirements [60]. It is recom-
recommended [4]. mended that short bowel patients receive education from an
experienced multidisciplinary team, using a combination of
written information and verbal education to improve under-
Osmolality standing of the physiological changes associated with short
bowel, the rationale for dietary and pharmacological thera-
Although ONS provide a ready source of energy, protein and pies [223] and intensive dietary guidance on suitable types
micronutrients, they are hypotonic and many are hyperosmo- and quantities of food/beverages, tailored to individual gas-
lar, which will increase sodium and fluid movement into the trointestinal anatomy, lifestyle, requirements and prefer-
bowel and increase stoma losses. Osmolality is a measure of ences to aid compliance, which is adjusted in response to
millimoles of solutes per kg of solvent [221]. ONS osmolal- changing needs [225].
ity is influenced by particle size and increased by electrolyte, The effectiveness of personalised nutrition advice sup-
amino acid/peptide or sugar but not fat content. Rud et al. ported by a booklet (containing information about the condi-
2019 [222] investigated the effect of ONS osmolality on tion, eating/drinking advice, medication use and long-term
stoma output, urine production and natriuresis in eight monitoring), on knowledge and clinical outcomes was evalu-
patients with an ileostomy (150–350 cm residual small ated over 3–6 months in 48 patients with intestinal failure
bowel) who ate their habitual diet and were advised to main- [224]. Patient knowledge improved significantly after
tain a constant fluid intake. They were randomised and dietetic intervention with verbal and written advice
crossed over to replace 800 mL of their daily fluid intake (p < 0.001). There was an increase in oral energy (p = 0.04)
with 200 mL four times per day of either an iso-osmolar and fat (p = 0.003) intake with an improvement in BMI
(279 mOsm/kg) or hyperosmolar (681 mOsm/kg) oral sup- (p = 0.02). Patients on HPN showed a reduction in parenteral
plement, each over 48 h in two study periods. There were no energy (p = 0.02), nitrogen (p = 0.003), volume (p = 0.02)
significant changes in stoma output, despite increased fluid and frequency of infusions (p = 0.003). This study demon-
intake, but in comparison with the hyperosmolar supple- strated that personalised nutritional advice in conjunction
ment, the iso-osmolar supplement induced a significant with an information booklet, tailored to individual require-
increase in urine volume (470 mL/day, p = 0.02) and natri- ments, significantly improved knowledge and clinical out-
uresis (36 mmol/day, p = 0.02), suggesting improved intesti- comes, highlighting the positive effect of on-going education
nal water and sodium absorption. Whilst iso-osmolar ONS in stable intestinal failure patients.
Micronutrients of alternative methods of supplementation such as intramus-

cular administration of vitamin D after PN weaning.
Parenteral multivitamin and multi-trace element prepara- A 9-day balance study in five jejunostomy patients (35–
tions are formulated to meet the requirements of most 125 cm jejunum), stable on HPN found that a high fat (60%
patients receiving PN [45, 226], but abnormal serum micro- kcal), low carbohydrate (25% kcal) diet increased stomal
nutrients concentrations continue to be reported [227], high- losses of calcium, magnesium, zinc and copper, which in
lighting the potential variation in individual requirements most cases were converted to net absorption by a low fat
with oral intake, nutritional status, underlying illness, sepsis, (30% kcal), high carbohydrate (55% kcal) highlighting the
inflammation, oxidative stress, absorptive capacity and importance of monitoring and supplementation in patients
abnormal losses [45]. Patients with short bowel have an with fat malabsorption [199].
increased risk of developing micronutrient deficiencies due A 5-day balance study in seven short bowel patients
to their underlying condition, fat malabsorption, high stoma/ (mean 64 (40–110) cm healthy small bowel in continuity
fistula or stool losses or inadequate intake. Optimising diet, with colon) who had been stable on diet mean 2.7 years
fluid intake and medications may permit adequate macronu- found normal serum concentrations and positive balance for
trient absorption to allow PN weaning, but it cannot be iron, zinc and copper suggesting that satisfactory status can
assumed that micronutrient intake or intestinal absorption be achieved from oral diet [232].
will be sufficient to maintain adequate body stores or func- In short bowel, guidelines for micronutrient prescription
tion [228]. and monitoring are based on expert opinion [4, 226], neces-
A study in short bowel patients on HPN found low micro- sitating the development of local protocols until more robust
nutrient consumption in association with avoidance of foods evidence becomes available. Micronutrient deficiencies may
that may increase stool losses (dairy products, vegetables) be prevented by regular monitoring during PN weaning and
and reduced dietary variety [60]. in those stable on diet, with or without intravenous fluid/
Short bowel patients receiving intermittent PN with a pre- electrolyte infusions. Key aspects of management include
scribed oral multivitamin and mineral supplement were defi- (1) the promotion of a balanced diet, guided by individual
cient in vitamin D [74] and had serum concentrations below tolerance, which may require periodic adjustment as the
the reference range for vitamins E [74, 229], A, C [229] and bowel adapts (2) optimisation of absorption through dietary,
copper [230], although interpretation is difficult as clinical fluid and pharmaceutical management (3) the provision of an
deficiency symptoms were not reported. oral general multivitamin and mineral supplement during PN
A study of 44 patients with intestinal insufficiency and weaning, which may need to be given in doses above those
varying degrees of fat malabsorption not requiring HPN recommended for healthy individuals to compensate for mal-
(160–250 cm residual small bowel; 17 no colon), found absorption [223] (4) if a deficiency arises, then the route of
reduced plasma retinol, α- and γ-tocopherol concentrations delivery, dose and duration of supplementation should be
in 7%, 61% and 32% of patients, which were rarely associ- guided by the patient’s bowel anatomy and individual char-
ated with clinical symptoms, so it was difficult to interpret acteristics [4] in conjunction with manufacturer’s guidance.
their significance, but the authors concluded that supplemen-
tation may be required [71].
Vitamin D status and bone mineral density (BMD) were Conclusion
measured in 60 short bowel patients (residual small bowel
length 89.6 cm) after weaning off PN (80% oral diet, 20% Nutritional management is a dynamic process that involves
enteral nutrition) [231]. All patients had suboptimal vitamin overlap or transition between PN, EN and diet, in response to
D status (5% vitamin D insufficiency and 95% vitamin D changes in the patient’s condition and intestinal adaptation.
deficiency), which was significantly correlated with residual The consequences of dietary manipulations, not only on
small bowel length (B, 0.072, p = 0.001) and duration of nutrient, electrolyte and fluid absorption, but also on overall
short bowel (B, −0.066, p = 0.020). Only 2 patients had a quality of life and patient autonomy should be taken in to
normal BMD with osteopenia and osteoporosis present in consideration. Dietary manipulations may affect diet palat-
68.3% and 28.3% respectively. Despite routine oral vitamin ability, satiety, abdominal discomfort or bloating and passing
D supplementation (1200 IU/day), 86.7% of patients did not of wind, faecal consistency and incontinence. Some patients
achieve satisfactory status, emphasizing the importance of cope with the hyperphagia, large stool volumes, fatigue and
regular vitamin D monitoring, annual BMD measurements chronic dehydration in order to avoid a life dominated by
[4], advice on diet and sunlight exposure and consideration having a central line and the need for parenteral supplements.
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Pro-adaptive Hormones
in the Rehabilitation of Adult Patients
with a Short Bowel
Palle Bekker Jeppesen
Key Points (e) Patients with an unmanageable high output (e.g.

1. Pro-adaptive hormone treatment includes growth factors >2 L/24 h) and whose quality of life if poor. These
which aim is to promote and often exceed the normal are patients who can be weaned off or have days off
structural adaptive process after a bowel resection. PS.
2. Pro-adaptive hormonal treatment aims to reduce the symp- (f) Patients who with treatment may be able to have
toms (less stomal output/diarrhoea) and help reduce or stop nights off parenteral support.
the amount of parenteral support required (i.e. to reduce
the severity of the intestinal failure). Goals may include a 4. Growth factors have the disadvantages of both being
reduction in stomal output of more than 1.5 L/24 h, stop- expensive (though prices may reduce considerably in the
ping or having more than 2 night off/week of parenteral future) and there is the fear that they may promote neo-
support and having an improved quality of life. plasia (or increase the growth rate if neoplasia is already
3. Growth factors may be considered in patients with a short present).
bowel and dependent upon parenteral support and/or: 5. Before growth factor treatment is given a baseline CT
(a) Have had a functioning colon in continuity for at thorax, abdomen and pelvis is performed and in patients
least a year to allow intestinal adaptation to occur. If with a residual colon, a colonoscopy should be performed
no functioning colon is in circuit then adaptation will to detect and remove colorectal polyps.
not occur and treatment can be considered sooner (at
about 6 months) after the surgery that resulted in the
jejunostomy.
(b) Have no defunctioned small or large bowel that can Introduction
be brought into continuity. Patients who are candi-
dates for surgical reconstruction should have this sur- In normal subjects, a wide range of complex neuro-endocrine
gery before growth factor therapy is considered. regulatory systems modulate the highly coordinated pro-
(c) Patients who have been stable on parenteral support cesses of appetite-regulation, food intake, digestion and
for 1 year, with the volume, nutrient and electrolyte absorption (i.e. assimilation) that ensure sufficient nutrient
content of the parenteral support and oral intake in- and uptake to meet the metabolic needs and ensure the
being optimised prior to starting. metabolic homeostasis of life, thereby preserving body com-
(d) A patient who, with therapy, may be able to stop par- position, function and the overall health.
enteral support. Thus, a plethora of hormones, mediators and nerve trans-
missions are involved in securing the optimal intestinal func-
tion at all times. In fact, the intact and healthy gastrointestinal
tract has a considerable reserve capacity for nutrient assimi-
lation [1]. However, in patients with inadequate oral intake,
intestinal diseases or increased metabolic needs, the nutri-
tional homeostasis may be jeopardized, and malnutrition,
P. B. Jeppesen (*) dehydration or other deficiencies may develop [2]. Short
Department of Intestinal Failure and Liver Diseases, Bowel Syndrome (SBS) patients with intestinal insufficiency
Rigshospitalet, Copenhagen, Denmark (INS) have preserved oral or enteral autonomy and can com-
pensate for maldigestion or malabsorption (i.e. malassimila-

682 P. B. Jeppesen
tion) by hyperphagia, by reduced physical activity and the tion far surpasses the complexity symphony performed by an
body may adapt temporarily to this situation of “semi- orchestra, an increased understanding of the roles of the indi-
starvation”, even without suffering from organ impairment, vidual musicians and especially of the conductor and the
by metabolic adaptation [3]. Patients with SBS and intestinal main soloists in the performance will be of significant
failure (IF) on the other hand need parenteral support (PS) to importance.
ensure the adequate provision of nutrients, fluid and/or elec- This chapter reviews the findings of from clinical trials
trolytes, to prevent permanent organ damage and ensure that have aimed to identify, mimic or even surpass the key
proper organ functions, avoid diseases and maintain life [4]. hormonal players in the spontaneous intestinal adaptation.
Based on the severity of the degree of malassimilation and Currently, these studies have mainly included the use of
the ability to compensate for this, SBS patients can be found somatostatin, growth hormone, glucagon-like peptides or
within a spectrum ranging from mild, moderate and severe epidermal growth factor either as native hormones or ana-
INS across a borderline to mild, moderate and severe IF [5]. logues. However, since only the glucagon-like peptide 2 ana-
Although the malassimilation seen in short bowel syn- log, teduglutide, has yet been approved as the first
drome patients following intestinal resection is frequently evidence-based drug for the long-term treatment of SBS, the
mainly explained by the reduction in the remnant absorptive effects of this peptide is the main focus of this chapter. Since
mucosal surface-area, it may also relate to detrimental patho- the use of these pro-adaptive hormones is relatively new, and
physiological changes in GI secretions (e.g. gastric and since more healthcare professionals outside the established
pancreatico-biliary), transit, blood-flow, mucosal function centres of experience are likely to be using these agents in
and even complex inter-organ communications (e.g. gut- the future, some introductory, general suggestions to their
brain and gut-liver axes). Depending on remnant bowel anat- use may be relevant.
omy, the alterations in the meal-stimulated neuro-endocrine In this chapter, the basis for the introduction of pro-
feedback mechanisms, caused by the associated under- or adaptive factors in the clinical rehabilitation of SBS patients
over-exposure of endocrine sensor-cells distributed through- is summarised and an update of current knowledge and sug-
out the gastrointestinal (GI) tract, may lead to a dysregula- gestions for future efforts is provided. In addition it recom-
tion and either impairment or a compensatory improvement mends when a peptide growth factor may be considered in a
of GI functions. patient with short bowel associated intestinal failure (SB-IF).
In general, given a more favourable remnant anatomy To outline the pre-treatment process and the monitoring
with more proximal bowel resection and preservation of the required, including when treatment should be stopped.
ileum and right-sided colon, positive neuro-endocrine feed-
back mechanisms may contribute to a “spontaneous intesti-
nal adaptation”, which is the process that gradually leads heoretical and Practical Consideration Prior
T
towards a restoration of the intestinal absorption to that per- to Initiating Treatments
taining before the intestinal resection. In contrast, distal ileal
and right-sided colonic resections tend to favour a condition Aim of Treatment
of GI hypersecretion, rapid transit, and a more severe malab-
sorption with less spontaneous adaptation [6]. The overall aim of any treatment in patients with SBS is to
Over the last decades, an increased awareness of the rela- reduce potential SBS- and IF-symptoms and -complications
tionship between the heterogeneity and pathophysiological thereby providing the best possible overall health-related
characteristics of SBS patients and the detrimental or benefi- quality of life and longevity in these patients.
cial neuro-endocrine changes following intestinal resection Due to the large heterogeneity in the SBS population, and
has emerged. Based on this knowledge and by the prospect since each SBS patient tend to define their individual disease
of having potent analogues (agonist or even antagonists) of according to their complaints fears and miseries, a focused
the relevant endogenously secreted GI hormones for clinical interview, objective and paraclinical examinations (e.g. hae-
use, a paradigm shift from the empirically based general and matology and biochemistry) should seek to determine the
symptomatic SBS treatments, consisting of off-label use of cause of the most troublesome inconveniences and poten-
anti-diarrheal and anti-secretory agents, to an evidence- tially, in an individualised approach, address the best means
based, personalized, targeted and “pathophysiological- for their successful amelioration or resolution.
phenotype-driven” treatment has been recommended [7]. It In general, treatments should maximize intestinal absorp-
is to be anticipated that a further understanding of the pro- tive capacity, at the same time alleviating the symptoms and
cesses of importance for best possible assimilation will inconveniences of malabsorption and prevent, minimize or
enhance our ability to intervene, when normal GI physiology eliminate the need for compensatory hyperphagia or the need
is disturbed by intestinal resection. Thus, although the com- for home PS (HPS). Total weaning from PS, with removal of
plexity of the normal gastrointestinal digestion and absorp- the tunnelled, central line, is the ultimate goal of treatment of
Pro-adaptive Hormones in the Rehabilitation of Adult Patients with a Short Bowel 683
Fig. 1 The benefits/progress Intestinal Intestinal

of intestinal rehabilitation failure
insufficiency Patients who can:
reduce PS time
Fluid or Nutritional Support

have days off
Compensatory
Parenteral
support
be weaned off
be kept off/stop
Additional oral intake

(hyperphagia)
Degree of Malabsorption
(Large Heterogeneity)
SBS-IF patients, but even providing days off and diminishing chological burden, anxiety and depression [8]. Figure 1
infusion times may be of significant value to the patients. shows the potential benefits and progress of intestinal
Evaluation of health-economic benefits should be considered. rehabilitation.
Even SBS patients with severe intestinal insufficiency,
who struggle on a daily basis to keep nutritional, fluid and
electrolyte balances, may benefit by pro-adaptive treatments Patient Selection
by gaining a better quality of life and preventing re-admissions
due to dehydration and other metabolic disturbances caused Successful management of SBS patients is often based on a
by accommodation-induced organ impairments. close dialog informing and teaching the patients about their
The physical symptoms that SBS patients experience may pathologic conditions, the consequences and the potential
also relate to their gastrointestinal condition leading to SBS options and risks of treatments (benefit-safety). Evaluations
or SBS in itself (e.g. diarrhoea, incontinence or stoma prob- and discussions around compliance, adherence and motiva-
lems, abdominal pain), imbalances in body needs leading to tion to support therapies may be helpful. It may also be help-
organ or system impairments (e.g. malnutrition, dehydration ful to discuss anticipated outcomes of interventions in order
and electrolyte disturbances, insatiable thirst, reduced physi- to align expectations to patient needs. Pre-set success criteria
cal energy level and/or sex drive) or the HPS infusions them- may be relevant or justified by high therapy costs.
selves (e.g. nausea, muscle cramping, headache). The In order to evaluate effects of new treatments, it is essential
administration of HPS potentially requires daily, timely and that the patients are in a stable condition and already have been
skilful adherence, is intrusive and disturbs the sleep pattern optimized according the best available, conventional, individ-
of the patients. Infusions are time consuming and restrict the ualized care. In all SBS-IF patients, absence in fluctuations in
leisure and social activities of the patients. SBS-IF patients their need for parenteral support, their urine production and
are at risk of catheter complications such as catheter related body weight will determine their stability, which is required
bloodstream infections or even sepsis and thromboembolic before the initiation of any new treatment interventions.
events. Catheter dysfunction or accidental tearing out of the Although often used in an off-label indication, conven-
catheter may necessitate hospital re-admissions. Chronic tional treatments are likely to be cheaper, and currently their
organ impairments (e.g. liver and renal failure) may be safety profile is often better documented.
caused by SBS in itself of by parenteral administrations. The In SBS patients with a part of their intestine out of conti-
factual or fear of all of the consequences and complications nuity, an attempt for a final restorative surgery should have
of SBS and PS, as well as the associated signs, symptoms been performed or rejected by an experienced surgeon in the
and inconveniences, may eventually lead to significant psy- field.
684 P. B. Jeppesen
In SBS patients with a functional colon in continuity, time ( h t t p s : / / w w w. e m a . e u r o p a . e u / d o c u m e n t s / p r o d u c t -

should be allowed for spontaneous intestinal adaptation to information/revestive-epar-product-information_en.pdf).
occur, unless an accelerated adaptation is aimed for. Cholecystitis, cholangitis and cholelithiasis as well as
Retrospective cohort studies suggest that as much as 75% of chronic and acute pancreatitis, pancreatic duct stenosis, pan-
SBS-IF patients with a jejuno-ileal anastomosis (Group 3 creas infections and increased blood amylase and lipase lev-
anatomy) have adapted and are weaned from PS at 5 years els could occur following treatments with pro-adaptive
following their final surgery [9]. hormones. In the case of these adverse events, the benefit and
In patients with a jejuno-colonic anastomosis (Group 2 need for continued treatment should be reassessed. Additional
anatomy) the continued, progressive adaptation and PS laboratory and appropriate imaging may be indicated.
weaning, at around 50% at 5 years, seems minimal from 2 to Cases of intestinal obstruction have been reported in clin-
3 years from the final surgery. ical studies using pro-adaptive hormones. Treatment of
Thus, aggressive attempts of weaning from PS seem to be patients with a history of chronic abdominal pain and the
indicated in these two anatomy group of patients. In patients detection of a narrow stoma should be avoided. In all cases,
with a jejuno- or ileostomy (Group 1 anatomy) adaptation treatments should be paused until resolution of symptoms
and total PS weaning is seen in less than 20% of patients at and in case of reoccurrence, the indication for treatment and
1 year, and no further adaptation seems to be evident on a the dose should be reassessed.
group basis from this point onwards. Therefore, an earlier It will be important to consider the overall prior medical
introduction of pro-adaptive agents is reasonable in these history of the SBS-IF patient, since the initiation of pro-
patients. adaptive treatments in the initial treatment phase may disturb
In centres, where metabolic balance studies can be made, the nutritional and fluid/electrolyte balance. This disturbance
a measurement of intestinal energy absorption may be help- may affect any co-morbidity that the patient may suffer from.
ful in individual SBS-IF patients, especially in patients with For instance, patients with a latent cardiac impairment may
Group 2 and Group 3 anatomy, before and a period of time suffer from overt cardiac decompensation.
after the initiation of a pro-adaptive treatment, since it is the Due to increased intestinal absorption, patients receiving
provision of the PS of protein-energy and not fluid and elec- oral medication with a narrow therapeutic index may suffer
trolytes that may be most critical in these patients. from the consequences of elevated drug levels (e.g. analge-
In SBS patients without a colon in continuity, i.e. patients sics, anti-coagulants, thyroid or anti-thyroid agents). The
with a jejuno- or ileostomy (Group 1 anatomy), objective prescribing or treating healthcare professionals should be
effects of interventions may be demonstrated early following aware of this risk and manage their patients accordingly.
treatment initiation in simple fluid balance studies or by hav-
ing the patients measuring their urine production and body
weight at home. Benefit-Risk Assessment
In general, patients with suspected or active malignancies
should not be treated with pro-adaptive agents. This also per- In the ideal setting, it should always be evaluated, if a drug is
tains to patients with a history of malignancies in the GI so effective that its benefit outweigh its potential risk to
tract, including the hepatobiliary system and pancreas, patients.
within the last 5 years. A colonoscopy with removal of pol-
yps should be performed at the time of starting treatment. Safety
Once yearly follow-up colonoscopies (or alternate imaging) Short Bowel Syndrome is considered a rare, orphan disease.
are recommended during the first 2 years of treatment. The care and treatment of SBS patients is often complicated
Subsequent colonoscopies are recommended at a minimum by a large inter-patient and effect-heterogeneity. Thus, in the
of 5 year intervals. An individual assessment, whether opinion of the author, the implementation of new pharmaco-
increased frequency of surveillance is necessary, should be logical treatments in SBS patients should ideally, at least ini-
performed based on the patient characteristics (e.g., age and tially, be limited to skilled, high volume intestinal failure
underlying disease). If a polyp is found, adherence to current centres, where sufficient resources are allocated to a dedi-
polyp follow-up guidelines is recommended. In case of cated inter- and multi-disciplinary specialist care and sur-
malignancy, the new therapy must be discontinued. In chil- veillance. Thorough effect monitoring and a close
dren and adolescents aged 12 years or less, faecal occult post-marketing surveillance are of great importance in order
blood testing should be performed prior to initiation of pro- to validate the post-marketing, long-term benefit-risk profile
adaptive treatments and annually thereafter. Positive tests of the specific treatment.
should lead to a colonoscopy. Colonoscopy is recommended Most of the pro-adaptive agents have multiple physiologi-
for all children and adolescents after 1 year of treatment, and cal effects and are likely to influence both GI mucosal growth
at least every 5 years thereafter of continuous treatment and secretions. Therefore, long-term treatments could induce
pathophysiological disturbances in various organ functions duction of these agents do not impair and deprive finances
and even neoplasia. Since the number of patients included is from a well-functioning healthcare system.
low and treatment duration is short in the phase 3 programs,
multi-national, multi-centre registry studies will be needed
to ensure long-term drug safety, when introducing new he Physiological Basis for Treatment
T
treatments. with Pro-adaptive Agents
ffect
E When discussing the use of pro-adaptive agents in the treat-
Although effects or benefit of pro-adaptive treatment may ment of SBS patients it is important to emphasize the con-
have been demonstrated in groups of SBS patients in ran- cept of the intestine as an endocrine organ. Thus, although
domised, placebo-controlled, phase 3 trials, a large inter- the enteroendocrine cells only constitutes 1% of the intesti-
patient and effect-heterogeneity often exist. Therefore, nal mucosal cells, a plethora of hormones released in relation
establishment of a clinical meaningful and objectively mea- to eating ensures the physiological actions required for the
surable effect in the individual SBS patient following the ini- optimal digestive process. The gastro-entero-pancreatico-
tiation of the treatment is the goal. hepatic system is now regarded as the largest endocrine
In the ideal world, the absolute intestinal absorption of organ in the body [11].
fluid, electrolytes and macronutrients in the individual In general, patients with intestinal resection and a jejuno-
patient may be determined at intervals before and after treat- or ileostomy are characterised by elevated post-prandial,
ment initiation. This may be done by performing 48–72-h pro-secretory and pro-motility hormones such as gastrin,
metabolic balance studies, where duplicate portions of oral cholecystokinin, secretin and motilin [12]. This favours rapid
intakes and faecal and urinary excretions are determined [3, propulsion and hypersecretion of gastric acid, bile and pan-
10]. The use of subjective tools or questionnaires is difficult creatic juice as well as bicarbonate secretion, which in turn
to implement and objectively evaluate in this orphan may contribute to large stomal losses. A lack of endogenous
condition. secretion of more distally secreted pro-adaptive feedback
In the real world setting, only few centres have the organ- hormones, such as glucagon like peptide (GLP)-1, GLP-2,
isation, logistics and skills to objectivize effects of treat- peptide YY (PYY), oxyntomodulin, and fibroblast growth
ments, but along with conventional standard of care, simple factor (FGF) 19, may aggravate the accelerated gastric emp-
fluid balance measurements with a tracking of changes in tying and various hypersecretions, rapid intestinal transit and
urine production, body weight and standard biochemistry impaired blood and lymphatic flow as well as mucosal func-
should be the minimum for adjusting PS. Subjectively per- tion [13]. Impaired post-prandial secretion of more proxi-
ceived benefits in relation to the treatment with pro-adaptive mally produced hormones such as glucose-dependent
agents may vary considerably in individual patients, even insulinotrophic peptide (GIP) may also contribute to the
when patients are allocated according to the various classifi- pathophysiological characteristic of patients with group 1
cations suggested by the ESPEN interest group [4]. Individual anatomy.
effects, that may seem subtle when using conventional mea- Patients with group 2 and group 3 anatomies differ by the
suring tools, may dramatically improve the quality of life in presence of a part of the terminal ileum and the right-sided
some patients, whereas others, who do not encounter this colon. Whereas the colon in itself possesses the ability to
problem, may find that the treatment has other preferred compensate for small bowel malabsorption by increasing its
effects. ability to absorb fluid (up to 5 L/day), sodium (up to
800 mmol/day) as well as energy derived from the fermenta-
tion of carbohydrates and protein (up to 4 MJ/day) [14], the
Cost Considerations terminal ileum and the right-sided colon may also be of sig-
nificant importance in the hormonal regulation of more prox-
Since the cost of developing new drugs in orphan conditions imal GI functions [15]. Thus, the constant hypersecretion of
is high and the potential patient group is relatively small, the the suggested pro-adaptive distal feedback hormones dem-
prices of new treatments are much higher than conventional onstrated in these patients may also account for the impres-
pharmacological treatments. It is also likely, that most sive spontaneous adaptation and ability to wean from PS
patients will require these treatments for the remainder of seen in these patients with down to 40 cm of remaining small
their life. Therefore, negotiations between health authorities bowel in the years following intestinal resection. In sum-
and companies are needed to ensure the right balance, so the mary, it is believed that future pro-adaptive treatments in
barriers to prevent developments that are ethically and scien- SBS will seek to mimic these effects, potentially by a
tifically motivated do not become too high, the economic replacement therapy including a combination of these bene-
incentives to sponsor this development is fair, and that intro- ficial feedback hormones.
686 P. B. Jeppesen
Overview of Results from Clinical Studies glucose was not affected. Small bowel transit time was pro-
longed from 76 to 134 min. Subsequently, the patient was
Somatostatin and Analogues given SMS 201-955, 50 μg subcutaneously twice daily, and
her stomal output remained below 2.5 kg/day thereby ren-
Somatostatin is widely distributed in the neuroendocrine dering PS unnecessary [28].
cells throughout the gastrointestinal tract and in pancreatic D The effect of octreotide was also demonstrated in a
cells. It decreases gastric [16], biliary and pancreatic secre- 5-year-old boy with an ileostomy placement after an opera-
tions [17–19] inhibit secretagogue-induced water and elec- tion due to volvulus. Following unsuccessful treatments with
trolyte secretion in the jejunum and the colon [20], stimulate parenteral nutrition for 8 weeks, loperamide, cholestyramine
sodium and chloride absorption in the ileum [21], decrease and antibiotics, efficacy of octreotide was demonstrated.
intestinal motility [22] and inhibit the release of hormones Following a phase with continuous analogue infusion fol-
that may contribute to the diarrhoea (e.g. VIP, GIP, gastrin) lowed by twice daily 50 μg subcutaneous octreotide injec-
[23]. However, somatostatin could inhibit glucose absorption tions, the average ileal output diminished from 1800 g/day to
and pancreatic enzyme secretion, which would impair the 350 mL/day and was paralleled by reductions in sodium and
macronutrient absorption in patients with SBS. Furthermore, chloride losses. No side effects were observed.
somatostatin reduces splanchnic blood flow [24] and it may Rodrigues et al. compared the effects of octreotide to the
reduce the use of amino acids for splanchnic protein synthe- effects of soy polysaccharide, oral and intramuscular
sis thereby interfering with the physiological process of codeine, and loperamide on nutrient fluid and electrolyte
adaptation to intestinal resection [25, 26]. absorption in four patients with short bowel syndrome and
Dharmsathaphorn et al. were the first to report the acute an end-jejunostomy receiving parenteral nutrition [29].
effects of a 24-h infusion of somatostatin (4 μg/min) in four Following a standardised test meal, the stoma output col-
patients with SBS due to multiple resections for Crohn’s dis- lected the following 6 h was reduced from 923 ± 213 g to
ease [27]. Total colectomy was performed in 3 out 4 of the 358 ± 78 g, sodium output from 95 ± 12 to 49 ± 9 mmol,
patients and their remnant jejunum was less than 3 m. Having calorie balance increased from 11 ± 6 to 35 ± 8%, and intes-
withdrawn all anti-diarrhoeal medications 2 days before tinal transit (evaluated as the median time taken to recover
admission, patients were placed on a standardised 2000 kcal 60% of a labelled marker) increased from 64 ± 23 to
diet containing 75 g/day of fat. Blood samples, urine and 205 ± 8 min. However, all four patients found that the subcu-
stool collections were obtained for three consecutive 24-h taneous octreotide injections were painful, and one patient
periods before, during and after somatostatin administration. experienced abdominal pain and distention.
Somatostatin infusion induced a reduction in stool weight in Nightingale et al. studied the effect of octreotide in six
all four patients (from 1892 ± 241 g/day to 1236 ± 254 g/day, SBS patients who all had undergone extensive small bowel
on average corresponding to 35%, p < 0.05) and a 59% resection [30]. Apart from one, who had a jejuno-rectal anas-
decrease in stool chloride content. Numerical reductions in tomosis, all patients had end-jejunostomies and a remnant
faecal excretions of fat (9 g/day), nitrogen (1.0 g/day), bowel length of less than 70 cm. Two of the patients received
sodium (30 mmol/day), potassium (7 mmol/day) and magne- codeine and loperamide in relation to participating in the
sium (47 mmol/day) were observed. The urinary volume and study. The mean daily intestinal output ranged from 3.6 to
electrolytes remained unchanged. Blood glucose levels rose 6.9 kg, and all patients needed at least 4.5 L of intravenous
from 25 to 40 mg/dL and fasting and postprandial glucagon, fluids per day. Following two control days, the patients were
GIP and peptide PP levels were suppressed by the somatosta- given octreotide intravenously through their central catheter
tin infusions. A rebound effect occurred immediately after in a dose of 50 μg (diluted in 10 mL 0.9% saline given over
infusions. 10 min) twice daily at 08:00 and 16:00 h for 2 days. This
The use of a long acing somatostatin analogue, SMS 201- mode of administration was chosen to avoid the painful
955 (octreotide), which prolonged the half-life from a few octreotide injections. When possible, the study was repeated
minutes to 3–4 h, was first reported in a woman with Crohn’s using 100 μg of octreotide three times daily, 30 min before
disease who after colectomy also had a subsequent removal each meal. Treatment with octreotide significantly reduced
of an ileorectal anastomosis. Four months after the creation the mean total intestinal output from 5.13 to 3.30 kg/day (dif-
of an ileostomy, her output was 4–6 L/day, when on her regu- ference 1.83 kg/day, range 0.60–5.01 kg/day, p = 0.04).
lar oral intake, and 2–3 L when fasting, and therefore she Sodium excretion was reduced from 405 to 248 mmol/day
required PS. In relation to 24-h of infusion of SMS 201-955 (difference 157 mmol/day, range 56–405 mmol/day,
(25 μg/h), the ileostomy output decreased from 5300 to p = 0.03) and potassium from 73 to 52 mmol/day (difference
1600 g/day, sodium excretion decreased from 656 to 21 mmol/day, range 6–61 mmol/day, p = 0.05). A non-
162 mmol/day and potassium from 48 to 20 mmol/day. In significant reduction in faecal energy from 6894 to 5625 kJ/
spite of these dramatic effects, the faecal excretion of fat and day was observed (difference 1270 kJ/day, range −1092 to
5083 kJ/day, p = 0.20). Increasing the dose to 100 μg TID in These studies were followed by a double blind, placebo
three patients did not increase the effect, but the patients pre- controlled balance study by Ladefoged et al. in six SBS
ferred this option since it reduced the usual inconvenient patients requiring PS [34]. Five of the six patients had a jeju-
postprandial rise in the intestinal output. No side effects were nostomy and less than 225 cm of small intestine, whereas the
reported. One patient was treated continuously for 1 year last patient only had a resection of 30 cm of the terminal
without evidence of tolerance occurring and no signs of ileum. Their stool masses ranged from 2320 to 8125 g/day
complications of diabetes, hypothyroidism or gallstones. and their stomal sodium losses ranged from 144 to 601 mmol/
Rosenberg et al. investigated the effect of octreotide in day. Four of the six patients were wet weight secretors, and
doses from 50 μg subcutaneously twice daily to 100 μg three all the patients were sodium secretors. During the study, the
times daily in SBS six patients; two with ileostomies and patients were maintained on a constant diet composed in
four with a gastrointestinal tract that was in continuity [31]. accordance with their habitual intake and they received a
Intractable diarrhoea decreased by 73 ± 7% in five of the six fixed fluid and sodium intake for all 12 days. After a basal
patients, but the actual raw-data is not presented in the pub- period of 2 days, the patients were randomly allocated to
lication. Although the treatment was very effective in con- intravenous placebo or octreotide 25 μg/h for 2 days each.
trolling diarrhoea, two patients discontinued treatment After a new basal period of 2 days, the patients were allo-
within 1 week of commencing treatment due to abdominal cated in the same manner to a subcutaneous administration
cramping and bloating. Two patients were treated success- of either placebo or octreotide in a dose of 50 μg every 12 h.
fully as outpatients for 6 weeks. Thereafter the treatment was In the whole period, double portions of the oral intake was
stopped without the occurrence of diarrhoea. Two other stud- prepared and analysed as was the stools and urine. Infusion
ies were only reported in abstract form. Shaffer et al. per- of octreotide caused a significant increase in the median wet
formed a randomised placebo controlled crossover trial in weight absorption of 1124 g/day (range 347–1854 g/day),
six patients with a persistently high stoma effluent (1.3–6 L/ p < 0.005 and sodium 126 mmol/day (range 52–191 mmol/
day) [32]. After a 2 day control period, the patients received day), p < 0.005, whereas no significant changes in the net
50, 100 and then 150 μg of octreotide or matching placebo absorption of potassium, calcium, magnesium, phosphate,
on three successive days. After a 14 days washout, the zinc, nitrogen or fat was seen during the infusion of octreo-
patients repeated the study with the alternative medication. tide. Subcutaneous injection of octreotide every 12 h caused
Octreotide significantly reduced the median stomal volume similar effects. However, one patient developed symptoms of
(2.39 L/day, range 0.62–4.48 vs placebo: 4.03 L/day, range ileus that resolved after discontinuation of octreotide and
1.28–5.98, p < 0.001), sodium output (153 mmol/day, range conservative treatment. In none of the patients, the improve-
27–271 vs placebo: 311, range 94–594, p < 0.001) and potas- ments in intestinal wet weight or sodium absorption were
sium output (39 mmol/day, range 8–58 vs placebo: 54, range large enough to make parenteral fluid or sodium supplements
23–154, p < 0.001). There was a corresponding increase in superfluous. Four patients opted to continue open label sub-
urine volume (2.09 L/day, range 0.75–6.62 vs placebo: cutaneous treatment twice daily for 21–28 weeks. In three of
1.16 L/day, range 0.47–5.13, p < 0.002). Body weight was these patients, the faecal mass remained below baseline val-
unaffected by the treatment, and no improvements in nitro- ues but in one patient, the faecal mass gradually increased
gen, magnesium, zinc or copper balances were seen. Two and exceeded baseline values even after doubling the octreo-
patients were followed for more than 2 years on treatment tide dose. No side effects were seen.
and did not develop any long-term adverse effects or evi- In an open label study, O’keefe et al. investigated the
dence of pharmacological tolerance. effect of 100 μg octreotide given subcutaneously TID,
In another abstract, Gilsdorf et al. reported finding in 30 min before meals on intestinal absorption after initial
seven SBS patients requiring HPN. Three patients had sto- 72-h balance studies at days 1–3 that were repeated at
mas and in these octreotide, given in doses ranging from 50 days 11–13 [26, 35]. Ten adult SBS patients with end-
to 300 μg subcutaneously in one to three doses, reduced jejunostomies performed at least a year prior to the investiga-
stoma outputs of 5.0, 4.0 and 2.0 L/day to 3.5, 2.5 and 0.6 L/ tion were examined. The remaining small bowel was 200 cm
day [33]. Daily bowel movements of up to 20/day decreased or below in all patients, and they all depended on PS (mean
in all cases to less than 6/day. Four patients eventually took PS volume 4.5 L/day, range 1–5.5 L/day and mean sodium
octreotide in their TPN bags and experienced the same effect provision 387 mmol/day, range 247–982 mmol/day). All
as when taken subcutaneously. One patient developed confu- patients had received H2 antagonist therapy until a week
sion, oedema and a 17 lb weight gain secondary to fluid over- before the study and all patients had been given trials of
load. One had labile blood sugars. All patients complained of common anti-diarrhoeas. The mean stomal output was 8.1 L/
dull headaches and nausea which they attributed to octreo- day (range 2.4–20.7 L/day) and sodium losses 510 mmol/
tide. Thus, three stopped the treatment, whereas three contin- day (range 247–982 mmol/day). The study protocol con-
ued the treatment by injecting it into their PS. sisted of a 3-day, baseline metabolic balance study, where no
688 P. B. Jeppesen
antisecretory or antimotility medications were given. two patients. Two patients complained of occasional abdom-
Octreotide therapy was then commenced as 100 μg TID s.c. inal cramps.
30 min before each meal for 8 days before the 3-day balance In the latest study employing octreotide, Nehra et al.
study was repeated during the same octreotide treatment. described the use of a long-acting release (LAR) deport,
After commencement of octreotide, reductions in the stomal octreotide preparation, sandostatin LAR, in a 15 week, open
fluid were counterbalanced each day by reductions in IV label trial in eight adult SBS-IF patients [36]. All the patients
fluid and electrolyte infusions maintaining urine output had been receiving PS for 1–22 years. Three of the patients
between 1 and 1.5 L/day. In addition, amino acid metabo- had a colonic segment in continuity and in all patients the
lism, pancreatic enzyme synthesis and secretion and mucosal residual bowel was 200 cm or less. Metabolic balance stud-
protein turnover were measured before and at the end of the ies and measurements of intestinal transit by radionucleotide
10 days of octreotide therapy. Likewise, mucosal biopsies scintigraphy employing an egg meal were performed on two
and hormonal secretions were evaluated before and during separate occasions 15 weeks apart. Following the initial 48-h
stimulation with pentagastrin and cholecystokinin. balance study, the patients received the first 20 mg, intramus-
The effect of octreotide treatment on stomal output was cular, Sandostatin LAR injection. This was repeated by self-
immediate in all patients, and in spite of a reduction in oral injection as an outpatient at weeks 3, 7 and 11. The PS was
fluid intake, this permitted a significant reduction in the par- kept constant throughout the study, and patients had fixed
enteral supplements in all but one of the patients. Thus, on habitual like diet during admissions. The average 48-h stool
average the stomal losses of fluids and sodium were reduced weight was 4.54 g/day (range 2.91–11.16 kg). Sandostatin
to 4.8 L/day and 340 mmol/day, respectively (both p < 0.03). LAR treatment did not lead to significant differences in body
However, despite increases in net absorption, none of the weight, 48-h urine volume, stool weight, faecal sodium or
patients could be weaned from PS. The average parenteral potassium losses or faecal fat excretion. However the depot-
fluid volume and sodium reductions were 1.3 L/day and treatment significantly prolonged small bowel transit time,
118 mmol/day, respectively (p < 0.03). In general, the largest whereas the gastic emptying halftime or in the proportion of
effect was seen in patients with the highest stomal losses and the meal emptied from the stomach at 2 and 4 h did not
highest parenteral needs. No changes in intestinal macronu- change.
trient absorption were observed in relation to octreotide According to the ESPEN guideline it is suggested that
treatment. octreotide is only used in the short term after intestinal resec-
Octreotide treatment resulted in a significant reduction in tion and in patients with high output jejunostomy in whom
the pentagastrin-stimulated acid secretion in all but one of fluid and electrolyte management is problematic in spite of
the SBS patients. The exogenous pancreatic excretion of conventional treatments. A careful monitoring is recom-
lipase in response to CCK stimulation was significantly mended to prevent fluid retention in relation to the initiation
reduced before and after 10 days of octreotide treatment, of treatment as well as potential adverse effects. Although
whereas numerical reductions were seen in trypsin and the effects potentially are dramatic in patients with the high-
amylase secretion. Although, the time taken to the appear- est outputs, it is of concern, that sandostatin and analogues
ance of carmine dye on average was 12 min longer in com- have global effects on hormonal secretions and that potential
parison with pretreatment values, this was not significant. negative interference with the process of intestinal adapta-
Mucosal protein turnover and duodenal villus growth rates tion may be seen following long-term use.
calculated from isotope incorporation and morphological
measurements showed a significant suppression. Plasma
concentrations of glucagon, insulin, gastrin and peptide YY Growth Hormone and Analogs
all decreased in relation to octreotide treatment. Evidence
for improved renal function was obtained from urea clear- The concept of “bowel rehabilitation” was introduced by
ance with findings of decreases in blood urea concentration Byrne and Wilmore in relation with treatment with high dose
and increases in urea nitrogen excretion in the urine. (0.14 mg/kg/day) of growth hormone, glutamine, and a high
However, although octreotide significantly reduced stomal carbohydrate diet in SBS patients [37, 38]. In eight SBS
output and increased fluid balance in the SBS jejunostomy patients with colon in continuity treated for 5 weeks, wet-
patients, concern was raised that the long-term treatment weight absorption increased from 1.7 to 2.4 kg/day, and
would interfere with the process of intestinal adaptation. sodium absorption increased from 74 to 113 mmol/day.
Seven patients continued treatment for over 2 years follow- However, although these patients were receiving PS, it is not
ing the study. Two of these patients died one from septicae- clear if they met the criteria for a diagnosis of intestinal fail-
mia and the second with intestinal failure associated liver ure as defined by Jeppesen et al. [3]. At the same time patients
disease. Two patient developed gallstones necessitating a were given a high-carbohydrate diet and oral rehydration
percutaneous cholecystectomy. Mild hair loss was noted by solutions as a part of the “rehabilitation-regimen”.
In a subsequent placebo-controlled, double-blind study After 3 weeks of treatment, the intake and absorption were
by Scolapio et al., the effect of growth hormone (0.13 mg/kg/ 2367 and 1759 kcal/day (~7363 kJ/day, 74%), respectively,
day) and oral glutamine on intestinal sodium and potassium which was a significant improvement in percentage
absorption was less than 5 mmol/day [39]. No effects on fae- (p < 0.003) but an increase of only 141 kcal/day (~590 kJ/
cal wet weight excretion were seen. day) in absolute amounts. As stated, the “rehabilitation”-
In a study by Szkudlarek et al., growth hormone (0.11 mg/ regimen included a high-carbohydrate, low-fat diet, which in
kg/day) and glutamine, both orally and parenterally adminis- itself is known to increase energy absorption in SBS patients
tered, tended to decrease wet-weight absorption and increase with a colon in continuity. Supporting the hypothesis that
faecal excretion of sodium and potassium, which reached diet alone accounted for the observed benefits, intestinal fat
significance (p < 0.05) in comparison with baseline values absorption did not improve. In the study by Scolapio et al.,
[40]. However, these findings were accompanied by clinical where only 2 of 8 patients had colon in continuity, high-
findings of generalized oedema, increased body weight, a carbohydrate diets were provided in both the placebo and
need for diuretics, and a reduction in parenteral saline during treatment arms [39]. Energy absorption was not measured,
treatment. It is believed that the patients were in the process but no changes were observed regarding nitrogen or fat
of excreting water and sodium accumulated during the treat- absorption with growth hormone. In the studies by Ellegård
ment at the time of the post-treatment balance studies 5 days et al. [41] and Szkudlarek et al. [40], no changes were found
after termination of treatment. in intestinal energy or in fat or nitrogen absorption. In the
In lower dose studies from Ellegård (growth hormone randomized, double-blind placebo-controlled cross-over
0.024 mg/kg/day) [41] and Seguy (0.05 mg/kg/day) [42], no study by Seguy et al., growth hormone (0.05 mg/kg/day, 9 of
significant positive effects on either wet-weight or sodium 12 patients with colon in continuity) and an unrestricted
absorption were seen. hyperphagic diet increased intestinal absorption of nitrogen
In the pivotal, randomised, double-blind parallel group by 14 ± 6% (p < 0.040), carbohydrates by 10 ± 4%
study of 41 patients with SBS (mainly with a preserved colon (p < 0.040), and energy by 15 ± 5% (p < 0.002), which in
and stool volume less than 3 L/day), who were dependent on absolute terms was 427 kcal/day (~1787 kJ/day) [42]. Fat
parenteral nutrition, the effect of the recombinant human absorption was unaffected. During growth hormone treat-
growth hormone, somatotropin (0.1 mg/kg/day for 4 weeks) ment the mean dietary energy intake was 192 kcal/day
and glutamine on the need for PS was investigated [43]. The (804 kJ/day) higher than during the placebo treatment phase.
protocol for weaning from PS was based on measurements In the pivotal study on somatropin, the mean reductions
of body weight, total body water by bioimpedance analysis from baseline in total parenteral calories were significantly
and measurements of serum sodium, potassium and bicar- greater in recipients of somatropin plus glutamine or soma-
bonate. A significantly greater reduction from baseline in tropin alone than in recipients of placebo plus glutamine
total parenteral volume occurred in recipients of somatropin 5751 and 4338 vs 2633 kcal/week, respectively [43]. Thus,
plus glutamine or somatropin alone than in recipients of pla- the effect of the combined therapy of somatropin plus gluta-
cebo plus glutamine (−7.7 and −5.9 vs −3.8 L/week, respec- mine would correspond to an effect of 445 kcal/day (1863 kJ/
tively). Thus, the effect of somatropin and glutamine day). No changes in the dietary energy intake in the three
averaged 557 mL/day. Balance studies on intestinal absorp- parallel study groups were reported.
tion were not performed and the results on urinary excretions In the growth-hormone study by Byrne et al., a weight
were not reported [43]. However, it has been reported that gain of 5.4 ± 1.2 kg was described in the eight patients after
growth hormone increases extracellular volume by stimulat- 21 days of treatment [37]. Occurrence of oedema was not
ing sodium reabsorption in the distal nephron and preventing reported, but increases in body weight of this magnitude are
pressure natriuresis [44]. Therefore, when employing bio- difficult to explain considering the cumulative effect of
electrical impedance analysis during weaning from PS, it approximately 12.4 MJ (590 kJ/day) on the energy balance
should be considered that the effects of growth hormone on over the 21 days of treatment. Neither body composition nor
fluid balance in SBS patients may also be related to effects urine creatinine excretion was measured. Changes in body
on the kidneys and the extracellular space rather than on the weight in the studies by Ellegård et al., [41], Scolapio et al.,
intestine. [39] and Szkudlarek et al., were minor and no changes were
Results on intestinal energy and macronutrient absorption seen in urinary creatinine excretion [45]. In the study by
in studies using growth hormone have been conflicting. In Seguy et al., body weight increased 2.0 kg (p < 0.003), and
the study by Byrne and Wilmore, the baseline dietary energy the lean body mass, measured by BIA, increased 2.2 kg
intake was 2692 kcal/day, and 1618 kcal/day (~6773 kJ/day, (p < 0.006) [42]. No adverse events to the lower dose growth-
60%) were absorbed [37]. Thus, according to the parameters hormone treatment were encountered.
that define intestinal failure suggested by Jeppesen et al. [3], In the PS weaning study of somatropin, a dramatic weight
the majority of these patients did not need parenteral energy. loss of 5.2 kg of body weight (from 63.9 to 58.7 kg) was
690 P. B. Jeppesen
observed from week 2 (pre-treatment) to week 18 (12 weeks gested to have anti-inflammatory effects [57, 58], and in
post-treatment) in patients receiving the combined therapy of addition, GLP-2 may decrease bone resorption [59]. The
somatropin plus glutamine. This weight loss closely reflected effects are mediated via GLP-2-receptors (GLP-2R), which
the anticipated weight loss derived by calculation of the are G-protein coupled receptors belonging to the class B
energy deficit obtained by reduction of the parenteral energy glucagon-secretin receptor family [60]. GLP-2R expression
support of 1863 kJ/day [43]. is primarily found in the gastrointestinal tract and the central
In summary, the overall impression is that the effects of nervous system, with limited expression in lung, cervix and
high doses of growth hormone were mainly confined to the vagal afferents [61]. Within the GI-tract the most abundant
wet weight absorption and mainly in SBS patients with a expression of GLP-2R is found in the jejunum, followed by
preserved colon, whereas the effects on energy absorption the ileum, colon and stomach. Different studies have identi-
were minor. At the lower doses of growth hormone, there fied expression of GLP-2R in enteroendocrine cells [62],
may be an effect on energy absorption in SBS patients with a enteric neurons [63] and subepithelial myofibroblast [64].
preserved colon, whereas the effect on wet weight absorption However, neither crypt epithelial cells nor enterocytes
was minor regardless of intestinal anatomy. express the GLP-2R and this finding has led to the hypothe-
In 2003, the United States Food and Drug Administration sis that GLP-2 requires an indirect signal, perhaps function-
(US FDA) approved Zorbtive® for 4-week treatments in SBS ing through a paracrine mechanism, to induce its effects on
patients. It has not been approved by EMA. The long-term intestinal growth. GLP-2R activation results in the release of
benefits of growth hormone and glutamine on intestinal several growth factors such as IGF-1, EGF and KGF [65].
absorption following discontinuation of treatment remain to The biologically active GLP-21–33 is broken down at the
be established. The effects of growth hormone are global and alanine residue in position 2 from the N-terminus, catalysed
not specific for the intestine. The global effects of growth by the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4),
hormone and the presence and severity of adverse events and it is thereby transformed into the biologically more inac-
(swelling, fluid retention symptoms, myalgia, arthralgia, tive metabolite GLP-23–33. Teduglutide is a GLP-2 analog, in
gynecomasia, carpal tunnel syndrome, nightmares and which a substitution of alanine with glycine at position two
insomnia) in relation to high dose growth hormone treatment results in a peptide resistant to degradation by DPP-4 and,
raises concern especially in relation to a long-term, poten- therefore, has a longer half-life than native GLP-2 [66, 67].
tially life-long use of this treatment modality. Trying to rec- Following subcutaneous (SC) injection, this corresponds to a
onciliate the conflicting findings in the growth hormone biological half-life for teduglutide of 2–3 h compared to a
studies a recent Cochrane review concluded: “The results half-life of 7 min for GLP-2.
suggest a positive effect of human growth hormone on In the first uncontrolled, clinical, “proof of concept” study
weight gain and energy absorption. However, in the majority with native GLP-2 by Jeppesen et al., 8 patients were treated
of trials, the effects are short-lived returning to baseline with the empirically derived dose of 400 μg of native GLP-2
shortly after cessation of therapy. The temporary benefit calls twice a day (corresponding to 0.013 ± 0.002 mg/kg/day, a
into question the clinical utility of this treatment” [46]. range of 0.011–0.017 mg/kg/day), given subcutaneously for
35 days in an open label study [55]. None of the patients had
colon in continuity. Their average wet-weight absorption
Glucagon Like Peptide-2 and Analogs was 1.2 ± 1.7 kg/day at baseline, and it increased by
420 ± 480 g/day (p = 0.04), whereas the effect on sodium
Glucagon-like peptide 2 (GLP-2) is a single chain polypep- absorption did not quite reach statistical significance
tide of 33 amino acid residues, which is produced by a tissue- (33 ± 49 mmol/day, p = 0.10). Native GLP-2 treatment
specific posttranslational processing of the 160 amino-acid improved the relative absorption of energy by 3.5%
proglucagon molecule in enteroendocrine L-cells. These (p = 0.04), and nitrogen by 4.7% (p = 0.04). The absolute
cells are distributed throughout the gastrointestinal tract with energy absorption tended to increase by 441 ± 634 kJ/day
the highest density in the terminal ileum and the colon. ([105 ± 151 kcal/day] p = 0.09). The effect of GLP-2 on fat
GLP-2 is secreted from the intestinal L-cells following meal absorption was not significant. The improvement in the abso-
ingestion. Repeated administration of GLP-2 promotes the lute amount of energy absorbed was obtained in spite of a
expansion of the intestinal mucosa via the stimulation of non-significant decrease in intake of 173 kJ/day, which
crypt cell growth and the reduction of enterocyte apoptosis means that the reduction in the energy malabsorbed (equal to
[47]. Exogenous GLP-2 administration inhibits gastric acid the stomal excretion) was proportionally larger: 617 kJ/day
secretion and gastric emptying [48, 49] stimulates intestinal [55].
blood flow [50–52] increases intestinal barrier function [53] The first clinical study of the efficacy of teduglutide in
and enhances nutrient and fluid absorption in both preclini- SBS was evaluated in an open-label, phase 2, pilot study
cal and clinical models [54–56]. GLP-2 has also been sug- published in 2005 [68]. In this phase 2, metabolic balance
study, 16 SBS-patients received three different doses of tedu- absolute or relative energy absorption, and it is possible that
glutide for 21 days [68]. The SBS patients were divided into this is due to variability in dietary intake during the study
three subgroups based on remnant functional anatomy: end- periods amongst the different groups.
jejunostomy (n = 10), <50% colon in continuity (n = 1) or In addition to the metabolic balance studies, the study
>50% colon in continuity (n = 5). The 10 SBS patients with also examined the possible histological changes in bowel
end-jejunostomy received 0.03 mg/kg/day (n = 2), 0.10 mg/ biopsies obtained from the patients. In the jejunum biopsies
kg/day (n = 5) or 0.15 mg/kg/day (n = 3) of teduglutide once (obtained from 8 end-jejunostomy patients in group 2) sig-
daily. The patient with <50% colon in continuity received nificant histological changes were seen in 7/8 patients. More
0.03 mg/kg/day, and the five patients with >50% colon in specifically, an increase in villus height (38 ± 45%,
continuity received 0.10 mg/kg/day. The doses were chosen p = 0.030), an increase in crypt depth (22 ± 18%, p = 0.010)
to examine dose response in SBS patients over a range of and an increase in mitotic index (115 ± 108%, p = 0.010)
doses expected to provide clinical benefit. It was intended were demonstrated. Small intestinal biopsies were not
that dietary intake was fixed during the balance studies, and obtained from the patients with colon in continuity (group
the study did not seek to evaluate the effects of teduglutide 5), but instead biopsies measuring the colonic crypt depth
on spontaneous dietary intake. Three 72-h balance studies were obtained in all five group 3-patients, and these showed
were performed: at baseline; during teduglutide treatment at an increase in crypt depth in 4/5 sets of biopsies. The mean
days 18–21; and after terminating teduglutide treatment at increase in crypt depth (13 ± 22%, p = 0.330) was not statis-
day 39–42. During balance studies, all oral intake, faecal/ tically significant, and neither was the increase in mitotic
stomal output and urine was collected, weighed and analysed index (76 ± 112%, p = 0.170). Most changes in intestinal
for energy, nitrogen, fat and sodium and potassium content. absorption and histology related to teduglutide treatment had
Likewise, intestinal mucosa biopsies were done at baseline, reversed at follow-up.
day 21 and day 42. The patients took their usual medications Having illustrated that increases in wet weight absorption
such as proton pump inhibitors, codeine or loperamide, and were paralleled by increases in urine production, the ability
oral and parenteral supplements were kept constant through- to reduce PS according to increases in urine production
out the study. served as the endpoint in the phase 3 clinical study develop-
Compared to baseline, 21 days of treatment with teduglu- ment of teduglutide.
tide increased absolute intestinal wet weight absorption in 15 In each of two 24-week, phase 3, outpatient studies,
out of 16 SBS patients. The average increase in wet weight patients with SBS had their PS and intake of fluids optimized
absorption was 743 ± 477 g/day (p < 0.001). The overall to produce a stable urine output of 1–2 L/day prior to ran-
increase in the relative wet weight absorption was 22 ± 16% domization and subsequent efforts to reduce PS require-
(p < 0.001), and the magnitude was similar for SBS patients ments while maintaining clinical status and hydration.
with end jejunostomy (20 ± 18%, p = 0.007) and those with The first long-term, multinational, double-blind random-
>50% colon in continuity (26 ± 16%, p = 0.023). In accor- ized placebo-controlled teduglutide trail was conducted as a
dance with the increase in wet weight absorption, faecal wet multicenter study in the US, Canada and Europe (“the 004
weight decreased significantly compared with baseline in the study”). Eighty-three patients with SBS-IF of various aeti-
entire group of SBS patients (711 ± 734 g/day, p = 0.001). ologies were included. Patients with SBS were randomized
Since the oral intake and PS were kept constant in this study, to teduglutide 0.05 mg/kg/day (n = 35), teduglutide 0.10 mg/
the benefits on intestinal wet weight absorption and hydra- kg/day (n = 32) or placebo (n = 16) for up to 24 weeks [69].
tion translated into an increase in urine production in 14 of The primary efficacy variable in the study was initially the
the 16 SBS patients. The urine weight increased by responder rate—that is, the percentage of patients who had a
555 ± 485 g/day (p < 0.001). Furthermore, a significant reduction from baseline in parenteral volume of 20–100% at
decrease in faecal energy excretion was observed in the week 20 of treatment and again at week 24. Later on, an
entire group of SBS patients (group 1 = 808 ± 1453 kJ/day, expanded graded primary end point was introduced to com-
p = 0.040), in the subgroup of patients with colon in continu- pare the patients treated with teduglutide versus placebo with
ity (group 3 = 1343 ± 916 kJ/day, p = 0.031) and in those respect to a graded response score (GRS) criterion. Secondary
patients with high dietary compliance (group efficacy end points included the number and percentage of
4 = 1060 ± 1083 kJ/day, p = 0.013). This reduction in energy patients who responded (defined as a parenteral volume
excretion translated well into both significantly improved reduction of 20–100% from baseline at week 20 and main-
absolute energy absorption (group 3 = 1027 ± 798 kJ/day, tained at week 24); the absolute reduction from baseline in
p = 0.045 and group 4 = 963 ± 1290 kJ/day, p = 0.043) and parenteral volume and parenteral kilojoules; and the
relative energy absorption (group 3 = 10 ± 7%, p = 0.030 and achievement of at least 1 day reduction in the weekly paren-
group 4 = 8 ± 11%, p = 0.040). Unfortunately, the results did teral administration or total weaning from PS. The patients
not translate into a general, significant effect with respect to were seen in the outpatient clinic at 2 weeks intervals. The
692 P. B. Jeppesen
investigators used a weaning algorithm that allowed PS vol- effect of either teduglutide dose on intestinal wet weight
ume to be reduced by maximum of 10% monthly. The pri- absorption is probably around 700 mL/day (i.e. 4.9 L/week)
mary efficacy end point of the study, the GRS, was not closely reflecting the effects demonstrated in the phase 2
significantly different from placebo in the teduglutide study.
0.10 mg/kg/day group. However, it was decided to explore The reductions in parenteral energy were not significant
the effect of the 0.05 mg/kg/day dose on the primary end when comparing the teduglutide groups and the placebo
point and these results showed a statistically significant group (p = 0.11), but in contrast to the phase 2 study, the oral
improvement compared with placebo in the GRS (p = 0.007). energy intake and faecal excretions were not measured. It is
The secondary efficacy end point—the responder rate—was suggested that the non-significance of the 0.10 mg/kg/day
not significantly different between the 0.10 mg/kg/day group dose vs. placebo could be explained by limitations imposed
and the placebo group, but the responder rate was signifi- by the protocol, such as the inability to start reduction of PS
cantly higher in the 0.05 mg/kg/day dose group compared until after 4 weeks of initiating teduglutide treatment, the
with placebo (46% (16/35) vs. 6% (1/16)), p = 0.005). Three maximally allowed reductions in PS of 10% per month, and
subjects were completely weaned from PS. Two patients in a trend towards larger baseline parenteral volume require-
the 0.05 mg/kg/day group became completely independent ments in the 0.10 mg/kg/day group.
of PS although they had received this treatment for 25 and The effect on body composition was evaluated by changes
6.5 years, receiving 5.4 L and 3.5 L per week at baseline, in fat mass, lean body mass and total bone mineral content
respectively. Another patient in the 0.10 mg/kg/day group (BMC). Body weight was registered at all appointments and
also became independent off PS at the end of treatment DEXA-scans were performed at baseline and again at
week 24 after having received 4.5 L PS per week for week 24. Body weight was significantly increased in both
3.7 years. teduglutide groups at various time points compared to pla-
None of the active treatment arms resulted in a significant cebo and this finding was mainly due to changes in lean body
reduction in the number of days on PS, which could be mass. The total bone mineral content (BMC), was signifi-
explained by the fact that the algorithm for weaning PS did cantly higher in both teduglutide groups compared to pla-
not specify for conversion of accumulated effects into days cebo, but did not result in significant changes in T and
off PS and many investigators probably found it easier to just Z-scores.
reduce daily parenteral volumes. In both teduglutide groups, a significant increase in small
In the 0.05 mg/kg/day teduglutide group an observation bowel villus height in biopsies was demonstrated. A signifi-
of significantly more urine production at all time points, in cant increase in colonic crypt depth was demonstrated in the
spite of maintaining a constant oral fluid intake and having teduglutide 0.10 mg/kg/day group.
parenteral volume significantly decreased, was seen. Since Plasma citrulline, an organic compound derived from the
urine output increased steadily during the study, this con- amino acid arginine, is used as a biomarker of a reduced
trasted to the objective of the study protocol, which was to enterocyte mass in SBS. Plasma citrulline was increased in
maintain constant urine output by progressively reducing the both treatment groups compared to baseline and the absolute
parenteral volume. Thus, the absolute effect of the teduglu- changes from baseline in plasma citrulline were significantly
tide 0.05 mg/kg/day dose on the reduction in parenteral vol- (p ˂ 0.0001) increased after the 24 weeks of treatment in both
ume appeared to be underestimated. The concept of “the treatment groups (15.7 ± 12.7 μmol/L in the teduglutide
fluid composite effect” reflects the sum of the reduction in 0.10 mg/kg/day and 10.9 ± 11.3 μmol/L in the teduglutide
oral fluid intake, the increase in urine volume and reductions 0.05 mg/kg/day) compared to placebo (1.9 ± 5.0 μmol/L).
in daily parenteral volume. Thus, highlighting the total effect Interestingly, while baseline values tended to be lower in the
of the 0.05 mg/kg/day teduglutide dose, the fluid composite teduglutide 0.10 mg/kg/day compared to placebo group
effect endpoint increased significantly by 816 ± 982 mL/day (p = 0.051), this group showed the highest increments.
compared with placebo (p = 0.03) at week 20. Highlighting No significant changes in QoL during treatment with
the total absolute effect of the 0.10 mg/kg/day teduglutide teduglutide were demonstrated.
dose, the composite effect increased significantly by Patients who completed the placebo-controlled study
489 ± 619, 700 ± 723 and 953 ± 830 mL/day at weeks 12, 16 were given the option to enter an open-label, 28-week exten-
and 20, respectively (all p-values <0.05) compared to the sion study (“the 005 study”) [70]. Fifty two patients were
placebo. Thus, the urine volume increased by ~350 mL/day enrolled for continuous treatment of the same dose of tedu-
and the parenteral volume was decreased by ~350 mL/day in glutide (25 patients receiving 0.05 mg/kg/day and 27 patients
the 0.05 mg/kg/day teduglutide dose group, whereas the oral receiving 0.10 mg/kg/day) for a total length of 52 weeks. As
fluid intake decreased by ~350 mL/day and the parenteral in the initial RCT, the primary efficacy end point was a clini-
volume decreased by ~350 mL/day in the 0.10 mg/kg/day cal response defined as reduction of 20–100% in weekly PS
teduglutide dose group. Thereby, it is estimated that the true volume at week 52 compared to baseline.
Throughout the study period a progressive PS volume jejunostomy/ileostomy; group 2, ≥50% colon in continuity
reduction was reported in the teduglutide-treated groups, without stoma; and group 3, other colon anatomies), and dis-
greatest in the 0.05 mg/kg/day group. At week 24 (end of ease features (with inflammatory bowel disease, mesenteric
Study 004) 46% of the patients in the 0.05-mg/kg/day group vascular diseases, or other conditions). The absolute effects
and 25% of the patients in the 0.10-mg/kg/day group had of teduglutide on absolute PS volume were significantly
achieved reductions of ≥20% of baseline PS volume. These greater in group 1 patients (reduction of 919 ± 644 mL/
numbers were 68% and 52% in the respective 0.05 and day)—not only compared with patients given placebo
0.10 mg/kg/day groups. Translated into ≥1 day(s) off PN, (reduction of 340 ± 436 mL/day; P = .0112) but also com-
this was achieved in 68% of the patients in the 0.05 and 37% pared with teduglutide-treated patients in group 2 (reduction
in the 0.10-mg/kg/day group. Four patients completely of 355 ± 306 mL/day; P = .0066). Teduglutide had an inter-
weaned off from PS (3 during study 004 and 1 during the mediate effect on patients in group 3. A minority of patients
28-week extension study). Interestingly, 11 of the 19 non- with SBS and inflammatory bowel diseases had colon in
responders at week 24 became responders and achieved continuity (10.5% [n = 2/19]), whereas most patients with
reduction of ≥20% of baseline PS volume at week 52. In SBS and vascular or other diseases had colon in continuity
comparison, 4 of the 24 responders at week 24 became non- (84.4% [n = 27/32] and 67.6% [n = 23/34], respectively).
responders at week 52 [70]. These findings may inform initial parenteral support volume
An increase in fasting plasma citrulline levels from base- adjustments and management of these severely disabled
line was seen at week 52 of 68% and 86% in the 0.05 and patients.
0.10 mg/kg/day groups respectively. The levels were Study 021 was an open label long term extension of study
decreased, but did not return to baseline levels, by 20% and 020 in which teduglutide 0.05 mg/kg/day was evaluated for
32% in the respective groups 4 weeks after end of treatment. up to 2 years [74]. A clinically meaningful response was
A second phase 3 pivotal study (the “020” or “STEPS” defined as a 20–100% reduction from baseline in weekly PS
study) was subsequently performed using a similar study volume. Eighty-eight patients were enrolled; 37 patients had
design but with a modified PS weaning protocol that allowed during the 24 week study (study 020) received teduglutide
for earlier (at week 2 vs. week 4) and more aggressive wean- (TED), n = 39 had received placebo (PBO) and =12 had been
ing (10–30% vs. 10%) of the optimized PS volume [71]. optimized and stabilized during 020, but not treated with
Forty-three SBS patients were randomized to a 0.05 mg/kg/ teduglutide (NT). All patients received daily subcutaneous
day dose of teduglutide and 43 patients to placebo for up to injections of 0.05 mg/kg/day teduglutide (TED). Thus, the
24 weeks. The proportion of teduglutide treated patients study population included three subgroups of TED/TED,
achieving a 20–100% reduction of PS at week 20 and 24 was PBO/TED and NT/TED. Including the 24 weeks in 020
significantly higher compared to placebo (27/43 patients, 63% study, total exposure to teduglutide was up to 30 months for
versus 13/43 patients, 30%, p = 0.002). Teduglutide treatment TED/TED and up to 24 months for the NT/TED and PBO/
resulted in a 4.4 L/week reduction in PS volume from a pre- TED subgroups.
treatment baseline of 12.9 L/week versus 2.3 L/week from a A total of 65 subjects (74%) successfully completed the
pre-treatment baseline of 13.2 L/week for placebo at week 24. 2 year study period. 28/30 subjects (93%) in the TED/TED
However, placebo-treated patients significantly increased their group demonstrated a clinical response with a mean reduc-
oral fluid intake by 1.6 ± 3.6 L/week (p < 0.009) in order to tion in PS volume from baseline of 7.6 (66%) L/week. This
maintain stable target urine output of 1.0–2.0 L/day. In patients number was 3.1 L/week (28 %) in 16/29 subjects (55%) in
treated with teduglutide, urine output continued to increase, the PBO/TED group and 4.0 L/week (39%) in 4/6 subjects
indicating increased net fluid absorption. Even at the end of (67%) in the NT/TED group.
the trial, further weaning appeared possible in patients treated Overall, TED resulted in clinically meaningful reductions
with teduglutide. The significant PS volume reduction with in PS requirements, allowing for additional days off PS per
teduglutide translated into additional clinical benefits: At the week; 25/65 (38%) subjects achieving an additional ≥3 day/
end of the treatment period (at Week 24), the need for PS infu- week reduction; 13 patients achieved total independence
sion was reduced by 1 or more days in more than half of the from PS versus 0 patients at the end of study 020.
patients in the teduglutide group (53.8%, 21/39) compared The effect on parenteral energy supply was reported only
with less than one quarter of those in the placebo group in the first of the two phase 3 teduglutide studies. Reductions
(23.1%, 9/39; p = 0.005) [72]. in parenteral energy at week 24 of 243 ± 450 kJ/day
Post-hoc analyses of the 020 study data have revealed that (p = 0.056), 447 ± 1051 kJ/day (p = 0.030) and 912 ± 1333 kJ/
a positive correlation between baseline PS volume and PS day (p = 0.001) were seen in the placebo group, teduglutide
volume reduction with teduglutide treatment 0.10 mg/kg/day group and teduglutide 0.05 mg/kg/day
(y = –0.3870x + 90.0279, r2 = 0.61; P < .0001) [73]. Patient group, respectively, compared with baseline. However, the
were divided in groups based on bowel anatomy (group 1, reductions in parenteral energy were not significant between
694 P. B. Jeppesen
active treatment (teduglutide 0.10 mg/kg/day and 0.05 mg/ with the potential weekly of monthly injections may be
kg/day) and placebo (p = 0.11) [69]. developed. However, in case of adverse events, a short half-
In the 35-day study with native GLP-2 treatment, the life would be desirable.
overall increase in energy absorption of 15 MJ translated into
a significant increase in body weight of 1.2 ± 1.0 kg
(p = 0.010) [55]. The study demonstrated positive findings Other Pro-adaptive Factors and Combinations
on urine creatinine excretion (0.7 ± 0.7 mmol/day, p = 0.02),
which suggests an increase in muscle mass or increase in As indicated, numerous growth factors may be involved in
renal function in relation to GLP-2 treatment. the postresectional intestinal adaptation, such as such as
In both the placebo-controlled clinical teduglutide phase glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide
3 studies, body weights remained stable in spite of PS reduc- YY, neurotensin, insulin-like growth factor-1, hepatocyte
tions. Numerical increases in body weight were seen growth factor, vascular endothelial growth factor, chole-
(0.9 ± 2.1 kg, at week 3 [68], 1.4 ± 2.5 kg, teduglutide cystokinin, epidermal growth factor, gastrin, insulin, vas-
0.10 mg/kg/day, and 1.2 ± 2.8 kg teduglutide 0.05 mg/kg/day cular endothelial growth factor, fibroblast growth factors
at week 24 [69], and 1.0 ± 2.8 kg, teduglutide 0.05 mg/kg/ and keratinocyte growth factor. GLP-2 is just one of many
day at week 24 [71]. However, none of these reached statisti- endogenously secreted hormones involved in the process
cal significance compared to placebo. of intestinal adaptation following intestinal resection.
Therefore, in theory, other hormones, or inhibitors of their
degradation enzymes, individually, or in concert with
Follow-Up Studies GLP-2, may have positive effects on the intestinal absorp-
tion in SBS patients. Results obtained so far have been
The post-drug consequences of teduglutide treatment were demonstrated in preclinical studies and in small, open-
assessed in a descriptive, follow-up study, following the label, pilot-studies. In mice, inhibiting dipeptidyl pepti-
Study 004 [75]. Data were obtained from clinical visits at 0, dase-IV (DPP-IV), which is a serine protease cleaving
3, 6 and 12 months relative to discontinuation. Thirty-seven dipeptides from the N-terminal end with l-proline or l-ala-
patients (25 responders, 12 non-responders) were included nine at the penultimate position (e.g. GIP, GLP-1 and
and classified according to whether their PS volume GLP-2), has been suggested as a novel approach to pro-
decreased (DEC), remained unchanged (NEUT) in NEUT/ mote adaptation in SBS patients with preserved L-cell
DEC group or increased in INC group. secretion [76, 77]. Other peptides such as peptide YY, gli-
During the 12 months post discontinuation, in the centin, oxyntomodulin and GLP-1 have also been sug-
responders’ group, 12 had increased their PS volume (INC) gested in the treatment of SBS patients. In a small 1-month
to pre-drug volumes while n = 13 had maintained the same study, all five consecutive SBS patients with less than
PS volume or had further PS reduction (NEUT/DEC). Of the 90 cm of small bowel (4 with colon-in-continuity) experi-
three patients who weaned off PS while on teduglutide in enced improvements in stool frequency and form follow-
NEUT, all remained off PS 12 months post-drug. Accordingly, ing treatment with the GLP-1 agonist exanatide [78]. PS
BMI was decreased at 3, 6, and 12 months INC group was stopped successfully in 3 of the 5 patients.
(P = 001), but not in NEUT/DEC group. NEU/DEC group Antroduodenal manometry revealed continuous low ampli-
was characterized by longer median short bowel length tude gastric contractions during fasting which completely
(58 cm vs 35 cm), longer median colon length (85 cm vs normalized with exanatide. Another pilot study employing
58 cm) and more patients with colon in continuity (92% vs the GLP-1 analogue, liraglutide, showed promising results.
57%) compared to INC group. Also the PS volume reduction In an 8-week, open-label, pilot study, liraglutide was given
while on drug was greater in INC vs NEUT/DEC (−4.7 vs subcutaneously once-daily to eight end-jejunostomy
−1.9 L, P = .04). The complication rate was higher in INC patients, aged 63.4 ± 10.9 years (mean ± SD) and with
(13 total in 3 patients) than in NEUT/DEC (5 total in 3 small bowel lengths of 110 ± 66 cm. Seventy-two-hour
patients); corresponding to complication incidence rates per metabolic balance studies were performed before and at
person year of 1.5 for INC vs 0.38 for NEUT/DEC (P < 0.01). the end of treatment. Food intake was unrestricted. Oral
The complications consisted of multiple hospitalizations in fluid intake and parenteral support volume was kept con-
the three INC patients and one bloodstream infection and stant. Liraglutide reduced ostomy wet weight output by
four hospitalizations in three NEUT/DEC patients. 474 ± 563 g/day from 3249 ± 1352 to 2775 ± 1187 g/day
Other GLP-2 analogues with longer half-lives than tedu- (P = .049). Intestinal wet weight absorption tended to
glutide are currently under development. It is the hope that increase by 464 ± 557 g/day (P = .05), as did urine produc-
instead a lyophilized powder that requires daily injections tion by 765 ± 759 g/day (P = .02). Intestinal energy
and reconstitution before use, a more ready-to-use product absorption improved by 902 ± 882 kJ/day (P = .02) [79].
Likewise, acute effects were observed on intestinal tion dependence in adult patients with the short bowel syndrome.
Gastroenterology. 1999;117(5):1043–50.
absorption in nine SBS patients (2 with colon-in-continuity)
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Drug Absorption in Patients
with a Short Bowel
Uchu Meade, Nadia Gabriel, Roshni Patel, Maryam Clark,

Pritha Singh, Jeremy M.D. Nightingale,
and Richard Ng Kwet Shing
Key Points 6. Lipid soluble drugs need a long length of bowel to be

absorbed so are likely to be poorly absorbed in patients
1. The movement of a drug in the body (pharmacokinet- with a short bowel.
ics—absorption, distribution, metabolism and elimina- 7. The formulation of the drug being prescribed must be
tion) is altered in patients with a short bowel or small considered. One that readily forms a solution is optimal
bowel disease due to a reduction in the surface area for but often a medication that by-passes the upper gastroin-
drug adsorption, altered gastric or luminal pH (so pre- testinal tract may be the best option (e.g., parenteral
venting ionisation), a loss of the specific area where drug (injection/infusion), topical, buccal or rectal).
absorption takes place and/or reduced drug metabolism 8. Carefully monitor the patient (sometimes with therapeu-
within the intestinal wall. tic drug monitoring, if available) for both the desired
2. Many physicochemical properties influence absorption of clinical outcome and adverse drug reactions. With appro-
an oral drug. These include its: solubility; stability; par- priate additional qualifications, the core healthcare pro-
ticle size; dissolution rate; salt form; acid dissociation fessions of the nutrition support team should be able to
constant (pKa); lipophilicity; pH of ionisation; polymor- prescribe medication (in most countries).
phism and molecular weight.
3. A good understanding of the patient’s gastrointestinal
anatomy and physiology, and the use of basic pharmaco-
kinetic principles should ensure the prescribed medica- Introduction
tion elicits a pharmacological response.
4. Caution should be used with drugs that are efficacious In many countries, with additional qualifications, the core
within a narrow therapeutic range. healthcare professions of the nutrition support team (NST)
5. A knowledge of the biopharmaceutical classification sys- may be legally allowed to prescribe medications. An under-
tem (BCS) class helps predict absorption of oral drugs. A standing of how the prescribing of medications for patients
drug with high solubility and high permeability (Class I) with a short bowel (SB) differs from prescribing for patients
are absorbed quicker and therefore achieve much faster who have a normal functioning complete gastrointestinal
(time to maximum drug concentration (Tmax)) and tract (GIT) is critical. The pharmacokinetics of drugs can be
higher blood concentrations (Cmax) so there is likely to altered in SB patients and there need to be strategies that
be some absorption even with a very short bowel. ensure that the desired pharmacological outcome is obtained
from the prescribed drug.
This chapter gives a guide on how to better predict the
U. Meade (*) · N. Gabriel · R. Patel · M. Clark · P. Singh degree of absorption of medications in this heterogeneous
J. M.D. Nightingale group of patients with a SB. Since there is little or no pub-
lished information on the drug absorption of most individual
e-mail: [email protected]; [email protected];
[email protected]; [email protected]; medicines in patients with a SB (except warfarin, digoxin,
[email protected]; [email protected]; cyclosporine, nortriptyline and procainamide [1]), it is nec-
https://www.lnwh.nhs.uk essary to apply basic pharmacokinetic principles to predict
R. N. K. Shing the absorption of oral medications (Table 1).
Clinical Development, Norgine, Harefield, Uxbridge, UK

700 U. Meade et al.
Table 1 Factors that influence drug absorption in patients with a SB cally. Locally acting drugs are applied only to the areas
(adapted [1, 2])
where they are needed. These include nasal sprays, inhalers,
Physiological factors eye drops and topical preparations. Topical medication is
Remaining small bowel length often prescribed to manage luminal GIT conditions such as
Condition (integrity) of remaining bowel
ulcerative colitis (e.g. mesalazine or steroid suppositories or
Intestinal motility (e.g. fast gastric emptying in jejunostomy patients)
Area where drug is normally absorbed (intact and with good enemas). Systemic drugs are those that enter the blood
integrity) stream/systemic circulation (from oral or parenteral routes)
Perfusion of the bowel and are delivered via the circulatory system to the targeted
Presence of bile and mucus site of action. Sufficient amounts of an active form of the
Biotransformation through gut bacteria medication must reach the site of action to elicit a pharmaco-
Physicochemical properties
logical response. The target cells for some medications are
Formulation of drug (tablet, capsule, elixir, enteric coated etc.)
Rate/extent of drug absorption
within the lumen of the GIT (e.g. loperamide) [3].
Drug solubility (ability to for a solution) and dissolution time/rate
Stability
Particle size Absorption and Bioavailability
Salt form
Acid dissociation constant (pKa) The most common route of medication administration is
Lipophilicity
oral, and the most common formulations are solid such as
pH of ionisation
Polymorphism
tablets and capsules. Alternatively, intravenous drug admin-
Molecular weight istration ensures that the entire dose enters the systemic cir-
Physiological requirement of drug (acid, alkaline, bile salts, culation, with bolus delivery allowing for high drug
enterohepatic recycling, ileal absorption, specific receptors, drug concentrations to be rapidly achieved or continuous infusion
interactions, food) used to give a more even and constant concentration and
Binding and localising in tissues
response. Only the intravenous route can achieve a desired
plasma concentration very rapidly [3, 4] thus it may appear a
desirable route for SB patients; however, there are disadvan-
Introduction to Pharmacokinetics tages with this route:
1. Only a limited number of drugs are formulated for intra-
The word pharmacokinetics is formed from two Greek venous use.
words; phamakon meaning drug and kinetikos meaning 2. Long-term intravenous access and its maintenance is
movement [3]. Pharmacokinetics is often said to be the effect needed for drugs requiring regular use.
of the body on the drug whilst pharmacodynamics is the 3. The patient will require training on the safe administra-
effect of the drug on the body. Pharmacokinetics follows the tion of drugs and the disposal of used ancillaries.
movement of medication through the body from intake or 4. There is a risk of sepsis and venous thrombosis.
administration to excretion [3]. Pharmacokinetics has four 5. In England primary care providers are not able to pre-
main components: scribe many drugs formulated for intravenous use and the
additional ancillaries needed for safe administration.
• Absorption (how the drug enters the systemic Drug bioavailability is the amount of medication that reaches
circulation) the systemic circulation, for example oral drug bioavailability
• Distribution (where the drug is dispersed once in the cir- is the amount of drug absorbed from the GIT. It ranges from 1,
culation, including binding and storage) meaning 100% of the drug reaches the systemic circulation, to
• Metabolism (how it is transformed or inactivated) 0, meaning none of the drug reaches the systemic circulation
• Excretion (how it is eliminated from the body) [4]. Oral bioavailability is usually determined in early phase
clinical studies and tends to be based on healthy male individu-
This forms the acronym ADME. als. The given value for an individual drug is usually available
Pharmacokinetics provides a quantitative and temporal from the pharmaceutical company that manufactures the drug.
concentration profile of the drug in the patient. Clinical The highest concentration is termed the maximum con-
teams may use this to predict how likely a drug is to be centration, Cmax. The time that the maximum concentration
adsorbed from the GIT of a patient with a SB. is reached is Tmax. (Fig. 1) Both Cmax and Tmax are depen-
When considering the pharmacokinetics of a drug, the dent on the rate at which the drug enters and is removed from
first step is to identify if the drug is acting locally or systemi- the body [1, 4]. Drugs that reach their Tmax quickly tend to
Drug Absorption in Patients with a Short Bowel 701
Serum concentraon
Drug Concentraon
Fig. 2 Therapeutic range of a drug

Fig. 1 Drug plasma concentration profile
be absorbed higher in the GIT so are more likely to absorbed

in patients with SB (e.g., fluconazole’s Tmax ranges from
0.5 to 1.5 h in the fasting state compared to amlodipine’s
range of 6–12 h post oral administration [5]).
Concentraon
Therapeutic Range of a Drug
The therapeutic range is the concentration range in which

the drug is eliciting a therapeutic response [6]. If the amount
of drug absorbed is too low then the concentration will fall
below the minimum needed to elicit the desired pharma-
ceutical response and so result in treatment failure, too high
and it results in toxic adverse effects (Fig. 2). As patients
with SB have numerous additional factors that can alter the
Fig. 3 Area under the concentration-time graph and half-life of a drug
drug absorption quite significantly from day to day, drugs
with a narrow therapeutic range should be avoided if alter-
native options are available. Drugs with a narrow therapeu-
tic range are those where small changes in blood The area under the concentration-time graph (AUC) is a
concentration can result in serious drug failure very quickly measure of the total systemic exposure the drug measured [7].
and should be closely monitored for adverse drug effects if The concentration profile before the peak is a measurement of
prescribed (e.g. warfarin, digoxin, cyclosporine, phenytoin, how quickly the drug enters the circulatory system and after
aminoglycosides and lithium). A higher dose than recom- the peak would be a measurement of how fast the drug is elim-
mended by the manufacturer, off label/off licensed, (see inated from the body. The half-life (T1/2) is the time taken for
below) is often needed to compensate for malabsorption of the plasma concentration of the drug to fall by half [3, 4]
a drug in SB patients. In this case great care must be taken (Fig. 3). With regular dosing and any required initial drug
to monitor for adverse drug effects; a list of these are pro- loading regimens, in line with the manufacture’s recommen-
vided by each drug manufacturer. All drugs have a thera- dations, it takes approximately five half-lives for a drug to
peutic range, drugs with a wide therapeutic range are most reach steady state (Fig. 2). Steady state is when the levels of a
desirable for SB patients as these have a wider margin of drug will stay within the therapeutic range for prolonged peri-
safety. ods, if the dosing and the rate of absorption remains unchanged
702 U. Meade et al.
[8]. Careful consideration needs to be given when prescribing absorption of digoxin is reduced while the absorption of
drugs with long half-lives for patients with a SB, as reaching paracetamol, aspirin and tetracycline is increased. Drugs such
steady state is needed to achieve a pharmaceutical outcome as codeine and loperamide are often used in patients with a
(e.g., the concentrations of antibiotics need to remain within high output stoma to slow intestinal motility so slowing tran-
their therapeutic range to ensure optimal treatment). sit, with the aim of increasing small bowel absorption [9].
Ultimately, the rate of absorption mainly depends upon
the time period the medicine is in contact with an appropriate
rug Absorption from the Gastrointestinal
D region of cell membrane (Fig. 4). If a medicine does find
Tract itself at such an appropriate site that absorption can take
place, assuming it has dissolved (is in solution), it can then
Formation of a solution is a prerequisite for drug to be permeate the cell membrane. In general there are four ways
absorbed from the GIT. For example, drugs in the solid for- in which medicines can cross the cell membrane. These are
mulations (tablets and capsules) must first be broken down to via passive diffusion (directly through the lipid membrane);
allow liberation of the drug from the protective outer cas- active transport (transporter mediated); facilitated passive
ing—called disintegration. Once disintegration has occurred diffusion (channel or carrier protein mediated); and pinocy-
the drug can form a solution—called dissolution. However, tosis (literally meaning cell drinking).
different formulation systems pose challenges. Some cap- Passive diffusion is where molecules that are small
sules and tablets are designed to remain intact for several enough can move from a region of higher concentration to a
hours after ingestion and/or only to disintegrate at a specified region of lower concentration through a selectively perme-
pH (modified-release/sustained-release preparations) [4]. able membrane down a concentration gradient. This is the
There are some capsules that have both rapid and prolonged simplest form of transport, not requiring any energy or spe-
release profiles, and some drugs that once liberated from the cial transporters. As cell membranes are amphipathic, have
main protective capsule or tablet coating, are themselves both hydrophilic and hydrophobic regions, small lipid solu-
coated for targeted purposes. For this reason, prolonged ble molecules diffuse most readily. Most medicines are either
release preparations (e.g., enteric coated steroids) are best weak acids or bases and therefore exist in either an ionised or
avoided in SB patients as they are likely to pass through the un-ionised form when in solution. The un-ionized forms are
short length of gut unchanged and without being absorbed. usually lipid soluble and can diffuse readily across the cell
The rate of gastric emptying is altered in SB patients and membrane. However, the proportion of ionised and un-
so affects the rate of drug absorption. Rapid or increased gas- ionised forms present at any specific region is also influenced
tric emptying (e.g., in patients with a high jejunostomy) by the pH and pKa. Simplistically, medicines that are weak
(chapter “Physiology and Problems of a Short Bowel”) may acids are better absorbed in acidic environments and weak
reduce the time available for disintegration and dissolution, bases prefer more alkaline environments, where their un-
and the exposure time to an acidic pH (if the patient is not ionised forms predominate. Strong acids (pKa less than 3)
taking a PPI). For example, when metoclopramide (which and strong bases (pKa 10 or above) are poorly absorbed as
promotes gastric emptying) is administered with digoxin, the they are fully ionised [4]. pKa is an acid dissociation con-
Fig. 4 Factors controlling

drug absorption
stant and should not be confused with pH. Absorption will The most common limiting factor to drug absorption via
occur at the site in the GIT where the pH is optimal to allow the GIT is poor aqueous solubility and permeability of a drug
sufficient drug molecules in the non-ionised form to be molecule. In order for permeation through the GIT membranes
absorbed into the enterocytes [10]. In reality, the majority of to occur, the active ingredient of the drug must first dissolve in
a drug is actually absorbed from the small intestine due to the gastrointestinal fluids. Hence, drugs which are poorly water
far greater surface area and epithelia specifically evolved to soluble will display dissolution rate-limited absorption [11].
be more permeable. In relation to gases for inhaled medi- The upper small intestine has a relatively high blood flow
cines, the same principle applies, but here we refer to the and contains long villi, which increase the surface area, as
gradient as partial pressures of the gas. well as having an optimal pH for drug absorption. Although
Active transport does require energy and occurs even against drugs can be absorbed in other regions of the gastrointestinal
a concentration gradient. For molecules to utilise this method, tract, the upper small intestine is the site of most absorption.
the molecule must attach itself to carrier proteins or transport- Minimal drug absorption occurs in the large intestine
ers found on the membrane surface. The rate of absorption is although some slow-release drugs are absorbed here, as well
now dependent on the number of compatible transporters that as drugs such as 5-aminosalicylates where their main target
are expressed on the surface of the membrane and are prone to is the large intestine. Patients with a colostomy and an intact
saturation. Transporters come in many various forms, but the small intestine are unlikely to experience significant issues
one thing they have in common is that they have evolved to with drug absorption [9].
extract those nutrients that we cannot synthesise ourselves. For Studies conducted in rats have demonstrated that drug
this reason, most of the medicines that use this method of absorption from the colon is of little significance. The pres-
absorption tend to resemble these nutrients such as vitamins, ence of efficient epithelial cell junctions within the colon is
minerals, amino acids, etc. For the same reason many trans- one explanation for the negligible paracellular absorption at
porters are only found in certain regions of the GI tract. this site within the gut. Also, due to the colon’s active role in
Facilitated passive diffusion can apply to those molecules water absorption, the colonic contents are highly viscous
that are not lipid soluble but seem to move through the mem- which leads to decreased dissolution and diffusion through
branes quite easily, again without the utilisation of energy the membrane of the dissolved drug molecules. As a result of
down a concentration gradient. This is because membranes this, drugs released in the colon remain exposed to the colonic
also contain various channels and carrier proteins that act like mucosa for prolonged periods compensating to some extent
small tubes or funnels connecting the outside to the inside. for the decreased surface area for drug absorption [12].
These channels and carrier proteins exist to allow ionised Consideration should be given when prescribing rectal drug
nutrients to be absorbed and so certain medicines can borrow formulations in SB patients if a systemic effect if desired.
these channels in a similar way to active transporters. The rate Following bowel resection (+/− stoma formation) there is
of absorption is dependent on the number of compatible chan- a relationship between remaining small intestine length and
nels or carrier proteins that are expressed on the membrane. drug absorption. Patients with SB experience impaired
Pinocytosis is where external products are engulfed absorption of macro- and micronutrients as well as fluids and
through invagination of the cell membrane to produce a ves- drugs. Another important factor is the quality of the remain-
icle holding the product inside the cell. This route of absorp- ing bowel, particularly in patients with underlying disease.
tion is rarely utilised in drug design. Patients with Crohn’s disease may experience absorption
Absorption of drug molecules is also determined by the issues despite having a normal length of remaining small
mucous layer, the expression and regulation of tight junc- intestine. In Crohn’s disease active inflammation reduces villi
tions, and the presence of trans-porters and enzymes in epi- contact and luminal permeability, and stricturing can prevent
thelial cells [10]. The expression of tight junctions differs tablets and capsules from reaching the necessary absorption
between the stomach, small intestine and colon thereby sites and in other situations may slow transit allowing more
affecting the rate of passive paracellular drug absorption time for absorption [9]. Relieving the stricture in some cases
within each region. This difference results in a relatively can lead to changes in absorption as the transit times suddenly
leaky barrier in the small bowel (most leaky in jejunum and change, so it is important to always monitor drug efficacy and
less so in ileum), and most efficient epithelial junctions within safety whenever an anatomical change occurs.
the gastric and colonic mucosa [10]. The intestinal absorption Worsening of inflammatory disease can also be a result of
of a few drugs depends on carrier-mediated transport; reduced bioavailability of oral drugs such as azathioprine
levodopa is absorbed via a carrier which usually transports and budesonide, therefore leading to increased inflamma-
phenylalanine and fluorouracil is absorbed via a carrier which tion, disease progression and further intestine resections.
usually transports natural pyrimidines. Calcium is absorbed Coeliac disease patients, if untreated have villous atrophy
via a vitamin D-dependent carrier system and iron is absorbed and a reduced functional absorptive area so will have prob-
in the jejunum via specific carriers in the mucosa [4]. lems in absorbing some medications [9].
704 U. Meade et al.
solves within 15 min in the following media: 0.1 M HCl or

Biopharmaceutics Classification System simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or
simulated intestinal fluid. The BCS Database is open access
The Biopharmaceutics Classification System (BCS) is used and can be found on the internet [13]
by: the US Food and Drug Administration (FDA), European BCS Class I (high permeability and high solubility) medi-
Medicines Agency (EMA), and World Health Organisation cations are likely to have a lower time to maximum concen-
(WHO) to standardise data relating to the aqueous solubility tration and more likely to be adequately absorbed even in
(disintegration and dissolution) and absorption (permeabil- patients with a very short bowel. Examples include metopro-
ity) of oral drug formulations made by different manufactur- lol and paracetamol. See Tables 4, 5 and 6 at the end and the
ers. The drugs are classified in BCS according to solubility, BCS Database (which can be accessed via http://www.ddfint.
permeability, and dissolution tests (Table 2). All drugs have org) for more examples of commonly prescribed drug’s BCS
had to be classified with this system since 2000. class and Tmax.
Solubility: A drug substance is considered “highly solu- Examples of Tmax and biopharmaceutical classification
ble” when the highest single therapeutic dose strength is for many commonly used drugs are given in Tables 3, 4, and 5.
soluble in 250 mL or less of aqueous media over a pH range
of 1–6.8 at 37 ± 1 °C. At least three pHs within this range,
Table 2 Biopharmaceutics classification system
including buffers at pH 1.2, 4.5 and 6.8, should be evaluated,
including solubility at the pH of lowest solubility if it is
within the specified pH range and should demonstrate that Permeability
solubility is maintained over relevant timeframes to accom-
modate the expected duration of absorption [13]. S High Low
Permeability: A drug substance is considered to be o
“highly permeable” when the extent of the absorption (par- l High Class I Class III
ent drug plus metabolites) in humans is determined to be u
≥85% of an administered dose, based on absolute bioavail-
b
ability or mass balance determination i.e., comparison of
i
bioavailability between intravenous and non-intravenous (in Low
this case oral) routes of administration. Alternatively for per-
l Class II Class IV
meability non-human systems can be used (such as in-vitro i
culture methods—e.g., Caco-2 cell lines) [13]. t
A product is considered rapidly dissolving when no less y
than 85% of the labelled amount of the drug substance dis-
Table 3 Common antibiotics and predicted absorption in patients with a SB

Class ABx Absorption site BCS Tmax (h)
Penicillina Amoxicillin Absorbed in the duodenum and jejunum, reduced absorption in ileum, not Class IV (high 1.5
absorbed in colon [14] solubility at
lowest dose)
Flucloxacillin Unknown – –
Penicillin V Unknown Class I –
Cephalosporin Cefalexin Not absorbed in the stomach. Absorbed mainly in upper intestine: mainly – 1
in duodenum, reduced absorption in jejunum [15, 16]. (One paediatric
study found 10–50% reduction in absorption in children with extensive
small bowel resection, but therapeutic range was still achieved) [17]
Marcolidesa Erythromycin Absorbed mainly in the duodenum [16]. Limited evidence suggesting Class II 1b
some absorption in jejunum and ileum
Azithromycin Absorbed mainly in the duodenum [18] Class II 2–3
Clarithromycin Absorbed throughout whole GI tract [16] Class II –
Quinolones Ciprofloxacin Absorbed mainly in upper GI tract/duodenum, limited absorption in Class III 1–2
jejunum (higher doses maybe needed/consider alternative routes) [16, 19]
Levofloxacin Absorbed mainly in upper GI tract/duodenum, limited absorption in Class III 1–2
jejunum (higher doses maybe needed/consider alternative routes) [16]
Table 3 (continued)
Class ABx Absorption site BCS Tmax (h)
Tetracycline Doxycyline Mainly absorbed in the duodenum [20] Class IV 2–4
Minocylcine Absorbed in stomach, duodenum and jejunum, but Less suitable for – –
prescribing as per BNF due to higher risk of lupus-erythematosus-like
syndrome
Others Linezolid Unknown. (absorption start in stomach and continued in small intestine, Class IV 2
maybe limited if administered directly in jejunum) [16]
Trimethoprim/ Unknown. One paediatric study found 10–50% reduction in absorption in Class IV (high 1–4
Co-trimoxazole children with extensive small bowel resection, but therapeutic range was solubility at
still achieved [17] lowest dose)
Metronidazole Unknown, no studies (well absorbed in the small intestines) [16] Class IV (high 1–2
solubility at
lowest dose)
Rifampicin Animal studies suggests maximum absorption in the stomach [21] Class II 2–4 (on
empty
stomach)
Isoniazid Animal studies suggest poor absorption in stomach, mainly absorbed in Class III –
duodenum, jejunum and ileum [21]
a
NB: a small study in five children with SBS (>100 cm SB resection) found inadequate absorption of oral penicillin and macrolide to achieve thera-
peutic concentrations. Author suggested alternative routes of administration [14]
b
Calculation based on erythromycin ethylsuccinate granules
Table 4 Common antifungal and antivirals drugs and predicted absorption in patients with a SB
Antifungal/antivirals Absorption site BCS Tmax (h)
Fluconazole Unknown (absorbs well in post-pyloric enteral tubes) [22]. Conflicting Class III 0.5–1.5 (fasting
recommendations from various guidelines/sources regarding dose adjustments in state)
jejunal administration [16]
Voriconazole Unknown (studies show similar absorption in administration via jejunostomy and Class II 1–2
oral administration) [23]
Aciclovir Upper GI tract—potentially duodenum? (Poor bioavailability even in normal Class IV –
individuals—15–30%) [24–26]
Table 5 Predicted absorption of drugs commonly prescribed (in the UK) to patients with a SB
BCS
Drug class Drug name Tmax (h) class Comments
Analgesics Paracetamol [27–29] 0.5–1 I –
Codeine Phosphate [27, 1 I –
30]
Morphine, liquid [29, 0.25 III Morphine undergoes significant first pass metabolism in the liver
31, 32] resulting in a systemic bioavailability of approximately 25%
Oxycodone [27, 33, 34] 1–1.5 IV This is for immediate release oral formulations
Fentanyl [27] – – Undergoes significant first pass metabolism in the liver, buccal
absorption is used to bypass GIT absorption
Gabapentin [27] 2–3 III Absorbed from the proximal small bowel
Pregabalin [27, 35] 1 I –
Antiarrhythmics Bisoprolol [27] 1–3 I –
Atenolol [27] 2–4 III –
Digoxin [27] 1.5 III Proximal small bowel
Amiodarone [29, 36] 4.5 II The Tmax is recorded when oral tablet administered with food
Anticoagulants Warfarin [27] 3–6 II –
Rivaroxaban [29, 37] 2–3 II Oral bioavailability increased when taken with food
Apixaban [29, 38] 3–4 III –
(continued)
706 U. Meade et al.
Table 5 (continued)
BCS
Drug class Drug name Tmax (h) class Comments
Anticonvulsants Sodium valproate [29, 5 I –
39]
Phenytoin [27] 2–4 II –
Levetiracetam [27] 1–1.5 I –
Lorazepam [27] 2 I –
Carbamazepine [27] 2–liquid II –
6–chewable
tablets
12–tablets
Antidepressants Citalopram [27] 2–4 I –
Fluoxetine [27] 6–8 I –
Amitriptyline [29, 40] 4 I –
Mirtazapine [27] 2 I –
Venlafaxine [27] 2 I –
Antiemetics Cyclizine [29, 41] 2 I –
Ondansetron [27] 1–1.5 I –
Metoclopramide [27] 0.5–2 III –
Antihypertensives Ramipril [27] 2 I –
Doxazosin [27] 2–4 I –
Losartan [27] 1 II –
Lisinopril [27] 7 III –
Amlodipine [27] 6–12 I –
Antihyperglycemics Metformin [27] 2.5 III The effective permeability at the proximal and distal small bowel
is similar
Gliclazide [29, 42] 2–4 II –
Diuretics Furosemide [27] 1 IV Jejunum
Bumetanide [29] 1–2 II –
Bendroflumethiazide 2 – –
[43]
Spironolactone [27] 1–4 II –
Sedatives Zopiclone [29, 44, 45] 1–1.5 I Time to peak plasma levels has been delayed in cirrhotic patients
(from 2 to 4 h)
Haloperidol [27, 29] 3–6 II –
Temazepam [27, 29] 1 II –
Midazolam [29, 46] 0.5–1 I After oromucosal administration midazolam is absorbed rapidly
lipid-lowering Simvastatin [27] 1–2 II –
medications
Atorvastatin [27] 1–2 II –
Pravastatin [27] 1.5 III –
Proton Pump Omeprazole [27, 29] 0.5 II Proximal to mid–small bowel
Inhibitors
Lansoprazole [27] 2 I –
Esomeprazole [27, 29] 1–2 II Proximal small bowel
Levothyroxine [27] 2 III Jejunum
Others Alendronic Acid [27, 1 III Better absorbed from jejunum than the duodenum
47]
Table 6 Pharmacokinetics of loperamide formulations [68–72]

Onset of Half-life Cost for 2 mg
Preparation action (h) (h) dose (£)
Loperamide syrup 1 11 0.11
1 mg/5 mL
Loperamide capsules 1 11 0.04
Loperamide tablets 1 11 0.05
Loperamide melts 1 11 0.76
rug Formulations and Routes

D lternative Routes of Administration in SB
A
of Administration for SB Patients Patients
Due to the difficulties of obtaining good oral absorption in When switching routes of administration (e.g. between oral
SB, alternative routes or methods often need to be consid- to oro-mucosal, transdermal, rectal, parenteral, etc.) or for-
ered. When switching from one route of administration or mulations of the same drug or to a different drug it is impor-
formulation to another, there are potential issues which need tant to ensure the desired clinical effect is still achieved. The
to be considered (e.g., with or without food, avoidance of switch must be done carefully while understanding the phar-
certain foods etc.) and additional monitoring may be needed. macokinetics of the medication, so the correct dose is pre-
For some medications such as mesalazine, the release scribed. Once a change is made, monitoring for side effects
profile and therefore the desired effect of the medication dif- and efficacy is also important and comes under the prescrib-
fers between brands. For example, Asacol® is released in the ing responsibilities.
terminal ileum and large intestine whereas Pentasa® begins
to release from the duodenum, therefore depending on where
the desired effect is intended can be affected by the brand of Oro-mucosal Route
medication prescribed. Brands may also have differences in
their licensed indications therefore may not be licensed to be The oro-mucosal route of drug delivery involves two meth-
prescribed for the same indications as other brands of the ods, buccal and sublingual.
same active drug. The buccal mucosa lines the inner cheek and is made of a
Switching formulations are often made with good reason, thin layer of keratinised and non-keratinised epithelia. Drug
for example swapping to liquid preparations can help in absorption occurs through the non-keratinised sections of the
administration via an enteral tube and reduce the chances of mucosa. Buccal formulations are placed in the mouth
the tube becoming blocked compared to the administration between the upper gums and cheek and absorption into the
of crushed tablets. Also, as mentioned above, in SB switch- systemic circulation occurs via the brachiocephalic vein
ing from a modified release to an immediate release formula- [50].
tion allows for better absorption, but switching may lead to Some drugs are extracted and metabolised to inactive
dosing changes and potentially more frequent drug forms by the liver and sometimes the GIT wall, this is known
administration. as first pass or presystemic metabolism. This results in
Another difference between various brands of the same reduced oral bioavailability which can be problematic in
active drug or between formulations of the same drug of the patients with SB who already experience reduced absorption
same brand are the excipients. Excipients are the constitu- after oral administration. Drugs that undergo first pass
ents of a drug apart from the active substance. These can metabolism include levodopa, propranolol, and verapamil
include fillers, disintegrants, lubricants, colouring, antioxi- [4].
dants, preservatives, adjuvants, stabilisers, thickeners, emul- The advantages of the buccal or sublingual route are that
sifiers, solubilisers, permeation enhancers, flavouring, drugs avoid hepatic first pass metabolism as they are absorbed
aromatic substances etc., as well as the constituents of the straight into the systemic circulation. The extensive blood
outer covering of the medicinal products, e.g. gelatine cap- supply and permeable membranes make the oro-mucosal
sules [48]. Excipients change when switching from one for- route an attractive one for drug delivery. Onset of action is
mulation to another and some of these excipients may not be rapid, for example in the case of glyceryl trinitrate in angina.
well tolerated by patients. For example, when switching to Drug delivery can be better predicted as there is avoidance of
liquid preparations, some may contain sweeteners such as numerous pH changes that would be encountered as the drug
sorbitol which can worsen high output stomas, or they may travel through the gastrointestinal tract. Administration is
contain alcohol which may not be appropriate for some easy and more appealing to patients in comparison to injec-
patients due to their religious beliefs. tions, for example administration of buccal prochlorperazine
Oral bioavailability of medicines can also change when for nausea and vomiting compared to intravenous cyclizine,
switching from one formulation to another. For example, which is often used in the UK [51]. If longer term anti-
digoxin tablets and liquid are not bioequivalent therefore emetics are required, buccal prochlorperazine is considered
dose adjustment may be required. In practice this change is when oral tablets have either not worked or not been well
made safer as digoxin levels are closely monitored, however tolerated by patients. In general, using the buccal route can
this is not always the case with other drugs. When switching avoid changes in gastrointestinal motility and gastric secre-
from oral opioids to topical patches adequate pain relief must tion which can be associated with nausea [52].
be maintained. Often a dose reduction is required when Problems can occur however as absorption through this
switching from oral opioids to patches and this can lead to a route may be erratic due to the production of saliva which
subtherapeutic effect [49]. can wash away the drug thereby reducing contact time. Taste
708 U. Meade et al.
or local irritancy can affect patient adherence. Large, due to possible opioid-induced hyperalgesia, the calculated
hydrophilic molecules are often not permeable through the equivalent dose of the new opioid should be reduced by one-
membrane and therefore not suitable via this route [51]. quarter to one-half [57, 58].
The availability of an oro-mucosal formulation option Another advantage are that formulations of buprenor-
may not automatically mean the drug is absorbed through the phine transdermal patches are available as 72-hourly,
buccal or sublingual route (e.g., loperamide and omepra- 96-hourly and 7-day patches. It is important to note the
zole). Such preparations result in the disintegration and dis- buprenorphine patches come in various brands which all
solution only starting in the buccal cavity with the aim of have different pharmacokinetic properties, and this should be
increasing time for absorption and or contact time with the taken into account if a patient is to switch from one brand to
target receptors in the gut, when the drug is in solution [53, another [58].
54]. However, drugs such as fentanyl are absorbed directly When evaluating the analgesic effect, the patch should be
from the buccal cavity so avoiding first pass metabolism by worn for 24 h before making a change to allow for the grad-
the liver [55]. ual increase in plasma concentration (e.g. of fentanyl) and
previous analgesic therapy should be phased out gradually
from the time of first patch application as it can take 20 h or
Transdermal more for the plasma-fentanyl concentration to decrease by
50% [57, 58]. Patients should be warned to remove old
The transdermal route of administration is often more desir- patches when placing a new patch as the old patch may con-
able to patients as it avoids the oral route altogether, there- tinue to provide sub-therapeutic doses of the drug in addition
fore reducing the daily pill burden, reduced GIT absorption to the new patch and could lead to overdose. In addition
issues and potential for GIT side effects of medications is changes in temperature have been known to increase drug
reduced. This route is particularly useful for patients with SB absorption, with pyrexia, hot bath or sauna or the application
where taking oral medications can cause nausea and vomit- of heat to the patch increasing local skin blood flow and
ing or in whom bowel transit time is too short and therefore hence increase absorption of the drug leading to overdosing
the drug is not absorbed. This route of administration is usu- [59].
ally in the form of creams, ointments, gels or as patches When conventional treatment does not work an alterna-
applied directly to a non-hairy part of the skin which can be tive analgesia to opioids is a lidocaine patch. However, lido-
hidden under clothing. The pharmacokinetic profiles for caine medicated plasters are only licensed for neuropathic
medications via the transdermal route provide fewer peaks pain associated with post-herpetic neuralgia as there is not
than with the oral route therefore reducing occurrence of tox- enough evidence on lidocaine to support neuropathic pain
icity [56]. Not many drugs can be administered via this route (on its own) or for management of any other pain both acute
as the drug needs to pass through several layers of skin or chronic but has been used in SB patients. This use is off
before it reaches the dermal layer where it can then enter the label/ off license.
systemic circulation. The two routes through the skin are
intercellularly, usually lipophilic molecules, or intracellu-
larly, usually hydrophilic molecules [56]. Parenteral Administration
For example, in SB, the oral route for opioids is not
always effective therefore some patients may be prescribed Parenteral refers to administering medications without going
analgesia via the transdermal route in the form of patches. It through the digestive system. The word “parenteral” comes
is important to note that when switching from an oral formu- from the roots ‘para-’, or ‘outside of’, and ‘-enteral’ which
lation to patches, dose modifications may be required. refers to the alimentary, or digestive, system. The most com-
Opioids tend to be the most common class of drug prescribe mon parenteral routes of drug administration are intrave-
for SB patients using the transdermal formulation route. nous, intramuscular and subcutaneous [60].
Available transdermal preparations, such as fentanyl and The advantages are that it can be used for drugs that are
buprenorphine, are not suitable for acute pain or in patients poorly absorbed, degraded, or ineffective if given orally and
whose analgesic requirements are changing rapidly because has predictable pharmacokinetics in SB patients, intravenous
the long time to steady state prevents rapid titration of the administration provides immediate quick onset of action
dose. The total daily dose of oral morphine can be switched with 100% bioavailability. However, it is invasive, can lead
to an approximate equivalent strength of fentanyl and to bruising, bleeding and blood clots at the infusion site. The
buprenorphine patches. For example, morphine salt 12 mg patient will also need to be trained on how to administer and
daily is approximately equivalent to a buprenorphine 5 μg reconstitute the medication at home, organise repeated visits
patch and morphine salt 20 mg daily is approximately equiv- to a healthcare professional or, if available, a home visit by a
alent to a fentanyl 12 μg patch. However, when switching healthcare professional may need to be organised to aid
administration and compliance. Intravenous access will need is important to check if switching is equivalent, for example
to be installed and maintained. It may also require additional with carbamazepine, 100 mg tablets are equivalent to 125 mg
medications and ancillaries to be prescribed such as water of suppositories. In general most drugs will not achieve the
for injection, sodium chloride infusion bags, syringes, etc. same plasma levels when equivalent doses are given rectally
The patient will also need to adhere to strict aseptic tech- compared to the oral route, but if oral delivery is proving to
nique, which can be tricky in a home environment. Moreover, be a real concern, then the rectal route can be very useful
considerations need to be made based on the patient’s phy- [62]. Additionally, consider monitoring drug levels when
sique as intestinal patients tend to be underweight and mal- doses have been changed or if there is concern about under
nourished and this can affect the suitability of injecting for or over-dosing [63]. Drugs commonly given rectally for a
example, subcutaneously which is injected into a fatty area systemic effect include analgesics (paracetamol), antiemet-
of the abdomen or upper thigh and in the muscle if prescrib- ics (prochlorpromazine) and antibiotics (metronidazole).
ing an intramuscular injection. Other considerations include
physical ability and dexterity that may be exacerbated by
conditions such as arthritis. Changing the Formulation
Specific drugs that are often utilised in SB are the soma-
tostatin analogues such as octreotide and lanreotide and are Altering a licensed drug formulation can be considered to
used off label/off license for controlling high output stomas, help improve drug absorption. Often crushing and dispersing
which are administered as injections. However, care must be tablets in water or opening capsules and dispersing the con-
taken as the use of octreotide in intestinal failure patients can tents in water before administration are tried. The theory is to
have disadvantages. The clinical response can be unpredict- start the disintegration and formation of solution sooner.
able, it increases the patients risk of developing cholethiasis, However, alteration of the dose form can cause risk to
it has been suggested that it may affect intestinal adaptation healthcare workers. For example, with cytotoxic medications
post-surgery, postprandial hypoglycaemia has been reported crushing can expose healthcare workers to aerosolization of
and injections can be unpleasant for patients [4]. Furthermore, the powder therefore this should be avoided. Crushing a tab-
it has been suggested that macronutrient absorption may be let can cause instability of the medication particularly if it
impaired by somatostatin in patients with SB, by inhibiting has a coating to protect it from light or the acidic environ-
glucose absorption and pancreatic enzyme secretion hence, ment of the stomach. This could lead to degradation of the
somatostatin analogues are only considered for patients when drug or irritation in the body due to release of irritants from
other strategies have not been effective, in reducing a high the dosage form. Alterations can cause changes in bioavail-
output [60, 61]. As lanreotide is a more expensive medication ability and this is important to consider with narrow thera-
and is being used off label/ off-license in this situation and it peutic range medications such as digoxin or phenytoin. Also,
is often not possible to obtain locally. Therefore prescribing, administration via an enteral tube can increase the chances of
cost and logistics will rest with the initiating specialised intes- the tube becoming blocked [64]. It is always advisable to
tinal rehabilitation team, in the UK. These considerations discuss any consideration to alter a drugs standard delivery
need to be made when trying to manage a high output stoma method with the local pharmacist.
that is not responding adequately to conventional treatment.
Classes of Drug Prescribed for SB Patients

Rectal
Antisecretory Drugs
While the rectal route is available for some patients, it may
not be available for many SB patients due to previous surgi- Acid production may be increased (gastric hypersecretion)
cal procedures where the rectum has been removed. Rectal in patients with a short bowel SB. High levels of gastric acid
drug administration can be erratic and less reliable due to can raise the amount of secretions entering the shortened
difficulties in drug retention particularly if a patient is suffer- bowel, and interfere with absorption. Drugs that reduce gas-
ing with diarrhoea or loose stools. It is also reported that only tric acid secretion reduce jejunostomy output. Omeprazole is
50% of drug absorbed via the rectum undergoes first pass readily absorbed in the duodenum and upper small bowel,
metabolism as the upper part of the rectal venous blood sup- but if less than 50 cm of jejunum remains, it may need to be
ply is connected to the portal system into the liver, whereas given intravenously. Proton pump inhibitors, such as panto-
the lower part is directly connected with the systemic circu- prazole intravenous, are commonly given to patients with a
lation. This is just an approximation as it may also depend on jejunostomy for long term administration; but may increase
the formulation of drug used, which tends to be as either a the risk of osteoporosis, so should maintain an adequate
solution or suppository. When considering the rectal route it intake of calcium and vitamin D [65, 66].
710 U. Meade et al.
Antiemetics have a product license to advertise and sell a medicine, also

known as a marketing authorisation. In the UK this is given
Nausea and vomiting is often experienced by patients with this by the Medicines and Healthcare Products Regulatory
SB. All formulations of cyclizine are often prescribed for SB Agency (MHRA), various national regulatory authorities or
patients, e.g., intravenous, subcutaneous, intramuscular and the European Medicines Agency (EMA) in Europe, and in
oral. Cyclizine is licensed for the treatment or prevention of USA by the Food and Drug Administration (FDA). The
nausea, vomiting and labyrinth disorders including vertigo licence is often referred to as the label of the drug, hence the
and motion sickness. It is a class 1 drug in the biopharmaceu- term off label. An unlicensed drug has no product license/
tical classification which means it has high permeability and marketing authorisation.
high solubility; hence most SB patients will achieve a phar- If the desired pharmacological affect is not being achieved
macological benefit with the oral formulation. However, all from the prescribed drug, as per its licenced dosing regimen,
formulation of cyclizine can cause euphoric and hallucina- first it is worthwhile determining if there are alternative
tory effects and there have been reports of misuse and abuse drugs that can be used as per their licence before considering
of cyclizine. Cyclizine can also damage central and periph- off licenced use or using an unlicensed drug to achieve the
eral lines and increase episodes of catheter-related blood desired effect. There must be governance in place when pre-
stream infections. For this reason, antiemetics such as ondan- scribing both off licensed and unlicensed medication or
setron (5HT3 antagonists) are preferred and are as effective routes, to protect the patient and the prescriber. There may be
as cyclizine (H1 antihistamine), although more expensive variations in local procedures in prescribing and obtaining
and commonly causes constipation [67]. off licensed and unlicensed medications. The prescriber
holds greater legal responsibilities when prescribing off
licensed/unlicensed medications and should monitor the
Antimotility Drugs drug’s therapeutic efficacy and safety. Cost may be a deter-
mining factor in choosing a treatment. There should be clear
When considering other formulations, it is also important to documentation of off licensed and unlicensed use. This
think about whether the new formulation is a better alterna- should include a rationale for the choice of drug, governance
tive or not. While switching from capsules or tablets to liq- procedures followed, monitoring, a prescribing plan and
uids may be easier for enteral administration or in those who documentation of discussions with the patient about risks
find it difficult to swallow, it may not always be suitable. For and benefits [73].
example, with loperamide for treating high output stomas, an
efficacious dose often requires many tablets or capsules,
2 mg are the only strength available in the UK, and patients Distal Administration of Medicines
often complain of seeing capsules being excreted whole into
their stoma bags. Switching to liquid loperamide may sound Information on the distal administration of medications is
attractive, however the volumes required to achieve the same poor and needs further research. Understanding the pharma-
dose can be significant which could worsen the output. cokinetics, and the individual properties of a drug help us
Loperamide liquid may also contain sorbitol that also wors- understand how a drug may be affected by distal administra-
ens outputs due to its laxative effect. Often the alternative is tion. As it is unlikely that manufacturers have tested this
to open capsules and dissolve the powder in a small amount method during the licensing process, it would be classified as
of water. This would be an unlicensed form of administration an unlicensed route, and therefore, a clinician recommend-
as opening the capsules is not covered in the manufacturers ing this method of drug administration would do so outside
licensing of loperamide capsules. Both options would be of a its license.
unlicensed however by using the capsules, the clinical out- There are several factors to be considered if using distal
come is more likely to be positive and costs can be reduced. administration; available drug formulations, the manufac-
One equivalent dose of liquid loperamide would cost more turer’s intended site of drug absorption, the anatomy of the
than double the price of an equivalent capsule dose, see distal stoma, consequences of potentially bypassing hepatic
Table 6. metabolism, and mechanisms for monitoring the drug’s
effects (chapter “Distal Feeding and Hydration”).
An important element to consider is the distal stoma site
Off Licensed Medicines location, as this will aid understanding and determine
whether the drug will be effectively absorbed/elicit its
An off licence (or “off label”) medication is one that is pre- desired effect. Distal administration of a medicine into an
scribed in a way that is not covered by its product license ileostomy or colostomy will differ considerably to a jejunos-
e.g., indication(s) and dosing regimen(s). A company must tomy that is in close proximity to the DJ flexure, for exam-
ple. As the latter is further up the GIT, the increased also on high risk drugs, or there are concerns with
downstream GIT length and surface area will enable a drug absorption.
to go through dissolution, absorption, and first-pass hepatic
metabolism, which may be required for certain pro-drugs i.e.
those that require metabolising to be converted to its active Chyme Reinfusion and Drug Absorption
form. Distal administration into a colostomy may only be
beneficial for drugs that are intended for release into the Chyme is the mixture of the digestive secretions, bile salts,
colon which may be the site of activity. and pre-digested food that is transformed into absorbable
Knowledge of the available drug formulations is impor- nutrients by enzymatic digestion [76]. Medication taken
tant, so that drug dissolution principles can be considered. A orally would also be present in this mixture, and once in the
solid tablet or capsule cannot be directly administered via a upper small intestine, drug absorption begins to occur into
distal stoma. the portal vein bloodstream to the liver, whereby hepatic
Drug efficacy principles are based around improving dis- first-pass metabolism takes place.
solution in the stomach or faster absorption of the active Chyme re-infusion (CR) is a technique used to artificially
ingredient throughout the GIT, or both [74]. If the disintegra- restore intestinal continuity between a proximal and distal
tion or dissolution in the stomach is bypassed, for distal stoma/mucous fistula [76]. The amount of chyme re-infused
administration to be an effective route, the drug needs to be is an important factor to consider, and this depends on the
administered in a dissolute form to allow absorption to occur; purpose, or intended outcome, of CR. One purpose is to use
this may be as a liquid preparation, crushed and dissolved CR as the main nutritional source, whereby the majority of
tablets or using the IV form enterally (the latter two options the stoma content (chyme) is re-infused. Studies have shown
being unlicensed routes). that this is an effective alternative method to parenteral nutri-
An awareness of the proportion of remaining small bowel tion, with the majority of the patients enrolled in these stud-
is also important as this will affect the amount of drug being ies being switched from parenteral nutrition to CR [77, 78].
absorbed, and hence undergoing hepatic first-pass metabo- In some centres or circumstances, only a small proportion
lism. Where absorption and hepatic first-pass metabolism is of chyme, 50–100 mL for example, is re-infused; the pur-
expected to be affected, it would be prudent to closely moni- pose of this is to maintain the distal gut function and reduce
tor a patient’s response to their medication both short and atrophic changes; however, the patient will still require nutri-
long-term. tional support using an alternative method.
It is also important to ensure that patients are monitored Knowledge of the amount of CR is crucial in understand-
for drug effect and/or toxicity. Some drugs have measurable ing how we may predict a drug will perform. Also, we must
effects, for example, measuring a patient’s blood pressure know what part of the bowel is removed, the bowel length
indicates that the antihypertensive prescribed is sufficiently upwards of the proximal and downwards of the distal sto-
controlling the blood pressure. Other drugs however, do not mas, and the anatomy of the two stomas.
possess outwardly ‘measurable’ effects, and so will require Patients with a high-output stoma, taking oral medication,
another form of monitoring. This is also important in patients will have had careful monitoring and fine dose adjustment to
who are established on a drug via the enteral route, and then ensure they are receiving a therapeutic drug dose. If they are
converted to administration via distal route, as this will eligible for a CR device, the drug(s) that were once discarded
require re-establishment of clinical effect/benefit, due to a along with the stoma output will be re-infused, the patient
potential shift in absorption site and concentrations. will be re-exposed to the drug, and this extended exposure
Drugs that are classified as having a narrow therapeutic may impact the plasma drug levels and the dose response
index, i.e. narrow window between the effective dose and curve. A study looking into a novel device mentions how
the dose at which they produce adverse toxic effects, are some patients recruited experienced changes to their medica-
regularly monitored by blood sampling [75]. This ensures tion absorption, for example, constipation requiring loper-
that patients are not put at risk and the dosing is within amide withdrawal, drowsiness requiring dose reduction of
acceptable limits. However, this requires accurate timing of analgesic/anxiolytic doses, and a flare of trigeminal neuralgia
testing and relying on patients to adhere to monitoring post stoma creation that resolved on initiation of CR, which
requirements and implementing dose adjustments. This is a all indicate that increased drug absorption occurred [78].
useful method to utilise wherever possible if considering Although these are only a handful of patients, they prove
administering medication distally. Consulting with local or the concept that patients should be monitored in the acute
national hospital laboratories as to what drugs they are able phase, and an investment made into observing and adjusting
to monitor would be useful especially where the patient is medication doses such that adverse effects are reduced [78].
712 U. Meade et al.
Box 1: Case Study—Heart Failure/High Output Stoma/Anticoagulation

A 62 year old woman has a high output ileostomy with approximately 2.6 L output over 24 h. She has dry oral mucus
membranes, dark rings round her eyes and reduced urine output of 560 mL/24 h.
Events Prior to Reviewing Patient
Recent Medical and Surgical History
–– 4th December—Pulmonary oedema secondary to acute coronary syndrome (ACS).
–– 7th December—Reduced ejection fraction of 24% and impaired right ventricle (RV) function
–– 10th December—underwent percutaneous coronary intervention (PCI) due to ACS, (Troponin 7113 ng/L on 05th
December and 3669 ng/L on 07th December).
–– 13th December—Developed new right unilateral weakness. CT Head showed a subacute infarct involving middle
cerebral artery region.
–– 18th December—One week history of pyrexia of unknown origin prompted CT scan of chest/abdomen/pelvis
which showed an intestinal ileus in association with a suspected area of bowel ischemia in the distal ileum.
–– 19th December—Emergency laparotomy, right hemi-colectomy, small bowel resection and formation of double
barrelled ileostomy. Approximately 190 cm of small bowel (SB) remaining from duodenojejunal (DJ) flexure to a
small bowel stoma.
Past Medical History
–– 11 years ago—Non-ST elevated myocardial infarction (NSTEMI) and PCI
–– 8 years ago—Myocardial infarction with a coronary artery bypass graft
–– Asthma
–– Type 2 diabetes
Current Medication—(No known drug allergies. Simvastatin caused nightmares)

Drug Dose Frequency Route Alternative for a high output stoma patient
Paracetamol 1g Four times daily Intravenous Not needed as not using enteral route
Omeprazole 40 mg Twice daily Intravenous Not needed as not using enteral route
Loperamide 16 mg Four times daily Oral Open capsules and sprinkle contents into water. 30–60 min
before food
Codeine 60 mg Four times daily Oral Not needed as very small tablets. Could switch to non-sorbitol
containing syrup or linctus, 30–60 min before food
Aspirin 75 mg At night Oral Use dispersible tablets, with food
Ticagrelor 90 mg Twice daily Oral Oro-dispersible tablets available which can be dispersed in
water or placed on tongue and swallowed without water
Rosuvastatin 10 mg At night Oral Tablets can be crushed and mixed with water for
administration
Sertraline 100 mg At night Oral Tablets disperse in water within 1–5 min. They can also be
crushed and mixed with food
Bisoprolol 2.5 mg In the morning Oral Tablets can be crushed and mixed with water for
administration. Tablets will also disperse in 1–5 min in water
Metformin 1g Twice daily Oral Consider switching to subcutaneous insulin as Metformin can
exacerbate loose stools
Gliclazide 160 mg Twice daily Oral Consider switching to subcutaneous insulin
Losartan 100 mg Once daily Oral Tablets can be crushed and mixed with water for
administration
Apixaban 5 mg Twice daily Oral Tablets can be crushed and dispersed in water, glucose 5%,
apple juice or puree
Switch to Warfarin to allow INR checks and effective
monitoring of anticoagulation
Therapeutic drug monitoring for apixaban is now available
from some specialist centres in the UK
Budesonide/ 200 μg/6 μg Twice daily Inhaled Not needed as not using enteral route
Formoterol
Dry powder inhaler
Salbutamol 100 μg 100–200 μg Four times daily Inhaled Not needed as not using enteral route
inhaler when required
The reason for her high output stoma (HOS) was poor bowel quality despite sufficient small bowel length.
Biochemistry 1st February 2021
Investigation Result Normal range

Sodium 160 mmol/L 133–146 mmol/L
Potassium 3.2 mmol/L 3.5–5.3 mmol/L
Urea 15.7 mmol/L 2.5–7.8 mmol/L
Creatinine 63 mmol/L 44–80 mmol/L
Random urine sodium 28 mmol/L <20 mmol/L indicates dehydration
C-reactive protein 0.8 mg/L 0–5 mg/L
Serum Osmolality 356 mOsmol/kg 275–295 mOsmol/kg. >300 mOsmol/kg can indicate dehydration
Fluid balance chart over last 24 h for 1st February 2021
In Out
IV = 1000 mL sodium chloride 0.9% Stoma = 2600 mL
NG = flushes post medication − 60 mL water Urine = 560 mL
NG = Enteral feed 1000 mL over 24 h
Total = 2060 mL Total = 3160 mL (negative 1100 mL/24 h)
Physical examination/test Findings

Abdominal system Abdomen was flat and non-tender. No abdominal mass noted (if present may indicate tumour or sepsis)
and no enlargement of the spleen or liver. Normal bowel sounds. No abnormal findings
Stoma assessment Stoma pink, warm and healthy, no bleeding or break of skin barrier and no soreness. Stoma protruded
approximately 1.5 in. from the skin and had a sealed see-through stoma bag around it. A finger inserted
easily into the stoma with no stenosis. Stoma output was dark green/brown in colour and watery
Temperature Apyrexial. But had been ≥37.8 °C over the last 2 days. (may suggest an underlying infection preventing
the stoma output from settling). Regular doses of paracetamol were being taken and this may mask a
temperature
Observation chart Weight 65 kg, height 170 cm. BMI = 22.4 kg/m2
NEWS = 1. No requirement of oxygen, and was stable with a heart rate of 93 bpm (could be increased
due to dehydration or sepsis). Lying blood pressure was normal
Bloods & Urine sodium Urine sodium was at the low end of the normal range, suggesting a degree of dehydration. Urea was
raised and may suggest dehydration but the creatinine is within the normal range suggesting a large
amount of protein has been broken down (a bleed or much oral or parenteral feeding)
Peripheral oedema check Peripheral oedema can prevent optimal hydration. The patient had some pedal oedema which may be due
to immobilisation post stroke. Alternatively it can represent excessive parenteral saline or general
inflammation
Mucous membrane check Dry or cracked mucous membranes indicate dehydration
The tongue was dry, with no saliva around the teeth or tongue and the patient felt very thirsty
Cramps No muscle cramps, (Muscles cramps usually reflect sodium depletion but may occur with
hypomagnesaemia caused by a HOS)
Fluid balance check Daily fluid balance checks and daily weight measurement are crucial when managing HOS patients. The
fluid balance for the last 24 h showed a negative balance of 1100 mL/24 h
Urine check Urine output was more than the minimum of 0.5 mL/kg/h. Urine colour was a dark orange
Considerations When Caring for This Patient Cohort

This patient has fluctuating fluid requirements due to both intestinal and heart failure, which depend on the output from
her stoma. She may quickly become dehydrated or overhydrated if the incorrect amount of intravenous fluid is given
to replace her losses.
According to the British society of gastroenterology (BSG) guidelines for the management of patients with a short
bowel, there is further medication optimization which should be done for this patient. This patient is experiencing net
loss of fluid and sodium, and so should be prescribed 1 L of an oral electrolyte mix, an unlicensed solution which leads
to more sodium being absorbed from the bowel lumen [77]. These guidelines advise that a patient with 150–200 cm
normal functioning SB should be able to manage their HOS with optimized medication and electrolyte mix [79, 80].
714 U. Meade et al.
At this stage she is requiring IV fluids; however, the addition of electrolyte mix could help to reduce and ultimately
prevent this requirement.
As the heart starts to fail, renal perfusion reduces. The kidneys respond to this by increasing renin production, lead-
ing to aldosterone production, which is consequently followed by sodium and water retention. Arginine vasopressin
(AVP) is also released, further enhancing fluid retention, and stimulating thirst [81]. This stimulation of thirst will
cause a patient to drink, which in this patient’s case is detrimental to her hydration status as it will cause more losses
from the stoma if hypotonic fluids are ingested.
It is necessary to consider the absorption of critical cardiac medication in this type of patient. Her anticoagulants
and antiplatelet drugs are necessary to prevent another stroke or myocardial infraction. It is advised to look for alter-
nate routes of administration of the medications that can avoid using the bowel, such as transdermal or intravenous or
preparations which partly use the bowel such as sublingual or buccal. These drugs may need to be rationalised, such as
switching to subcutaneous insulin to manage diabetes rather than metformin, which may cause loose stools. See the
last column on the medication table which gives possible alternatives.
Nutrition teams should consider creating a care plan for their patient if they are to be discharged with intravenous
fluid. A care plan provides guidance on deciding the volume of fluid required, it utilizes physical assessment skills to
follow the plan appropriately.
Daily Monitoring Instructions

• On waking-up please empty your stoma bag and then weigh yourself and record your weight on your daily weight
chart.
• Over a 24 h period, measure and record your intakes and outputs on your daily fluid chart.
• Monitor signs of dehydration by noticing whether you feel thirsty, experience any dizziness on standing, pass less
urine than usual or whether your urine is darker than usual
• Monitor signs of over hydration by noticing whether you develop any worsening swelling of your ankles or short-
ness of breath after IV fluid.Use the information in the following care plan to decide fluid requirements:
Option A: Adequately hydrated
– Weight is stable E.g.

– Not thirsty & passing adequate amounts of urine Give 0.5 L 0.9% saline with 10 mmol MgSO4 three times a week (overnight)
– No worsening ankle swelling over 12 h Monday, Wednesday & Friday
Option B: Dehydration
• Weight loss of more than 2 kg E.g.
– Feels thirsty, or Give additional 1 L sodium chloride 0.9% over 10 h
– Passing less urine which is darker than usual, or
– Feels dizzy on standing
Option C: Over-hydration
• Weight gain of more than 2 kg E.g.
– Worsening swelling of ankles, or Do not give IV fluid until back to dry weight (only use 5% dextrose if any fluid
– Feels short of breath has to be given)
Planned Follow-Up and Monitoring Including Applicable Timeframes

The outcome of additional electrolyte mix measured on any given day reflects the day it is taken. Therefore, 2 days
shows two 24 h periods of fluid balance charts, etc., a useful timeframe to make any further changes. The electrolyte
mix may need to be stopped if it is simply adding to the fluid loss via stoma output, indicating very poor bowel
quality.
It is crucial to re-check the same blood investigations at the next patient review, with a priority to check serum
sodium as this was markedly increased due to dehydration.
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Distal Feeding and Hydration
Laurence Lacaze, Denis Picot, and Ronan Thibault
Key Points 7. Feed is delivered through a distal feeding tube using a

1. Infusion of feed and fluids and/or proximal bowel con- polymeric or semi-elemental enteral nutrition solution, or
tent into distal bowel (ileum or colon) via a temporary chyme, and/or hydration by using fluid containing salt.
loop enterostomy or an entero-atmospheric fistula may 8. Besides technical issues, the main side effects of DFH
be used as the sole source of nutrition/hydration as an may be abdominal pain and disturbed intestinal transit.
alternative to parenteral support. It is called ‘distal feed- 9. DFH acts by reducing upper gastrointestinal secretions
ing and/or hydration’ (DFH). and motility, increasing intestinal absorption capacity
2. Enteroclysis and chyme reinfusion with special pumps or and thus proximal stomal/fistula output, leading to the
devices are two techniques for DFH, and can be contin- reduction of the amount of nutritional/fluid parenteral
ued until surgical reestablishment of bowel continuity. support. These beneficial effects are driven by neural
3. Distal feeding improves nutritional status and liver func- and humoral mechanisms, including the release of gut
tion, and avoids the complications of parenteral nutrition hormones by the distal small bowel.
(especially central venous catheter infections and 10. DFH is making the surgical reestablishment of bowel
thrombosis). continuity more likely to be successful (technically eas-
4. DFH is safe, low-cost and easy-to-use in hospital and at ier, faster post-operative recovery of function, lower risk
home, providing contraindications (fistula, perforation of anastomotic leak).
or stenosis in the downstream small intestine) are taken
into account.
5. DFH needs to be integrated into multidisciplinary care,
handled by specialized trained teams, and should be Introduction
included in patient’s education to avoid technique
failure. In the course of an intra-abdominal surgical procedure, several
6. Proximal and distal contrast studies of the bowel prior clinical situations lead the surgeon to perform a double (loop or
to starting DFH must be performed to ensure there is double barrel) temporary enterostomy on the small bowel (e.g.
no disease, obstruction or leak present in the distal Crohn’s disease, mesenteric ischemia, peritonitis, fistulae, and
bowel. anastomosis protection). Entero-atmospheric fistula (EAF) can
also arise spontaneously as a post-operative complication of
peritonitis or anastomotic leakage. Initially these conditions
leads to type 1 intestinal failure (IF), and then become type 2 IF,
especially when the stoma/fistula output is equal or higher than
L. Lacaze · R. Thibault (*)
1500 mL/24 h [1], and this lasts until the surgical re-establish-
Home Parenteral Nutrition Centre, Nutrition Unit, Department of
Endocrinology, Diabetology and Nutrition, INSERM, INRAE, ment of digestive continuity. All these situations could lead to
Univ Rennes, Nutrition Metabolisms and Cancer, NuMeCan, CHU serious complications resulting in hospital readmissions (40–
Rennes, Rennes, France 50%) [2, 3]: acute or chronic dehydration (18–29% of patients)
e-mail: [email protected];
[4, 5], renal failure [6], electrolyte disturbances, micronutrient
[email protected]
and mineral deficiencies, and malnutrition, thus increasing
D. Picot
healthcare-related costs [7] and affecting patients’ quality of
Department of Nutritional and Digestive Rehabilitation,
Clinique Saint Yves, Rennes, France life. According to the clinical classification of the intravenous
e-mail: [email protected] support (IVS) based on daily fluid [8], electrolyte and nutri-

718 L. Lacaze et al.
tional requirements provided by parenteral route, in case of IF, hat Is Distal Feeding and/or Hydration?:
W
most of these patients are in categories 3 and 4, defined by very Definitions
high hydration and nutrient requirements [9, 10].
After such complicated surgeries, it is recommended to Enteroclysis and CR are the two main techniques of DFH. To
wait for at least three months from the last surgery to per- be eligible for DFH, patients should have a loop or a double-
form the surgical re-establishment of digestive continuity barrelled enterostoma or two stomas apart of the small bowel
and stoma closure. During this time, nutritional support or an EAF, with access to the downstream small bowel
should be effective, at low-risk and sufficient to prepare the (Fig. 1). DFH will be feasible only if the downstream small
patient for this surgery. At this time, the current gold stan- bowel can be catheterized.
dard therapy indicated for IF patients until the surgical re- Enterocutaneous fistula are aberrant connections between
establishment of digestive continuity, is parenteral nutrition the gastrointestinal tract and the skin or atmosphere. They
(PN) and/or hydration (IVS) [1]. However, home PN has its occur in 75–85% of cases after surgery and in 15–25% spon-
own morbidity and, in the absence of expertise, the risks of taneously [1]. Most close under medical treatment. EAF is
infectious, hepatic dysfunction, mechanical, and metabolic an enterocutaneous fistula developed in a wound in the
complications are increased [11]. PN has been associated abdominal wall with a mucocutaneous continuity where the
with infectious and hepatobiliary (e.g cholestasis, steatosis openings are visible as enterostomies. Closure almost always
and fibrosis) complications [12–14]. In many developing requires surgery.
countries, PN is not available as it is considered too expen- Enteroclysis consists in infusing water, electrolytes, and/
sive or there are no home PN homecare providers [15]. or enteral nutrition solution through an enterostomy or an
Distal feeding and/or hydration (DFH) techniques, namely EAF into the distal (downstream) small bowel. Fistuloclysis
enteroclysis, and chyme reinfusion (CR), are alternative ther- is enteroclysis through an EAF. The term enteroclysis seems
apies to IVS for type 2 IF patients. Although IVS has long preferable to fistuloclysis as it refers to the instillation of a
been the standard of care for IF, the use of DFH in patients fluid (-clysis) into the small intestine (entero-) regardless of
with EAF or temporary intestinal enterostoma has been the nature of the orifice, enterostomy or EAF, and the nature
described by many authors for a long time [10, 16–18]. DFH of the fluid, hydration, nutrition or both.
by CR was first described by Etienne Levy in 1977 [16]. CR, also called “re-feeding enteroclysis”, consists in
The scope of this chapter is to describe the technical prin- reinfusing the chyme collected from the proximal stoma
ciples of enteroclysis and CR, to overview their indications, (from the upstream small bowel) through the distal stoma,
contraindications and clinical benefits, and to give practical into the downstream small bowel [9, 10, 14, 19, 20]. The
details for their use. chyme is composed of digestive secretions (including
This chapter does not discuss the use of small volume growth factors), nutrients from oral food and/or tube feed-
bolus fees given once or twice daily into defunctioned bowel ing and drugs. CR reestablishes the functional continuity
to help maintain anatomical structure and motility before a of the anatomically present small bowel through an extra-
surgical anastomosis is performed (see chapter Insertion, corporeal circulation of the chyme [16]. The CR and
Types and Care of Enteral Feeding Tubes). enteroclysis could be considered as enteral nutrition tech-
upstream
small bowel stoma
downstream
small bowel stoma
Feeding tube
Fig. 1 Example of a temporary double enterostomy [Authorized repro- a downstream efferent segment, totally deprived of digestive secretions,
duction from [19]]. The small bowel continuity is disrupted with two bowel flow and succus entericus. The feeding tube is inserted in the
small bowel segments exposed to the abdominal wall: the upstream downstream small bowel, and is ready for enteroclysis or chyme
afferent segment, with impaired digestive and absorptive function, and reinfusion
Distal Feeding and Hydration 719
niques [20]. It means that two options of enteral nutrition In case of temporary double enterostomy or EAF, the IF is
could be available in patients with IF. The first, our pref- type 2. DFH is particularly indicated in patients with type 1
erential one, consists in feeding the patient orally with and type 2 IF, and with EAF or double stoma with high intes-
pureed food and reinfusing the chyme into the down- tinal outputs (≥1200 mL/24 h). ESPEN has endorsed repeat-
stream small bowel. If oral ingestion is insufficient, addi- edly recommendations for using CR in this setting [21–23]
tional enteral nutrition is infused “en Y” in the CR tube or, and American Society for Parenteral and Enteral Nutrition
rarely, by nasogastric tube or gastrostomy if present. The (ASPEN) clinical guidelines published in 2016 [24] suggest
second is to use enteroclysis to directly infuse the enteral the use of enteroclysis for enteral nutrition in patients with IF
nutrition solution into the downstream small bowel, as is with double enterostomy or EAF. We propose in Fig. 2 an
done for enteral nutrition by jejunostomy. The supposed algorithm of decision for the nutrition support of patients
advantages of the first is to keep functional all the diges- with a double enterostoma or EAF.
tion functions that prepare food into absorbable nutrients, Many people who have enterostomies have episodes of
to increase the intestinal absorption surface area, to dehydration that require readmissions to the hospital for
restore the enterohepatic cycles of digestive secretions, short stays during which they receive intravenous rehydra-
certain nutrients and drugs and to restore entero-hormone tion [2–5]. Because of the absorptive capacities of the colon,
secretions by ileal and colonic L-cells. However, to our enteroclysis in the terminal ileal or colonic downstream seg-
knowledge, no study has compared both methods, so that ment of a mixture of water, salt, and bicarbonate is an alter-
it not possible to recommend one from another. Both native to intravenous fluids for hydration [25].
methods achieve weaning from IVS by 90% or more. The DFH is safe, low-cost and easy-to-use if some practical
choice between the two should be made based on the mul- aspects and contraindications are well taken into account
tidisciplinary team expertise and the availability or not of [15, 19]. Indeed, before starting DFH, there is a need to per-
chyme reinfusion devices. form GI imaging, i.e. X-ray intestinal radiography or CT
enterography to follow the progression of the contrast prod-
uct. The aim is to ensure that the downstream small intestine
hat Are the Indications
W is clearly shown and that there is no contraindication to feed-
and Contraindications of DFH? ing: fistula, perforation, occlusion or stenosis in the down-
stream small intestine. This will also allow the measurement
The European Society of Enteral and Parenteral Nutrition of the length of the downstream small intestine: indeed DFH
(European Society of Clinical Nutrition and Metabolism) can only be offered to patients with a functional small intes-
(ESPEN) has defined intestinal failure as the reduction of tine of at least 15 cm. To achieve GI imaging, a tube is intro-
gut function below the minimum necessary for the absorp- duced into the first 15 cm of the downstream small bowel; we
tion of macronutrients and/or water and electrolytes, such advise to use a 14F polyurethane nasogastric tube or feeding
that intravenous supplementation is required to maintain gastrostomy (balloon of 5 mL max), and not a Foley® cathe-
health and/or growth [1]. Enteroclysis or CR are indicated ter because of the risk of ischemia if the balloon is inflated to
mainly in type II IF. The ESPEN IF specific interest group 20 mL. The contrast product should be infused under real
defines three types of IF. Type I IF is defined by an acute, time X-ray imaging to check the luminal progression to the
short-term and usually self-limiting condition. Type II IF is right colon [19] (Fig. 3).
defined by prolonged acute condition, often in metaboli- DFH needs to be integrated into multidisciplinary care,
cally unstable patients, requiring complex multi-disciplin- handled by specialized trained teams, and should be included
ary care and intravenous supplementation over periods of in patient’s education, to avoid technical failure [19, 26].
weeks or months. Type III IF is defined by a chronic condi- Enteroclysis or chyme reinfusion are actually part of intesti-
tion, in metabolically stable patients, requiring intravenous nal rehabilitation, especially for complex management of
supplementation over months or years. It may be reversible opened abdominal wounds or patients with high intestinal
or irreversible [1]. outputs [23].
Double enterostoma or entero

-atmospheric fistula
Maintenance ofnut
ofnutritional status and
hydration with oral route alone
Yes No
Need for IV hydration

Oral feeding and hydration alone: and/or parenteral nutrition;
Intestinal output < 1200 ml/24h in usually in case of intestinal
most situations output ≥ 1200 ml/24h
• Ability to catheterize the efferent small

mall b
boweland more
than 15 cmpresent
• No fistula, perforation, or stenosis of the intestine
No
Yes
Entero/Fistulo-clysis
/Fistulo-
o clysis IV hydration
and/or chyme reinfusion and/or parenteral nutrition
Side effects
Diarrhea, abdom
abdominal pain, rectal incontinence,
recurrence of small bowel, colon or rectal
disease
Fig. 2 Proposal for an algorithm of decision for the nutrition support cessible or diseased, or in case of uncontrolled side effects, making the
of patients with double enterostoma or entero-atmospheric fistula. distal feeding contraindicated. In every situation, the patient’s agree-
Parenteral nutrition would be chosen only if distal small bowel is inac- ment must be obtained
Fig. 3 Opacification of the

downstream small bowel
through a feeding probe. The
presence of fecal residues in
the right colon makes the
patient at high risk of
constipation or subocclusion.
The administration of
laxatives through the feeding
probe is indicated, as well as
the stop of anti-motility drugs.
In the second image you Intraluminal
could observe the progression contrast
of the intraluminal contrast opacification
into the right colon attesting through a
that there is no proximal feeding tube
intestinal occlusion. The inserted in the
downstream
progression should be
Stool small bowel
observed to the rectum (not
residues
shown)
in the
right colon
Opacification of
the right colon
Benefits and Side Effects of DFH small bowel output [16]. This is one of the reasons to quickly
start DFH in patients with EAF or a high output stoma
Enteroclysis, or chyme reinfusion performed with auto- (≥1200 mL/24 h). DFH contributes to the improvement of
regulated pumps can be performed until the surgical reestab- nutritional status and liver function, and prevents parenteral
lishment of continuity and stoma closure. One of the first nutrition complications, mainly central venous catheter-
reported benefits of DFH is the reduction of the proximal related infections and thrombosis, and liver complications
Table 1 Summary of the key clinical studies that evaluate the benefits of DFH in patients with intestinal failure
Type of
Patients distal
Author Year Study design (n) Type of patients feeding Main findings
Nagar et al. [15] 2018 Retrospective 35 Proximal stoma with a CR Cost-effective and could effectively substitute PN
case series remnant upstream
small bowel ≤120 cm
Picot et al. [9] 2020 Retrospective 306 Double entererostomy CR Improvement of nutritional status, citrulline, plasma
case series or EAF liver tests, and feasible at home, weaning from IVS
Wu et al. [29] 2014 Retrospective 95 High-output upper DFH Improvement of hepatic and nutritional parameters
case series EAF, particularly
biliary fistula
Coetzee et al. [14] 2013 Retrospective 20 EAF DFH Feasible in selected patients with a proximal enteric
case series fistula or stoma. Weaning from parenteral nutrition,
reduction of IVS infectious. Adequate nutrition, water
and electrolyte balance achieved without the need of PN
Cosnes et al. [27] 1990 Retrospective 10 EAF DFH Effective nutritional support. Weaning from IVS
case series
Teubner et al. [18] 2004 Retrospective 12 EAF DFH Effective nutritional support. Weaning from IVS
case series
Levy et al. [17] 1989 Retrospective 335 EAF CR Viable method of nutritional support in patients with
case series high-output small bowel external fistula(s)
CR chyme reinfusion, EAF enterocutaneous fistula, EN enteral nutrition, EF enteroclysis/fistuloclysis, IVS intravenous support
[9, 10, 13, 14, 17, 18]. Besides technical issues, the main side (n = 10), during a median of 7 (range 5–7) nights per week.
effects of DFH are transient abdominal pain, during the first Median length of proximal small intestine from the duodeno-
few hours, and motility disorders (e.g. diarrhoea) [18, 19]. jejunal was 105 (range 45–200) cm and that of the distal
Table 1 reports the main clinical studies having evaluated the small bowel, 120 (range 75–400) cm. Patients had an oral
benefits of DFH in patients with IF. diet. The median fistula losses were 1360 (range 690–
3190) mL/day. Enteroclysis was made with a standard poly-
meric enteral nutrition solution (n = 3) or, if intolerance, a
Enteroclysis semielemental or elemental solution (n = 4 each). One patient
did not tolerate the enteroclysis. Eleven patients were weaned
Enteroclysis has many benefits especially in patients with a from IVS after a median of 28 days.
high-output fistula. In summary, enteroclysis is a safe technique and can
Cosnes et al. [27] performed an enteroclysis of an ele- replace IVS to maintain or improve nutritional status and it
mental diet in the distal small bowel in ten patients with a reduces the complications and costs of IVS and parenteral
double enterostomy located between 10 and 95 cm from the nutrition.
duodeno-jejunal flexure. The length of the distal limb was
215 ± 58 cm. Five of these patients had undergone small
bowel resections of more than 1 m. All patients were receiv- Chyme Reinfusion (CR)
ing parenteral nutrition. The jejunal losses averaged
3 kg/24 h. The enteral nutrition solution provided CR consists in the chyme collection from the proximal
31.9 ± 10.5 kcal/kg/24 h in a volume of 2860 ± 803 mL/24 h. stoma and reinfusion through the distal stoma within the
Enteroclysis lasted for 39 ± 9 days until intestinal continuity downstream small bowel. In many case reports or short
was restored, 20 h/24 h. Patients had an oral diet. The diges- series publications, CR was performed with enteral nutri-
tive nitrogen absorption balance (n = 6) was positive between tion pumps or sequentially with a syringe [19]. Nowadays,
5 and 15 g/24 h in all patients, despite nitrogen losses through CR could be performed with specifically designed devices
the upstream segment. Sodium balance was positive in 9 or pump [15, 18]. During three decades, Enteromate® pumps
patients, negative in one patient who required intravenous have been specifically marketed for automated CR [9, 10,
fluids. Downstream intestinal sodium absorption was mea- 18]. The advantages were considerable. In a closed circuit,
sured to be between 176–297 mmol/24 h. Parenteral nutri- and therefore without unpleasant odor, they continuously
tion was discontinued in 9 patients. adjust the flow rate of the CR to that of the upstream enter-
Teubner et al. [18] included 12 patients with EAF, depen- ostomy, without needing human manipulation to transfer
dent on IVS for hydration balance (n = 2) or nutritional needs (and/or sieve) the chyme. Portable pumps with adjustable
continuous flow were also available from 2008, allowing Previous studies have suggested that CR could improve
CR to be continued at home [9] until the surgery to close the liver tests and function. Picot et al. showed that the number
enterostomy or EAF. CR ensures the use of the entire poten- of patients who had one or several plasma liver tests abnor-
tially functional intestine and the correction of the IF. CR malities decreased from 83 to 40% (p < 0.0001) [9].
restores the function of the entire anatomically present The retrospective study by Wu et al. [30] included 95
bowel prior to the surgical restoration of continuity, includ- patients with high output EAF located between 10 and 95 cm
ing increasing absorptive capacities, restoring enterohepatic from the duodeno-jejunal flexure. They were receiving par-
cycles and enterokine secretions, and improving trophicity enteral nutrition. The distal intact small intestine was longer
of the downstream bowel. Patients are fed with what they than 100 cm. The authors compared 60 patients with exclu-
eat. Some patients with a short or pathological downstream sive enteral nutrition (EN) and 35 patients with exclusive
intestine still have intestinal insufficiency but it is less enteral nutrition and chyme reinfusion (EN-CR). Patients
severe. Picot et al. published the largest case series studies with EN-CR had greater liver function test improvements
of CR [9, 10, 28]. It included 306 patients with intestinal and better one year survival than patients with EN. In addi-
failure patients due to temporary double enterostomy tion, in the EN-CR group, bile reinfusion and succus enteri-
(n = 269) or EAF (n = 37). They demonstrate that CR cor- cus from duodenal fistulas resulted in a greater improvement
rects the IF by restoring intestinal absorption. CR decreased than jejunal chyme.
intestinal losses by 85% and allowed strong improvements In contrast, Cosnes et al. observed no change in liver tests
in nitrogen and fat digestive absorption coefficients. Plasma during the duration of enteroclysis, despite weaning from
citrulline levels improved and there was a strong reduction IVS [27].
in the proportion of patients with plasma citrulline In summary, CR allows to reestablish the small bowel
<20 μmol/L. Nutritional status improved, especially in continuity, to correct the intestinal failure, to restore the
patients with body mass index <20. According to the ESPEN intestinal function, to normalize the nutritional status, to
clinical classification of intestinal failure IVS [8], CR wean off IVS and to restore the enterohepatic cycle of bile
allowed 94% (46/49) of patients receiving only fluids and salts that help with the improvement of IFALD.
electrolytes, and 88% (142/162) of those receiving paren-
teral nutrition to stop IVS. The remainders required lower
volumes of PN-IVS (p < 0.001). Future Perspectives
Research is needed to better understand the positive effects

DFH and Liver Dysfunction of DFH and determine if CR is more beneficial than entero-
clysis with an enteral nutrition solution alone. The mecha-
Intestinal failure associated liver disease (IFALD) results in nisms underlying the improvement of intestinal and liver
part from the interruption of enterohepatic cycles of bile salts functions are incompletely understood. One hypothesis
(BSs). Under physiological conditions, BSs reabsorbed in the could be that CR restores several endocrine functions of ileo-
terminal ileum and right colon, return to the liver where they caecal L-Cells through the effect of signaling molecules.
are re-secreted into the bile. In the L-Cells of the ileo-cacecal BSs are signaling molecules. The targets of BSs are dedi-
area, the transcellular flow of BSs stimulates the secretion of cated nuclear and plasma membrane bound receptors, in par-
FGF19 into the portal blood. In the liver, FGF19 inhibits ticular the nuclear transcription farnesoid X receptor (FXR)
cytochrome 7-α-hydroxy-4-cholesten-3-one (C4), which [31, 32]. By targeting these receptors, BSs could influence
controls the activity of 7-α-hydroxylase responsible for BSs various metabolic and biological processes including BS and
synthesis from cholesterol. In case of a high flow enterostomy glucose homeostasis, hepatic inflammation, intestinal barrier
or EAF, BSs are lost, this enterohepatic cycle is broken, FGF function, trophicity of the intestinal mucosa, regulation of
19 secretion stops, C4 activity increases and the liver secretes gastrointestinal motor function, and intestinal barrier
BSs in excess. The prospective study RESCUE shows in 12 function.
patients that CR restored bile salt reabsorption and, within a The choice to perform CR rather than enteroclysis cur-
few days, normalized enterohepatic signaling which cor- rently depends on the availability of medical devices or
rected the hypersecretion of BSs by the liver [29]. Plasma equipment specifically designed to perform CR in a closed
FGF19 levels increased within a few days, C4 levels fall, and circuit, without manipulation or odor, convenient, easy to
plasma alkaline phosphatase (ALP) and gamma-glutamyl- learn by caregivers and patients, feasible at home, inexpen-
transpeptidase (GGT) activity decreased. The increase in sive, and reimbursed by health insurance. New CR devices
FGF19 correlated with the decrease in C4, the increase in are in the advanced stages of development and are awaiting
citrullinemia, and the decrease in plasma ALP and GGT approval for hospital and home use and reimbursement by
activity. Medicare [33].
Side Effects of Enteroclysis and CR elemental formulas [24]. During DFH, if diarrhea occurs,
loperamide can be used. In case of abdominal pain, antispas-
As reported above, DFH is a safe technique of enteral nutri- modic can be used. In selected patients, CR was feasible at
tion if its contraindications, namely intestinal stenosis, home thanks to portable pumps [20]. Picot et al. showed that
occlusion, fistula and perforation, are well respected. The this was possible for 30% of patients with an enterostomy,
side effects are mainly represented by abdominal pain, diar- and in this study, no patient had to stop CR [9]. However, in
rhea, or constipation (see below paragraph ‘Practical aspects France and other countries, home CR is not yet recognized
of DFH’). The most frequently reported technical problem is by health insurances as a nutrition support technique, and
the accidental expulsion of the feeding tube, because of the unfortunately cannot be recommended.
peristaltic contractions of the small bowel, requiring its repo-
sitioning. Its prevention is based on adequate fixation of the
tube to the stoma and stopping drugs that slow down intesti- Conclusions
nal transit [14, 20]. Patients with downstream occlusion, for
example due to peritoneal carcinomatosis, cannot be candi- Enteroclysis and CR, the two techniques of DFH, are recom-
dates for DFH because of the major risk of complication and mended by international clinical nutrition societies as nutri-
the lack of benefits. The other difficulties of DFH are tube tion support techniques in patients with type 2 IF and a
displacement/leakage, and diarrhoea with unpredictable double enterostomy or EAF. DFH has many benefits: it
absorption. In the latter, despite DFH, the risk that the patient decreases upstream stoma or fistula output, improves intesti-
remains dependent to parenteral support seems high, and nal and liver functions, and nutritional status. Consequently
surely difficult to predict. the major benefit of these techniques is that it allows IVS
weaning, thus can decrease the IVS and PN-related compli-
cations, mainly of central catheter-related infections. DFH is
Practical Aspects of DFH safe if the contraindications and a dedicated protocol are
respected. It is important to emphasize the need to integrate
Figure 1 shows a double enterostomy with a feeding tube DFH into multidisciplinary intestinal rehabilitation, under
inside the downstream small bowel. Before initiating DFH, the supervision of dedicated and trained teams of a physician
i.e. enteroclysis or CR, it is mandatory to perform GI imag- (with a special interest in nutritional support), a surgeon,
ing, i.e. X ray or tomodensitometry with luminal contrast, to dieticians, and nurses. Based on these large benefits for
ensure that there is no contraindication: fistula, perforation, health, DHF may become routine practice in an IF patient
occlusion or stenosis in the downstream small intestine (see before a temporary stoma or fistula is surgically closed.
above paragraph “What are the indications of DFH?”). The
presence of a stenosis or of a bowel perforation contraindi-
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Chronic Abdominal Pain
Peter Paine and Justin Turner
Key Points This global definition allows for all conditions that have
pain. For example acute appendicitis and irritable bowel syn-
1. Pain is an unpleasant sensory and emotional experience drome, where abdominal symptoms are present for both, but
associated with or without tissue damage. the underlying cause and treatment options may be signifi-
2. Pain related to intestinal failure can be due to a surgical cantly different.
catastrophe, inflammatory bowel disease or dysmotility. The definition also highlights that pain is an emotional
3. Psychological support is needed to help manage chronic experience and therefore there is a component of pain which
pain. is part of a conscious process. Pain is a reported problem and
4. Due to absorption problems analgesia may need to be so the way the patient interprets their symptoms and then the
given by topical, buccal (including lozenges), or rectal way in which they are able to communicate those symptoms
routes. will vary. How a person interprets their experience of pain
5. Narcotic bowel syndrome may occur with chronic opiate can be altered by mood, activity or distraction.
use for chronic pain and is characterised by gastrointesti-
nal dysmotility and hyperalgesia.
6. Chronic pain should not be treated with opioids; neuro- Acute Pain
modulator drugs may be beneficial
7. The approach to chronic pain has changed and there is a Pain is protective. At the time of initial injury for example
shift from that of a cure focus to a care focus with an when you take a hot drink, the burning pain causes you to
understanding that chronic pain cannot be cured medi- stop to prevent significant injury to your mouth or
cally but can be helped. oesophagus.
Pain is then protective by preventing further activity and
allowing healing to occur. For example if you fracture a bone
this will lead to reduced movement and limiting the weight
Definitions bearing on the bone, allowing for healing.
Pain
Post-operative Pain
The International Association for the Study of Pain (IASP)
defines pain as Surgery is trauma where the normal responses to pain in the
an unpleasant sensory and emotional experience associated short term have been prevented by anaesthesia. This leads at
with actual or potential tissue damage, or described in terms of a later stage to a situation where the subsequent responses to
such damage [1] pain are to a degree no longer helpful and in fact may be
detrimental to recovery. For example abdominal pain follow-
ing laparotomy leads the patient to minimise movement,
P. Paine (*) which in turn prevents deep breathing. This in turn increases
Department of Gastroenterology, Salford Royal Foundation Trust, the risk of chest infection and delayed recovery from sur-
Salford, UK
gery. Surgical techniques are aimed at minimising the degree
of trauma and anaesthetic techniques aimed at improving
J. Turner
pain relief to aid in early return to normal physical function.
Chronic Pain Centre, Salford Royal Foundation Trust, Salford, UK

728 P. Paine and J. Turner
Chronic Pain Biological
Whilst the IASP global definition for pain is generally At the more biological end of the biopsychosocial spectrum,
accepted, the definition of chronic or persistent pain is not as pain is largely divided into nociceptive and neuropathic.
clearly defined. A pain which persists beyond the time of Nociceptive pain describes the normal and appropriate func-
healing can be considered chronic. However the difficulty tion of the pain nervous system in response to potentially
with this definition is for some patients, for example osteoar- damaging stimuli and the reversible adaptive pain hypersen-
thritis, healing may not be possible. For this reason an alter- sitivity ensuing as a protective mechanism for proper heal-
native definition for chronic pain is a pain which has lasted ing. Neuropathic pain however reflects damage and
longer than 3 or 6 months. For many forms of chronic pain prolonged dysfunction to the pain nervous system itself,
the protective nature of pain is no longer apparent and the whereby pain can occur spontaneously, its threshold may fall
pain itself becomes disabling. Chronic pain within the gen- dramatically such that innocuous stimuli produce pain (allo-
eral population is common [2]. dynia), and the duration and amplitude of its response to
Intestinal failure patients may have chronic non-GI pain noxious stimuli are amplified. This should be considered as
which relates to another problem such as osteoarthritis or an autonomous disease state of the pain nervous system in its
vertebral compression fracture. The management of these own right [4].
pains is beyond the remit of this chapter. However consider- A summary diagram of the pain “hardware” involved fol-
ation needs to be given to the effect of intestinal failure on lowing nerve injury or inflammation in chronic neuropathic
the medications available to the patient. Equally the medi- pain states, and possible sites of abnormal function under-
cines used would need to be considered with respect to their pinning chronic pain is shown in Fig. 1. It is quite possible
impact on bowel function. that more than one or indeed all of these levels of abnormal
pain nervous function could be in operation at once. It is
beyond the scope of this chapter to detail these changes fur-
Acute on Chronic Pain ther, but they are outlined in a helpful review article [5].
The structural diagram of the pain nervous system
A patient with chronic pain still has the risk of developing changes however does not convey that endogenous pain
new medical problems relating to their intestinal failure e.g. modulation is also a dynamic process and it is likely that
a parastomal hernia or a new Crohn’s disease inflammatory there may be a “tug of war” happening between inhibitory
mass. New pains that have different characteristics in terms and facilitatory processes and between bottom up and top
of the nature of the pain or location may still need to be down sensitisers [6]. A practical consequence of this infor-
investigated. Increased intensity in pain that has been estab- mation on neuropathic pain pathophysiology is that it can be
lished to be a chronic pain however, a “flare up”, is unlikely helpful to patients to be given explanatory models (together
to benefit from further investigation and the costs, both eco- with the use of simplified diagrams e.g. Fig. 2) of the “wir-
nomic for the service, and emotional for the patient would ing” of their pain alarm system, including sites of malfunc-
need to be considered. tion. In particular, the instantiation of chronic pain within
the spinal cord, brainstem and central nervous system can
help explain why surgical procedures aimed at a peripheral
echanisms of Chronic Pain
M target (such as adhesiolysis or organ removal) are unlikely
and the Biopsychosocial Model to remove the pain. Helpful explanatory analogies here can
be made with “phantom limb” pain and with a broken fire
An understanding of the pathophysiological mechanisms of alarm, whereby the peripheral element or trigger may be
chronic pain can be helpful in both characterising the pain, resolved, but the central component perpetuates the pain
tailoring appropriate therapies and in explanatory models to experience. Such “central mediation” of chronic pain helps
delimit realistic treatment expectations. These mechanisms to explain why this is not readily fixable surgically and why
need to be considered within a biopsychosocial model [3]. centrally acting drugs (“neuromodulators” such as anti-
From a holistic perspective, the biological, psychological depressants and anti-epileptics) might be helpful to alter
and social components of the pain experience cannot be fully central pain neural function. Indeed, the Rome IV classifica-
disentangled, and it is likely that there will be disordered tion has recently recast chronic continuous or nearly con-
processes in play at all these levels concurrently. It is possi- tinuous abdominal pain as “centrally mediated” and
ble however for one or other of these levels to predominate highlighted the problematic association with opiates for this
and therefore they will be deconstructed, albeit somewhat kind of chronic pain and the potential role of neuromodula-
artificially. tors [7].
Chronic Abdominal Pain 729
Fig. 1 Sites and mechanisms

of chronic post-surgical cortex
neuropathic pain. (1) 7
Peripheral sensitisation (distal
chemicals), (2) Neuroma at thalamus
injury site (ectopic
excitability), (3) Dorsal root
ganglion gene expression limbic
(excitability), (4) Central system
sensitisation (dorsal horn gene 6
expression, inhibitory
interneurone loss, microglia
activation), (5) reduced
Descending Noxious
Inhibitory Controls
(brainstem), (6) Limbic and
brain stem
hypothalamus (emotion,
behaviour, Autonomic
Nervous System), (7) Cortex
(cognitive-evaluative) 5 dorsal root ganglion
3
nerve
4
2
peripheral nerve injury
spinal cord
Another important biological concept for understanding the patients and the team looking after them but is important
and explaining the clinical features of chronic abdominal pain to recognise and understand that this has a molecular bio-
in particular is that of viscerosomatic convergence at the level logical basis which appears to be largely reversible by care-
of the dorsal horn of the spinal cord. This can help explain to ful controlled opiate reduction and withdrawal [10].
patients why a previous internal injury is often associated with
extreme cutaneous pain sensitivity (allodynia). An example of
this is seen in patients with chronic pancreatitis [8]. Furthermore, Psychological
chronic pain that has been triggered or initiated from the vis-
cera may also be quite diffuse and poorly localised because of Psychological risk factors for patients developing disabling
the multi-level spinal inputs. Moreover the close association of chronic pain include pre-existing anxiety, depression and
the viscera with limbic and autonomic areas may predispose pain catastrophizing. Pain catastrophizing combines rumina-
chronic visceral pain to greater levels of autonomic upset and tion (preoccupation with fear of worsening pain), magnifica-
fear/anxiety components. Lastly, the role of the microbiome in tion (amplify the significance of pain) and helplessness
the bioactive luminal chemical soup in chronic pain is an area (inability to control the pain experience). A dissociative cop-
of increasing but poorly characterised interest. ing style may be a risk factor for opiate abuse [9].
Finally, opiate induced hyperalgesia is a specifically Psychological factors that make patients more resilient
important mechanism to consider here. Whilst the clinical and protect from disability with chronic pain include Pain
aspects of recognising and managing this will be dealt with Acceptance which involves activity engagement (engage in
later, in brief chronic opiate usage likely produces molecular activities even if pain is experienced) and Pain Willingness
biological changes in pain neural pathways such that the net (not attempting to control or avoid pain). Pain self-efficacy
result is further exacerbation of the underlying chronic pain which is the confidence to cope with pain and engage with
state [9]. This is a highly counterintuitive concept for both activities despite pain [5].
Fig. 2 An example of a
simple diagram that can be
used with patients to explain
concepts such as
viscerosomatic spinal
convergence giving rise to
cutaneous allodynia, central
sensitisation in the spinal cord
dorsal horn, and increased
afferent barrage
Fig. 3 Psychological factors

involved in chronic pain
outcomes
Some of the psychological vulnerability and resilience memory and pain meaning can also be important psycho-
factors associated with outcomes are summarised in Fig. 3, logical aspects of the pain experience for a patient and
which includes the key concept of maladaptive fear avoid- therefore it is essential that clinical pain psychology forms
ance and both other maladaptive psychological processes part of any approach to chronic pain assessment and
and rehabilitative therapeutic approaches [11]. Trauma management.
Social with or without nociceptive activation, suffering and pain

behaviours [14].
Finally, it should also be recognised that pain behaviours If treatment of pain as a “signal” removes the signal com-
take place in a social context as displays of distress to elicit pletely then there is no progression to suffering and conse-
support. In a similar way to psychological responses, some quently no need to consider a model of pain as the wider
of these pain behaviours and ways of attempting to elicit sup- experience described above.
port can become maladaptive. At an extreme end of this Whilst teams treating patients are often guided to treatments
spectrum are manipulative and deceitful behaviours such as by pain, in chronic pain, it is an unrealistic goal that medical
in Munchausen’s syndrome or in malingering for secondary interventions will provide a resolution of the pain [15].
financial or emotional gain. More commonly however, mal- Unfortunately, in chronic pain associated with intestinal
adaptive social dimensions of pain can reflect the values and failure, treatment of pain as a “signal” very rarely produces
meaning given to certain expressions of pain within the absolute relief, and so the aim should be to manage pain as
learnt behaviour environment of the family or culture [12]. the larger experience and resultant problems.
Pain behaviours can also sometimes therefore serve as prox- Treatment of pain in the intestinal failure unit for most
ies for other kinds of emotional, psychological or social dis- patients should be multimodal with medical, psychological
tress when direct expression of these have been suppressed, and physical therapies considered.
for example when patients experience bereavement or rela- When assessing any patient it is important to firstly
tionship breakdown. Patterns of maladaptive social interac- exclude new symptoms which may represent new pathology
tions with health care providers can also form a sociological and consequently should be investigated as felt to be clini-
vicious cycle exacerbating the pharmacological vicious cally appropriate.
cycle in the narcotic bowel syndrome [13]. Clear agreed and The assessment of Chronic Pain should consider the vari-
consistently practiced boundaries and sometimes written ous components of pain, the impact of pain on levels of phys-
contracts can be necessary in some cases where maladaptive ical function, psychological well-being, and resultant levels
social interactions, for example frequent emergency depart- of disability.
ment attendance for injectable opiates, is occurring.
Assessment of Pain
Patients in Pain
The assessment of the components of pain [16, 17] should
Each patient in an intestinal failure unit presents with their include:
own story, their own pain and how they present and manage
their pain will be different for each individual Fig. 4. These • Pain intensity—A 11 point numerical rating system
will include components of nociception, the pain experience (0–10 with 10 being the worst pain) is a repeatable system
that is easy to administer.
Fig. 4 Components of Flare up of inflammatory bowel disease

individual pain presentations Bowel distension from obstruction
nociception Can occur without nociception

Chronic post surgery pain
pain Effects on mood, anxiety, depression, fear

Sleep disturbance
isolation
Posture, facial expression
Activity levels, withdrawal from
social activities and work
suffering Medical consultations and
medication usage
pain behaviour
• Distribution of Pain—Both origin of the pain and radia- be on opiates. The majority will have started these opiates
tion are useful in assessing possible causes of pain. Pain during an acute exacerbation of pain, but at some stage their
Diagrams may provide useful information that can be pain will have changed from acute to chronic but the opiates
repeated. remain in place. Reasons for particular routes of administra-
• Sensory quality of the Pain—Pain described as colicky in tion of opiates needs to be elicited and also why other routes
nature and following feed would suggest a mechanism for are no longer used. For example it is important, if a patient is
pain different to a neuropathic pain with burning or stab- using a subcutaneous opiate regime management, to clarify
bing pain, or pain on light touch (allodynia). It is possible why subcutaneous morphine was prescribed and what pre-
to use various scales to assess the descriptive components vents use of other routes of administration.
of pain with standardised questionnaires such as the Short Patient concerns about therapy are also important to
Form McGill Pain Questionnaire. review. For a significant group of patients concerns may be
• Temporal Nature of Pain—Duration of Pain is an impor- about medical desire to reduce opiates, and if this occurs
tant factor since chronic pain in intestinal failure does not without patient understanding and agreement, our experi-
exclude the patient from the risk of developing new ence is this leads to increasing levels of iatrogenic distress
pathology, for example a flare up of Crohn’s disease or and a poor experience for both the patient and the staff car-
development of parastomal hernial. Equally chronic pain ing for that patient. It is important therefore to understand
which has increased in intensity or flared up is unlikely to the patient’s perspective on the role of medication. For
need further investigation. Triggers for worsening and other patients the awareness that opiates are not helpful in
improving pain are important to explore, they help sug- the long term and concerns about addiction are significant
gest a cause for the pain such as ischaemia or obstruction and management of those patients will have different
or alternatively they may be linked to changes in psycho- priorities.
logical or social state. For some patients a Pain Diary is a An assessment of ongoing pain and the potential chal-
useful tool to look at intensity overtime. lenges to management of pain or any change in therapy is not
possible without an assessment of the psychological risk fac-
These aspects of assessment may guide which therapies may tors the patient may have. Patients understanding of what
be helpful in the management of their ongoing pain. their pain means in terms of further damage (hurt/harm), and
For the majority of patients on the intestinal failure unit, pain catastrophizing needs to be explored.
medical management of their condition has been an ongoing Disability for patients on the intestinal failure unit is mul-
process for a significant length of time. tifactorial. Understanding the patient’s level of disability and
Aetiology of the individuals’ intestinal failure needs to be their perception as to how pain plays a part in ongoing dis-
elicited as well as the amount of functioning bowel. Choices ability needs to be explored, to aid in the setting of realistic
in terms of medications may well vary depended upon the goals for treatment.
length of small bowel available and transit times through the
bowel.
Assessment needs to include a review of previous pain Examination
therapies and the reasons particular therapies were found not
to have any value. A significant degree of distress occurs if For some patients on the intestinal Failure unit, examination
therapies that have previously been found to be unsuccessful is complicated by the stoma dressing and wound dressings
are revisited without addressing patients concerns and expec- that are required.
tations linked to each therapy. For example patients who For some of those patients, any pain related to inflamma-
have trialled gabapentin and found it to cause recognised tory irritation to the abdominal wall is best treated by man-
side effects such as drowsiness or forgetfulness are unlikely agement of the cause of that problem which is covered in
to find it helpful to retry the same medication again. other parts of this book.
Current medication usage and the reasons for usage needs Examination is important however to look for signs asso-
to be elicited. Medication route of administration and fre- ciated with neuropathic pain. These include:
quency of dosing need to be clarified. The reasons why par-
ticular routes of administration have been adopted also needs • Numbness
to be explored. This is of particular importance when looking • Dysesthesia (e.g. tingling, burning)
at opiates. In our experience many patients will continue to • Allodynia—Pain on light touch
Table 1 Summary of assessment and examination for chronic pain Table 2 Common themes/phenotypes
Pain Onset, intensity, distribution, quality, Initial cause of
duration, triggers intestinal failure Triggers for pain
Cause of Bowel function, previous surgery Surgical catastrophe Chronic post-surgical [5, 19]
gastrointestinal Adhesions or Stricture formation leading
failure to obstruction
Current therapies Medication dosages, frequency, route of Inflammatory bowel Ulceration of bowel
administration other therapy e.g. disease Stricture formation.
physiotherapy Fistula formation.
Previous therapies As for current therapies and reason stopped Surgery to remove stricture, which may
Past history Medical, pain, psychological need to be repeated [20]
Psychological factors Hurt/harm, anxiety, depression Dysmotility Abdominal distension
Function Levels of disability and cause, family and Opiate bowel dysfunction
friends, financial pressures Narcotic Bowel syndrome [21]
Examination Inflammation, infection, stoma output,
neuropathic signs, nerve entrapment
• Hyperalgesia—Increased pain on pinprick group outcome data as the prevalence of this group of patients
• Summation—Increasing pain on repeated stimuli rather in IFU practice would appear to be increasing.
than the normal reduction in stimulus
• Altered Temperature sensation—Reduced or increased
sensation to cold or heat. reatment of Pain in Intestinal Failure
T
Patients
It may be possible to elicit pain associated with scars from
previous surgery. The treatment of chronic pain in all patients on the intestinal
If anterior abdominal wall nerve entrapment is considered failure unit needs to be considered within a biopsychosocial
a possible diagnosis, a specific tender area is located, it is model. No single therapy is likely to provide the solution to
then possible to ask the patient lift their legs and contract the a patient’s ongoing symptoms.
abdominal wall. If this is associated with increased pain this Therapy for patients with chronic pain associated with
may suggest a nerve entrapment—Carnett’s sign [18]. intestinal failure therefore needs to be multimodal and inter-
The approach to assessment and examination is sum- disciplinary with coordinated care often from multiple medi-
marised in Table 1: cal specialties, nursing care and allied healthcare professionals.
The staff on the intestinal unit are key to coordinating the care.
Assessment not only provides the information to guide
hronic Pain “Phenotypes” on the Intestinal
C further therapy but also provides an opportunity to allow the
Failure Unit patient to know they have been listened to about their ongoing
problems and for some patients this in itself is therapeutic.
Whilst the assessment and examination approach outlined For a significant group of patients’ psychological factors
above emphasises an individualised approach, nonetheless will play a significant role in their presentation and a full
we do see common clusters or themes of three main groups psychological assessment by a clinical psychologist will be
of patients presenting with chronic pain on the intestinal fail- necessary and psychological therapies to aid in the ongoing
ure unit which may be taken into consideration (Table 2). management of pain will be needed.
There tends to be a reasonable degree of overlap in the There are a group of patients in the intestinal failure unit
approaches for the surgical catastrophe and IBD group of who due to multiple factors including the length of stay in
patients, but there is a perception that the dysmotility group hospital, previous surgeries and recovery, underlying medi-
may present with some particular assessment and management cal conditions who become increasingly de-conditioned and
challenges. This may in part reflect more general difficulties in physiotherapy aimed at increasing strength, range of move-
characterising and determining aetiology for the dysmotility ment and endurance is essential. Occupational therapy
patients [22]. This is an emerging and not well evidenced based assistance with managing ongoing disability may also be
area currently, and would merit more multi-centre comparative required.
Medical Management The ideal situation therefore is not to commence opiates

for chronic pain in the first place, even if no alternative pain
It is important to recognise that there are no currently avail- medication is available [25]. However, many patients in the
able drugs which can abolish chronic pain completely in all IFU setting will have already been started during acute
or even most patients. A rule of thumb is that in patients who exacerbations of pain. Unfortunately, often as the pain set-
have some response to analgesics, will find a 30–50% reduc- tles they are not removed due to on-going low level symp-
tion in the intensity of the pain experience useful and are toms. Overtime with further exacerbations of pain the
likely to continue that medication. Furthermore, it is clear opiates are increased. The result is a significant group of
that in a majority of patients with chronic pain, opiates are patients arriving at a gastrointestinal unit do so with large
ineffective and indeed can be counterproductive and harm- doses of opiates already on board. The immediate priority in
ful. Non-opiate drugs for chronic pain are often termed adju- this situation is stabilisation of the opiate dose and optimi-
vant or neuromodulator drugs. We will deal first with opiate sation of the route.
management however, as this appears to be particularly As the medical profession increasingly recognises the
problematic in intestinal failure patients. potential for harm of opiate usage in all patients with chronic
pain it is understood that opiates play only a small role in the
management of ongoing pain and high-dose opiates (equiva-
The Management of Opiates lent to more than a 120 mg/day) should be discouraged.
In assessing opiate usage in intestinal failure areas of
For the majority of patients with gastrointestinal failure, due management that need to be explored are:
to the chronic nature of the condition it is usually possible to
take a considered approach to management of pain and med- • Route of administration: due to various factors including
ication changes. nausea, vomiting, short small-bowel, gastrostomy,
Alterations to therapeutic regimes are more successful patients are prescribed opiates via multiple routes of
with patient agreement and there is less risk of reversion to administration.
treatment that the patient believes to be more successful in –– Intravenous route is preferred by some patients.
symptom alleviation whilst the treating team believes it to –– Intramuscular injection.
have a greater risk of harm. For example, ongoing use of –– Subcutaneous injection.
subcutaneous opiate injections despite oral intake. –– Sublingual or intranasal.
There has been increasing awareness of the harmful and –– Oral
indeed counterproductive effects of opiates on gastrointesti- –– Transdermal
nal function and chronic pain management. At the extreme
end of the spectrum of negative effects, the “narcotic bowel The reason why a patient continues to use their opiates
syndrome” has been described. This is a combination of via one or other of these routes needs to be explored as
severe opiate induced gastrointestinal dysmotility (including does their understanding of potential risks and benefits of
sometimes pseudo-obstruction), combined with opiate that route compared to other routes of opiates.
induced hyperalgesia. This is described as occurring in a • Frequency of dosing: When opiate use becomes pro-
context of a vicious cycle of inadvertent iatrogenic health- longed the half-life of all the drugs is at least 3 h and so it
care re-enforcement of dependence on short acting and esca- seems reasonable to expect opiate usage to be less fre-
lating opiate use, often via the emergency department route quent than this, however some patients are using opiates
[7]. On the other hand, evidence has accrued that “detox” more frequently and it is important to assess what factors
from opiates, especially if sustained, can be associated with lead to more frequent dosing with opiates.
a significant improvement (although not abolition) of pain • Dose: A significant group of patients in the intestinal fail-
levels and improvement in GI motor function [10]. In the ure unit will be on a greater dose of opiates than the upper
intestinal failure setting, there is some evidence that opiate limit of currently recommended doses.
use is associated with some greater risk of harms, in particu- This is likely to be multifactorial. For example, during
lar catheter related blood stream infections [23]. Opiates at “flareups” of pain or acute admission opiates may have
high doses suppress aspects of immune function including been increased to aid in analgesia at that time, however if
inhibitory effects on humoral and cellular immune responses the patient has an ongoing chronic pain it is unlikely the
including antibody production, natural killer cell activity, opiates alleviate the symptoms completely, once the acute
cytokine expression, and phagocytic activity [24] leading to episode settles however due to the ongoing pain the opiate
greater susceptibility to infections. Finally, the risks of opi- dose often remains unaltered and therefore escalated. The
ates in regard to addiction and abuse is well known. risk is that this happens with multiple admissions.
Pain and perceived improvement in symptoms tran- Intramuscular injection Historically this was used for
siently from dose increases also leads to a reduction in dis- patients with ongoing pain, however as subcutaneous
tress for the patient and consequently the treating team. injection is equally effective in the majority of patients
Unfortunately, once the initial improvement abates and pain this is no longer part of the practice within our intestinal
returns, as does ongoing distress for the patient and then as failure unit. Patients who use repeated intramuscular
a result the treating medical team. As the dose increase was injections to manage their pain are at risk of myofibrosis
effective in alleviating the problems previously, the same and muscle contractures and so long-term usage is dis-
behaviour can be repeated, and the result is further dose couraged [26].
increases. In the literature on the narcotic bowel syndrome,
a “soar and crash” phenomenon of escalating doses of opi- Subcutaneous opiates have the advantage of not requiring
ates is described where the opiate side effects on GI func- an oral route and for some patients allow the use of a syringe
tion, opiate induced hyperalgesia and withdrawal side driver to allow continuous dosage. The placement of a but-
effects on de-escalation are actually driving the dosage pre- terfly allows repeat injections without the need for multiple
scribing higher and higher [9]. This seems to be a particular needle stabs. Whilst this route is used particularly during epi-
problem with the shorter acting opiates. sodes of vomiting if opiates are required, there is still the
• Aims of therapy: Opiates for a significant group of intes- potential for developing infections at the site of the needle
tinal failure patients, particularly those with slow transit and so there is still a potential for harm which can be avoided
times such as enteric dysmotility, are unlikely to be help- if the opiates are either stopped or the route of administration
ful and so reduction of opiates and if possible removal of changed.
opiates can be considered the long-term goal.
For other patients where slowing transit time is not an For all the routes of administration detailed above it is
issue, opiates nonetheless remain of limited benefit and our practice to inform patients of the potential risks not
therefore again dose reduction to recommended limits is only of the opiate but also of the route of administration
necessary and removal of opiates should still be considered. and the potential therefore of harm to the individual from
Rapid changes are likely to produce withdrawal symp- on-going injection therapy and that this risk will increase
toms which in an intestinal failure unit may be very simi- with prolonged reliance upon each route. One option would
lar to the symptoms of a flareup of pain. The result being be to reduce opiates and then stop the opiates without
further changes are met with opposition from patients. changing the route of administration, however for many
If patients are willing to make multiple changes then patients the removal of opiates is not at this point an achiev-
this may be an option, however in a reluctant patient in able goal and so alteration of mode of delivery is more
our experience it is better to make gradual changes achievable.
with the patients’ agreement. However, dose escalation
or reversion to previous route of administration is Sublingual and Intranasal Opiates offer a route of admin-
discouraged. istration of opiates that avoids absorption via the intestinal
system. For patients with intestinal failure this potentially
may be seen as advantageous in allowing opiate administra-
Alteration of Opiates Regime and Route tion. These medications are licensed only for palliative care
and are designed for pain episodes which are relatively short
lived. The speed of onset is relatively rapid, but they are not
Intravenous opiates The use of intravenous opiates is encour- designed for multiple uses per day. The cost of these medica-
aged in the management of acute pain and patient-controlled tions is relatively high and therefore this needs to be consid-
analgesia systems allow the self-administration of opiates ered when considering their usage. It is our practice to use
within set parameters. These systems are very useful in the these only as a potential option for the management of pain-
acute pain setting, however in a chronic pain setting intravenous ful dressing change.
opiates are no longer appropriate. The use of lines for opiates
which are aimed primarily at on-going nutrition increases the Transdermal opiates in intestinal failure represent an ideal
risks of line infection and in our opinion is an unnecessary risk. route of administration as the absorption of the opiate (fen-
Bioequivalent doses of opiates can be achieved using subcuta- tanyl or buprenorphine) is through the skin and not the gas-
neous injections in the short-term and this can be considered as trointestinal system. They provide continuous opiate release,
an alternative route in the shorter term for patients unable or absorption can however be altered by fever and caution with
unwilling to manage other routes of administration. hot baths is also advisable. It is important to consider the
relative potency of these medications to morphine when con- Table 3 Dose equivalences of commonly used opiates
sidering dosage. Oral opiate Dose Oral morphine dose
Codeine Phosphate 60 mg 6 mg
Oral Opiates usage is dependent upon both tolerability Dihydrocodeine 60 mg 6 mg
by the patient and also bowel transit time. Modified release Tramadol 50 mg 7.5 mg
Hydromorphone 1.3 mg10 mg
medications often have a limited role as bowel transit
Oxycodone 5 mg 10 mg
times may be short and so absorption of the opiates is lim- Tapentadol 50 mg 20 mg
ited. Immediate release opiates however which can be Transdermal opiate Dose Oral morphine equivalent per
given as a liquid or tablets do appear to be effectively 24 h
absorbed for many patients on the intestinal failure unit. Fentanyl 25 μg/h 90 mg
They allow for medications to be given during flareups of Buprenophine 20 μg/h 50 mg
pain, however as the half-life is over 3 h for all these medi- Approximate dose equivalents for opiates compared to morphine
cations our policy is to provide opiates no more frequently Based on faculty of pain medicine dose equivalent and changing doses
webpage, Royal College of Anaesthetists 2018
than three hourly.
For the majority of patients, the initial goals in manage- of immediate release opiates and then consider how to
ment of opiates are ensuring the route of administration is achieve dose reduction.
either transdermal or oral or a combination of both. Overall opiate doses should be considered for all, with a
reduction of opiates encouraged with patients on higher
doses. It is important to start a process of dose reduction but
Opiate Reduction at a rate of reduction that is acceptable to the patient. Table 3
below summarises dose equivalences for commonly used
Due to the absence of supporting data for any benefit from opiates.
opiates in chronic pain and increasing evidence of harm from There are no evidence-based guides on reduction but in
high-dose opiates, it is important to engage the patient in dis- broad terms a reasonable aim is a 10% reduction at agreed
cussion about the risks of harm from opiates as well as any intervals, not more frequently than weekly but potentially
benefits. longer, and no dose increases.
An explanation of the effects of opiates on the bowel and The method of administration will be an important factor
also the increasing evidence of effects of opiates on hormone in deciding which opiate is used during dose reduction.
production, potential effects on white blood cell function and It is possible to reduce any opiate gradually and so the pref-
immunity, as well as paradoxical worsening of pain are erence of patient and the familiarity of staff with a drug on the
among risks that should be discussed with patients. There is unit are important factors in deciding which drug to use.
evidence from the narcotic bowel syndrome literature that a In addiction clinics, methadone is used due to the once
sustained detoxification from opiates is associated with a daily dosing and some patients in pain clinics find it an effec-
reduction (but not abolition) in pain intensity, thought to be tive opiate for analgesia. Unfortunately, due to the stigma
due to improved gut function and removal of opiate induced attached to the drug from the association with addiction
hyperalgesia [9]. many patients are unwilling to see this as a therapeutic
Explanation of gradual reduction in opiates to prevent option. Buprenorphine is a partial opiate agonist which has a
withdrawal symptoms, and that it is unlikely that there will ceiling effect to the opiate action. This has been used increas-
be worsening of pain symptoms despite dose reduction need ingly in opiate reduction and therefore is an option available
to be clarified. if a change of opiate is desired.
Also, the potential benefits of improved pain relief during If opiate rotation or switch is used at the time of change a
any acute episode of pain needs to be explained. lower dose (than equipotent) should be used to prevent toxic-
Opiate reduction needs to be considered in two parts—(1) ity at the time of change.
The frequency of dosing and (2) total daily dose of opiates. Adjuncts to opiate dose reduction to minimise withdrawal
The frequency of immediate release opiates should not need side effects might be considered such as clonidine [9]. Where
to be more frequent than every 3 h and for patients with opiate abuse is suspected, there may be a role for engaging
chronic pain and a background of sustained-release opiates, liaison psychiatry drug and alcohol input.
breakthrough doses should be needed less frequently than Peripherally acting mu opiate receptor antagonists,
this. As opiates have only a limited role in chronic pain, dose including naloxegol and methylnaltrexone may also be use-
escalation of sustained opiates based upon breakthrough ful adjuncts to mitigate against some of the bowel dysmotil-
dosing is of minimal value. Prior to commencing dose reduc- ity side effects of opiates, however they do not appear to help
tion, it may be necessary to limit frequency of administration pain symptoms [9].
Neuromodulator (Adjuvant) Drugs Augmenting Agents
The Rome foundation have reviewed evidence for the use of The Rome Foundation working party on neuromodulators
drugs which have activity in the brain-gut axis for pain and also supports a concept of “augmentation treatment” where
associated symptoms, which have been termed gut-brain combinations of different classes of the neuromodulators may
“neuromodulators” [27]. In the chronic pain setting these give rise to synergistic positive effects. They also provide
drugs are also called adjuvant analgesics. some data for adding in the atypical antipsychotic quetiapine
to a TCA or SNRI at low doses of 25–200 mg. If this approach
is considered then awareness of the hazards of serotonin syn-
Tricyclic Antidepressants drome should be considered and also monitoring for meta-
bolic syndrome and involuntary movements [27].
Tricyclic antidepressants (TCAs) are recommended for
use in the range of 25–75 mg at night for chronic abdomi-
nal pain, with amitriptyline and imipramine more likely to Other Drugs
produce anticholinergic and anti-histaminic dose limiting
side effects than desipramine and nortriptyline. Their Cannabis and cannabinoids act via cannabinoid receptors, the
analgesic efficacy is thought to be due to combined 5-HT endogenous cannabinoid system is found throughout the
and NA reuptake inhibition. Muscarinic1 receptor antago- body’s neural system including the viscera [28]. Cannabis is
nism accounts for side effects of dry mouth, constipation, not currently available in the United Kingdom and there are no
drowsiness and blurred vision. The constipating side cannabinoid treatments licensed in the U.K. for use in chronic
effect can be useful therapeutically in the setting of diar- pain. Cannabis may be a potential treatment for chronic pain
rhoea. Alpha 1 adrenergic receptor antagonism may lead in neuropathic and visceral pain although there is limited evi-
to dizziness, drowsiness and orthostatic hypotension. dence of benefit and the value of this reduction in pain com-
Histamine 1 antagonism may lead to weight gain which pared to risk of longer term side-effects is unclear [29].
can be helpful in functional dyspepsia. Sodium channel Gastrointestinal side-effects that have been associated
blocking properties can risk arrhythmias and seizures in with cannabis usage include visceral pain with acute heavy
overdose. cannabis use and in prolonged usage cannabinoid hypereme-
sis syndrome [30].
Ketamine acts at the N-methyl-d-aspartate receptor and it
Serotonin Noradrenalin Reuptake Inhibitors may also act on descending inhibition of pain pathways. It is
an anaesthetic drug that has been used at sub-anaesthetic
Serotonin Noradrenaline Reuptake Inhibitors (SNRI) may doses to treat resistant chronic pain syndromes. It has been
have at least equal benefit as TCAs for chronic GI pain. They given as short-term infusions and also orally over prolonged
have a more favourable side effect profile than TCAs as they periods. There has been limited research into its use in
are largely devoid of other receptor affinities. Venlafaxine chronic pain and no evidence of improved functionality
may be more prone to side effects than duloxetine. Duloxetine despite its use. Potential side-effects include memory effects
has equal affinity for 5HT and NA transporters and at lower and urological problems although most of this evidence is
doses than venlafaxine and so should be the preferred SNRI gathered from recreational ketamine users [31].
to use.
Nerve Blocks and Ablation

Delta Ligand Agents (Gabapentinoids)
For some patients’ injections may produce an improvement
Delta ligands (Pregabalin and Gabapentin) have less direct in symptoms which enables reduction in medications and
data in chronic abdominal pain but nonetheless are consid- potentially increased levels of function. The aim of a nerve
ered of potential benefit, and there is also some data that block is to alter the conduction or transmission of pain signals
gabapentin may be helpful in reducing opioid-induced by blocking the nerves involved in carrying the pain signal.
hyperalgesia [9]. They block the alpha2delta subunit of Injections can be diagnostic, using only short-acting local
voltage-sensitive calcium channels to reduce excitatory glu- anaesthetic. If injections produce a short-term improvement
tamate production. This likely underpins their anti- in symptoms and then symptoms recur this is suggestive that
convulsant, anxiolytic and analgesic actions. a further block may be therapeutic.
Longer term pain relief can be achieved in some patients Potentially this may be a treatment option for some patients
using a combination of local anaesthetic and steroid which with chronic abdominal pain and gastrointestinal failure [34,
can produce a longer-term effect. For those with chronic 35].
abdominal wall pain this may be possible to consider as an
injection to the abdominal cutaneous nerve [18].
It is possible to consider neurolysis for some nerve blocks. Psychological Approaches to Pain
This involves the injection of a neurotoxic drug e.g. phenol
which may produce longer term effects, however due to the There is considerable evidence that various psychological
risk of recurrence of symptoms and also more serious and interventions such as cognitive behavioural therapy and
long-term side-effects with neurolysis, this is often reserved mindfulness training for chronic pain can be effective. There
for palliative care. is also data to support hypnotherapy for chronic abdominal
Radiofrequency ablation is increasingly used as a modal- pain [9]. The treatment of co-morbid anxiety and depression
ity of treatment to provide prolonged pain relief. It works by may indirectly also improve patients coping with chronic
using a high-frequency alternating current to heat tissues to pain. Psychological aspects and treatments in general on the
temperatures (above 45 °C) which will cause denaturing of IFU are dealt with in greater detail in chapter “Psychological
the tissues at the tip of an electrode which is placed near the Aspects of Intestinal Failure”.
nerve. This has been used to provide pain relief for patients
with abdominal pain although not within an intestinal failure
setting. Chronic Pain: A Paradigm Shift
Splanchnic nerves and coeliac plexus blocks have been
used as treatments for managing visceral pain [32]. Finally, an optimal approach to chronic pain requires a series
of “paradigm shifts” for both the patient and the doctors
looking after them. The first element of this paradigm shift is
Spinal Cord Stimulation from that of a cure focus to a care focus. At the most basic
and simple level this is an understanding that chronic pain is
Melzack and Wall described the gate theory of pain in 1965. “chronic” and currently cannot be cured medically.
The principal being that transmission of pain signals could A second shift is from the biomedical model of “test and
be altered by stimulation of other pathways that would stop treat” to a biopsychosocial model. On-going fruitless and
onward transmission of noxious information and as a result frustrating cycles of investigations and searches for the
reduce pain. “cause” of the pain can be costly, harmful, and counterpro-
Spinal-cord stimulation was introduced as a way to alter ductive in preventing patients from moving on with engage-
the experience of pain. ment with a chronic pain rehabilitative focus. There is no
Spinal cord stimulation involves the implantation of an objective reliable test that can show the abnormal nerve
electrode either percutaneously or surgically into the epi- function underpinning chronic pain and so after initial struc-
dural space. A pulse generator is then implanted in the sub- tural evaluations, unnecessary rounds of repeated tests
cutaneous tissue and this then produces the stimulation to the should be avoided. Explanatory models of the pain system
spinal-cord. and the role of the central nervous system, and eliciting spe-
Initially it was thought spinal-cord stimulation acted in cific clinical features of neuropathic pain, can be helpful as a
the dorsal horn of the spinal-cord, however it is thought positive alternative to negative tests.
spinal-cord stimulation also acts via posterior columns of the Since most of these patients are not in the terminal phase
spinal-cord to recruit endogenous inhibitory pathways. There of their lives, rather than a palliative approach of increasing
is also an autonomic effect. However, mechanisms of pain narcosis, a third shift therefore is to minimise approaches
relief are still not fully understood. which reinforce dependence and helplessness (avoidant
Spinal-cord stimulation has been found to be effective in coping) and to improve self-efficacy in patients (active cop-
the treatment of neuropathic pain following back surgery, ing), with an aim to promote improved function and coping
complex regional pain syndrome, neuropathic pain second- in the face of on-going chronic pain—a rehabilitative
ary to peripheral nerve damage and pain associated with approach.
refractory angina [33].
Medical contraindications to spinal cord stimulation
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Psychological Aspects of Intestinal
Failure
Yoram Inspector

1. Attend to the person who has the disease as much as to
the disease a person has. Reflecting on the title I gave to my chapter, I immediately
2. Psychological support is normal and essential for most felt the urge to amend it to:
patients with intestinal failure (IF) and especially if need- The Psychological support offered to the person who experi-
ing PN at home. ences Nutritional Failure
3. The needs are different if the IF is acute (e.g. mesenteric
infarction) or chronic (e.g. Crohn’s disease). This title allows us to acknowledge the reality that IF occurs
4. All patients will go through the 5 stages of mourning within the body of a unique human being who needs to
(denial, bargaining, anger, depression and finally accep- recruit all possible psychological resources in order to cope
tance) at different rates. with this extreme condition. As William Osler said: “You
5. Ask the patient how they experience their condition and have to be interested in the person who has the disease as
what do they think about it. much as you are interested in the disease the person has” [1].
6. Psychopharmacology, Cognitive Behavioral Therapy, Each patient faces different challenges and needs and there-
Acceptance and Commitment Therapy, Psychodynamic fore an individually tailored therapeutic approach must be
Interpersonal Therapy, Eye Movement Desensitization formulated to suit her/his different medical history, life story,
and Reprocessing, and Gut Directed Hypnotherapy are personality and their various adaptation capacities. This is
all useful and helpful for our patients. one of the most important lessons I have learnt from the last
10 years of providing weekly psychiatric and psychological
treatment to the patients of the Intestinal Failure Unit (IFU).
“Funny little thing about this tummy o’mine, The name of the unit was changed around 3 year ago to The
doesn’t wanna work like once upon a time, Intestinal Rehabilitation Unit (IRU). The word Failure has
I can eat the food but it just sits,
been purposefully replaced by Rehabilitation in order to pro-
making my tummy hurt and throw a lot of fits!
The food doesn’t wanna stay, vide a rather more hopeful and constructive message to the
I feel like a cow chewing cud all day. patients and the medical staff alike. IF, which nearly always
Then there is the pain with no end in sight, involves the need for PN, will affect all domains of one’s
I hurt all through the day and through the night.
existence: physical, emotional, social and even spiritual. All
Off comes the weight down another size,
God how I miss those burger and fries! these aspects need to be addressed by the multidisciplinary
But gone are those foods, this is hard to endure. team in order for the treatment to succeed to significantly
What can I have? improve the patient’s wellbeing and quality of life.
Oh, Goody Ensure!!!”
The poet was a patient at the Intestinal Rehabilitation Unit of St Marks’
Hospital.
She called herself “a Gastroparesis Fighter”. he Psychiatric and the Psychological
T
I want to dedicate my chapter to all the fighters of the Intestinal Assessment
Rehabilitation Unit of St Mark’s Hospital- to all the patients and to all
the members of the multidisciplinary team who fight for having a good,
happy and fulfilling life alongside intestinal failure. St Mark’s Hospital has a dedicated in-house Psychological
Medicine Unit (PMU) that provides psychiatric and psycho-
logical treatment and support for patients who suffer from
Y. Inspector (*)
various gastrointestinal diseases and disorders, among which
The Psychological Medicine Unit, St Mark’s Hospital, Harrow, UK

742 Y. Inspector
are a large group of patients who cope with IF. The PMU’s As the causes of IF vary considerably, so do its psychologi-
team meets weekly with the IRU’s team to discuss patients cal consequences. It is rather different to find oneself need-
with IF who need and/or possibly would benefit from a psy- ing home PN after gradually losing, over the course of some
chiatric and psychological assessment. Getting to know the years, most of one’s intestine due to aggressive inflammatory
background of the patient usually begins in this this joint bowel disease, for example, than to be needing the same after
meeting, when the nurse, dietitian and or the gastroenterologist an acute mesenteric artery occlusion that was incurred spon-
presents the patient’s information to the PMU. This is then taneously. In the first instance one might actually experience
naturally followed by the PMU clinician’s first meeting with relief due to the improved quality of life PN can provide, yet
the patient at the IRU after the patient has given consent to in the latter situation one would perhaps enter a state of
the meeting. shock and grief in reaction to the sudden and brutal loss of
one’s capacity to digest food. In any case the experience is
traumatizing.
he Physical Condition: It Is Not Just in Your
T The word trauma in Greek means “wound”. It is also ety-
Head! mologically related to the word Trema which means a mark
or a “hole” (used for the dots on dice, for example) as well as
Although I already know something about the patient from the words “tremor” and “tremendous”—indeed, trauma des-
the initial team meeting, I do not know him or her yet. To ignates an event as beyond the realm of the ordinary. The
know is to experience. I try to put aside the information and wound has created a hole that marked you and that has
start afresh. After I introduce myself I always tend to add: brought about a physical and emotional trembling. Every
“Don’t worry, the fact that you’ve been asked to see a psy- person who faces IF has experienced trauma along his jour-
chiatrist and a psychotherapist doesn’t mean that you are ney to recovery through PN.
mad; It means that your gastrointestinal system became a This may seem like stating the obvious, but it is neverthe-
bit mad and if this happens it can madden anyone and as I less crucial to state it: PN is a life-saving therapy in patients
am allegedly an expert on madness you are seeing me”. I with severe IF. Importantly, these patients do not chose PN
have found that this sentence immediately puts a smile of out of their free will, but it is usually the ultimate remaining
relief on patients’ faces as it validates the fact that whatever option to maintain or improve their nutritional status [3].
they experience mentally and emotionally, as extreme as it This lack of choice means that every patient undergoing
may be, is a normal reaction to the abnormal situation of treatment necessarily experiences the five stages of the
the IF. mourning process that was described by the Swiss-American
To consolidate this message, in which I strongly believe, Psychiatrist Elisabeth Kubler Ross [4].
I tend to start my assessment with taking a detailed account
of the history of their gastrointestinal disease. When and Denial: “I feel fine, this cannot be happening to me”
Bargaining: “I can still do something to change the situation”
how did they start suffering from it? How it behaved over
Anger: “Why me? It’s not fair; how can this happen to me? Who is
the years? I always also endeavor to create the space to to blame?”
speak about the physical pain the disease causes and inquire Depression: “I am so sad, why bother with anything?”
how the patient manages to live with it. Many gastrointesti- Acceptance: “I can’t fight it, I may as well prepare for it; It’s going
nal diseases and conditions can involve an acute or severe to be okay”
and enduring IF and each patient has her/his unique jour-
ney, an account of which one must listen to carefully. It is Granted, this should not be understood as some linear
important for the mental health clinician who works in the ideal chronology by which a patient’s attitude always and
psychosomatic field to fully embrace the physical bodily unvaryingly develops and progresses. It may start and end
experience of the patient—“The Body Keeps the Score” with any stage - but all the above five stages will at some
[2]. point in time be encountered. We hope to end with accep-
It is not just psychosomatic (the psyche affecting the tance, yet many researchers have found that depression is the
body) it is also, first and foremost in the case of IF, the most common emotional response to home parenteral nutri-
impairment of this vital, crucial physical function to which tion (HPN) (the most common end result of IF) and can be
the psyche acutely reacts. found in up to 80% of the patients who are commonly over-
whelmed with feelings of worthlessness, helplessness and
hopelessness [3].
How Does IF Affect The Psyche? Most of us take for granted our ability to eat spontaneously
and be nurtured through our mouth. Imagine that this capacity
“Losing my colon felt like losing a part of my mind” a patient is suddenly taken away from you; you will obviously feel
on the IRU
deprived and deeply frustrated. So much of one’s communal
Psychological Aspects of Intestinal Failure 743
activity revolves around food that not being able to eat in a I am poured out like water and my bones are out of joint;
My heart melted like wax;
natural way might give anyone a feeling of being a “second
It melted into the midst of my bowels.
class citizen” in normal society. It is easy to comprehend how
having a permanent catheter inserted in a central vein in your This has been confirmed in modern scientific literature: 62%
neck for feeding can make you feel like an alien. of women with idiopathic gastroparesis (which often ends
Many HPN patients suffer as a result of their condition with HPN) reported a history of physical or sexual abuse,
from poor self-esteem and body image. and physical abuse was significantly associated with abdom-
A constant source of concern for almost all patients was inal pain, somatization, depression and life time surgeries
the cosmetic effect of multiple surgical procedures and the [6]. Approaching such issues should be undertaken with
actual location of the catheter. Some patients perceived great sensitivity and at the right timing as childhood and/or
themselves as unattractive or even repulsive, experiencing adult trauma often is not merely remembered—it is relived.
feelings of embarrassment and shame concerning disfigure- Opening up these wounds can be retraumatizing.
ment due to scars and weight loss. Such embarrassment and
shame often lead to impairment in sexual relationships.
Other psychological problems include: changes in depen- The Treatment-How to be the Second
dency (mostly loss of independence), changes in one’s abil- Mouse?
ity to travel (which was the activity most disturbed by HPN),
the feeling of being a nuisance or burden to others, feeling When I need to define what the PMU does, I always write (as
that one lacks understanding of others as well as perceiving mentioned above): “The PMU provides psychiatric and psy-
a lack of understanding from others [3]. chological treatment and support for patients who suffer
All the above states are accompanied and even maintained from various gastrointestinal diseases and disorders”. A
by anxiety. IF and HPN naturally provoke various fears; of mental health clinician suggested to me to omit the word
the unknown, of catheter infection, of pump malfunction, support from this description, as according to them it is not
liver damage or fear of death. Anxiety is composed of two suitable to the highly specialized service we provide. The
major elements: (1) uncertainty and (2) dread that something word support might be perceived as too broad or unspeci-
irreversible will happen. Any psychological support pro- fied—your aunt or friend can support you as well. After
vided will need to address this anxiety in order to transform reflecting on this issue for a while I told them that while I see
overwhelming fear into a constructive life affirming and cel- their point, I believe that the word support is the most impor-
ebrating attitude. In the treatment section I will reflect on tant one for me in this definition and would be the last one I
how this might happen. In the assessment—I ask how does it would be omit. I went on to talk about the Supporos in Greek
affect you? antiquity—those who supported you when you came to heal
yourself in the “The Asklepion” the temple of Asclepios -
The God of Medicine [7]. After being given a bath with all
How Does the Psyche Affect IF? sorts of aromatic oils and healing plants the patient was sent
to “incubate“, have a dream at night which will hopefully
The brain-gut axis is a “dual carriage way”: What happens in contain a healing symbolic message from the Gods and in
the gut affects the brain through the gut microbiome and the the morning the Supporos would come and support you
enteric nervous system and at the same time what is happen- physically from both sides (by the way the world support is
ing in the brain is perceived by the gut through the auto- related etymologically to the word Sub-from underneath, to
nomic nervous system. It is not rare to hear from patients support bottom up, which is very connected to gastroenterol-
who suffer from IF that their gastrointestinal disease erupted ogy). Then they would accompany you to stand in front of
following an emotional trauma: An attachment trauma, being the image, the sculpture of Asclepios and say: “We Support
bullied at school or other various forms of abuse. Our ances- and God Heals”. I said to my colleges that in my view this
tors thousands of years ago already knew about such a pos- humility regarding our role in healing and at the same time
sible linkage: Chapter 22 of the Book of Psalms in the Old the crucial role of the humane support in this process that is
Testament opens with the poignant Hebrew words which embodied in the Support of the Supporos, should guide us
Jesus quoted on the cross: [5]. even more now in our technological age of the 21st and
Eli Eli Lama Azavtani”—“My God My God why have you for- added that Hippocrates the father of scientific medicine was
saken me. initially a follower of Asclepios and that maybe from this
period he came with his important sentence: “You com-
In line 14 of this poem we can find an accurately moving pletely cure rarely, you give therapy (makes things better)
description of what the lonely, abandoned, trapped, trauma- frequently and you must comfort always. Comfort and sup-
tized person experiences in his body: port are naturally interwoven.
744 Y. Inspector
The question is how to support the patient who is suffer- because you will not be alone, the patient can become your
ing from IF? The first thing I would recommend is: Be the protecting second mouse in the “electrocuted cage of IF”.
second mouse! This suggestion needs obviously a bit of The remedy to “My God My God why have you forsaken
explanation. It is based on the experiment done with mice me”, in Psalms 22, mentioned above, can be with found in
presented by the French surgeon Professor Henri Laborit in the next poems Psalms 23:“Even though I walk through the
the French Director Alain Renais’s film: Mon Oncle valley of the shadow of death, I will fear no evil, for you are
d’Amerique which translates into English as “My American with me.” Again it is about being with!
Uncle” in which mice are used as an illustration to the In addition to the core essential healing modality of com-
humane condition. What happens in the experiment? It has passion or “being the second mouse” we have two more
three stages: additional “specialized”, “professional” tools aimed at
improving the patient’s quality of life and wellbeing: psy-
1. A mouse is put in a cage but the door of the cage remains chopharmacology and psychotherapy.
open. The mouse received a disturbing but not a danger- Psychotropics drugs can help to improve various mental
ous electrical shock and it immediately escaped through disorders:
the open door of the cage to avoid further pain. Its health The different types of anxieties, depression, post-
was not affected. traumatic stress disorder and mood swings. I encountered all
2. A mouse receives the same disturbing but not dangerous of them at the RIU and if indicated I would prescribe psycho-
electrical shock, but this time the door of the cage is tropic drugs to reduce the psychic pain of the patients. Being
locked. It cannot escape and is alone! This lonely, also a psychotherapist, inspired by the Swiss Psychiatrist
trapped mouse starts to become ill-it develops alopecia Carl Gustav Jung saying: “Man cannot stand meaningless
and a peptic ulcer and vomits blood. suffering”, I know that medications are not enough to address
3. Two mice are put in a locked cage and are electrocuted the suffering of a person who suffers from IF. Finding the
(given same non dangerous electric shock). They cannot unique meaning she or he attributes to this radical condition
escape like in the first stage of the experiment but they are is crucial to their healing and recovery.
together- not alone! They interact with each other, dis- Psychotherapy—“The Talking Cure” aims at widening
charge their pain on each other and share it. These mice the repertoire of how the person relates to himself and to oth-
remain physically healthy! ers, which is helping in getting redeemed from the feeling of
being trapped. Psychotherapy aims at creating a sense of
There is scientific evidence that “stressed mice look like self-agency (you can reflect about and influence your life)
depressed humans. This is actually the subtitle in a fairly and at providing tools for affect regulation. Many times it is
recent textbook on The New Mind-Body Science of not only focusing on fixing psychopathology ‘it is also a
Depression [8]. Which explores fascinating and surprising mean to support individual development and growth in every
interlinks between inflammatory processes and depression. aspect of one’s life including the spiritual domain.
Not being alone and interacting with others has a healing There are numerous psychotherapies based on different
potential for depression and according to the above textbook psychological theories and I will mention just a few of them,
even for inflammation. How then to interact with the patient the ones we commonly use at the IRU:
who is trapped in the “Electrocuted cage of IF”? In order to
really help, healthcare professionals need to step into the
cage of the IF patient and be ready to be “Electrocuted”: Be Cognitive Behavioral Therapy
ready to compassionately take the patient’s experience in.
A basic assumption of cognitive behavioral therapy (CBT) is
the recognition that there is a reciprocal relationship between
he Word Compassion in Latin Means
T our cognitive processes (what we think) and our affect (emo-
to Suffer With! tional experience), physiology and behavior. Although Cognitive
Behavioral treatments for individual disorders differ in both
Compassion does not require one to achieve complete under- their form and application, they all emphasize the importance of
standing of the other’s perspective and circumstances, engen- changing cognitions and behaviors as a way of reducing symp-
dering exactly the same feeling; it merely calls on one to toms and improving the functioning of the person.
imagine what it might be like to suffer in a way that the other In CBT we commonly challenge automatic thoughts -The
is suffering. If achieved, this will engender the correspond- self-critical or exaggerated negative self-statements that go
ing emotion, which can then be conveyed [9]. If you are through a person’s mind and are accepted as true by the per-
really ready to “suffer with, and have a true genuine rapport son without testing their accuracy [10]. We put question
with the patient don’t worry about being “electrocuted”, marks after the exclamation marks-!? For example, if a
patient who is diagnosed with IF thinks that he is a worthless The use of ACT at the IRU focuses on consolidating the
human being because of it, that he is helpless and there is commitment to life alongside the IF. We hope that future
nothing he can do to improve his life and that he is hopeless - work may show that ACT is helpful in the treatment of
the situation will never get better, he will feel deeply chronic abdominal pain and so provide an alternative to the
depressed and will withdraw from many life affirming activi- abuse of analgesics (especially opiates).
ties (thought changes feeling which alter the behavior). The
CBT therapist will explore together with the patient the
validity of his assumptions which lead to his depressing con- Psychodynamic Psychiatry/Psychotherapy
clusions and with the technique of “Cognitive restructuring”
will help the patient to realize that they can be modified. As the name indicates, this type of therapy is engaged with
The CBT therapist will assess the patient’s beliefs about exploring and facilitating the dynamics between all levels
the causes for the IF, the consequences, symptoms experi- and aspects of the psyche—the conscious as well as the
enced, personal and treatment control, chronicity and recur- unconscious ones. This is how the psychiatrist Glen O
rence and the feeling of anger, upset, anxiety, low mood and Gabbard describes the psychodynamic attitude:
fear that accompany their beliefs. “Psychodynamic psychiatrists approach their patients by try-
The principal predictors of the above negative feelings in ing to determine what is unique about each one-how a par-
IF patients were: ticular patient differs from other patients as result of a life
story like no other. Symptoms and behaviors are viewed only
1. Poorer appraisals of patients’ ability to exert personal as final common pathways of highly personalized subjective
control over aspects of their condition and treatment experiences that filter the biological and environmental
2. The perception that the condition and treatment makes determinants of illness. Furthermore, dynamic psychiatrists
little sense to the patient [11]. place paramount value on the patient’s internal world -fanta-
sies, dreams, fears, hopes, impulses, wishes, self-images,
Therefore the CBT therapist at the IRU has also a psycho- perceptions of others and psychological reactions to symp-
educational role-they need to be knowledgeable and fully toms” [14].
understand what it entails to live with IF in order to help the In the context of IF the psychodynamic oriented psychia-
patient to have a sense of coherence of their illness and dis- trist might then be interested in exploring childhood early
cover the meaning they give to their suffering. feeding experiences, relationships with parents siblings, the
relationship with the therapist the possible symbolic mean-
ing the patient might attribute to the central venous catheter:
Acceptance and Commitment Therapy An intrusion or maybe a feeding umbilical cord?
Will this encourage regression, separation or individua-
This is a “third wave” CBT therapy that has some similarities tion? The meaning the patient will give to the HPN might be
to the way the Buddhist philosophy approaches pain-with influenced by his attachment patterns that can be for example
compassion and acceptance. The acceptance and commit- reenacted with the medical team caring for him/her or with
ment therapy (ACT) model holds that culturally supported the psychotherapist.
attempts to control and eliminate unpleasant experiences
result in personal suffering, behavior disorders and lack of
vital and purposeful living. ACT attempts to teach clients to Psychodynamic Interpersonal Therapy
accept, rather than control or eliminate painful experiences
that are not amenable to first order change. Acceptance is Psychodynamic interpersonal therapy (PIT) is a form of
accomplished through teaching the client to see these experi- Psychotherapy [15] that was developed by the Jungian
ences as conditioned verbal responses, rather than literal Psychiatrist Robert Hobson. His Unique Conversational
truth. ACT emphasizes that the patient approach rather than Model to Psychotherapy is presented in his Book—Forms of
avoid, valued life goals, even though pursuing such goals Feelings—The Heart of Psychotherapy [16]. It has been
may stimulates uncomfortable experience [12]. Further adapted by Professor Else Guttery to treat unex-
ACT uses Mindfulness, an approach, a technique which plained and or Functional Bowel Disorders [17]. It is now a
aims at “Consciously bringing awareness to you’re here and relatively short term therapy up to 8–10 sessions but what is
now experience with openness, interest and receptiveness.” It special about it is that the first session is not restricted to an
makes no attempt to reduce symptoms, its goal is to create a hour. The therapist allows the patient all the time needed to
rich and meaningful life, while accepting the pain that inevi- describe in his own language the physical experience of his
tably goes with it. ACT has proven effective with a diverse gut disorder and waits patiently for the unique metaphors of
range of clinical psychiatric conditions [13]. the patient to organically emerge from the description in
746 Y. Inspector
order to create a bridge to the patient’s feelings. For example, Disorder and the Atypical Eating disorder (which has some
if the patient is using a metaphor of a volcano to describe elements from each of the other groups but does not fulfil the
bouts of pain it may lead to exploring feelings of rage and full criteria to any of them).
anger; speaking about trapped air in the bowel may lead the A “transdiagnostic model” has been suggested by Fairburn
patient to speak about how he feels trapped in life. This [20] who argues that this division should be abandoned as
approach frees us from needing to decide is it physical or 50% of the patients who suffer from anorexia nervosa will
psychical, as it holistically embraces the gut disorder turn into bulimic patterns and because the largest group is
experience. actually the atypical one. Moreover, they all share according
to Fairburn the same psychological problems:
ye Movement Desensitization
E 1. Core Low Self-Esteem
and Reprocessing 2. Clinical Perfectionism
3. Mood Intolerance
Eye Movement Desensitization and Reprocessing (EMDR) 4. Interpersonal difficulties.
is an eight -phase treatment approach that facilitates resolu-
tion of distressing historical events, desensitization of pres- One of main issues that maintains the Eating Disorder is that
ent triggering stimuli, and acquisition of desired behaviors self-esteem becomes totally dependent on body shape and
[18]. It is a structured therapy that encourages the patient to weight. This is definitely not the case with the patients who
briefly focus on the trauma memory while simultaneously suffer from disordered eating due to IF. Rarely an Eating
experiencing bilateral stimulation of the brain (typically by Disorder might be unveiled or triggered by IF due to the fact
eye movements), which is associated with a reduction in the that in addition to PN some patients are encouraged to have
vividness of the intrusion of post traumatic flashbacks and a hyperphagic diet to compensate for the malabsorption they
the overwhelming emotions associated with the trauma experience aiming for 3000 Kcal/day [21].
memories. It can be very useful in treating severe avoidance More often I found myself needing to redeem patients
behaviors and phobias. at the IRU from an Eating Disorder diagnostic label that
was put on them unjustly in the past. This became com-
monly the case with young women that developed IF due
Gut Directed Hypnotherapy to gastroparesis and or severe gut motility disorders that
was part of a previously undiagnosed Ehrler Danlos
Hypnotherapy is a NICE recommended treatment for Syndrome (EDS). The gastrointestinal manifestations of
Irritable Bowel Syndrome that can be also a very efficient EDS which appear all along the gastrointestinal track have
tool to reduce the intensity of various forms of anxiety that received little attention despite the observation that they
many patients at the IRU are coping with them, to enhance represent a considerable symptom burden on sufferers
deep relaxation as well as improving self-confidence and [22]. In addition to abdominal pain they include: Oral:
esteem [19]. periodontitis, loss of teeth and bone; Oesophagus: hiatus
hernia (33.3%) rarely rupture; Stomach: nausea and vomit-
ing (29–34%), gastric emptying abnormalities (75%) with
isordered Eating or an Eating Disorder?
D most frequently a delay in gastric emptying; Small bowel:
And Why Does It Matter? perforation; Colon: spontaneous colonic perforation,
chronic constipation; Rectum and Anus: fecal inconti-
All the patients who suffer from IF experienced disordered nence, obstructed defecation.
eating. Until PN had been introduced they could not eat nor- The EDS patients I have seen are mostly young women
mally: vomiting if they have gastroparesis, gut dysmotility or and nearly all of them had a long and painful “Via
obstruction, or diarrhea due to poor absorption of food as Dolorosa” until their symptoms were taken seriously and
result of a short bowel or intestinal inflammation. However properly diagnosed. Often as they were young women who
few of them suffered from an Eating Disorder. struggled to eat they were misdiagnosed as suffering from
An Eating Disorder is a psychiatric disorder in which eat- an Eating Disorder or Somatization-meaning that a psy-
ing becomes disordered due to psychological and social rea- chological conflict or distress is expressed through their
sons not due to physiological reasons. bodily symptoms. The risk of ignoring the reality of a
The Eating Disorders are classified into four main catego- physical disorder when the mind of the psychiatrist is
ries (see also chapter “Eating Disorders in Adults). Anorexia already set on a psychological cause for the physical symp-
Nervosa (restricting and binge-purging type), Bulimia toms is unfortunately not an uncommon mistake and can
Nervosa (purging and non- purging type), Binge Eating be fatal.
It happened even to “the father of Psychoanalysis “I am afraid that if a fire will burst in the ward and I will
“Sigmund Freud: be connected to the PN pump, I will not be able to escape”.
“A little girl was sent to him (to Freud) suffering abdominal Her unexpected surprising answer made sense later when we
pains. He diagnosed her as an ‘unmistakable” case of Hysteria were able to link it to her feeling of being trapped in the
and “cured” her with psychoanalysis. Two months after he Eating Disorders unit being misdiagnosed with Anorexia
discharged her she died, the cause being abdominal lymphoma. Nervosa and to the ongoing feeling of being trapped in her
Apparently unabashed, Freud denied all culpability, insisting
that he had cured the hysteria which he declared: “had used the body that is not capable to absorb and food. Her answer reas-
tumor as a provoking cause”. Dr. Anthony Stevens the Jungian sured what all my best mentors in psychiatry and medicine
Psychiatrist who discusses this case in his book: An intelligent taught me: Don’t assume! First ask the patient what do they
guide to Psychotherapy [23] says that “clinical arrogance of this think about their condition, they know! they are the one who
degree and magnitude was ill-designed to protect Freud against
the kind of missed physical diagnosis of which all psychothera- has the experience! This is true in any specialty of medicine
pists live in dread”. but should especially not be forgotten in mental health where
the danger is that the opinion of the person will be disre-
garded as already he has a label that challenges his capacity
to make a sensible judgment.
The Story of S
The treatment of S. at the IRU and the PMU illustrates the o What Happened to S? How Did Her
S
complexities that are at the core of the confusing gray area Problems Evolve?
between Disordered Eating and an Eating Disorder and high-
lights the importance of taking the time and the patience to Her mother confirmed that when she was one year old she
make the right diagnosis as it crucial for finding the right ther- contracted a campylobacter infection in a swimming pool
apeutic approach that will improve the wellbeing and the qual- that might have been followed by a post infectious irritable
ity of life of the patient. When I first met S. she was 19 years bowel syndrome as since she was a little girl she has com-
old. Her BMI was extremely low −12 kg/m2! She presented plained a lot about “tummy pains” which were diagnosed
with recurrent episodes of low potassium due numerous epi- as “tummy migraine”. She also had unexplained bouts of
sodes of vomiting especially after eating any amounts of food vomiting from a young age. At the age of 3 she had two
and at times even after drinking. In her vomit there were lumps episodes of a prolapsed rectum. S. who was hyper mobile
of undigested food even from the previous day. She also suf- and very flexible became an outstanding athlete. She won a
fered from continuous feeling of nausea and constant acid national competition for under 10 years old in her field.
reflux and regurgitation. To complicate matters, she had a During that time her coach made a thoughtless, unsensitive
period of 18 months during which she was a patient in an inpa- remark: He told her that she needs to be careful how she
tient Eating Disorders’ unit where she was at times under eats as she might become too heavy to compete in the team.
extremely strict 2:1 observation for 24 h 7 days a week. S. pas- As her success in her sport was so important to her at that
sionately insisted that she does not have an Eating Disorder! time and part of her identity she took his comment extremely
that she doesn’t have a body image problem! and that wants to seriously and nearly stopped eating completely. She started
restore a healthy wait but simply cannot do it physically! obviously to lose weight and when it started to become too
As a specialist for nearly 30 years now in the field of much she was diagnosed with Anorexia Nervosa. However;
Eating Disorders, I made a conscious choice to firstly fully when she was threatened with admission to a hospital and
believe my patients although I know that at times they tend cessation of her sporting activity, she immediately started
to disguise or hide their disturbed eating patterns. They do to eat and restored a healthy weight. This is something that
not lie about it because they are immoral, they are simply a “true Anorexic” will never do. She recovered very quickly
afraid these maladaptive eating habits will be taken away, from this period but then at the age of 14 she started to suf-
leaving them with no other coping mechanism to regulate fer from projectile vomiting up to 3–4 times a day and
their emotional traumas. started to lose weight again.
When S. told me that she tried to eat fish and chips numer- Although she did not have any Anorexic Ideations at that
ous times but couldn’t hold it in, I knew she did not suffer time she was “accused” of making herself vomit on purpose.
from Anorexia Nervosa. She did not have a conscious drive When she reported that she vomits “white lumps looking like
toward thinness and did not induce vomiting. On the other hard dumplings” she was told that this is imaginary.
hand her initial refusal to receive PN raised again the suspi- When the symptoms continued at some point feeding
cion that she is “hiding something”. So I asked her why are with a percutaneous endoscopic gastrostomy (PEG) was
you refusing to receive PN? She answered me tried followed by a percutaneous endoscopic jejunostomy
straightforwardly: (PEJ). During its insertion a bowel peroration occurred
748 Y. Inspector
which was followed by peritonitis. Then she was as men- believed she came regularly to the meetings and was able for
tioned above treated in an Eating disorder unit and as this the first time to have a life outside hospital whilst maintain-
had not succeeded to improve her state she was referred to ing a safer bodily state and a stable potassium level.
the IRU for further assessment and PN. At the end of each session she gave me a little animal
Believing her narrative, taking it seriously as her own made of paper. I realized that she is a master of Origami
experiential truth was the most important initial step to work. Then she showed me her drawings which were abso-
enable her to engage in therapy and regain trust in the medi- lutely amazing in their originality and delicacy. I then dis-
cal team that tried to help her. After I explained to her and covered that she dreams to be an illustrator for children’s
warmly reassured her that even if a fire would burst in the books. She did not believe that she will be able to be accepted
ward she will not be trapped even if she is connected to the to an art or an illustration school or class. I actively encour-
PN pump; thus she agreed to receive the PN. aged her to do that. It was not hard for me to do as I was
The traumatized person does not remember the trauma deeply moved by her images. I told her: “Just show them
they re-live it! your work and you will be accepted”. Exactly this happened!
They immediately enter a Fight-Fight-Freeze mode. They She started to study illustration in a professional highly
become stupefied with fear (this is the origin of the word regarded art school and kept herself nurtured and physically
stupid) and cannot reflect or think rationally because they are safe as much as possible.
fighting for their life. Creating a secure, safe base within the When she was discharged she gave me this picture (Fig. 1)
therapeutic relationship is the most essential component in that she drew:
enabling engagement in the treatment process. For me this moving symbolic image of hope and fragility
Unfortunately, during the PN S. developed sepsis and it is her self-portrait. It is also what life with IF is about: The
had to stop but as she was already motivated to try and restore
a better nutritional state she was willing to see me on a
weekly basis as an out-patient at the PMU. Once the right
name to her condition was given -a gut motility disorder with
delayed gastric emptying/gastroparesis most probably as
part of the gastrointestinal manifestations of EDS and she
was “redeemed” of being misdiagnosed as an “Eating
Disorder patient” she became significantly less anxious, and
very motivated to work together .
The psychiatric differential diagnosis of Gastroparesis is
complex and in addition to Eating Disorders includes
Somatization Disorders, Post-Taumatic Stress Disorder and
other Anxiety disorders, Opioid Withdrawal and even
Schizophrenia. In addition the Gastroparesis itself in a
vicious cycle triggers a Phobia to eat, Panic Attacks and per-
sonality changes [24]. The key thing that helps to navigate in
this “labyrinth” is to address the uniqueness of each patient-
to find his/her “Pin Number”. This can be found only through
mutual work.
An old Chinese proverb says:
Tell me something and I will forget,
Show me and I will learn,
Involve me and I will understand.
The psychotherapist working with patients on the IRU needs

at times to actively involve the patient with psychoeduca-
tional material about the brain-gut axis, the links between
stress and fatigue and inflammation etc. With S. I had to
speak with her a lot about the importance of maintaining a
stable safe potassium level, about its influence on the regular
heart rhythm; we had to think creatively about what she can
absorb and when and how to be more “jazzy” and improvise
with what she can eat. As she was no longer afraid to be dis- Fig. 1 Picture drawn by patient
paper boat can represent her fragile body that carries her 10. Roth DA, Eng W, Heimberg RG. Cognitive behavior therapy, ency-
clopedia of psychotherapy, vol. 1. Amsterdam: Elsevier; 2002.
motivation represented by the fisherman in the yellow coat
p. 451–8.
and hat who patiently waits to find, to bring something from 11. Donal GF, Varden J, Parker S, et al. Illness beliefs of patients on
the depth of the lake. In German the word lake is SEE and the home parenteral nutrision (HPN) and their reaction to emotional
word Soul is SEELE. The lake and the soul are connected. distress. Clin Nutr. 2005;24(6):896–903.
12. Strosahl K. Acceptance and commitment therapy, encyclopedia of
She doesn’t give up on the connection with her soul. The yel-
psychotherapy, vol. 1. Amsterdam: Elsevier; 2002. p. 1–8.
low color symbolizes the sun, consciousness, joy and humor. 13. Harris R. Embracing your demons: an overview of acceptance and
S. was only one of the many patients at the IRU who hum- commitment therapy. Psychother Aust. 2006;12:2–8.
bled, inspired and thought me each day about courage, resil- 14. Gabbard GO. Chapter 1. In: Psychodynamic psychiatry in clini-
cal practice. 4th ed. Philadelphia, PA: American Psychiatric
ience and about how with the right motivation and support IF
Publishing; 2005. p. 6–7.
stops being an obstacle for living life to the full. 15. Barkham M, Guthrie E, Hardy GE, Margison F. Chapter 11. In:
Psychodynamic-interpersonal therapy, a conversational model.
London: Sage; 2017.
16. Hobson RF. Forms of feeling, the heart of psychotherapy. London:
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Part VI
Outcome of Intestinal Failure
Home Enteral Nutrition in Adults:
Indications and Outcomes
André Van Gossum, Asuncion Ballarin,

Marianna Arvanitakis, Xavier Hébuterne,
Key Points 8. The initiation and monitoring of HEN should be per-

formed by a multidisciplinary nutrition support team in
1. The use of Home Enteral Nutrition (HEN) is increasing collaboration with the community/family/caregivers.
throughout the world.
2. The prevalence of HEN is variable at about 100–1400/
millions inhabitants in Western countries.
3. HEN is indicated in patients who are at high nutritional Introduction
risk or malnourished, who are unable to meet nutritional
requirements by the oral route and who have a functional The use of HEN started in the early seventies in response to
gastrointestinal tract. the interest and need for ambulatory care. For the majority of
4. Dysphagia due to neurological disorders or head-and- the patients, enteral nutrition is initiated during their hospital
neck cancer are the main indications for HEN. stay and then continued at home. Procedures and funding for
5. Most (80%) of HEN is through a gastrostomy tube. Some home parenteral nutrition (HPN) preceded that of HEN in
are by a naso-gastric tube or rarely a jejunostomy. many European countries [1]. Globally, HEN is used for
6. Survival on HEN depends upon the prognosis of the patients with oral failure (OF) but having a functional gut.
underlying disease. On the contrary, home parenteral nutrition (HPN) is indi-
7. The objectives of HEN must include nutritional targets cated in patients with severe chronic intestinal failure requir-
(e.g. achieving/maintaining a pre-determined body ing intravenous supplementation to meet nutritional or fluid
weight), quality of life, ethical issues and the criteria for requirements [2].
stopping. The use of HEN progressively increased around the world
after the introduction of the percutaneous endoscopic gas-
trostomy (PEG) technique [3], the availability of
commercially-designed enteral formula and the development
of home care services.
A. Van Gossum (*) HEN must be considered as a medical treatment. Before
Nutrition Support Team, Department of Gastroenterology, Hopital starting HEN, not only nutritional needs but also prognosis,
Erasme, Brussels, Belgium
quality of life and ethical issued have to be discussed and
Institut Bordet, Brussels, Belgium regularly evaluated [4]. Although HEN can be initiated by
any medical team, it is highly recommended that the route of
A. Ballarin · M. Arvanitakis administration, timing and composition of feeding, organiza-
Nutrition Support Team, Department of Gastroenterology, Hopital
Erasme, Brussels, Belgium tion or services are best made by a multidisciplinary nutri-
tional support team (NST).
X. Hébuterne
Institut Bordet, Brussels, Belgium OF is often unrecognized, partly because it is not thought
of and partly because these patients are looked after by a
J. M.D. Nightingale
Department of Gastroenterology and Clinical Nutrition, CHU of myriad of medical specialties. This contrasts to IF which
Nice and University côte d’azur, Nice, France usually recognized because these patients tend to be under
Department of Gastroenterology, St Mark’s Hospital, the care of appropriate specialists and have more immediate
Harrow, Middlesex, UK problems. It is paradoxically more difficult to recognize and
e-mail: [email protected] treat the problems of OF than IF.

754 A. Van Gossum et al.
a week or if the energy intake is less than 60% of estimated

Epidemiological Data requirements for 1–2 weeks [19].
There are three major underlying physiological reasons
The incidence and prevalence of HEN is not known in many for HEN to be needed: dysphagia, anorexia (OF) and intesti-
countries but when reported is increasing [5–7]. There are nal failure. Dysphagia and anorexia cause a reduced intake,
few national registries that try to record all patients receiving and intestinal failure results in reduced absorption. Some
HEN (BANS in UK or NADYA-SENPE group in Spain), [7, patients may have several reasons for needing HEN (e.g.
8] but still are likely to give an under-estimate as registration anorexia and moderate intestinal failure) (Table 1).
is not compulsory (perhaps only a third were registered in Globally, neurodegenerative, and neurovascular diseases
UK) [7]. In the USA, information comes primarily from account for 50–60% of the indications. Dysphagia due to
Medicare and Medicaid Services [6]. Many other hospital/ head-and-neck or upper GI cancer is the second most com-
university centres in different countries report their own mon indication. In the recently published experience in
case-series. Poland, the primary diseases for a total of 4586 patients were
There is no standardization in the way in which incidence 54.5% neurological, 33.9% cancer (20.2%—head and neck,
(new cases/registrations), prevalence (one-day point and 11.7% gastrointestinal, 2.5% gastroenterology and 1.5%
annual occurrance) and outcome data are presented. Most inherited diseases [14]. In the UK in 2015 (3216 patients)
prevalence data are per 106 inhabitants (or population). 42.9% had cancer (mostly head and neck), 39.6% central ner-
Comparison between these data sets can be difficult to vous system and mental health problems, 9.0% non-malignant
interpret. gastrointestinal disease and 8.4% others [7] (Table 2).
During the nineties, it was estimated that the number of
patients receiving HEN was ten times higher than those on
HPN [9–11]. For example, in the UK, the one-day preva- Table 1 Clinical features that lead to the need of HEN
lence of HEN in 1998 was 200–267 patients/106 inhabitants • Swallowing disorders because of neurological diseases
and for the region of Nice in France, the annual incidence of • Dysphagia because of malignancies (mostly head and neck
HEN was 99 patients/106 million inhabitants [12, 13]. In cancer or upper GI tract)
• Cancer-related cachexia
2017, the Spanish Home Enteral Nutrition Registry reported
• Chronic malnutrition related to chronic obstructive pulmonary
a prevalence of 102/106 million inhabitants [14]. It is esti- disease/chronic heart disease or chronic infections (i.e. cystic
mated that 18,232 people (284/million population) received fibrosis)
home HEN in the UK in 2013 [15]. In Italy the incidence was • Malabsorption/maldigestion because of liver, pancreas or
406 ± 58 patients/million inhabitants/year for patients living intestinal disorders
at home and 319 ± 44 for patients living in a nursing home in
2012 [5]. In USA. 437,882 patients (1385 per million U.S. Table 2 Common underlying disease for which HEN is given to new
inhabitants) were receiving HEN in 2013, which was a large adults in the UK in 2009 [19] and Poland 2007–13 [20]
increase from 1992 (415 per million) [6, 9]. UK Poland
In some countries, HEN reports combine oral supple- UK classification n = 3282 n = 456
CNS and mental health Cerebrovascular 649 137
ments and enteral feeding (via a tube) [16]. For example in (n = 1226) disease
New South Wales (Australia), the HEN population of partici- Motor neurone 197 17
pating hospitals was approximatively 7600, with 81% oral disease
nutritional support and 19% tube-fed patients [17]. Multiple sclerosis 122 17
It is estimated that 10% of nursing home residents in the Parkinson’s disease 109 7
USA are receiving HEN [8]. Cerebral trauma 75 22a
Dementia 48 18
Cerebral palsy 36 74
Anorexia nervosa 26 1
Indications for HEN Cancer (n = 1226) Head and neck 673 23
Oesophageal 239
HEN is indicated in patients who are at high nutritional risk Oropharyngeal 183
or malnourished, who are unable to meet nutritional require- Gastric 45 19b
ments by the oral route and who exhibit a functional gastro- Non-malignant Dysphagia 58
gastrointestinal (n = 291) (unknown cause)
intestinal tract [18]. They should have a life expectancy of Crohn’s disease 20 4
more than a month [18]. Short term or predicted short term Dysmotility 15
enteral nutrition for 4–6 weeks is usually via a naso-gastric Other (n = 205) Cystic fibrosis 24 6
tube [18]. According to the ESPEN Guidelines, an inade- a
Includes spinal injury
quate nutritional state is confirmed if patients cannot eat for b
Labelled as abdominal cancer
Home Enteral Nutrition in Adults: Indications and Outcomes 755
Most adults are over 60 years though those with cerebro- Persistent Vegetative State
vascular disease tended to be older; 66% were aged 71–90
[7]. Head and neck cancer patients tend to be younger and Persistent vegetative state (PVS) is a clinical condition of
have HEN due to dysphagia (69%), disease-related malnutri- complete unawareness of self and the environment, accom-
tion (19%) or gastrointestinal obstruction (3%) [7]. panied by sleep–wake cycles, with either complete or partial
preservation of hypothalamic and brain stem autonomic
functions [22]; there is no interaction between the patient
Physiological Reasons for HEN and others, and the patient is doubly incontinent [23]. Some
authors argue that physicians are not obliged to provide
Dysphagia nutritional support in this condition because there is no clini-
cal benefit although physiological functions can be main-
Dysphagia is the major reason for a patient to receive HEN. It tained [24]. Others strongly disagree with this attitude on the
may be secondary to a neurological problem (usually cere- basis that every human being has the right to food and water,
brovascular disease), a vegetative state, a head and neck can- even in situations in which medical interventions can be ethi-
cer, or a rare benign cause. In most cases dysphagia will cally withheld [25]. The physician needs to explain all out-
remain a permanent problem; in some cases it is temporary, comes to the family and then, in some countries, let them
for example, during radiation therapy or chemotherapy or decide. In the UK, an application to stop the feeding has to
prior to removal of an upper gastrointestinal cancer. be made to the High Court. If the family wishes to care for
their family member at home, it can be argued that the medi-
cal profession must provide both the means by which food
Anorexia and water can be given, and the feed itself (Chap. 53).
Anorexia represents a growing indication for HEN and

defines a patient without dysphagia who cannot take ade- Reasons Not to Give HEN
quate nutrition by mouth to meet his or her nutritional
requirements. Some patients may have associated increased Before starting HEN, the absence of contraindications must
energy requirements (cancer or rarely AIDS patients). be checked (Table 3) and the criteria for starting confirmed
Anorexia is generally found in very old patients, is second- (Table 4) (Fig. 1).
ary to an acute or chronic illness (surgery, infection, demen- The success of HEN depends on patient selection, safe
tia or psychological disorder) and is associated with the placement of a feeding tube/device, suitable nutrients and
problems of undernutrition. Active dietetic support is needed administration system, adequate education about enteral
for these patients; if sip-feeds are unsuccessful, enteral feed- feeding, and regular monitoring. The European and interna-
ing in the hospital may be given for 3–4 weeks. If voluntary tional guidelines advice against initiating tube-feeding in
intake improves significantly during this time, enteral nutri- patients with severe dementia. Orlandi et al. challenged this
tion can be stopped; if not, there is a high chance that long- issue reporting a series of 585 consecutive patients of the
term HEN will be needed. mean age of 85 ± 7 years [26].
Table 3 Contraindications to HEN [18]

Intestinal Failure
1. A life expectancy estimated to be less than 1 month
2. The existence of severe functional disturbances of the bowel,
In the case of intestinal failure, oral intake is insufficient gastrointestinal obstruction, gastrointestinal bleeding, severe
regardless of the gastrointestinal problems that have led or malabsorption or severe metabolic imbalances
will lead to undernutrition. A patient with chronic diarrhoea 3. Patients and/or their legal careers who do not agree to a HEN
may be a candidate for enteral rather than parenteral nutri- program or are unlikely to comply with and/or if there are
organizational/logistic problems which cannot be overcome
tion if the daily stool weight is less than 500 g and the daily
faecal fat less than 20 g (72 mmol). There are many diagno-
ses responsible for maldigestion (e.g. chronic pancreatitis or Table 4 Criteria for proposing that a patient be started on HEN
previous gastrectomy) or malabsorption (e.g. short bowel,
Oral failure and a functional/usable gastrointestinal tract
small bowel dysfunction or HIV/AIDS). Patients with more Ability to tolerate enteral nutritional therapy in the hospital (for at
than 200 cm of small intestine remaining and a functioning least 7 days)
colon may need a period of enteral support. Long-term No other medical or surgical problems—ready to be discharged
enteral support may be needed in patients with a jejunostomy A clean and safe home
and 100–200 cm of remaining small intestine [21]. Patient or carer able to perform all enteral procedures safely
Fig. 1 Algorithm for starting DYSPHAGIA

HEN
PROGRESSIVE DISEASE NON-PROGRESSIVE DISEAS
Potentially effetive Only palliative Ambulatory

Non-ambulatory
treatment treatment
Is the quality of life Is the quality of life and/or

expected to be improved physiological state
by nutrition? expected to be improved
by nutrition?
Yes No No or ? Yes
Is the life duration expected Has the patient a high risk for
Offer and to be more than 30 days? complications related to HEN? Offer and
recommend recommend
HEN HEN
No Yes No Yes
Propose HEN to Do not Propose HEN to Do not recommend but

the family recommend the family explain risks and
HEN benefits of HEN
Table 5 Items to address before the patient can discharged (adapted 390 adults on HEN did not have any record of visiting a com-
from [18]) munity registered dietitian up to 6 years after tube placement
• The quantity of EN, and which brand should be administered [28].
• Total amount of fluid administrated
• Duration of administration, during day or night
• The use of the enteral feeding pump and what to do in case of
dysfunction of the pump (if a pump is used at all) Mode and Method of Delivery
• Whether the patient is allowed to have oral intake next to HEN
(any restrictions?) The most common tube inserted is a gastrostomy, usually
• Personal care, impact of HEN on daily life (shower, swimming, done endoscopically (percutaneous endoscopic gastrostomy
party, holiday) (PEG)). In the UK in 2015, 80% of HEN patients were fed
• Who will take care of the administration of the EN (patient,
family, [home care company] nurse)
via a gastrostomy, 10% via a nasogastric tube, 6% via a jeju-
• How to secure the tube adequately nostomy and 3% by a nasoduodenal or nasojejunal tube [7].
• How to administrate medications through the tube In Spain in 2012, 45.3% were fed by a nasogastric tube and
• Who will change or reinsert the tube in case of dislocation 29.4% by a gastrostomy [8]. In Poland in 2018 a gastrostomy
• What to do in case of blocked tube: tube was used most commonly (PEG 65.3%, other gastros-
– Who to contact in case of material or physiologic tomy 11.6%), 14.3% had a naso-gastric tube, 7.0% a jejunos-
complications (material: dislocation, blocked tube and/or breaking
material) and physiologic complications (diarrhea, constipation,
tomy, 0.6% a naso-jejunal tube and 0.2% a gastro-jejunostomy
aspiration, change of weight, dehydration) (PEGJ).
• How often the patient should be evaluated, by whom and where Feeding through a tube may be by a continuous infusion
(with pump assistance), intermittent drip, or a bolus tech-
nique. Bolus feeding involves 4–6 feeds a day of 200–400 ml
Interestingly, Velapati G et al. described a series of 72 given by a 50 ml syringe over 15–60 min [18]. Overnight
patients who presented with malnutrition due to bariatric sur- feeding tends to be over 10–12 h using a static or mobile
gery [27]. They reported that HEN was safe and effective pump. In Poland 74.4% had feed given as a bolus, 17.6% by
leading to avoidance of parenteral nutrition in most cases. gravity flow and only 8.0% through a pump [29]. In most
Before discharging the patient at home, a checklist must countries feed is currently given with the aid of a pump.
be completed for assuring a good quality of care at home However in the USA Medicare will provide reimbursement
(Table 5) [18]. A Canadian survey underlined that 74% out of for a pump if: The administration rate is less than 100 ml/h,
if circulatory overload, if increased aspiration risk/pneumo- Table 7 Outcome of patients on HEN (follow-up 18–65 months) [34]
nia or if diarrhoea, dumping syndrome, gastrointestinal Full oral Continued Died Stopped for
reflux, vomiting or blood glucose fluctuations [30]. nutrition HEN n = 19 n = 93 other reasons
n = 51 (%) (%) (%) n = 20 (%)
The feed may be polymeric (with or without fibre) or
Neurological 16 13 65 6
increasingly consist of homemade blenderized food. disease
Head and neck 33 5 54 8
cancer
Outcome of HEN Digestive 49 3 26 22
disease
Post-traumatic 14 43 0 43
Data about the complications of nutritional support are often dysphagia
given as the proportion of patients developing a specified Anorexia 30 6 58 6
complication though it is better (as for PN) to be per EN (elderly)
feeding days. AIDS 0 0 100 0
Fourteen percent of those who had a stroke returned to Other 50 25 17 8
oral feeding, thus it is important to assess continually a
patient’s ability to swallow as it may improve and allow tube
Table 8 Survival at 1 month, 1 year and 5 years [35]
feeding to be stopped [31].
n 1 month (%) 1 year (%) 5 years (%)
Neurological disease 148 83 41 21
Digestive disease 76 90 59 49
Survival Head and neck cancer 64 88 37 24
Dementia 54 54 20 3
Folwaski [29] et al., in Poland, described a series of 4586 Anorexia 32 81 56 21
HEN patients in 2018. The median overall survival on HEN
was 354 days but 615 days for neurological diseases and
209 days for cancer patients (Table 6) [29]. Ruggeri et al. The overall probability of survival was 44% at 1 year and
reported a mean survival of 22.1 weeks in cancer patients 29% at 5 years in one study (Table 7) [34], and similar results
with dysphagia who received HEN [32]. A retrospective of 80, 42 and 25% at 1 month, 1 year and 5 years respectively
Italian study found a median duration of HEN of about in another (Table 8) [35].
196 days [17]. Regarding the underlying disease, duration There is a low mortality for cerebral palsy, cystic fibrosis
was 261 days for neurovascular diseases, 251 days for neuro- and multiple sclerosis. However it is higher for patients with
vegetative disease, 118 days for head and neck cancer, motor neurone disease, dementia and malignancy (30–60%
82 days for abdominal cancer, 788 days for head injuries. In in the first year. Patients who had a cerebrovascular accident
this series, only 7.9% of the patients resumed oral nutrition; and were over 75 years were 3–4 times more likely to die
the median survival was 9.1 months. The median survival while on HEN than those patients aged less than 65 [31].
and the rate of complications were similar between those Patients with small bowel malabsorption needing HEN are
with or without dementia [26]. uncommon, but at 1 year 82% were alive, 43% had ‘com-
Cawsey et al. reported a series of 727 adult patients [33]. plete rehabilitation’, and 45% had stopped HEN and resumed
Median duration of HEN for cancer patients was 122 (range, an oral intake [36].
1–1259) days, duration for neurological disorders was 187 In a retrospective cohort study of 253 older patients with
(range, 1–1752) days, and duration for GI disorders was 161 dysphagia in Japan 180 patients were randomised to PEG
(range, 1–1849) days. and EN feeding and 73 to TPN. The PEG group had a signifi-
cantly longer survival time (median, 317 vs 195 days); but a
significantly higher incidence of severe pneumonia (50.9%
Table 6 Outcomes of adult HETF during 2015 [7] in UK and 2018 in
Poland [29] vs 25.5%); however the incidence of sepsis was significantly
UK Poland lower (10.9% vs 30.9%) [37].
n % %
Continuing 6270 70 48.5
Died 1436 16 40.2 Quality of Life
Return to oral diet 1039 12 5.3
Lost to follow up 131 2 4.7 While the health-related quality of life for patients with gas-
In hospital 14 <1 trostomy tubes is poor (usually due to severe physical dis-
Withdrawn/refused 14 <1 1.2
ability) compared to that of the general population, the
majority of patients and carers rated the gastrostomy ‘posi- 2. Pironi L, Arends J, Baxter J, et al. ESPEN endorsed recommen-
dations. Definition and classification of intestinal failure in adults.
tively’ [38]. The recorded quality of life for most patients in
Clin Nutr. 2015;34:171–80.
the UK receiving HEN is poor. 72% in UK were living alone 3. Gauderer MW, Ponsky JL, Izant RJ Jr. Gastrostomy without lapa-
at home. 42% were able to manage independently but most rotomy: a percutaneous endoscopic technique. J Pediatr Surg.
needed total 37% or some help 22%. Only 10% were house- 1980;15:872–5.
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bound and 15% bedbound. 25% were in residential care.
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required nursing home care. Those with head and neck can- home and in nursing homes: an 11-year (2002–2012) epidemiologi-
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bound. 24% of these patients returned to oral feeding alone,
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29. Folwarshi M, Klek S, Zoubek-Wojcik A, et al. Home enteral 40. Norton B, Homer-Ward M, Donnelly MT, Long RG, Holmes
nutrition in adults – Nationwide multicenter survey. Nutrients. GKT. A randomised prospective comparison of percutaneous endo-
2020;14:2087. scopic gastrostomy and nasogastric tube feeding after acute dys-
30. Martin K, Gardner G. Home enteral nutrition: updates, trends, and phagic stroke. Br Med J. 1996;312:13–6.
challenges. Nutr Clin Pract. 2017;32(6):712–21.
Home Parenteral Support for Adults
Laura Cohen, Francisca Joly, Simon Gabe,

and Jeremy Woodward
Key Points 5. Some patients maintain a good quality of life on HPS

1. Improved availability and safety of home parenteral sup- whereas others carry a significant burden of symptoms
port (HPS) has led to a significant (two- to fourfold) and interference with daily activities.
increase in its usage and indications over the last two 6. Failure of HPS (for reasons of impending loss of vascular
decades. access, IFALD or unmanageable/intolerable complica-
2. The most common reasons for HPS are surgical compli- tions of intestinal failure) can be managed by intestinal
cations, Crohn’s disease and mesenteric infarction. transplantation. Early detection of IFALD or those at high
3. Complications include those due to the venous access, the risk and treatment with pre-emptive isolated intestinal
non-physiological route of delivery, and the pharmaco- transplantation is preferable to allowing end stage liver
logical composition of the PN and are often difficult to disease to develop, that then requires combined liver and
separate from the effects of the underlying intestinal intestinal transplantation.
failure.
4. Long-term survival is possible on HPS, and most deaths
on treatment are due to the underlying disease. Less than
25% of deaths are due to HPS-related causes, most fre- Introduction
quently IF-associated liver disease (IFALD) and catheter-
related blood stream infection (CRBSI). It is currently just over 50 years since the first demonstration
of successful life support using sole intravenous nutrition in
beagles by Stanley Dudrick [1]. Given that intestinal failure
(IF) was a rapidly terminal condition at this time, the first use
of parenteral nutrition in humans followed shortly after-
wards, with patients learning how to manage their own par-
L. Cohen
Department of Gastroenterology and Nutrition Support, Beaujon enteral nutrition at home from the early 1970s [2, 3]. Over
Hospital, University of Paris VII, Clichy, France the intervening half century, it is surprising how little has
F. Joly (*) changed in the basic principles of intravenous nutrition and
Department of Gastroenterology and Nutrition Support, Beaujon its delivery. However, with greater understanding of the
Hospital, University of Paris VII, Clichy, France complications and risks involved in home parenteral nutri-
Inserm UMR1149, Centre de Recherche sur l’Inflammation Paris tion (HPN), and subsequent developments in nutrient com-
Montmartre, Paris, France position, monitoring and support of patients, HPN therapy
has become safer and more efficient. As a consequence the
S. Gabe indications for HPN have broadened, it has become more
Lennard Jones Severe Intestinal Failure National Reference Centre
widely available, and new challenges in its use have inevita-
& Intestinal Rehabilitation Unit, St Mark’s hospital, London, UK
e-mail: [email protected] bly arisen.
In this chapter we address the need for HPS, the econom-
J. Woodward
Department of Gastroenterology and Clinical Nutrition, ics of its use, the requirements for establishing HPS, the
Addenbrooke’s Hospital, Cambridge, UK practical avoidance of its complications and developing
e-mail: [email protected] changes in HPS provision. The term home parenteral support

762 L. Cohen et al.
(HPS) is used except where the data or information relates Table 1 Indications for home parenteral nutrition (HPN) (adapted
from [5])
only to parenteral nutrition (PN) when the term home paren-
teral nutrition (HPN) (which excludes those who receive par- Pathophysiological Mechanism of
group intestinal failure Examples
enteral fluid alone) is used.
Short bowel • Reduced absorptive • Intestinal resection
surface area due to:
• Increased fluid • Mesenteric infarction
The Need for HPS losses arterial or venous,
volvulus, Crohn’s
disease, radiation
Long-term PN and fluid support as an inpatient in hospital is enteritis, trauma
not a valid option for most patients with intestinal failure. In • Secondary reduced • Congenital intestinal
order to retain any meaningful quality of life, this treatment oral intake to control malformation,
needs to be available in the home environment. HPN may be losses gastroschisis, atresia
required for only a limited period of time where there are • Rapid
gastrointestinal
surgical options available for the restoration of sufficient transit
intestine in continuity (‘type 2 intestinal failure’), or it may Intestinal fistula • Bypass of • Iatrogenic due to
be required indefinitely (‘type 3 intestinal failure’) [4, 5]. gastrointestinal surgical bowel injury
Whilst a useful classification in clinical use, the distinctions absorptive mucosa
between type 2 and type 3 IF are not always clear given the • Increased fluid • Trauma
losses
heterogeneity of conditions requiring PN support and the • Secondary reduced • Crohn’s disease
increasing medical and surgical options for treatment, oral intake to control
including intestinal transplantation. losses
HPN is expensive [6, 7] with costs that escalate when • Metabolic demands • Tumour
due to associated
nursing care is required for the connection and disconnection
sepsis or
of infusions. Nevertheless, in most westernised health econ- inflammation
omies it is still more cost effective to provide PN at home • Infection (TB,
rather than in hospital where capacity for inpatient treatment actinomycosis)
is in high demand. It is this cost differential (rather than con- Intestinal • Intolerance of oral/ • Chronic intestinal
dysmotility enteral feeding due pseudo-obstruction
cern for improving quality of life) that has largely driven the to symptoms either primary
use of HPN for increasingly short periods of time whilst (visceral myopathy or
awaiting restorative surgery. neuropathy) or
Organisational improvements that have led to increased secondary to a wide
variety of underlying
efficiency, support and safety in HPS provision, have enabled medical conditions or
a significant increase of HPS use in many countries over the medication use
first two decades of the twenty-first Century. In the UK for • Small bowel
instance, the number of patients receiving HPN has increased bacterial overgrowth
from around 10 per million population in 2000 [8] to 40 per • Increased fluid
secretion in
million in 2015 [9]. However there remain significant differ- obstructed segments
ences in HPN prevalence between countries—for instance in • Increased GI losses
2013, Spain reported 4.2 cases per million [10] whereas due to vomiting,
there were approximately 79 per million in the USA [11]. diarrhoea or gastric
drainage
Interestingly, in the USA, HPN prevalence has actually
Mechanical • Reduced oral intake • Obstructing tumour of
dropped from 157 cases per million in 1992 [11], possibly obstruction due to symptoms the GI tract
due to an increase in availability of home enteral nutrition and lack of
support or due to issues related to charging and benefits asso- absorption
ciated with the healthcare system. • Increased fluid • Obstruction due to
secretion in peritoneal disease
obstructed segments including tumours or
adhesions
Indications for HPS • Increased GI losses
due to vomiting,
diarrhoea or gastric
HPS is indicated for the long-term support of any condition
drainage
where enteral feeding is either impossible or inadequate. A
(Continued)
pathophysiological definition (rather than the above ‘func-
Home Parenteral Support for Adults 763
Table 1 (continued) ensure that the patient fully understands the importance of
Pathophysiological Mechanism of this as it is not uncommon for patients to comply with such
group intestinal failure Examples fluid restrictions in hospital only to take hypotonic fluids ad
Extensive intestinal • Inefficient nutrient • Refractory coeliac libitum when at home, resulting in rapid readmission with
mucosal disease absorption or nutrient disease, Crohn’s
and fluid loss from disease, common acute kidney injury. The clinician is often best advised to
mucosal surface variable allow the patient to set a fluid regimen in hospital that they
immunodeficiency will be able to comply with in order to maintain the same at
with chronic noroviral home, even if this is at the expense of a larger PN fluid
infection, tufting
enteropathy, volume.
microvillous inclusion Whereas hospital PN is often run over 24 h for patients
disease with type I IF, patients generally prefer shorter infusion
times at home so that they can feed overnight, allowing them
to be active during the day. There is some evidence to sug-
tional’ classification of IF types) identifies five main types of gest that this cyclic PN is also preferable from a metabolic
indication [5] (see Table 1). In the UK, the British Artificial viewpoint [15]. In some countries such as the UK it is tradi-
Nutrition Survey (BANS) [9] has kept comprehensive data on tional not to add lipid to all of the PN bags but to provide the
the usage of home enteral and parenteral nutrition since 1996. patient’s full lipid requirements in just 1–3 bags each week.
Short bowel remains the commonest indication, but has Initial reasons for this were that daily lipid containing feeds
dropped from 44% of patients receiving HPN in 2005 to 34% were found to clog central venous catheters (and required
in 2015, largely accounted for by a proportionate reduction in ethanol flushes to clear). Subsequent evidence suggested that
patients with Crohn’s disease. In the UK, malignant bowel parenteral lipid is associated with hepatotoxicity, although
obstruction and dysmotility disorders contribute approxi- this evidence is largely limited to the former use of soy-based
mately equal proportions of existing HPN patients, however ‘intralipid’ as the main parenteral nutrition lipid source [16].
the UK-BANS registry collects separate data for ‘point’ prev- Indeed, many patients describe symptoms of nausea and
alence (on a specified census date) and ‘period’ prevalence headache after receiving lipid-containing infusions, but not
(between two time points). Patients with malignancy gener- after aqueous bags. The mechanism of such symptoms
ally have a shorter life expectancy than those patients with requires further study. As a result, clinicians have attempted
dysmotility and therefore contribute approximately a quarter to reduce the lipid component of the PN. Whilst this can be
of new HPN registrations compared to around 7% for chronic achieved by providing a smaller amount of lipid on a daily
intestinal pseudo-obstruction. Ovarian cancer is the common- basis in every PN bag, it risks physical instability and shorter
est malignant indication for HPN in the UK. shelf life of the PN mixture.
The proportion of new HPN registrations for malignancy The downside of reducing the lipid content of the PN is
in the UK has doubled over the last 10 years and a similar that a higher proportion of calorie requirements are then pro-
trend is apparent in other national registries such as Canada vided by simple carbohydrate, and (especially given the
[12] and Spain [10] where malignancy now comprises the pressure by patients to reduce infusion times) it is possible to
commonest indication in adults. exceed the body’s glucose oxidation capacity. This can result
in de novo lipogenesis in the liver which is associated with
steatosis, inflammation and fibrosis through increased local
Establishing a Patient on HPN generation of reactive oxygen species [17]. Clearly a balance
needs to be achieved for each patient regarding lipid fre-
A hospital providing an HPN service requires a comprehen- quency and the overall PN infusion times. At the moment,
sive and integrated nutrition support team that comprises the underlying cause of IFALD is not established and it is
nutrition nurse specialists, medical staff with appropriate likely to be multifactorial.
expertise and training, pharmacists, and dietitians. The team Reducing the infusion time of PN needs to take place
will require close links with vascular access and community whilst still in hospital in order to confirm tolerance—particu-
homecare teams [13]. larly in the elderly or those with myocardial compromise
To be suitable for receiving parenteral nutrition at home, where high fluid infusion rates may not be tolerated.
a patient requires a stable PN prescription with regard to Prior to discharge on HPN, the prescription needs to be
nutrient and electrolyte composition and volume [14]. This stable on a day-to-day basis but also to have proven physico-
may take several days or weeks to establish as volume and chemical stability to ensure suitable shelf life for weekly or
electrolyte losses can vary from day to day in patients with fortnightly deliveries to take place. Pharmaceutical tables of
high output fistulae or proximal stomas. Much will depend stable additive ranges now allow for this to be calculated
on their ability to limit hypotonic fluid intake. It is crucial to without recourse to ‘trial and error’, but may limit the quanti-
764 L. Cohen et al.
ties of electrolytes or trace elements that can be provided. In chain delivery capability and 24 h telephone support
practice this requires a hospital pharmacy to have the capa- availability for problem solving.
bility for ‘scratch’ or ‘bespoke’ bag compounding. While this model of delivery and providing PN for use at
Patients need a suitable central access device for infusion home may be ideal, it is costly for healthcare services and
of HPN. Increasingly patients are being discharged initially requires considerable infrastructure. In some countries (e.g.
with ‘PICC’ lines (Peripherally Inserted Central venous Poland) the PN components are delivered to patients who are
Catheters), although these are associated with an increased trained to mix the components together into an infusion bag
risk of thrombosis and require extension sets to allow patients and then subsequently infuse this directly. It may be viewed
the ability to access them [18]. Therefore, such devices would that the risk is higher regarding bacterial contamination but
be used only as a temporary access until a tunnelled central if infused immediately and a 0.2 μm filter is used on infusion
line can be placed. A tunnelled, cuffed CVC should be con- (this is standard anyway) then infections may not necessarily
sidered to be the central venous access device of choice. occur. In addition, the issues relating to stability of the PN
However, other options that can be considered are implant- over time are much less of an issue. As less infrastructure is
able ports (portacaths) and even using an arterio-venous fistu- required, this is a cheaper way of delivering HPN.
lae. Some patients prefer implanted subcutaneous ‘portacath’
devices that require needle access. These have the advantage
of permitting activities such as swimming and exercising and Supporting HPS
may be more cosmetically satisfactory—they may therefore
be more popular with younger and fitter patients. However The support of patients on HPS requires close communica-
there is no evidence that infection rates are lower with such tion between the hospital nutrition team and the homecare
devices, they have a limited lifespan depending on how often support team [22]. Liaison prior to discharge will co-ordinate
the membrane is punctured for access and associated infec- the first delivery of feed and homecare nursing visit. One of
tions may be more severe and difficult to treat than for tun- the clear advantages of patients learning to manage their own
nelled central lines [19, 20]. In addition, a small number of PS at home after discharge is that there is ongoing regular
centres preferentially use surgically created arterio-venous (usually twice daily) contact with nursing staff who can
fistulae for PN access for their patients [21]. instantly report any problems back to the hospital nutrition
Before discharge on HPN patients will have to find space team or the homecare delivery team. Despite having achieved
for a large enough refrigerator to hold the bags for weekly or electrolyte stability prior to discharge it is often necessary to
fortnightly deliveries. Standard domestic specification refrig- recheck blood tests shortly after the patient returns home. It
erators are inadequate as they rarely have uniform tempera- is important to ensure that wherever possible patients do not
ture distribution (bags might freeze at the back, yet be too become dependent on nursing support at home—for eco-
warm at the front) or have adequate responsiveness for tem- nomic and logistical reasons as well as the benefits for
perature fluctuations outside the necessary limits. They will patients in having a greater degree of freedom and confi-
also require dedicated space for ancillaries and for sterile dence to manage their own PN.
connection and disconnection of their feed. Patients will When patients are able to manage their own connection
need to be educated to handle the settings of their infusion and disconnection and are therefore liberated from twice
pump (which may be different at home from that in hospital) daily nursing visits, they need to be confident of 24 h back up
and be able to know what to do in case of unexpected events arrangements and to be aware of whom to call in case of
such as inadvertent disconnection, refrigerator failure or problems arising. At this stage, the homecare delivery driver
pump faults. There is good evidence to suggest that patient often plays a role in reporting back quantities of unused feed
education is able to reduce central venous catheter infection or ancillaries which can give the hospital team an idea of
and hospital readmission rates. compliance with therapy and early warning of problems.
In many countries, dedicated homecare nursing for feed Home healthcare providers have identified significant bene-
connection and disconnection is not available and patients or fits in providing continuity in delivery drivers in order to fos-
their family members need to be trained in sterile procedures ter trust with patients which provides an additional safety net
in order to do so themselves. This can substantially delay of support.
discharge (by an average of around 3 weeks), and economics As well as having an overall umbrella of care and support,
currently dictate that where suitable community nursing sup- the hospital nutrition team should arrange a clinic follow up
port is available, patients return home with twice daily visits appointment within the first month after discharge and there-
for connection and disconnection and are trained to manage after at regular intervals dependent on clinical stability
their PN themselves whilst at home. (Table 2).
HPN provision is often undertaken by specialised homec- For patients on long term HPN, in addition to regular
are companies with dedicated compounding facilities, cold- anthropometric assessment and adjustment of feed nutrients,
Table 2 Outpatient check list with multidisciplinary team (doctor, practical advice and tips on aspects such as travelling and
nurse, dietitian and pharmacist)
insurance.
Review and treat underlying diagnosis
Assess symptoms (e.g. diarrhoea, vomiting, abdominal pain etc.)
Assess hydration/nutrition status
Assess the vascular/enteral access and catheters/enteral tubes
Living with HPS
Review catheter care regimen
Review wounds/stomas The impairment of quality of life on HPN should not be
Check for complications (e.g. CRBSI, thrombosis, liver, bone or underestimated by clinicians. Although many patients adapt
kidney disease) their lifestyles extremely well to manage the burdens of their
Assess surgical plans (if any) and bowel mapping status chronic condition and treatment, many experience ongoing
Review deliveries and storage of equipment, ancillaries and feed
and long term difficulties. The ability to adjust will depend
Review medications and PN prescription, consider stopping/
changing HPS (e.g. nights off feed) on the prior illness experiences of the patient, their stage in
Assess the goals of the nutritional support life and expectations, and the degree of family and commu-
Consideration of transplantation/links to other units or services nity support available. Tragically, many patients with short
Review the psychological state, coping mechanisms, ways of bowel syndrome are young, previously fit and well and expe-
improving the quality of life rience a sudden catastrophic mesenteric vascular insult that
Put information onto local or national register (eBANS in UK)
results in a high output proximal stoma and the need for life
long HPN. Many will have ongoing symptoms such as thirst,
monitoring from the hospital clinic should include a baseline hunger, pain, nausea and vomiting as well as a high stoma
bone density scan and liver ultrasound (to determine the output risking dehydration and acute kidney injury and
presence or absence of gallbladder and stones, liver texture socially embarrassing noise and leakage from the stoma
and degree of steatosis), and intermittent measurement of itself. Some patients will have additional gastric venting
micronutrients and trace elements. tubes or enteral feeding tubes to cope with as well. These
Renal and liver function tests should be performed reg- will have profound psychological consequences and affect
ularly as well as checking magnesium, zinc, haematinics physical intimacy with partners and their relationships.
(B12, folate, ferritin/iron studies) and vitamins (vitamins A, On top of these issues are the need for central venous
D, E are the most easily measured). A lipid profile is valu- access which may be visible to others and can limit physical
able occasionally to ensure that triglycerides are ade- activities, and poses a worry of infection. Overnight paren-
quately cleared from the circulation. A CRP should also be teral nutrition can lead to disturbed sleep, waking with pump
checked at the same time and measuring a spot urinary alarms (occlusion or air in the line), and nocturnal polyuria
sodium concentration can be helpful to assess hydration due to the altered diurnal fluid delivery.
status. Generally patients are followed up every Social consequences also include mealtime embarrass-
3–4 months, depending on their stability (“Monitoring of ment and exclusion, especially if patients are unable to eat,
Parenteral Nutrition at Home” chapter). However a survey the need to take large amounts of paraphernalia with them
from the ESPEN-HAN working group in 2008 showed that when away or visiting friends restricting travel and holidays.
there was considerable variability in the follow-up fre- Medical insurance cover can be problematic, and security
quency and the type of blood tests performed for these arrangements at airports and borders need to be addressed
patients [23]. given the excess baggage and fluid requirements. Often the
Manganese accumulation and subsequent neurotoxicity is patient advocacy groups are best placed to advise patients of
a rare complication in this patient group. It is excreted in bile these issues and also they often have information relating to
(and a degree of cholestasis is not uncommon with HPN), holiday insurance as well that is helpful to patients.
and the quantity present in proprietary trace element Tools have recently been developed to attempt to quantify
admixtures was previously excess to requirements. It is also the quality of life impact on patients needing HPN—the
sensible to optimise selenium and iron quantities in the PN HPNQOL [26] and the PNIQ (Parenteral Nutrition Impact
according to blood measurements. Questionnaire) [27]. Surveys generally show a significant
Voluntary patient advocacy groups such as PINNT detriment to quality of life [28] that tends to improve over
(Patients on Intravenous and Nasogastric Nutrition Therapy) time, but is affected markedly by the age of onset and nature
[24] in the UK and the Oley Foundation in the USA [25] are of the underlying disease and the number of nights over
a key element to supporting patients on HPN. They can pro- which HPN is required. Patient-related outcome measures
vide shared experiences and open up routes of communica- (PROM) may be the best approach and the PNIQ was devel-
tions for new patients on HPN to talk to others with oped on that basis. However, more studies are required using
experience of living with the condition, as well as useful this tool to see if it is effective.
766 L. Cohen et al.
Complications of HPS micelles rather than chylomicrons. Initial formulations

required a high phospholipid:triglyceride ratio for emulsifi-
Many complications of long-term parenteral nutrition are cation and led to phospholipid accumulation in the reticulo-
consequent to its non-physiological route of delivery that endothelial system. Abnormal lipid accumulation in the
bypasses enteroendocrine regulation of metabolism and gut reticulo-endothelial system can also rarely result in ‘sea blue
function (Table 3). These can aggravate or be difficult to histiocytosis’ syndrome causing hepatosplenomegaly,
separate from the effects of intestinal resection in those with thrombocytopaenia and bleeding [30]. Original soy-based
a short bowel [29]. Such metabolic complications include lipid formulations contained significant amounts of phytos-
the lack of co-ordinated incretin stimulation of insulin secre- terol and contributed to intrahepatic cholestasis and steatosis
tion to match intravenous carbohydrate delivery, and altered by direct inhibition of the liver Farnesoid X receptor [31].
levels of other gut hormones such as oxyntomodulin and Delivery of >1 g/kg/day of soy-based lipid emulsion has
ghrelin which influence glucose and lipid metabolism and been identified as a risk factor for advanced IFALD [16].
regulation of energy intake. Gastrointestinal effects of Newer lipid preparations with a higher omega 3:6 fatty acid
reduced oral intake include cholestasis and high risks of gall- appear to be better tolerated and metabolised and can reverse
stone formation due to lack of cholecystokinin secretion. cholestasis associated with soy-based lipid [32].
This is exacerbated by interruption of the enterohepatic cycle Hepatotoxicity is still probable although the effects of the
and altered bile acid pool. Impaired epithelial barrier integ- PN and the underlying cause of intestinal failure are difficult
rity and reduced villus height result from a lack of luminal to dissociate—the increased risk of IFALD associated with
nutrients and consequent reduced secretion of GLP-1 which ‘ultrashort’ intestine (<20 cm to stoma) may be due to the
has trophic effects on the mucosa. Malabsorption may be anatomy or the associated need for more calories to be deliv-
increased by rapid intestinal transit due to reduced secretion ered intravenously [33].
of PYY, GIP and GLP1 from distal intestine or colon that act Metabolic complications of HPN also relate to the inflexi-
to slow motility. Patients with short lengths of residual intes- bility of a fixed composition of the feed unregulated by entero-
tine are prone to overabsorption of oxalic acid from the endocrine signals that affect not only overall energy intake
colon—thought to be due to preferential complexing of diva- through satiety and hunger regulation but can also alter the
lent cations with malabsorbed free fatty acids—and lead to volitional intake of specific nutrients under normal physiologi-
renal calculus formation. cal circumstances. There is therefore little opportunity with
The composition of PN compromises the physiological HPN for ‘fine-tuning’ nutrient intake, absorption and disposi-
form of the nutrients in order to provide physico-chemical tion on a day-to-day basis. As a result, nutrient deficiencies
stability in a complete mixture. The lipid component in par- and/or excesses may occur. Impaired salt and fluid balance can
ticular has been problematic in view of its delivery as lipid lead to fluid overload, fatigue, or acute or chronic kidney
Table 3 Complications of HPN

Complication Related to Mechanism Frequency
Sepsis Catheter care, gut disease Catheter related blood stream infection CRBSI 0.35–2.27/1000 catheter
(CRBSI) days
Thrombosis/stenosis Catheter tip position, PN Vein damage, high osmolality solution 0.027–0.082/1000 catheter days
composition, coagulation
abnormalities
Gallstones Pigment gallstones Gallbladder stasis, biliary sludge 38% at 20 years of HPN, 76% of
these have complications
IFALD Sepsis, drug therapy, pre- Excess macronutrients, copper or Variable frequency 15–40%
existing liver disease or PN manganese; deficiency of choline, May be more common if ultrashort
composition taurine, carnitine, essential fatty acids bowel 3–26% of deaths on PN
Renal impairment High gut fluid losses, sepsis, Dehydration, repeated kidney injury, eGFR <60 mL/min—15% at
medication excess oxalate absorption, CRBSI related 5 years
glomerulonephritis
Osteoporosis Young when starting PN, low Chronic high acid load, vit D and K Osteopenia occurs in 13–57%,
BMI, underlying disease deficiency, reduced physical activity, low osteoporosis in 18–44% of
sunlight exposure, smoking/alcohol, long-term HPN patients
chronic inflammation and medication
Anaemia PN composition, disease, Inadequate iron, folate, B12 or copper Common
remaining gut anatomy
Reticulo-endothelial Gut absorption and PN Phospholipidosis “Sea-blue histiocytosis” Rare
dysfunction composition
Neurological dysfunction Gut absorption and PN Manganese toxicity; thiamine or B12 Rare
composition deficiency
injury. The aetiology of muscle ‘cramps’ is poorly understood rates of venous return can affect cardiac and renal physiolog-
but this is the commonest symptomatic complaint of patients ical responses.
receiving HPN and is thought to relate to membrane electro-
lyte imbalance. Magnesium and calcium deficiency can lead
to painful muscle spasm and tetany. Trace elements are often Changes in HPS Provision over Time
required as the catalytic centres of enzymes or to form tertiary
protein structures—zinc for instance is required in over 10% Since the introduction of HPN as a possibility for selected
of human proteins and deficiency can profoundly affect pro- patients in the 1980s, there have been considerable advances
tein synthesis. Copper deficiency can result in microcytic in the equipment and homecare service that have occurred
anaemia resembling that of iron deficiency, and copper has over time, to the benefit of patients. Regarding equipment,
previously been shown to precipitate with some amino acid previously the pumps were large, noisy and had to be con-
mixtures used in PN [34]. Excess manganese can result in neu- nected to the mains electricity supply, now they are much
rotoxicity through basal ganglia deposition [35]. Selenium is smaller, portable and able to run on batteries. In addition,
required in glutathione oxidase and is fundamental for redox the PN infusion needed to be attached to a drip stand at
balance—deficiency is not uncommon in HPN patients. home, which was cumbersome but now the whole system
Vitamins are also provided in PN, with the usual excep- (PN infusion and pump) will usually fit into a backpack that
tion of Vitamin K which might interfere with attempts to can be carried or pulled on wheels, making this much more
therapeutically anticoagulate. In some patients with a short convenient at home or when travelling. Regarding the tun-
bowel who require warfarin anticoagulation, vitamin K nelled CVCs, these were initially placed surgically by cut-
deficiency can be a difficult problem to overcome. As fat down into the subclavian vein and the method used (with a
soluble vitamins can now be provided in a form that is mis- purse string to secure) usually resulted in loss of the vein
cible with aqueous solution, the removal of lipid from HPN once the CVC was removed. Now a minimal access
formulations is less likely to result in their deficiency. approach means that the CVCs can be placed under local
However, vitamin D deficiency is common in HPN patients, anaesthetic with or without sedation. The jugular veins are
particularly those with significant fat malabsorption, likely preferably used as well as there are fewer complications
due to interruption of the enterohepatic cycle. Bone density that occur when using this approach (e.g. pneumothorax).
can be adversely affected, leading to osteoporotic vertebral These minimally invasive techniques mean that central
and long bone fractures and skeletal deformity. However, venous access is maintained for longer. Also, the homecare
metabolic bone disease in patients receiving HPN is service has developed over time in many countries, allow-
undoubtedly multifactorial and not solely related to vitamin ing more patients with comorbidities to receive HPN safely,
D deficiency [18]. Aluminium toxicity was previously with a specialist nursing service allowing patients to receive
implicated due to high levels found in casein hydrolysates HPN who are not able to do the connections and disconnec-
and has been prevented by using alternative amino acid tions themselves. Finally, with the digital revolution it is
sources. The optimal PN solution pH of 5–5.5 (that main- becoming possible for data relating to the infusions (vol-
tains calcium phosphate in solution, prevents lipid micellar ume, time, pump infusion pressures) to be collected
aggregation and prevents toxic Maillard reactions between securely on a platform that may enable the early detection
glucose and amino acids) may also contribute a significant of complications [37].
renal acid load. Whilst not demonstrating overt metabolic A large single centre survey over a period of 36 years has
acidosis this could lead in the chronic state to buffering demonstrated that since the 1980s, the mean age of patients
through bone loss [36]. receiving home parenteral support increased from an average
Remaining complications of HPS relate to the need for of 31 to 52 years [38]. In addition, the percentage of patients
central venous access that provides a potential portal for bac- receiving home parenteral support due to surgical complica-
terial and fungal bloodstream infection (“Prevention, tions increased (3.4–28.8%). This clearly demonstrates that
Diagnosis and Management of Catheter-Related Blood older patients with more comorbidities are being offered
Stream Infections” chapter), and can be compromised by home parental support. While this has affected long-term
thrombosis or stenosis of large veins up to and including the survival when analysed by era, overall life expectancy
vena cava (“Central Vein Thrombosis” chapter). As well as remains good (55% 10 year survival for non-malignant aeti-
threatening future access for PN, the latter can lead to venous ologies). In addition, the frequency of complications for
hypertension in the draining territories with resulting facial patients on home parenteral support has been reducing over
swelling and headaches (from intrathoracic vein occlusions) the last 30 years (catheter-related bloodstream infections
or resistant peripheral oedema of the legs. Large collateral [71% to 42%], CVC thrombosis [36% to 5%] and IFALD
vein formation can present a surgical hazard, and reduced [10% to 2%]) [38, 39].
768 L. Cohen et al.
Life Expectancy on HPN Use of HPN in advanced malignancy It was previously

impractical to consider using HPN for patients with advanced
Sustenance by parenteral nutrition can provide long term malignancy (even if there was no other route of nutrition
survival in patients who would otherwise succumb rapidly available) as patients required prolonged admissions for
to the nutritional and hydrational depletion of intestinal fail- HPN establishment. With limited life expectancy this would
ure. The wide heterogeneity of underlying causes of intesti- mean spending a large proportion of their remaining time in
nal failure, patient ages and comorbidities make unselected hospital. Homecare nursing and HPN training at home have
mortality figures difficult to interpret. However, it is clear now facilitated early discharges, and this allows the possibil-
that the majority of deaths of patients on HPN result from ity of feeding such patients parenterally at home. The down-
the underlying disease rather than complications of the HPN sides of HPN remain, as described above, and may further
itself. impair quality of life which is already adversely affected by
Unselected survival data demonstrate a 1 year survival the underlying disease. There is also very limited evidence to
of 86–95%, a 5 year survival of 66–82% and a 10 year sur- suggest that life is prolonged by HPN at all even in the pres-
vival of 55–71% [39–43]. Outcomes depend on age (better ence of complete bowel obstruction [46]. However palliative
when young) and underlying disease (better with Crohn’s benefits include maintenance of performance status and the
disease or pseudo-obstruction than other causes of intesti- energy and wellbeing to allow patients even in the last weeks
nal failure) (Table 4). HPN related complications are of life to put their affairs in order and adjust to their situation.
responsible for 13–22% of deaths with approximately equal Nutrition support may also empower patients to make deci-
proportions due to liver disease and catheter related blood- sions regarding their end of life, including choosing the time
stream infection. Nearly two thirds of deaths occur within of stopping PN. The balance of benefits and burdens of HPN
2.5 years of commencing HPN [40]. Some studies have is therefore highly individual and needs careful consider-
demonstrated an inverse association of survival with length ation by an experienced multi-professional team and a well
of residual intestine for patients with short bowel [43–45], informed and supported patient [47].
whereas others have not [42] although in the latter case sur-
vival was shorter in those with a stoma compared to those As the key aim of HPN in this setting is to preserve qual-
without. ity rather than length of life, it follows that patients with
good performance status at initiation are most likely to ben-
efit. This is unusual in patients with advanced malignancy
Evolving Considerations in HPS and therefore by using this as a selection criterion, the num-
ber of potential candidates for HPN is small. It is most often
With increasing ease of establishing patients on HPS in the used in the setting of malignant bowel obstruction. Ovarian
community, and the possibility of educating and training cancer and appendiceal or colonic tumours causing ‘pseudo-
patients in their own homes rather than in the hospital, the myxoma peritonei’ [48] can be associated with a survival of
use of HPS has increased significantly over recent years. many months or even some years despite widespread perito-
This is reflected in the number of patients receiving HPS and neal metastasis. Such patients may outlive many who are
also the nature of the indications. As a result new challenges commenced on HPN for ‘benign’ indications demonstrating
are emerging: that decisions made on this distinction are artificial and
potentially discriminatory. Prognosis nomograms have been
Table 4 Percentage survival on HPN based upon IF aetiology from St Mark’s Hospital [39]
Percentage survival (%)
Aetiology Number of patients 1 year 5 years 10 years 15 years 20 years 30 years 35 years
Surgical complications 244 83 65 50 50 18 – –
Crohn’s/IBD 242 95 77 68 52 30 15 15
Malignancy 62 33 0 – – – – –
Mesenteric infarction 183 88 61 46 43 35 29 –
Intestinal dysmotility 93 92 79 70 60 45 45 –
Radiation enteropathy 53 80 28 18 9 9 – –
Volvulus 15 71 71 71 71 71 71 –
Scleroderma 21 80 52 33 17 – – –
Congenital 10 100 88 88 88 88 88 –
developed in order to aid appropriate patient selection [49], likely to wean from HPS in the near future, but sequential
but unfortunately these have not been adequately validated. liver and intestinal grafts have been undertaken.
Needless to say, more data is required on the outcomes of
patients with advanced malignancy started on HPN. HPN and diabetes The carbohydrate load of HPN may
result in hyperglycaemia in patients with impaired glucose
HPS in the elderly and with additional organ dysfunc- tolerance or overt diabetes, and can be difficult to manage.
tion With the possibility of long-term survival, some Oral hypoglycaemics may be contra-indicated or poorly
patients started on HPS may reach old age and have to cope absorbed in patients with intestinal failure. Rebound hypo-
with its associated burden of accrued co-morbidity. The abil- glycaemia after stopping the PN infusion may require a
ity to provide HPS in care home settings also allows the pos- slow ‘ramp down’ rather than sudden cessation. With over-
sibility of offering it to more elderly patients. This brings night infusion there is a risk of uncontrolled hyperglycae-
additional challenges as older patients may lose the ability to mia and the use of insulin as a bolus regimen with corrective
manage their own infusions, to comply with fluid restriction doses may risk hypoglycaemia or further nocturnal distur-
and medications (which may be poorly absorbed due to the bances for blood sugar monitoring. Currently, glycaemic
underlying intestinal failure) and require more nursing assis- control is either achieved through subcutaneous basal-bolus
tance. However, it is the advent of additional organ dysfunc- insulin regimens or the addition of insulin to the PN solu-
tion that most complicates the use of HPS in the elderly. tion. By combining insulin with the PN, the risk of unop-
posed insulin (for instance with unexpected PN pump
Loss of cardiac reserve makes fluid and salt balance more failure) is mitigated. Although used in this way routinely in
precarious with an increasingly narrow therapeutic window some countries such as the USA, there is still reluctance to
between fluid overload and inadequate renal perfusion. The do so in others due to the potential for incomplete mixing or
duration of PS infusion may need to be increased as well as insulin adsorption to the container and giving set [50]. In the
reducing the volume or sodium content in order to compen- future, the use of continuous glucose monitoring devices
sate. It is unclear whether there are additional benefits of and closed loop algorithms for subcutaneous insulin infu-
central veno-dilatation by using loop diuretics in this sion devices will significantly improve the safety of HPN in
circumstance. diabetics.
Renal failure may also compound fluid and electrolyte
balance in patients with HPS and increase the risk of compli-
cations such as osteoporosis due to acidosis. Maintenance of HPS in performance athletes With the growth of paralym-
renal perfusion may be challenging and the long term effects pic sports there are now athletes who are dependent on HPS
of significant central volume depletion during the day with who wish to compete in endurance sports [51]. This high-
restoration by overnight PS infusion are unclear. However, in lights the problems associated with the inflexibility of day-
patients with high stoma or fistula losses the omission of to-day variation in requirements, particularly with regard to
even one infusion due to mechanical line or pump issues may fluid and sodium intake due to excessive loss in sweat and
result in acute kidney injury. Repeated such insults can lead breath rather than the gastrointestinal tract. There is also the
to permanent renal failure. Additional risks to the kidney in desire to alter body composition and provide suitable amino
HPS patients arise from CRBSI sepsis causing hypoperfu- acid sources for muscle building. Experience in this area is
sion or infection related glomerulonephritis. currently limited. In our practice we meet the requirements
Venous access may be severely limited for haemodialysis, through a complex additional PN bag regimen that can be
and the lifestyle detriment of requiring two separate intrave- provided for the athlete’s use on training days and infused
nous organ support modalities may be unacceptable. Volume over a short time course after the exercise.
management may be challenging and even require daily dial-
ysis to remove excess fluid in those who do not have high
volume stoma losses (which can be unexpectedly advanta-
geous). The outcomes of renal transplantation in patients Failure of HPS
requiring HPN are not reported but this scenario usually
leads to consideration of a combined intestine and kidney HPS can be considered to have failed when central venous
graft when feasible. access is no longer achievable, when it is associated with life
Similarly, the effect of long term HPS after liver trans- threatening CRBSI or organ dysfunction (such as IFALD or
plantation is still unclear, and is again usually avoided by the renal failure), or when it becomes unmanageable due to gas-
use of a combined graft. Where isolated liver transplantation trointestinal fluid losses or unacceptable quality of life. In
has been used in this setting it is usually in children who are these situations intestinal transplantation with or without
770 L. Cohen et al.
other organs (liver, stomach, pancreas, colon) can be composition (particularly the lipid component). Financial
considered. and logistical (for instance nursing support) constraints are
The indications and optimal timing of intestinal transplan- likely to limit the expansion of HPN provisions even in
tation have changed considerably due to significantly improved wealthy countries. However, the outcomes of isolated intes-
outcomes and greater experience of the management of such tinal transplantation are already excellent and with continued
patients with and without transplantation. Complete loss of improvement it is likely that it will begin to supplant long-
vascular access is rare and new techniques for recanalization term HPS in suitable candidates as it more cost effective and
and stenting have improved access for central venous cathe- has the ability to improve quality of life. Further and ongoing
ters—however it is currently unclear how sustainable these are systematic study of the symptoms of intestinal failure and
for the long term and at present such measures may be seen as the burdens of HPS in comparison with intestinal transplan-
merely providing the temporary central access required for the tation will be required.
transplant operation to go ahead.
Recent evidence of improvement in IFALD related
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Home Enteral and Parenteral Support
for Children
Theodoric Wong and Gabriela Jiménez-Arguedas
Key Points Home Enteral Nutrition

1. Dietary foods for special medical purposes are classified
into three categories: nutritionally complete foods with Definition of Enteral Nutrition
standard nutrient formulation, nutritionally complete
foods with a nutrient-adapted formulation specific for a The term EN in paediatrics is often recognized as refer-
disease, and nutritionally incomplete foods. ring to liquid feeds (e.g. formulas). Currently, dietary
2. EN is indicated when energy and nutrient requirements foods for special medical purposes as defined by the
cannot be met by regular food intake in a patient with at European legal regulation directive 1999/21/EC of March
least a partially functional gut. 1999 [1] is classified into three categories: (a) nutrition-
3. Fifty percent of patients receiving home enteral nutrition ally complete foods with standard nutrient formulation,
(HEN) have neurological or genetic reasons and about (b) nutritionally complete foods with a nutrient-adapted
25% have digestive diseases. formulation specific for a disease and (c) nutritionally
4. There are three types of patient with IF needing PN. Type incomplete foods. EN can be encompassed by all three of
1 have a loss of intestinal function for less than 2 weeks these categories.
(e.g. acute gastroenteritis or post operative ileus); type 2
for less than 28 days (e.g. intestinal atresia or uncompli-
cated gastroschisis), and type 3 long term. Prevalence of HEN
5. Reasons for HPN include necrotising enterocolitis (NEC),
atresia, intestinal resection/short bowel syndrome as well The use of home enteral nutrition varies across the world.
as enteropathies (e.g. tufting enteropathy and microvil- This is due to availability of enteral equipment (e.g. feeds,
lous inclusion disease). tubes, pumps and syringes), trained community support and
6. Survival of patients receiving HPN has steadily improved access to regular reviews by clinicians. The lack of consen-
from around 50% in the early 1990s to 90% in sus in HEN eligibility criteria has meant that reported data
2008–2013. are not comparable. However, the general trend has been an
increase in the use of HEN in developed countries (Table 1).
The prevalence varies between 1.4 per 100,000 to 69.5 per
100,000 [2, 3]. These studies have large time gaps between
them, geographic as well as patient demographic differences
making them difficult to compare.
T. Wong (*) Indications and Considerations for HEN

Department of Gastroenterology and Nutrition, Nutrition Support
and Intestinal Failure Team, Birmingham Women’s and Children’s
Hospital, Birmingham, West Midlands, UK EN is indicated when energy and nutrient requirements can-
e-mail: [email protected] not be met by regular food intake in a patient with at least a
G. Jiménez-Arguedas partially functional gut. Every possible effort should be
Department of Gastroenterology and Nutrition, Hospital Nacional made to ensure that those patients who have no mechanical
de Niños “Dr. Carlos Sáenz Herrera”, San José, Costa Rica

774 T. Wong and G. Jiménez-Arguedas
Table 1 Showing the comparison of the prevalence of HEN in different countries

Country Total/prevalence of HEN Reference Date completed Age group
New Zealand Total: 630 Jelleyman 2013 2013 <15 years
69.5 per 100,000
Spain Total: 529 Gomez-Lopez 2010 2007 Paediatric
Poland Total 525 Szlagatys-Sudorkiewicz 2012 2010 Paediatric
1.375 per 100,000
United Kingdom Total: 1336 BANS 2011 2010 <16 years
7.9 per 100,000 Pironi 2007 2003 <16 years
Italy 3.47 per 100,000 Diamanti 2013 2009 0–18 years
0.84 per 100,000 Pironi 2007 2005 <18 years
Table 2 Examples of aetiology of HEN patients

Insufficient oral intake [6]. The selection of an enteral access device is an important
Oral motor immaturity or dysfunction step and requires evaluation of the following [7]:
Neurologic impairment
Maldigestion and malabsorption • patient’s disease.
Type II/III intestinal failure including short bowel syndrome
• past surgeries and current anatomy.
Cystic fibrosis
Inflammatory bowel disease
• gastric and intestinal motility and function.
Chronic liver disease • intended length of therapy.
Increased nutritional requirements
Cyanotic heart disease Normal gastric emptying with no obstruction or fistula is
Burns required for a gastric placed enteral access device. Direct
Metabolic diseases small bowel feeding maybe appropriate for patients with
gastric outlet obstruction, gastroparesis and in those with
known gastro-oesophageal reflux disease (GORD) and aspi-
issues be fed orally where possible and have any psychologi- ration of gastric contents.
cal barriers are looked at and managed accordingly.
There is no strict consensus as to when HEN would be
indicated. Generally speaking, this is determined by (a) Nasoenteral Tubes/Devices
anticipated length on EN, (b) financial considerations of pro-
vision of EN and (c) ability of family/community support for Although the tubes/devices are often described according to
EN. This decision should ideally be made at the start of start- access point and/or entry point in the gastrointestinal tract,
ing enteral nutrition and not in an unanticipated fashion. their only difference is the material, the length (cm) and the
Setting goals such as target weight, target volume, target diameter (Fr sizes) of the tube/device. The materials can be
calories or resolution of symptoms (e.g. lack of diarrhoea or polyvinyl chloride (PVC), silicone or polyurethane. PVC
vomiting) will allow healthcare professionals and patient/ tubes use are generally short term (3–5 days) whilst the sili-
families to know what to expect over a particular timeframe. cone/ polyurethane tubes/devices can be used for up to
Clinicians have mainly used clinical judgement when 8–12 weeks. The length of the tube/device should be selected
deciding whether a patient requires HEN. That is usually according to the age of the patient and anatomy so that the
patients with insufficient oral intake and those who present access point (stomach or jejunum) can be reached. The diam-
with wasting and stunting [4, 5]. There are also patient groups eter of the tube should be selected also according to the age
who, due to their medical diagnoses, are more likely to require and size of the nasal passage (if this is the route of entry).
HEN than others (e.g. patients with neurological disorders, Methods for tube insertion are detailed elsewhere [8] but
feeding disorders and intestinal failure) (Table 2). In one study, all tubes/devices should be inserted only by trained staff or
about 50% of patients on HEN have neurological or genetic caregivers because of the risk of misplacement and oesopha-
reasons and about 25% were due to digestive diseases [3]. geal or pulmonary perforation [4]. Confirming the position
of the NG tube is essential not only on insertion but also on
subsequent use. Radiology is the recommended method but
Enteral Access Devices has the drawback of radiation exposure. Other methods of
confirmation of placement such as pH of aspirates or auscul-
Enteral access devices such as nasogastric tubes (NGT) has tation for “bubbling,” when air is flushed down the tube are
had a long history and were first described by Hunter in 1790 unreliable [4, 9].
Home Enteral and Parenteral Support for Children 775
There are a number of methods that can be employed for peritoneal metastases, left ventriculoperitoneal shunts) and
the placement of nasojejunal tubes. They include a “blind” terminal illness with limited life expectancy [4].
bedside insertion with the use of a prokinetic agent such as Many centers also now use laparoscopic assisted placement
metoclopramide or erythromycin, use of weighted/magnetic of gastrostomies to allow direct visualization. This is thought to
tubes [10], string tie on the end of the tube, fluoroscopic and be a safer method avoiding inadvertent colonic injury.
endoscopic placement. Despite the use of these techniques, Gastrostomy feeding appears to have better outcomes
the success rates have not surpassed 75–80% [11]. compared to NGT feeding with better comfort and less irrita-
Radiological confirmation of position would still be required tions, ulcerations, bleeding, displacement or clogging.
in most of these methods. Improved nutritional adequacy and reduced rate of GOR and
aspiration pneumonia are also seen [13, 14].
Complications of Nasoenteral Tubes In patients with high risk of aspiration or a dysfunctional
Complications associated with nasoenteral tubes are less fre- stomach, a long term jejunal access should be considered i.e.
quent since the introduction of fine-bore tubes. Passage gastrojejunal tube, jejusnostomy tube or surgical jejunos-
maybe facilitated with guidewire. Currently available tubes tomy. A surgical jejunostomy is a part of the intestinal tract
are more flexible and less likely to cause erosions, oesopha- brought out to the surface of the skin and requires intubation
gitis or strictures. by a tube for delivery of enteral nutrition. They are fashioned
Tube related complications include blockage, dislodge- to bypass any upper GI anatomical or mechanical issues.
ment, nasopharyngeal discomfort and trachea-oesophageal
fistula. Blockage can occur when the tube is not properly Complications of Gastrostomy Tubes
managed, for example: leaving drug remnants, having a vis- Initial one piece system PEGs can be exchanged to low pro-
cous formula, using gravity and not a pump, a small lumen or file devices (with removable attachments to the device). This
yeast colonization. Up to 24% of neonates have a NGT for should only be done once the gastrostomy tract is matured
feeding with oesophageal and gastric perforation in low birth and this may take from 6 to 12 weeks. As with nasoenteral
weight babies seen in 4% of cases [9]. tubes, gastrostomies can present with blockage or dislodge-
Tube misplacement may occur in patients who have lack ment. Dislodgement might cause catastrophic complication
of gag, swallow and cough reflexes, for example in children of peritonitis if dislodged into the peritoneal space.
on mechanical ventilation or altered consciousness but may Local complications like pain around site and skin irrita-
also occur in an otherwise well child. Reinsertion of guide- tion can be seen in patients who have a tight fixation, infec-
wire, with the feeding tube in situ, is not recommended. tion or leakage. In these cases, fixation needs to be checked;
infection treated and consideration of the use of PPI for leak-
astrostomy Tube/Jejunostomy Tube
G age. Granulation tissue, also known as hypergranulation tis-
As a general rule, when EN is expected to be long term, feed- sue, has been reported in up to 44–68% of patients with
ing via a gastrostomy, or in certain situations enterostomy, gastrostomy tubes [15]. It presents as a red, spongy, prolif-
should be the preferred route [4]. Gastrostomy allows access eration of tissue that produces exudate and bleeds easily
directly into the stomach and enterostomy directly into the [16]. It can be removed using silver nitrate or cauterisation.
small intestine. This allows the patient the option of being Application of a steroid ointment (hydrocortisone/dexameth-
free from having tapes on the face, which can cause skin asone/betamethasone) with antibacterial agent might help to
breakdown and pain on removal. The presence of a tube in reduce granulation tissue.
the oesophagus is also thought to be a hindrance to oromotor Leakage of nutrients or gastric juice can occur with a
skills development. large stoma. This can be improve by replacement with a
There is much debate is as to the minimal time on EN to smaller tube size. In severe cases, feeding needs to be stopped
justify gastrostomy insertion but generally should not be for and parenteral nutrition considered in order to reduce the
less than 12 weeks, and in many cases should be longer. stoma size and heal the surrounding skin.
Percutaneous endoscopic gastrostomy (PEG) technique, ini-
tially described by Gauderer et al. [12] has largely replaced
open gastrostomy placement via laparotomy. Absolute con- Enteral Feeds
traindication for PEG insertions include: (1) inability to per-
form UGI endoscopy (laryngeal or oesophageal stricture) Formulations
and (2) uncorrectable coagulopathy. Relative contraindica- EN can be offered as liquid ready-to-feed formulations or pow-
tions could be: failure to transilluminate abdominal wall, dered preparations that are mixed with cooled boiled water
patient’s comorbidity (portal hypertension, severe gastritis or before feeding. Products available for children can be catego-
gastric ulcer, massive ascites, peritonitis, peritoneal dialysis, rized as either “enteral feeds” or “supplemental feeds” [4].
Current medical enteral feeds are designed to be nutri- For those patients (e.g. with short bowel syndrome) where
tionally complete when taken as the only source of nutrition there is no commercially available feeds to complement the
to meet caloric requirements. The nutrient composition of absorptive capacity of the gut, a modular feeds might be
enteral feeds should be age adapted [17]. Most of the new- required. This involves providing the individual macronutri-
born formulas have energy density start at 0.67 cal/ml. The ent and micronutrient components in a special combination
energy density can be increased to beyond 1 kcal/mL depend- that the gut can tolerate and absorb. This should only be done
ing on tolerance and age. Feeds with a high energy density in specialized units where there is technical dietetic experi-
(1.5 kcal/mL) are used in children with increased energy ence in managing these patients.
requirements, however, it may not always provide sufficient
fluids to meet requirement. Blenderised Diet
Supplement feeds (“sip feeds”) may be provided in addi- Blenderised diet refers to using everyday foods and atom-
tion to normal food to increase energy and nutrient supply ising them into a puree consistency. There has been an
when required. Supplements contain a concentrated source increased interest and shift towards blenderised diets as
of energy, protein, and other selected nutrients, but do not this is seen by parents and caregivers as more natural than
need to provide all of the nutrients in a balanced commercially available formulas in providing nutrition.
composition. Studies have also shown improved stooling, weight and
Most formulas are cow’s milk (protein) based and is usu- height gain in patients with intestinal failure who transi-
ally referred to as polymeric feeds. Protein molecules tion to Blenderised tube feeding (BTF) [19]. Other benefits
(usually casein) can be broken down into smaller less anti- such as improve gagging and retching in children post fun-
genic units by heat treatment, enzymatic hydrolysis and also doplication [20] has also been reported.
final ultrafiltration to separate larger molecules. When the In another study, blenderised tube feeding analysis found
degree of hydrolysis is >50% then the formula can be referred that the samples provided 50% less energy and macronutri-
to as extensively hydrolysed. The size of the protein is usu- ent values than prescribed and had higher water content [21].
ally less than 1000 Daltons. Partially hydrolysed or exten- Good candidates for blenderised diet are:
sively hydrolysed formulas are usually the first line
specialized feeds in those patients with cow’s milk protein • children who are on bolus feeding via their gastrostomy.
intolerance/allergies. It can also be used in those children • stable growth and otherwise healthy.
with short bowel syndrome when expressed breast milk is no • with a motivated family.
longer available.
Note that some formulas might use porcine enzymes to Patients who are contraindicated for BTF [22] are:
break down proteins and so might not be halal. A lot of com-
mercially available hydrolysed formulas not only manipulate • those with acute illness or immunosuppression.
the protein component of the formulas but also the percent- • gastrostomy tube size of less tan 10 Fr.
age of long chain fatty acids (e.g. higher medium chain tri- • fluid restricted.
glyceride) and carbohydrate source (i.e. lactose free) and so • continuous feeding.
the effects from the formula might not be purely from the • jejunstomy tubes.
protein component. • multiple food allergies.
Elemental feeds are those feeds that have amino acid as • lack of resources.
their source of nitrogen. Elemental feeds are usually pre-
scribed when infants cannot tolerate hydrolysed formulas Blenderised tube feeding is labor intensive and requires addi-
for due severe cow’s milk protein reactions. Prescribers tional food storage space and equipments which might not be
should also be cautioned that some elemental formulas covered by medical insurance. Blenderised diets should be
might use soya as their protein source. This might con- discussed with a qualified dietitian to ensure that caloric and
tinue to cause reactions in those infants who are nutrient requirements are met. Often blenderised diets are
susceptible. used in conjunction with formulas, at least initially.
High osmolality feed (such as elemental feeds) can induce
diarrhoea, so iso-osmolality (300–350 mOsm/kg) is prefera-
ble. This is particularly important in patients with transpylo- Organization of HEN
ric continues feeds. Fibre and its fermentation products
(short-chain fatty acids) have potential beneficial effects on Discharge Planning
intestinal physiology and the prevention of both diarrhoea In order for discharge to take place, there are a number of
and constipation [18]. requirements must be satisfied prior. They consist of:
Table 3 Example of some HEN equipment required experience [24]. Although the prevalence has increased but
Pump, Stand, Frame, Feed bags/bottles/containers, sets, syringes, the long term survival and rates of significant complications
hooks connectors have decreased.
pH indicator strips Tape and dressings The criteria for offering Home parenteral nutrition (HPN)
Disinfectant wipes Gloves
are the following:
• Training; this includes practice of basic hygiene, setting –– Requiring inpatient PN for at least 3–6 months
up of pump and giving sets, making up of feeds (if –– Not requiring any imminent further surgery
required), NGT testing and/or reinsertion (if applicable). –– Clinically stable (e.g. without fluctuating electrolyte
• Suitable home environment (to clean water, secured elec- requirements)
tricity)with available storage space –– Suitable PN formulation
• Community support (usually nursing as well as medical) –– Suitable long term venous access
for troubleshooting. –– Suitable home setting (both physical and social)
• Home care company who is able to supply feeds and con- –– Contract of engagement for ongoing reviews
sumables (Table 3).
If possible, a multi-disciplinary meeting should take place

with parents/caregivers, community services and hospital Aetiology and Classifications
staff prior to discharge to discuss what has been achieved
during the admission, what is to be expected after discharge Currently, a combination of aetiology and intestinal function
and clear guidance as to who to contact in what help to predict and describe those patients who might require
circumstances. HPN. In children, aetiologies that are commonly seen requir-
ing HPN include: necrotising enterocolitis (NEC), gastros-
Ongoing Review chisis associated with other aetiologies, atresia, intestinal
Patients on long term HEN should be reviewed on a regular resection/short bowel syndrome as well as enteropathies
basis. Issues that should be looked at during these reviews such as tufting enteropathy and microvillous inclusion dis-
include issues with managing EN at home, tolerance of EN, ease just to name a few.
nutritional and growth status of the child on HEN, whether In the last 10 years, intestinal function/failure has been
HEN could be weaned and adequacy of community support. classified into three main groups [25]. Type 1 pertains to
Goals should be set with the caregivers at each review and loss of intestinal function for less than 2 weeks. Patients in
this could be used as a measure of progress or lack of it. this category might require iv fluids and/or short term par-
Weaning patients off HEN might require a multi- enteral nutrition during their illness. Aetiologies which
disciplinary approach with the skills of nurses, dietitians as might be in this category could include acute gastroenteri-
well as speech and language specialists. The central goal is tis or post-operative ileus. Type 2 pertains to the require-
to be weaned off tube feeding in the quickest possible time ment of PN for less than 28 days. Typically patients in this
whilst maintaining nutritional and growth status. For those category might have intestinal atresia(s) or uncomplicated
children who are at school, a comprehensive plan that offers gastroschisis with prolong dysmotility. Type 3 intestinal
input from the school is also vital for success. failure are those who are might benefit from HPN due to
the need for prolong PN. The concept of permanent intes-
tinal failure refers to those patients with aetiologies which
Home Parenteral Nutrition for Children are unlikely to ever become independent of PN. This will
include patients with ultrashort intestinal length and enter-
The survival of children on HPN has increased significantly opathies such as microvillous inclusion disease. The defi-
over the last 20 years to the point that death is the exception nition of ultrashort has changed through the last decade
rather than the norm. Even so, the provision of HPN is not with patients now surviving with little or no small intesti-
entirely risk free. A lot of the improvements in HPN survival nal length, where previously a length of 30 cm has been
come from a team approach in training children and families proposed.
in recognising early signs of complications and line infection
and getting prompt treatment.
The prevalence of type III intestinal failure in the paediat- Clinical Stability
ric population varies between countries. The UK experience
has been that it had risen from 4.4 per million in 1993 to 16.6 Patients who have ongoing intensive nursing needs are
per million in 2012 [23]. Other centres have had similar unlikely to benefit from being sent home with PN. These
patients might include those with large variable daily stomal Infusion
output and require close fluid and electrolyte monitoring.
Stability of bespoke PN might be influenced by the electro- Currently, there are a number of presentations of PN bags for
lytes added to the PN. Traditionally, calcium and phosphate administration into the patient. (1) Separate lipid and aque-
are the minerals that are looked at closely as precipitation can ous bags, (2) separate chambers (roll in one) and (3) all in
occur. one bag. The infusion requires a portable pump. These
Those patients with ongoing repeat line infections and pumps are usually light weight, allow programming of dif-
requiring definitive line care management are also not eligi- ferent settings (e.g. maximum infusion rates or maximum
ble to be discharged home on HPN. See below with respect pressure to deliver infusion) and allow delivery of PN with-
to line care. out constant need to be plugged into a power source after
charging.
The infusion is prescribed as ml/h over a set number of
PN Formulation hours (e.g. 50 ml/h over 12 h). When the hours of PN infu-
sion is condensed, this is termed cycling of PN. Most units
Paediatric HPN are usually tailored made (bespoke). This is aim to cycle PN over 12 h. There are several rationale behind
due to HPN patients often have electrolyte and macronutri- this is for (1) for practical reasons, 12 h free from PN would
ent requirements that are not standard from the recommended allow relatively normal activities to be performed during the
guidelines to account for stomal/stool, renal losses or altered day such as schooling and work. (2) reduce the total time that
metabolic demands. the liver is exposed to glucose from the PN. This has been
Although this must be common knowledge, consider- suggested to provide a beneficial role in minimizing IFLAD
ation for PN composition should include the following [28].
macronutrients: amino acid, carbohydrate and lipid source. There needs to be caution not to become too fixated on
Whether all macronutrients are to be provided with each achieving a12 h infusion time as some patients who cannot
infusion will depend on clinical need of the patient and tolerate any oral/enteral intake may develop dehydration and
local practices (e.g. some units might have lipid free electrolyte disturbances. In some patients, sudden cessation/
nights). In addition to macronutrients, electrolytes, trace increase of a glucose infusion precipitates hypoglycaemia/
elements and vitamins supplementation would need to be hyperglycaemia. In these patients, it may be beneficial to
considered. Although guidelines (e.g. ESPGHAN 2018) include a stepping up and down regime depending on glu-
exist for providing the maintenance requirement, they do cose tolerance. The stepping up or down rate of infusion is
not take into account the pathology of the individual patient generally half the full rate for 30–60 min at the start or prior
and each patient will need careful review as to whether to the cessation of PN infusion.
guideline recommendations for electrolytes or micronutri- Early morning vomiting is not an uncommon symptom
ents suit that of the patient to ensure toxicities and deficien- voiced by patients and family who have overnight PN. The
cies are avoided. Biochemical monitoring is often used to exact reason for this is unknown but maybe related to large
assist in this determination. fluid shifts in the body over a short period of time. Other
Having mentioned the above, there is guidance when for- causes for vomiting should be sought before diagnosing it to
mulating HPN. be PN related vomiting.
From an energy point of view, lipid should represent about
25–40% of non-protein energy, and linoleic acid should be
1–2% of total energy. The maximum lipid utilization rate is PN Administration
about 3.3–3.6 g/kg/day [26]. The maximum infusion rate of
glucose through a central vein should be 1.0–1.5 g/kg/h; if it Aseptic non touch technique (ANTT) has largely replaced the
is greater than this glycosuria may occur [26]. use of sterile gloves to prepare the person for connection and
Ingredients that generally require special attention are: disconnection of PN at home. The main principles of the
calcium and phosphate (as they might precipitate out of ANTT is that sterile products are used and the sterile part of
solution and greater amount will be required for prema- the product does not come into contact with anything that is
ture infants), cation and anion imbalances, trace elements not sterile, thus preventing contamination from occurring
and vitamins contributing to longevity of formulated bag. [27]. The identification of key parts e.g. the tip of a syringe,
Before supplying PN as formulated, manufacturers need and these should be kept sterile so that the use of sterile gloves
to certify the stability of and shelf life of the and/or a sterile field is not required [27] (chapter “Nursing
composition. Care of Patients Receiving Home Parenteral Support”).
Table 4 Equipment required for HPN when choosing a particular provider. Some hospitals have
Pump (with clamps, Towel dispenser filters Sharps elected to choose from a selected number of providers and
leads, backpack, container rotating the providers for each new patient. The advantages of
wheels, admin set)
doing so is to distribute risks of relying on only one provider
Drip stand Soap dispenser IV caps/ Waste
bungs bags but this might not match suitable companies with suitable
Fridge (thermometer) Extension cords Towel Hand patients.
wash/soap
Collapsible trolley Dressing (for line Needles
site, line end)
Venous Access
Blue procedure tray Elasticated tubular Dressing
bandage pack
Blue clamps Gloves and aprons Syringes Home parenteral nutrition cannot be delivered without cen-
Patient thermometer Wipes Tape tral venous access and the maintaining of their integrity (i.e.
(chlorhexidine) Free from breakage or infection) has been the cornerstone of
the delivery of parenteral nutrition.
Line care begins even before the line is inserted.
The delivery of PN will require certain basic equipment to Considerations include:
be available in the home (Table 4). These can be procured
from the hospital or from the home care companies. –– Position of venous access (e.g. stoma site & vascular
anatomy).
–– Type of access (e.g. peripherally inserted central catheter,
Storage of PN port or skin tunnelled lines).
–– Number of lumens.
Stability of PN is a major consideration and factors such as –– Thrombotic risk (patients with coagulopathy).
temperature variability will affect the chances of precipita- –– Previous line infection and preventive measures (skin
tions or of the browning effect of carbohydrate within PN. To washes prior to insertion).
increase the longevity of PN, refrigeration is often required –– After line care (regular skin washes, line locks and fre-
(especially for bespoke bags) while off the shelf multi- quency of use).
chamber bags (standard bags) can often be stored at room
temperature for a long period of time. Refrigerators will There are some general principles/recommendations that are
need to be able to accommodate the number of bags for each to be adhered to [29]:
delivery from the manufacturing company and this might be
in access of 2 week’s supply of PN bags. The PN fridge –– Avoid using the femoral vein for central venous access.
should not have any other food or beverages in it as the open- –– Where possible, ultrasound guidance is used for place-
ing and closing of the fridge will contribute to temperature ment of central venous access to avoid multiple attempts
fluctuations. of cannulation.
–– Use the minimum number of ports or lumens essential for
the management of patient.
Home Care Company –– Promptly remove the central venous catheter when no
longer required.
Every country will have different national/regional procure-
ment laws and policies. In essence, the responsibility for the Integral to reducing catheter related blood stream infection
PN prescription lies in the nutrition support team looking after (CRBSI) is also the selection of appropriate hubs for central
the patient and the home care company’s responsibility will be venous access [30]. Catheter hubs which allow turbulent flow
to deliver the PN and other associated consumables. Some and easy wear and tear at the access points are to be avoided.
home care companies also offer nursing services to compli- In addition to good line care, good skin care should also be
ment the PN delivery service. In the UK, the current setup with incorporated into any HPN protocol to reduce the risk of skin
HPN is that each patient needs a unique high cost drug number contamination. These can be in the form of skin washes such
and the services need to be commissioned locally. There is a as octenidine and the use of chlorhexidine gluconate impreg-
list of approved providers from which the hospitals can choose nated sponges/patches applied to the skin exit site [31].
or be assigned with. Hospitals will need to take into account With adherence to these principles, the rate of CRBSI has
different factors such as previous service performances, decreased over the years with reported rates of 2–3 per 1000
responsiveness to issues arising and geographical constrains catheter days [32]. Local data from Birmingham Children’s
Hospital suggests that this could be further decreased to 0.2 Long Term Management
CRBSI in 1000 catheter days with the aim to achieve 0
CRSBI infections in the HPN cohort. Growth and Nutrition
All children receiving long-term parenteral nutrition at home
need to be regularly reviewed by the multidisciplinary team
Home Setting in the specialist centre.
A number of studies have documented the growth of
A home assessment will need to take place prior to discharge. patients on HPN. These in general have been much poorer
This is to assess a number of different factors: than the general population [34] especially during the first
2 years of life [35, 36]. It has also been shown that perhaps
–– Cleanliness and hygiene of house and rooms. these growth and developmental abnormalities persist even
–– Enough space to house the child and equipment. when parenteral nutrition has been weaned off [37]. It is
–– Access for deliveries and emergency escapes. uncertain as to the reasons for this but it has been postulated
–– Number and relationship of family members who will that this might be related to e.g. nutrient insufficiency, con-
reside at the same address. stitutional short stature.
The current methods of measuring growth and nutrient
In general, the house should not be overcrowded both with sufficiency have many flaws. The use of weight and height
people and belongings. This is so that PN could be place on measures might be inaccurate due to variation in equipments,
and taken off without chances of contamination. body fluid fluctuations and technical problems with children
The space available for storage should be large enough to not being still when they are measured. Anthropometric
hold at least 2 weeks’ worth of ancillaries and equipment as measures can supplement weight and height measurements
well as a PN fridge. Proximity of handwashing facilities to to give a better picture in terms of progress and these include
the place of PN being put up/taken down. mid arm circumference and tricep skin folds.
Biochemical measurements do not often reflect actual
macro/micronutrient status until late in the piece. Even so, cli-
utrition Support Teams and Intestinal
N nicians often measures full blood count, electrolytes, liver
Rehabilitation Programs functions, trace elements and vitamins to guide them in PN
prescriptions. As a guide, children receiving long-term PN as
Nutritional support teams (NST)/intestinal rehabilitation inpatients should have weekly measurements of blood count,
programs (IRP) have been the cornerstone of nutritional care urea, sodium, potassium, calcium, magnesium, phosphate and
for patients with intestinal failure. Although the composition liver function tests and monthly copper, zinc and selenium
of team members vary in their title, in essence the skill mix measurement until they are stable. In those patients who are
that is required are: stable, 2–3 monthly biochemical estimations should be suffi-
cient. 6 monthly measurements of fat-soluble (ADEK) vita-
1. Parenteral nutrition: detailed knowledge of PN composi- mins is advised. Yearly liver/gallbladder ultrasound as well as
tion, stability (and aseptic manufacturing knowledge and B group and C vitamins and thyroid function need to be
managerial skills if making PN on site), medication inter- checked [26].
actions with PN, procurement of PN (if it is not made in
house).
2. Caloric requirement, nutrient selection, body composi- Outcome
tion determination.
3. Nursing, Line care, organisation and continuing support Survival
of home PN provision. The Survival of children on HPN has steadily improved from
4. Medical overview of progress, medication review. around 50% in the early 1990s to 90% in 2008–2013 (Table 5).
5. Social and psychological support of families. Much of the improvement in survival has been attributed to
the understanding of the benefits of early use of enteral nutri-
It is difficult to pinpoint the exact reasons as to why a NST/ tion, more aggressive PN weaning practices, multi-discipline
IRP would produce benefits to patients with intestinal failure nutrition support teams getting involved early on [38, 39].
and on HPN. What is clear though from a number of studies
is that the benefits can be seen in a number of different out-
comes. They include decrease mortality whilst on HPN, ear- Weaning and Stopping Parenteral Nutrition
lier achievement of enteral autonomy, improvement in
intestinal transplant success rates, decrease in CRBSI, The ability to wean patients off parenteral nutrition is depen-
improved mortality and morbidity related to IFALD [33]. dent on a number of factors. Patients with congenital mucosal
Table 5 Survival of HPN patients through different era at Birmingham Clearly there is much need to have a universally agreed
Children’s Hospital (Table courtesy of Ms T Johnson)
QoL instrument to allow better description of paediatric
1987– 1998– 2008– intestinal failure patients on HPN and their parents/caregiv-
1997 2007 2013
ers’ QoL.
Number of patients 15 45 46
Outcome:
Full EN 6 (40%) 23 (51%) 24 (52%)
Full EN after liver transplant (2) (1) Transition of Paediatric HPN Patients
Full EN after bowel (1) (1)
transplant With the increase in the number of paediatric HPN patients
Continues HPN 2 (13%) 7 (16%) 18 (39%) as well as the better survival of these patients, it is inevitable
Overall Survival 53% 67% 91%
that more patients will graduate into adult services.
Died 7 (47%) 15 (33%) 4 (9%)
IFALD (on transplant list) 5 (4) 5 (1) 2(1) It is imperative that both paediatric and adult services are
Post transplant 0 3 2 equipped in making sure that not only the medical needs are
Sepsis 0 3 0 met for these young persons but their educational and psy-
Underlying diagnosis 2 4 0 chosocial needs are being met. It is in this light that NICE
has produced guidance [45] to assist healthcare professionals
in delivering a unified approach to transitioning for young
persons. The important points are:
diseases such as tufting and microvillous inclusion disease
will take years to come off PN completely, if at all. Those • The transition process is to set young persons to develop
patients with short bowel syndrome secondary to bowel independence to meet their healthcare, educational and
resection are more likely to come off PN but this is depen- psychosocial needs.
dent on a number of factors e.g. total small bowel length, • Transition should begin no later than 13/14 years of age.
associated intestinal dysmotility and bowel dilatation [40]. • Young person’s needs and views are to be taken into
As there is no marker for intestinal failure (unlike in liver account in individualised plans.
or renal failure), the only way is to challenge the gastrointes- • Joint statement (paediatric/adult/young person) for vision
tinal tract’s function until symptoms appear or the appear- of transition in writing.
ance of unabsorbed substances in the stool (faecal reducing • Transition should be developmentally appropriate.
substances, pH, faecal fat globules and alpha 1-antitrypsin). • A key worker should be identified to lead this process
When there is malabsorption of particular components, with the young person.
changing the relative composition of them in the enteral feed • Process should encompass before, during and after move
to achieve the same caloric provision might be necessary e.g. to adult services.
via a modular feed.
With respect to young persons with intestinal failure, the fol-
uality of Life on HPN
Q lowing are examples of some goals that are to be agreed as a
There are a number of disease specific quality of life (QoL) marker for readiness for transition into adult services:
instruments in paediatrics such as that for biliary atresia and
liver transplant but there is currently no such instrument for • Young person understands their underlying medical
paediatric intestinal failure or HPN. Despite this, a number condition.
of centres have produced some qualitative measure of paedi- • Physically allowing, be able to manage home PN
atric patients on HPN. These studies have found that the QoL independently.
is reduced and in domains such as physical and cognitive • Know and administer any medications/feeds
functioning in 13–24 months old and physical health and independently.
social functioning in the 2–6 years old [41]. Abdominal pain • Discuss aspirations, issues or concerns independently.
and stool frequency >3 times per day was associated with • Knowledge of access to help (medical, psychological or
higher parental stress. Longer time interval since the last social) when required.
bowel operation and hospitalisation was associated with
lower parental stress level [42].
Children with IF and their parents also might have common
themes of concerns such as thoughts about living with illness, References
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Home Parenteral Support for Patients
with Incurable Advance Cancer
Mani Naghibi and Federico Bozzetti

1. Patients with incurable advanced cancer may be consid-
ered for home parenteral support (HPS) if they have When a malignant disease reaches a stage where curative
intestinal failure (IF) or significant nutrition deficiencies treatments are no longer available, or amenable, this is
from bowel obstruction (partial, intermittent or com- termed ‘incurable’ or ‘palliative’ cancer. The term palliative
plete), enterocutaneous fistula(s), a short bowel, dys- is not clearly defined in the medical literature, although ‘pal-
motility or severe mucosal disease (often following liative care’ is defined by the World Health Organisation
chemotherapy or radiotherapy). (WHO) as “the approach that improves the quality of life of
2. The patients with the best survival and quality of life on HPS patients and their families, facing the problems associated
are those with higher performance status and low serum with life-threatening illness, through the prevention and
markers of inflammation (C-reactive protein <10 mg/L and treatment of pain and other problems, physical, psychosocial
albumin >32 dg/L). and spiritual” [1]. For this reason the use of parenteral sup-
3. Some guidelines (e.g. ESPEN) suggest selecting patients port (PS) for patients with incurable cancers does not fully
with an expected prognosis of 2–3 months or greater but meet the definition for palliation, as one of its main aims is to
this is challenging in practice. also increase survival length.
4. All patients who may be considered for HPS should have In this chapter we will explore the effect on survival and
an early multidisciplinary team (MDT) review by the quality of life for patients with incurable cancer when treated
nutrition support team (NST), oncologists and palliative with PS and consider tools available to optimise patient
care teams. The desired aim(s) of starting PN and the selection. We will also consider the health economics of this
plans for withdrawal (either at the end of life, or any time treatment.
after commencing) should be discussed.
5. Patients who require HPS support for bowel obstruction
should be considered for a venting gastrostomy place- Cancer, Nutritional Status and Outcomes
ment (20F or larger) in order to palliate vomiting and, if
wanted, to allow eating and drinking of a limited diet. Involuntary weight loss is often present as a symptom of can-
Abdominal interventions do risk the tumour growing cer. Depending on the site of the cancer, between 31% and
along any medically or surgically created tract, although 87% of patients have involuntary weight loss [2–5]. In pan-
this is less clinically relevant in the palliative phase and creatic cancer, it has been shown that 85% of patients have
symptom control should take priority. weight loss at diagnosis, with 30% displaying severe weight
loss of greater than 10% in the preceding 6 months [2].
Weight loss correlates with stage of cancer, as well as the
clinical outcome [6]. Malnourished cancer patients have a
poorer response to medical oncology treatments [7–9]. There
is also evidence that malnutrition negatively influences
length of hospital stay, readmission rates, symptom burden
M. Naghibi (*)
and quality of life in cancer patients [10].
Department of Gastroenterology, St Mark’s Hospital, London, UK
e-mail: [email protected] The causes of weight loss in patients with cancer vary by
the primary site and metabolic activity of the tumour, but
F. Bozzetti
Faculty of Medicine, University of Medicine, Milan, Italy common themes are reduced intake through inflammatory

784 M. Naghibi and F. Bozzetti
and cytokine driven loss of appetite [11–13] or obstructed Cancer and Intestinal Failure
gastrointestinal tract, increased resting energy expenditure in
some cancers [14–16], insulin resistance leading to increased The cause of intestinal failure (IF) in patients with can-
gluconeogenesis [17] and lipolysis [18, 19]. cer is most commonly bowel obstruction (BO), followed
Cancer cachexia differs from simple starvation, as it by fistulation, short bowel resulting from surgery, infarc-
encompasses weight loss despite sufficient or excess supply tion or dysmotility. BO is estimated to occur in 10–28%
of nutrients, which can be via natural or artificial routes. of colorectal cancers and 5–50% of ovarian cancers
Cachexia is a complex multifactorial syndrome that leads to [27].
progressive functional impairment [20]. When IF occurs in the context of palliative cancer, life
The pathophysiology of cancer cachexia is characterised expectancy is dramatically reduced. Without parenteral sup-
by reduced food intake and abnormal metabolism. The hall- port the immediate cause of death would be dehydration
marks are anorexia, early satiety, weight loss, muscle wast- rather than tumour progression or, if hydration is maintained,
ing, anaemia and in the late stages, oedema. The definition of malnutrition. Commencement of burdensome PN would be
cachexia overlaps with other diagnosis such as sarcopenia neither ethical nor acceptable in most patients with incurable
and malnutrition, and can be distinguished from them by the cancer. The challenge is, therefore, to optimally select patients
presence of a disease process, which may be benign or with end stage cancer in whom the benefits outweigh the
malignant. drawbacks of treatment. However, the proportion of patients
The current understanding of cancer cachexia has led to suitable for HPS treatment in end stage cancer is still
its classification into pre-cachexia, cachexia and refractory unknown.
cachexia [20]. To combat the progression of cachexia early
supplementation of nutrition need to be combined with ther-
apies that can slow or stop the metabolic process contribut- Prevalence of HPS for Incurable Cancer
ing to its development. The term refractory cachexia is being
challenged, as multimodal treatments in cancer, including Table 1 summarises the published data for prevalence rates
nutritional supplementation, are showing reversal of cancer across the world for PN use in cancer patients. These data can
cachexia previously termed refractory. be challenging to evaluate and compare directly with each
Many cancers induce inflammation, causing peripheral other as the prevalence rates are expressed differently (i.e.
and centrally mediated catabolism and appetite suppression, period prevalence vs. point prevalence) and from varying time
with inverse correlation of survival length in those with periods. Nevertheless, despite these limitations, it is clear that
higher markers of inflammation [21]. A systematic review of the practice of HPS therapy for incurable malignancy is com-
the use of non-steroidal anti-inflammatory drugs (NSAIDs) mon in economically developed countries, but varies consider-
in cancer cachexia, identified 13 trials, of which 11 demon- ably, even between countries with comparable health
strating stabilisation in weight or lean body mass where systems.
NSAIDs were used, though the studies were small with risk In those countries with published data, the lowest appear
of false positives [22]. to be in the UK [28, 29] and highest in Italy and North
These findings suggest that we may be able to manipulate America [30, 31], with evidence of increasing prevalence in
the processes leading to weight loss associated with cancer, all reporting countries [31–33].
with potential for effective utilisation of nutrient intake to
positively influence clinical outcomes including response to
anti-cancer medical and surgical treatments. HPS in Incurable Cancer Patients
The ability to alter the type of nutrients supplied to cancer
patients may also play a role in improving utilisation of HPS is defined as ‘total’ when the intravenous administra-
energy. Waterhouse and Kemperman in 1969 [23] demon- tion of nutrients represents the exclusive (or the near-
strated that fat is metabolised more efficiently than carbohy- exclusive) way of feeding the patient. In cancer patients this
drates in cancer patients. The mechanism for this may be the happens most frequently due to gastrointestinal obstruction
increased inherent reliance on mobilisation of fatty acids, from the tumour or due to metastatic peritoneal invasion. In
from fat deposits, as the major source of energy in any semi- such cases the obstruction may be incomplete, where it
starved state. Further studies have also observed improved worsens when patient attempts to eat and is associated with
fat metabolism in cancer patients [14, 24, 25]. For example, early satiation, nausea, vomiting, abdominal distension and
lipid clearance, after intravenous administration of short pain.
chain and medium chain triglycerides, has been found to be In this context a randomised control trial (RCT) is con-
more effective in malignancy patients, compared to healthy sidered to be unethical. If the incurable cancer patient is
controls [26]. suitable for HPS therapy, randomising to non-HPS, when
Home Parenteral Support for Patients with Incurable Advance Cancer 785
Table 1 Prevalence of malignant conditions as indication for home parenteral nutrition

Number of Proportion of
Total HPS HPS patients HPS with Period or point prevalence
Study Country patients with cancer cancer (%) (years) Data source
Vafa et al., Belgium 125 60 48 Period prevalence Single academic centre
2010 [34] (1987–2007) database
Soo and Gramlich, Canada 158 38 48 Period prevalence (Jan–Dec North Alberta Home Total
2008 [31] 2006) Parenteral Nutrition program
database
Cozzaglio et al., Italy 125 75 43 Period prevalence Italian Home Parenteral
1997 [35] (1983–1990) Nutrition registry
Wanden Berghe Spain 148 29 20 Period prevalence (Dec Nutricion Artificial
et al., 2011 [33] 2009–Dec 2010) Domiciliaria y Ambulatoria
(NADYA) database
Gillanders et al., Australia and 124 19 15 Period prevalence (July Australian Society of
2011 [36] New Zealand 2010–July 2011) Parenteral and Enteral
Nutrition (AuSPEN)
database
Jirka et al., Czech 138 51 37 Period prevalence (2010) National Home Parenteral
2011 [37] republic Nutrition registry (Poster
abstract)
Takagi et al., Japan 231 93 40 Period prevalence up to National survey
1995 [38] 1990 (start not reported)
Baxter et al., Scotland 72 7 10 Period prevalence (Aug Managed Clinical Network
2003 [29] 2010–Aug 2011) Database
Smith et al., UK 523 42 8 Point prevalence 31/12/2010 British Artificial Nutrition
2011 [28] (Percentage of new Survey (BANS) database
registrations during
2010—14%)
Howard et al., USA 4520 2122 47 Period prevalence North American Home
1995 [39] (1985–1992) Parenteral Nutrition
database
the deleterious effects of a prolonged starvation in mal- Outcomes: Survival Length

nourished subjects are well known and as the benefits of
HPS have been demonstrated, would not be ethical. The The survival of ‘healthy’, non-cancer individuals undergoing
control group for such a study may be those who are hypo/ extreme starvation, but not dehydration, is approximately
aphagic due to incurable cancer, qualify for HPS, have been 2 months, as observed in the tragic events of the Leningrad
offered HPS, but have chosen, for personal reasons, to siege [44], Warsaw ghetto [45] and Irish hunger strike [46],
decline. This would allow for observational studies, but where the longest length of survival was 2.4 months
precludes randomisation. To date this group has not been (73 days). The longest length of survival of cancer patients
studied. undergoing a total or almost total nutrients deprivation is
HPS is ‘supplemental’ when the patient is able to main- similarly reported to be approximately 2 months in hospital-
tain a limited oral intake of nutrients, and the PN is given in ized patients [47] and only 17–29 days in patients followed
parallel to meet requirements. In cancer patients this occurs at home [48, 49], though the survival is often shorter due to
secondary to low grade gastrointestinal obstruction, severe predisposing weight loss even before the onset of bowel
uncontrolled anorexia, or due to high stoma or fistula obstruction. Since the 1990s International Consensus [50]
output. has existed to support the use of HPS in advanced hypo/
In 5–23% of cancer patients the main cause of death has aphagic cancer patients if the expected survival due to the
been reported as cachexia [40–43] and weight loss of cancer cancer is approximately greater than 2 months, in combina-
patients is proportional to the severity of anorexia or to the tion with other favourable factors outlined in Table 2.
reduction of nutrients’ intake or to the persistence of a nega- Most of the studies on HPS in advanced cancer patients
tive energy balance. There is now a growing bulk of evi- are retrospective, with small case series leading to inherent
dence showing that a PN support for incurable cancer limitations that come from small patient numbers, with wide
patients can improve survival and is able to improve not confidence intervals that lead to data which is not clinically
only the body weight but also the lean tissues. reliable. Naghibi et al. (2014) systematically reviewed these
Table 2 American and European guidelines regarding parenteral nutri-

tion therapy in palliative malignancy
American Society of Enteral and Parenteral Nutrition (2009)
[51]
1. Must be physically and emotionally capable of participating in
their own care
2. Should have estimated life expectancy of >40–60 days
3. Require strong social and financial support, including a
dedicated in home lay carer
4. Must have failed trials of less invasive medical therapies such as
appetite stimulants and enteral feeding
European Society of Enteral and Parenteral Nutrition (European
Society of Clinical Nutrition and Metabolism) (2009)a [10]
In intestinal failure and incurable malignancy, long-term PN should
be offered, if:
1. enteral nutrition is insufficient Fig. 2 Kaplan Meier survival curves, based performance status (mea-
2. expected survival due to tumour progression is longer than sured by Karnofsky performance score) (p = 0.01)
2–3 months
3. it is expected that PN can stabilise/improve performance status
and quality of life
4. the patient desires this mode of nutritional support 4.7 months and 3.0 months mean and median survival,
There is probable benefit in supporting incurable cancer patients respectively [54].
with weight loss and reduced nutrient intake with “supplemental”
These studies have lead to two main considerations: first,
PN
if we accept a threshold of 3 months as the longest potential
Updated in 2016 with further narrative guidance
a
survival in patients undergoing total starvation, HPS will
prolong survival in over half of patients (though likely to be
a higher proportion); second, while this patient population is
heterogeneous and several factors can finally affect the
length of survival, large multi-centred and international ret-
rospective and prospective studies have resulted in similar
survival lengths.
Quality of Life and Body Composition
Data on quality of life (QOL) for incurable cancer patients

treated with HPS are scanty and difficult to interpret. QOL
can only be assessed by the person who is experiencing the
factors studied, hence, retrospective studies of QOL scores
completed by clinicians or family members are not validated
methods, which currently make up the majority of the data in
Fig. 1 Proportion of patients alive at monthly intervals during the first
6 months, with corresponding 95% confidence intervals (n = 244)
this field.
A prospective QOL study by August et al. (1991) reported
that in 14 patients (82%) both patients and their families per-
studies and applied random effects modelling to meta- ceived their therapy as beneficial or highly beneficial [55].
analyse the data, incorporating 12 studies and 244 patients in Their Nutritional Support Team agreed with this assessment
the final meta-analysis of survival length (Fig. 1) [52]. This in 11 patients, but did not share this perception in three
demonstrated 3.9 months and 2.8 months mean and median patients. These three patients had a short duration of HPS
survival, respectively. In this systematic review it was also (less than 25 days) or minimal rehabilitation.
demonstrated that higher performance status at baseline of In another prospective study [45] investigating the QOL
HPS therapy for advanced cancer patients is predictive of in 69 incurable cancer patients using the validated cancer
longer survival (Fig. 2). QOL tool, Rotterdam Symptom Checklist questionnaire,
Only a few studies in this patient group have been carried variables were collected at the start of HPS and then at
out prospectively [45, 53, 54]. The largest prospective study monthly intervals. Results showed a median survival of
is by Bozzetti et al. (2014) on 414 incurable cancer patients 4 months (range 1–14) and QOL parameters remained
treated with HPS, reporting a comparable survival length of approximately stable till 2 months before death.
Table 3 Prospective studies on the effects of HPS on QoL measured through validated scores in malnourished advanced cancer patients on
chemotherapy
Author #PTS Mode of sHPS Methods Results Comments
Finocchiaro 70 27 Kcal + 1.1 gAA/kg/d TIQ at >2 months QoL: =48%, ↑31.5%, Evaluated 27 patients
2002 [58] ↓20.5%
Culine 2014 437 Usually overnight FACT-G day 1–28 ↑ Physical, functional, Responsiveness to therapy may
[61] 26 Kcal + 1.1 gAA/kg/d emotional, familial/social affect QoL
status
Seys 2014 221 Overnight FACT-G day 1–28 ↑BW and global QoL in 68% Regimen of NPS ill-defined; No
[57] and 59% of pts. (and statistical analysis;
sub-score physical, Responsiveness to therapy may
functional and emotional) affect QoL
Vashi 2014 52 Cyclic, total oral + PN Kcal EORTIC QLQ-C30 ↑Global QoL index at 1–3 Small sample, loss of patients;
[60] and AA: 25–30 and 2 g/ mos Responsiveness to therapy may
kg/d affect QoL; Assessment of
requirements unpractical
Girke 2016 23 – EORTIC-QOL-C30 ↑Emotional/social domains Nutritional regimen not assessed;
[59] day 1–28 = muscle strength, physical Large drop out of patients
activity, BMI
↓ phase angle
Cotogni 2017 111 21 Kcal + 0.8 g AA/Kg/d EORTIC QLQ-C30 ↑Global QoL, physical High attrition rate due to death
[63] monthly for functioning, role functioning, 49/111 completed at 4 months
1–4 months emotional functioning,
appetite loss and fatigue
scores
Obling 2017 47 Overnight, 2–4 times/week, Bioelectrical ↑ at 3 months of FFM and Loss of patients during the study
[62] random 10 Kcal + 0.5gAA/ impedance analysis overall QoL
HPS VS Kg/d × 3 months and EORTIC
QLQ-C30
These studies are also in keeping with QOL assessed by Table 4 Karnofsky performance status
Orrevall et al. [56], where structured interviews were carried Score,
out with incurable cancer patients and their family members. % State of health
This study reports both positive and negative aspects. The 100 Healthy, no symptoms or signs of disease
positive aspects were centred around the sense of relief and 90 Capable of normal activity, few symptoms or signs of
security in both patients and relatives because the nutritional disease
SO Normal activity with some difficulty, some symptoms or
needs were being met through HPS. The burden of treatment signs
did have reported negative effects on the patient and family 70 Caring for self, not capable of normal activity or work
social life, but the salient summary was of positive effects 60 Requiring some help, can take care of most personal
out weighing the negative. requirements
Given HPS in context of incurable cancer is often for a 50 Requires help often, requires frequent medical care
short period of time, this leads to few patients and/or family 40 Disabled, requires special care and help
30 Severely disabled, hospital admission indicated but no risk
members fully training in the care of HPS. Hence, HPS treat- of death
ment is accompanied by up to twice daily visits by trained 20 Very ill, urgently requiring admission, requires supportive
nurses, who often give emotional support and security to measures or treatment
patients in addition to the technical procedures that they
carry out. The security felt by patients and family members
on HPS may be, in part, be related to this close relationship Patient Selection
with a health professional.
As regards the QOL of patients receiving supplemental In the above mentioned international prospective study by
parenteral nutrition, multiple studies [57–61], using vali- Bozzetti et al. (2014) three prognostic factors for survival at
dated methods (Therapy Impact Questionnaire, Fact-G, the multivariable analysis were identified [54]; performance
EORTC-QOL-C30) have also reported an improvement in status, as measured by Karnofsky performance Status
quality of life (summarised in Table 3). These findings were (Table 4), Glasgow Prognostic Score and presence of tumour
also observed in the RCT by Obling et al. which found that metastasis. The prognostic value of these variables coupled
PN also increased fat-free mass [62]. with type of primary tumour, was subsequently validated on
Fig. 3 Cox model based 0 10 20 30 40 50 60 70 80 90 100

Points
nomogram for predicting 3-, N.A. 2
Glasgow prognostic score
6-month and median length of 0 Yes 1
survival. Score are added up Metastases if Site = Ovary Yes
if Site = GI No
for each patient factor and the No
Yes
total points correspond to if Site = Other
No N.A.
survival estimates at the Karnofsky performance status
>50 <=50
bottom of the figure Total points
0 20 40 60 80 100 120 140 160 180 280 220 240 260 280
Median survival time
9 8 7 6 5 4 3 2
3-month survival probability
0.6 0.7 0.6 0.5 0.4 0.3 0.2 0.1
6-month survival probability
0.6 0.55 0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05
a separate series of patients [64] and led to the construction given more information [65–68]. A survey of over 2000
of a prognostic nomogram (Fig. 3). patients with metastatic cancer, carried out in Italy in 1999,
It is worth noting that a sub-analysis of patients with so- found that 39% believed it to be ‘difficult to cure’ and 47%
called ‘refractory’ cachexia according to an International considered their disease ‘severe’ [69]. In Spain only 12% of
Consensus [20], showed a 3- and 6-month survival of 29.4% patients with a terminal diagnosis knew about their short-
and 8.4%. These figures were 31.7% and 12.2% for patients term prognosis [70]. More recent studies suggest there is evi-
without vital organ involvement, 27.1% and 5.9% for those dence that these practices and attitude have changed
with vital organ involvement. These figures would suggest significantly. In a multicentred Italian study, Costantini et al.
such patients can still benefit from HPS therapy, and we [71], reported that 87% of patients were aware of their can-
would advise multidisciplinary team assessment of perfor- cer diagnosis, although 49% of those with metastatic cancer
mance status as the most predictive of favourable outcome were of the opinion that they have curable disease.
for these patients. Family members may sometimes be responsible for the
In these incurable patients HPS was generally withdrawn patient’s ignorance regarding their diagnosis and prognosis.
a few days before death. In one third the main reasons for In some cultures, those surveyed (73%–84%), reported a
stopping HPS treatment was tumour progression (73%), wish not inform the patients in a straightforward manner
patient choice (20%) and HPS central venous catheter com- about the state of disease advancement [65, 70].
plications (CVC) was the least common cause (6%). The The Council of Europe (European Treaty Series, Chapter
cause of death was vital organs failure (46%), progressive III, Article 10, Convention for the Protection of Human
wasting (34%) and HPS CVC complications (1%) and Rights and Dignity of the Human Being with regard to the
unknown in the remaining patients. Application of Biology and Medicine) came into force on 1st
December 1999, states that ‘everyone is entitled to know any
information collected about his or her health. However, the
Ethical Considerations wish of an individual not to be so informed shall be observed.’
One third of physicians in Europe, questionnaire at the turn
Both the decision to commence HPS, as well as to withdraw of the millennium, believed that patients never want to know
it, should directly involve the patient, which requires the the truth [65], while an equal percentage believe that
patients be aware of their diagnosis and their prognosis to informed consent is necessary to respect patient autonomy
express informed consent. However, the conveyance of the [72].
information can be challenging and there are considerable While adequate information should always be given to
variations between countries, within countries, cultures and patients when actively or implicitly requested, there is much
health systems. There has been a trend for increased direct uncertainty about the true comprehension of the communica-
involvement of the patient over the last few decades, with tion. Indeed, the ability of the patient to actively negotiate in
evidence that a greater proportion of patient would welcome a decision with the caregiver requires four intact cognitive
this information. Clinical experience suggests the presence functions: (1) the ability to clearly understand the informa-
of a multidisciplinary team, involving palliative care practi- tion relevant to the decision; (2) the ability to fully appreciate
tioners to fully explore the alternatives of not accepting this the situation and the consequences of alternatives approaches;
high burden treatment to be highly valuable. (3) the ability to elaborate and weigh the information ratio-
In the 1990s, in Southern Europe, only 25–38% of patients nally in the context of a coherent set of values and goals, and
were aware of their cancer diagnosis at an advanced stage (4) finally, the ability to communicate or transfer choices to
and studies suggested less than half of these wanted to be the physician regarding care.
A self-report survey measuring ‘desire for death’ distrib- Health Economics

uted to 92 incurable cancer patients with a life-expectancy of
less than six months demonstrated substantial fluctuations in The costs of medical therapies are relevant when considered
this score over time, within various intervals of time (hours in the context of a health economy with limited financial
to 1 month) [73]. Therefore, the assessment of a patient’s resources. When comparing the cost of treatments, the abso-
will to live (and consequently to accept a HPS program lute costs may be misleading because of the variable impact
which primarily aims to prevent an early death from starva- of treatments on survival length and QOL. Incremental cost
tion) may be repeated several times during the assessment effectiveness ratio (ICER) is currently the most prevalent
and only if the answers are consistent should this informa- measure of the cost of a treatment per quality adjusted life
tion be utilised to determine whether to initiate or withdraw year, allowing for direct comparison of a wide variety of
a life-sustaining treatment. treatment with variable impacts.
It is noteworthy that a study carried out in a Canadian In addition to allowing comparison of different treat-
palliative care centre in the mid-1990s reported the pres- ments, ICERs also allow for thresholds to be set when treat-
ence of cognitive deficit in 44% of patients at the moment ments are assessed for economically viability. While there is
of hospitalization and in 55% at time of death or upon hos- debate about the existence of a fixed ICER thresholds used
pital discharge [74]. Asking for informed consent by antic- by the National Institute of Clinical Excellence (NICE) in
ipating some situations before they occur is also fraught England and Wales, there is evidence that £30,000/QALY is
with difficulties. Coppola et al. (1999) have shown in 2536 often used as a cut off threshold [78, 79]. It has been demon-
patients that there was no constancy in the choices of pref- strated that treatments associated with ICER over £30,000/
erences regarding life-saving treatments expressed in QALY only have an 8% probability of approval [80].
advance, both verbally and in writing [75]. Specifically, Comparable thresholds are used in several other countries,
the desire to undergo artificial nutrition as a life-sustaining but controversy exists about the threshold that should be
procedure ranged from a very low percentage of subjects used, for example, in the Netherlands a threshold of up to
by Coppola et al. (1999) to about 70% of patients by Euros 80,000/QALY has been proposed according to sever-
Pearlman et al. (2000) [75, 76]. Many factors would con- ity of disease [81].
tribute to this variability; the context, manor of communi- In health systems where thresholds are used, when the
cation, symptom burden, chance of treatment success ICER for a desired treatment is above the threshold, the justi-
conveyed and cultural/religious background of the patient, fication for that treatment needs to be strong, with increasing
clinicians attitude and background society will have vary- justification needed with higher ICERs. In an example only
ing effects. directly relevant to England and Wales, criteria have been set
A survey of the UK based intestinal failure clinicians in by NICE for appraisal of ‘end of life’ treatments that exceed
2013 [77], showed that clinicians would support HPS for £30,000/QALY. These are: a limited number of patients
incurable cancer more often for improvement of QOL rather expected to require the treatment, the treatment should be
than increased survival time alone. While the attitude of expected to extend life by greater than three months, the
intestinal failure clinicians influences the treatment advanced extended survival length is experienced at a QoL anticipated
cancer patients receive, the attitude of oncologists, gastroin- for a healthy individual at a similar age and health economic
testinal surgeons, gynaecologists, palliative care teams and assessment models would need to be carried out.
other clinicians who meet incurable cancer patients is also The only detailed analysis of the health economics of
paramount to referring patients to intestinal failure services, benign indication HPS was carried out in the UK in the study
and this is, as yet, unstudied. of Richards and Irving in 1996 [82] and did not include any
Withdrawing of HPS can be a difficult task and should be patients with incurable cancer. In their model they calculated
discussed with the patient and relatives prior to the start of the absolute cost of HPS over the first year to be £44,288
HPS. Should the patient’s condition change causing a dete- with a corresponding ICER of £85,825/QALY. The ICER
rioration of general status the composition and frequency of value reduced to £68,975/QALY after 4 years due to the
PN may change or treatment withdrawn. Reassurance should health economic concept of ‘discounting’ with longer sur-
be given that this joint decision will be taken with the direct vival (initial set up cost only needed once, QOL slowly
involvement of the patient and family with the multidisci- improves in conditions such as inflammatory bowel disease
plinary team. HPS complications such as medically resistant and short bowel on commencing HPS, thereby the ICER is
ascites or pleural effusions, central line blood stream infec- reduced over time).
tions and thrombosis related to the HPS therapy should also The health economic assessment of HPS treatment for
trigger treatment cessation discussions. incurable cancer in the UK was carried out in 2013 [52]
showing the ICER for this circumstance is higher at 6. Bozzetti F, Migliavacca S, Scotti A, Bonalumi MG, Scarpa D,
Baticci F, et al. Impact of cancer, type, site, stage and treatment
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on the nutritional status of patients. Ann Surg. 1982;196(2):170–9.
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would need to be taken into account. With uplifting to 2013 8. Tubiana M, Attié E, Flamant R, Gérard-Marchant R, Hayat
M. Prognostic factors in 454 cases of Hodgkin’s disease. Cancer
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14. Fredrix EWHM, Soeters PB, Wouters EFM, Deerenberg IM, Von
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Monitoring of Parenteral Nutrition
at Home
N. M. Clermont Dejean, N. Somlaw, D. Brundrett,

and J. P. Allard
Key Points 5. If the CRP is raised (>25 mg/l), transferrin saturation is

1. The haematological and biochemical monitoring of used as a measure of iron status. In the presence of sepsis
patients receiving parenteral nutrition at home should be or inflammation, do not measure zinc, copper, selenium
individualised and may change with their clinical or vitamins A, D or E.
condition. 6. Urine sodium concentration is useful for assessing
2. Routine blood tests include sodium, potassium, chloride, sodium balance in patients with a jejunostomy and a
bicarbonate (as a measure of acid-base balance), calcium, 24-hour urinary oxalate collection for assessing the risk
magnesium, phosphate, urea or blood urea nitrogen of renal stone formation in patients with a short bowel
(BUN) /glomerular filtration rate (GFR), creatinine, liver and colon in continuity.
function tests (albumin, bilirubin alanine transaminase
(ALT), aspartate tranaminase (AST), alkaline phospha-
tase, gamma glutamyl tranferase (GGT), international
normalised ratio (INR)), glucose, blood count, ferritin Introduction
and C reactive protein (CRP)) and are performed every
1–4 months depending upon the stability of the patient. Home parenteral nutrition (HPN) is a life-saving treatment
3. At discharge from hospital patients should have their pro- that allows patients with intestinal failure to return in the
thrombin time (INR), cholesterol and triglyceride, community while receiving appropriate nutrition. Monitoring
Haemoglobin A1c, vitamin D & B12 and folate concentra- HPN is important for multiple reasons. It ensures that treat-
tions checked. These are rechecked every 6–12 months. If the ment goals are met, it helps to prevent, recognise and treat
triglyceride concentration is elevated a fasting level is taken. complications arising from HPN, it allows an audit of out-
4. Baseline vitamins A&E, zinc, copper, manganese and comes and more importantly it secures and improves patient’s
selenium concentrations are checked initially then every quality of life.
6–12 months.
Guidelines and Studies on Monitoring

N. M. C. Dejean
Department of Gastroenterology, Hull Hospital,
A series of guidelines (1–7) have been published and cover
Gatineau, QC, Canada
the topic of monitoring patients on HPN. Most of them rec-
N. Somlaw
ommend that a multidisciplinary team with experience with
Department of Medicine, Chulalongkorn University and King
Chulalongkorn Memorial Hospital, The Thai Red Cross Society, HPN be responsible for the monitoring and that patient care
Bangkok, Thailand be assigned to a particular person in the group. The core
D. Brundrett members of the team include a gastroenterologist, a surgeon,
St Marks Hospital, Harrow, UK specialist nursing, dietitians and pharmacists. The guidelines
e-mail: [email protected] also emphasize the fact that monitoring should be guided by
J. P. Allard (*) outcomes that will have been set with the patient prior to
Department of Medicine, Toronto General Hospital, University initiation of the treatment. In addition to these goals, impact
Health Network, Toronto, ON, Canada
on quality of life, morbidity, anthropometric measures and
Department of Medicine, University of Toronto, incidence of complications related to HPN should be consid-
Toronto, ON, Canada
ered. A study by Dreesen (8) conducted in an international

794 N. M. C. Dejean et al.
cohort of 300 HPN patients, all with benign disease, showed own local guidelines. The interval for clinical assessment of
that the most important outcome indicators for patients were patients ranged from 1 to 6 months with more than half the
incidence of catheter related infection, survival and quality centers reporting a range of 2–3 months. At each visit body
of life. weight and anthropometry were monitored in all centers.
The monitoring regimens found in the major international Less than half took blood pressure and pulse at every visit;
guidelines (1–6) propose different frequency and timing of 88% of centers evaluated the state of hydration and 74%
monitoring based on the consensus reached by their authors. inquired about oral intake. 86% checked the mood of their
None of these guidelines are based on randomized controlled patients at every monitoring visit.
trials and a study has yet to show the impact of the different For laboratory tests, between 95 and 81% of centers mea-
regimens on patient outcome. sured haematology, biochemistry for liver function, creati-
The current literature (1–6) outlines a similar biochemical nine, electrolytes, magnesium, calcium, phosphate and
monitoring between articles which includes extended elec- glucose at every visit. 48% of centers also monitored triglyc-
trolytes (sodium, potassium, chloride, phosphate, magne- erides, cholesterol and albumin. Trace elements and analysis
sium, calcium), glucose, HbA1C, liver function test (albumin, of vitamins and folic acid took place at every visit in 19%
bilirubin, aspartate aminotransferase(ALT), alanine amino- and 14% of centers respectively. Other centers also moni-
transferase (ATL), alkaline phosphatase (ALP), gamma- tored these variables regularly but not at every visit. In some
glutamyltransferase (GGT) and International Normalized cases it was only done if a problem arose. More than 60% of
Ratio (INR)), renal function test (creatinine, glomerular fil- the centers requested BMD once or twice a year and quality
tration rate (GFR), urea, bicarbonate), complete blood count, of life was assessed in 10 of the 42 centers; 6 of which used
trace elements (zinc, copper, manganese, selenium), iron, the SF 36 questionnaire. The other 4 had their own local
ferritin, folate, lipid panel (triglycerides, cholesterol), vita- questionnaire. In case of complications, patients contacted
mins (vitamin A, B12, D, E) and Dual-energy X-ray absorp- the HPN in 76% of centers and if admission was needed it
tiometry bone scan (DEXA) and C-reactive protein (CRP). was arranged in the HPN-teaching hospital in 95% of cases.
Regular clinical assessments are also recommended with When distance was an issue patients were directed to the
monitoring of anthropometric measures including weight, local hospital. In Scotland, the HPN managed clinical net-
height, mid upper arm circumference, triceps skinfold mea- work studied the frequency and adequacy of monitoring in
surement, mid arm muscle circumference and grip strength. their patient group with their results indicating that length of
Evaluation of fluid status, oral intake, mood and quality of time on HPN was found to be inversely associated with fre-
life are recommended to be part of the assessment. quency of monitoring without an increase in complication
Interestingly, in a study conducted by Smith et al. in 2002 rates (11).
(9), affiliation with organizations that provide patient sup-
port and education was a factor that improved HPN patients’
outcomes by improving the quality of life index, lowering Core Monitoring
depression scores and decreasing the cumulative incidence
of catheter-related bloodstream infections over 18 months. Hospital patients need to be metabolically stable on a paren-
The authors suggested that contact between these organiza- teral nutrition prescription before being discharged home.
tions and patients be facilitated by the HPN programs. Based on the previously mentioned literature and clinical
When comparing clinical practice to guideline recom- experience, core monitoring for HPN patients is summarized
mendations, Wengler et al. found in 2005 that of 42 studied in Tables 1 and 2.
European centers, most varied from the recommendations After discharging a new HPN patient initially, blood work
found in the literature (10). 92% of the centers had a multi- should be considered every 1–2 weeks for the first 2 months.
disciplinary HPN team and in most of these centers the main If stability is achieved, the interval can be lengthened to
responsibility for monitoring a patient was assigned to one monthly for 3 months and then every 3 months (see details in
member of the team. After hospital discharge, 81% of cen- Table 1). Assessment of trace element and vitamin status
tres continued to monitor patients’ skills for HPN adminis- should be done annually in the stable patient and more fre-
tration, with 31 centers organizing home visits carried out quently in situations that require closer monitoring such as in
either by the HPN team, a home care agency, a community severe malnutrition or increased losses, when deficiencies or
nurse or a general practitioner. After more than 1 year of toxic levels are suspected or when a deficiency or toxicity
HPN, stable patients continued to be monitored by the dis- has been diagnosed and is being treated. Clinical interpreta-
charging hospital in 73% of centers, a local hospital in 12% tion of plasma vitamin and trace element results can only be
and a general practitioner in 11%. done with knowledge of the patients CRP level. The effects
From this report (10), 28 centers had written guidelines of the acute phase response on micronutrient levels have
for monitoring practices and 23 of those had developed their been well described by Duncan et al. (12). In patients at risk
Monitoring of Parenteral Nutrition at Home 795
Table 1 Suggested laboratory monitoring practice for stable Home of oxaluria and kidney stone such as those who have steator-
Parenteral patients
rhea and colon in continuity, 24-hour urine oxalate should be
Monthly for Every monitored every 3–6 months initially, and then yearly, while
Baseline 3 months 3 months Yearly
on a low oxalate diet (see chapter “Nephrolithiasis and
Electrolytes X X X –
Glucose X X X –
Nephrocalcinosis”). Bone density should be assessed at
Liver function test X X X – baseline and yearly thereafter (see chapter “Bone and Joint
Albumin X X X – Disease”).
INR X X – Clinic visit should be organized within the first 3 months
Renal function test X X X – after discharge. After this initial assessment, future appoint-
Complete blood X X X – ment schedule will depend on the stability of the patient. The
count
intervals should range between 3–6 months and eventually
Lipid panel X – X –
Iron and ferritin X – – X yearly. If a patient lives far from the center responsible for
Vitamin D 25-OH X – – X monitoring it is possible to rely on technology with the use
and PTH of tele-health for clinical assessments (13). Evaluation of
Vitamin A, E, C X – – X quality of life should also be done yearly with a validated
Vitamin B12 and X – – X tool (see chapter “Home Parenteral Nutrition for Adults”). At
folate
every clinic visit, weight, anthropometric measures, oral
Trace elements X – – X
DEXA scan X – – X intake, fluid status, central line patency, medications, physi-
24 hr. urine X – – X cal signs of nutritional deficiency, the need for continuation
collection for of HPN as well as the symptoms linked to the underlying
oxalate disease which led to the need for HPN should be assessed
Suggested core monitoring based on clinical experience and current (Table 2).
guidelines (1–6)
Electrolytes include sodium, potassium, chloride, magnesium, phos-
phate, calcium. Liver function test include aspartate aminotransferase
(ALT), alanine aminotransferase (ATL), alkaline phosphatase (ALP), Monitoring of Complications Related to HPN
bilirubin. INR = International Normalized Ratio. Renal function test
include creatinine, GFR, BUN. Lipid panel includes triglycerides and
Besides metabolic complications associated with the admin-
cholesterol. Trace Elements include zinc, copper, manganese, selenium
and chromium. DEXA = Dual-energy X-ray absorptiometry bone scan istration of parenteral nutrition (PN), long term HPN support
is associated with central venous catheter complications,
parenteral nutrition associated liver disease, and bone dis-
Table 2 Suggested clinical monitoring for Home Parenteral patients ease. Close monitoring of HPN patients as recommended
Between 1 and Every above may reduce this risk. In addition, patients should be
3 months after 3–6 provided with information regarding these complications
Baseline dischargea monthsa Yearlya and how to monitor themselves at home.
Anthropometry X X X X
Calculation of X X X X
nutritional
requirements Monitoring of Blood Glucose
Vital signs X X X X
Physical X X X X Self-monitoring of blood sugar at home is not a routine prac-
examination tice in non-diabetic patients whose blood glucose is well
Fluid balance and X X X X
evaluation of fluid
controlled before hospital discharge if there is no difference
status between inpatient and home regimen. However, if there is a
Oral intake X X X X significant change in the amount of glucose infused and/or
Mood X X X X cyclic infusion occurs at home or patient relies on PN as the
Quality of life X – X – sole source of carbohydrate (e.g. ultra-short bowel), then
CVC examination X X X X blood glucose should be monitored 4–6 hourly (14, 15) to
Suggested clinical monitoring based on clinical experience and current assess risks of hyperglycemia and/or rebound hypoglycemia
guidelines (1–6)
Anthropometry includes weight, height and body mass index calcula- (16). If these occur, reducing infusion rate by half in the first
tion. Evaluation of quality of life should be done with recognized and 2 h of infusion and the last 2 h of infusion as well as a dia-
validated tools (see chapter “Home Parenteral Nutrition for Adults”). betic team review should be considered. Monitoring of blood
CVC central venous catheter glucose in non-diabetic patient can be discontinued when the
a
Evaluation done in person during clinic or with telehealth
results show consistently normal levels although it is impor-
tant to be aware that previously stable patients may go on to
develop hyperglycaemia (17). On the contrary, in diabetic investigated with blood cultures to eliminate a central venous
patients who require either intravenous insulin in PN or sub- line infection and an abdominal ultrasound to assess for hep-
cutaneous insulin injection, the monitoring is indefinite, but atobiliary complications, depending on the clinical
frequencies and subsequent managements should be based situation.
on clinical judgement. For more details on diagnosis and management of hepato-
biliary complications please refer to chapter “Intestinal
Failure Associated Liver Disease”.
Monitoring for Catheter Infections
Catheter related blood stream infection (CRBSI) is one of Metabolic Bone Disease Monitoring
the most serious complications in patients receiving
PN. Signs and symptoms of this infection include fever, Long-term HPN increases the risk of bone loss on top of pre-
chills, hypotension, elevated white count, and, sometimes, existing individual’s risk factors (e.g. lack of exercise, post-
elevated liver function tests. There are also other catheter menopausal, etc.). Factors associated with intestinal failure
related infections with fewer systemic symptoms, which can and HPN are multiple and include suboptimal vitamin D lev-
eventually progress to blood stream infection. Exit site infec- els and low calcium absorption or intake, high amino-acid
tion is commonly detected by redness and purulent discharge load, electrolyte imbalance, aluminum contamination, and
at the exit site of the catheter. Tunnel infection usually pres- cyclic infusion (21, 22). The prevalence of vitamin D insuf-
ent with redness and tenderness along subcutaneous tract of ficiency and deficiency is well documented in patients on
tunnelled catheter. Tenderness, induration and/or necrosis of home parenteral nutrition, even in those receiving additional
skin overlying the implanted device are presented in pocket oral and IV supplementation (23, 24). Thus, annual or bi-
infection (18). HPN patients and their carers must be edu- annual bone mineral density testing (DEXA Scanning)
cated to identify the potential signs of a CRBSI, an exit site should be considered and PN modification, high dose vita-
infection or a tunnel infection and know the importance of min D supplementation and other managements should be
seeking medical advice should symptoms occur. If a blood addressed accordingly.
stream infection is suspected, blood cultures from both cath- For more details on diagnosis and management of meta-
eter and peripheral vein should be obtained immediately. bolic bone disease please refer to chapter “Bone and Joint
Although the current clinical guideline for catheter related Disease”.
infection does not define how to manage PN in this situation,
it is recommended to temporarily discontinue PN when
CRBSI is suspected or confirmed, and administered broad Weaning off Parenteral Nutrition
spectrum antibiotics (14). The practice of withholding PN is
based on one study showing that continuing PN after a posi- The fate of the intestinal failure patients is determined by
tive blood culture resulted in longer hospitalization (19). types (acute, prolonged acute, or chronic) and aetiologies
For more details on diagnosis and management of cathe- (short bowel, dysmotility, fistula, mechanical obstruction,
ter complications please refer to chapter “Prevention, mucosal disease, etc.) and treatments of each individual. In
Diagnosis and Management of Catheter-Related Blood general, it is widely accepted that intestinal adaptation in sur-
Stream Infections”. gical short bowel syndrome reaches maximum extent within
2 years after the last bowel resection in adult. Prior to the era
of novel growth factor therapies, if elimination of PN is not
Monitoring for Hepatobiliary Complications accomplished in the first 2 years, the probability of perma-
nent PN requirement is 94% (25). Several factors influence
Long-term HPN may result in intestinal failure-associated the success of PN weaning in this group of patients. Length
liver disease, also known as PN-associated liver disease of remaining small bowel, the presence of colon and ileoce-
(PNALD). The clinical presentation of PNALD varies from cal valve in short bowel play important roles in weaning of
asymptomatic transient elevated liver function tests that PN because of the impact on nutrients and fluid absorption.
improve with modifying PN prescription (e.g. reduction in Residual disease in the remaining small bowel also deter-
total parenteral glucose or lipid energy, or a change in lipid mines the outcome of weaning in patients with inflammatory
emulsion), to cirrhosis (20). Thus, as recommended in bowel disease and radiation enteritis. Other factors that may
Table 1, it is necessary to have serial measurement of liver be associated with the success of PN weaning include use of
function tests in every patient on PN to monitor and detect novel medications (Glucagon-like peptide-2 agonist (GLP-2
early, any elevations in liver enzymes or bilirubin. Patients agonist), recombinant human growth hormone), age of the
who have sudden or persisting elevations should be further patient, duration of time on PN, and nutritional status prior to
Monitoring of Parenteral Nutrition at Home 797
weaning (26, 27). Weaning will also be more rapid if growth An optimal interval for making PN reduction decision
factors are used (e.g. GLP2-agonist), requiring closer moni- should be also individualized and based on feasibility of
toring, initially on a weekly basis until patients are more monitoring and PN modification by PN team. Once a week
stable in their weight gain and hydration status. Individualized reduction is possible but need close monitoring especially
plans to reduce or stop PN should be established in all from hydration perspective. During the process of weaning,
patients except for those with a predicted short term survival, patient should be monitored, as mentioned above, to ensure
such as intestinal failure from inoperable malignant bowel adequate nutrition and hydration on weekly basis until sta-
obstruction, and patients with ultra-short bowel syndrome. ble. This interval of laboratories monitoring should be based
The aim is to provide the minimum amount of parenteral on reduction regimen. Besides modification of calories and
support to maintain an acceptable nutritional status and pre- fluid in PN solution, electrolytes especially magnesium,
vent dehydration. potassium, and phosphate should be of concern. Anti-
Transition from PN support to oral and/or enteral nutri- diarrheal medications and oral vitamins plus trace elements
tion requires the effort from both patient and multidisci- should be adjusted and serum levels of trace elements and
plinary team. Patient’ motivation and compliance should be vitamins closely monitored. 1–6 mg intramuscular or subcu-
assessed. General education about their underlying diseases, taneous vitamin B12 supplement is required in patients with
physiological changes of remaining small bowel, as well as, history of gastrectomy or distal ileal removal when multivi-
dietary and pharmacological therapies should be reinforced. tamins is discontinued together with PN (in UK 1 mg
Furthermore, patients have to understand that the process of hydroxocobalamin is given intramuscularly every 3 months).
PN weaning generally requires life style modifications which Some patients will maintain weight with withdrawal of par-
include increasing daily oral food intake, modification of enteral macronutrients but overtime may develop micronu-
daily fluid intake, taking more supplements and medications, trient deficiencies despite oral micronutrient supplementation
and switching some intravenous medications to other and will need an ongoing plan to support their micronutrient
formulations. status parenterally.
Optimization of diet, fluid intake, and medications is nec- A trial of PN discontinuation is considered when PN infu-
essary and should be achieved before weaning of sion has gradually been reduced to 3 days or less per week.
PN. Clinicians in PN team should establish caloric require- Weaning of PN is not equal to elimination of all parenteral
ment of individual patients based on their resting energy support. Some patients with a high stomal output require
expenditure, activity factor and malabsorption factor. Serial intravenous hydration to prevent fluid and electrolyte imbal-
measurements of body weight and actual caloric intake by ances when PN is reduced or terminated.
food diary or food recall should be assessed to confirm if
nutritional status is optimized. Adequacy of hydration can be
addressed by fluid intake and output records. A pragmatic Conclusion
approach to monitor hydration in clinical setting is daily
urine more than 1 L. However, if urine output is not easily Monitoring of HPN patients is extremely important in order
measured, urine sodium >20 mmol/L and serial measure- to maximize the benefits of receiving HPN while reducing
ments of blood urea nitrogen (BUN), serum creatinine and complications. This requires a multidisciplinary PN team
electrolytes are also useful. Enteral balance (oral fluid intake that has the expertise and experience in following these
minus stool output) more than 500 mL per days is suggested patients as well as protocols to monitor and avoid or treat
by the expert (26), however, it is not a good parameter in promptly any complications. Weaning should be attempted
short bowel with high ostomy output. in most patients, in order to improve quality of life and
Reduction of PN can be done by either decreasing the reduce HPN associated complications. This also requires
days of infusion per week or decreasing the daily infusion continuous monitoring that needs to be more intensive if
volume equally throughout the week (10–30%). Most growth factors like GLP2-agonist are used.
patients prefer the former because of psychosocial benefits
and a potential reduction in catheter infections. However an
assessment of the patient’s fluid dependence needs to be References
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Quality of Life
Ashley Bond and Simon Lal
Key Points 9. Transplant recipients score better than HPS patients in

1. QoL reflects a complex interplay of physical and psycho- ability to holiday/travel, fatigue, gastrointestinal symp-
logical health. It is influenced by a person’s indepen- toms, stoma management or bowel movements. However
dence, position within their environment, social they have more psychological issues which in addition to
relationships and social standings. being post traumatic, partly relate to fear of graft rejection
2. QoL in IF may relate to the underlying disease, having a and the consequences of severe immunosuppression.
short bowel, medication or needing parenteral support.
3. QoL involves a physical and psychological assessment. It
also includes assessing how daily activities have been
affected (including employment), eating/drinking, social- Introduction
ising and often stoma/wound management.
4. The SF-36, Euroqol, HPN-QOL, SBS-QoL, PNIQ and Patients with a reduction in gut function to the point that they
HPN-PROQ have and still are used to assess quality of life. require home parenteral support (HPS) are said to have type
5. HPS patients who require the greatest number of nights 3 intestinal failure (IF) [1]. The overarching aim of HPS is to
per week (and greatest volumes of PS) consistently report enable long term survival, while also maintaining, wherever
the worst QoL which may improve when the PS require- possible, quality of life (QoL). There is no doubt that the
ments can be reduced. requirement for HPS can be burdensome and time-
6. Patients with a short bowel are mainly affected by thirst. consuming, requiring a significant degree of adjustment for
7. Patients with poor social networks and those of working patients and their families [2–5]. Thus, not only may activi-
age who had ceased employment are particularly at risk ties of daily living be affected, patients can also encounter
of depression and anxiety. sleep disturbance as well as emotional reactions of fear,
8. HPS-dependent patients with SBS and their family mem- anger, disbelief or depression [6]. Economic and social
bers, described restrictions on activities of daily living restraints associated with the need for HPS can lead to a fur-
and physical functioning, highlighting that patients’ lives ther restriction of leisure activities and employment opportu-
were dominated by their condition. nities, elements of life that many people may take for granted
[7–9]. HPS is frequently life long and, whilst preserving life,
it is associated with inherent risks of complications such as
catheter related bloods stream infection, thrombosis, bio-
chemical instability and liver disease [5, 10–12]. Readmission
to hospital with complications associated with HPS can fur-
ther impair a person’s QoL, as can worry over the develop-
ment of such complications [13]. Frequent hospitalisation is
A. Bond (*) seen in this cohort of patients which in turn will, of course,
Department of Intestinal Failure, Salford Royal Foundation Trust,
have a negative impact upon wellbeing [14–16].
Salford, Greater Manchester, UK
e-mail: [email protected] Maintaining QOL has been identified to be of key impor-
tance to patients when dependent on HPS [2]. The World
S. Lal
Salford Royal & University of Manchester, Health Organization has defined QoL as ‘an individual’s per-
Salford, Greater Manchester, UK ception of their position in life in the context of culture and
e-mail: [email protected] value systems in which they live and in relation to their goals,

800 A. Bond and S. Lal
expectations, standards and concerns’ [17]. QoL reflects a ated with HPN duration (better after longer-term depen-
complex interplay of a person’s physical and psychological dency), underlying disease (better in Crohn’s disease and
health and is influenced by an individual’s independence, mesenteric ischemia) and living status (worse for those liv-
position within their environment, social relationships and ing alone) and, after adjusting for the other factors, with the
social standings. Tools or questionnaires that are used to number of HPN infusions per week [20]. A smaller single
evaluate QoL can be grouped into generic measures, thus centred assessment using HPN-QoL analysed 193 patients
applicable across a wide range of conditions, and disease- and their care givers, demonstrating that those with intestinal
specific measures. dysmotility reported the lowest quality of life [21].
The Parenteral Nutrition Impact Questionnaire (PNIQ)
was developed and validated in the U.K. to measure patient
QoL Assessment Tools reported QoL and lived experiences of HPS [9, 13, 22]. An
initial series of semi-structured qualitative interviews with
General HPS-dependent patients were used to identify the impact of
HPS on need fulfilment and then to create a needs-based
Across the available literature, the generic Short Form-36 model and item response theory to design the final version of
(SF-36) has been the most commonly used tool for QoL PNIQ. The tool comprises 20 questions, specifically related
measurement in clinical trials [2, 18]. An advantage of a to the impact of HPS on QoL. Each question has a dichoto-
generic tool is that it allows for comparisons and summation mous response of ‘True’ or ‘Not true’, with scores summated
from a wide range of studies examining different disease up to give a total score ranging from 0 (good quality of life)
types; for example, a comparison between the QoL of those to 20 (very poor quality of life). In contrast to HPN-QoL,
living with chronic IF and those with end-stage renal failure, PNIQ tests patients’ response to HPS and QoL indepen-
both of whom require life preserving therapies that impact dently of the underlying disease. Notably, PNIQ can typi-
upon daily activity and also share the need for long term cen- cally be completed in under 10 min by the patient without
tral venous access [2, 19]. The EuroQoL is also frequently assistance, making it a useful tool for QoL assessment in
utilised to evaluate QoL and cost-utility; this is a relatively routine day-to-day clinical practice [13, 23].
simplistic tool that is often used in conjunction with a second The HPN patient reported outcome questionnaire (HPN-
measure such as SF-36 [2]. However, neither EuroQoL nor PROQ) was developed as a disease specific tool in order to
the SF-36 specifically address the unique issues for patients allow patients to identify and address lifestyle concerns they
living with chronic IF, such that disease-specific tools have may wish to discuss with their clinician and these, in turn, may
subsequently been developed, particularly given the more lead to more in-depth conversation about psychosocial feel-
recent and evolving need to evaluate the impact of novel ings and QoL [24]. HPN-PROQ consists of 23 HPN related
therapies such as growth factors on the QoL of HPS- questions, each with a 5-point Likert response scale as well as
dependent individuals. questions from HPN-QoL. This includes items relating the
number of HPN nights, medical devices used in the adminis-
tration of HPN and the organisation of the service delivery in
HPS Specific the community. In addition, questions also specifically assess
perceived QoL. The HPN-PROQ provides a way to help foster
The first attempt to derive a disease specific tool was by patient-clinician communication about lifestyle adaptation
Baxter et al., who developed the HPN-QOL after validation and QoL [24]. The tools are summarised in Table 1.
in U.K. patients [20]. The questionnaire contains multi and
single-item scales for functional and symptomatic assess-
ment. The functional scales cover general health, ability to Short Bowel
holiday or travel, physical function, ability to eat and drink,
employment and sexual function, amongst others; for these More recently, the short bowel syndrome (SBS)-QoL tool
scales, a high score indicates a high level of functioning. The was developed primarily for self-administration specifically
symptom or problem scales, in which a high score represents in those living with SBS, with or without HPS-dependency.
high severity or more problems, include body image, fatigue, The SBS-QoL relies on Visual Analogue Scale assessment
sleep pattern, pain, stoma presence or absence and body with scores summated to a maximum value, with a recall
weight. Two questions relate to nutrition teams and the avail- period of the preceding 7 days. Due to its disease specific
ability of specific equipment related to HPN, in which a high nature, SBS-QoL has been particularly used to evaluate the
score represents a good outcome [20]. The largest study impact of growth factor therapies such as glucagon-like pep-
using HPN-QoL included 699 patients across 14 countries tide-2 (GLP-2) on HPS dependency and SBS-related symp-
and demonstrated that QoL scores were significantly associ- toms [25, 26].
Quality of Life 801
Table 1 Key features of available HPN or CIF specific QoL measure- as GLP-2 analogues, have the potential to reduce require-
ment tools
ments and thus improve QoL. While the GLP-2 analogue,
QoL Teduglutide, has been shown to effectively reduce PS
measurement
tool Key features
requirements in a large randomised controlled study [27], it
HPN-Qol • Developed using classical test theory is noteworthy that initial post-hoc analysis of these data did
• Scales for functional and symptomatic not demonstrate an improvement in SBS-QoL compared to
assessment, with questions also relating to placebo [26, 27]. However, when considering these initial
nutrition teams data, it is important to recognise that QoL was not the pri-
• Assessment of nutritional team support and
HPN related equipment mary outcome of the studies, which were also of relatively
SBS-QoL • Developed using classical test theory short duration and, as such, may have been underpowered to
• Visual analogue scale assessment achieve an effect on QoL. Indeed, more recently, Jeppesen
• Disease specific tool for short bowel et al. reported that Teduglutide resulted in volume reduction
syndrome
that was significantly associated with improvements in SBS-
PNIQ • Developed using item response theory
• Dichotomous response questions QoL [28]. The strongest association was observed with
• Evaluates impact of PN on the individual 80–100% PN volume reduction and the effect on QoL was
HPN-PROQ • 5-point Likert scales and items from particularly notable in the IBD cohort [28]. A study in 2020
HPN-QoL reported that those with the highest baseline PS requirements
• Aimed at encouraging dialogue with provider
derived the greatest improvements in QoL from the use of
teduglutide [25], which may be expected given that patients
with the largest PS requirements report the worst baseline
actors Affecting Quality of Life for HPS-
F QoL [16].
Dependent Patients and Their Family
Members
Eating and Amount of HPS
When viewed in isolation, the available disease-specific QoL
tools identify a number of factors that influence an HPS- The ability to eat and maintain oral intake has been described
dependent person’s QoL, such as the number of infusions per as key goal for HPS-dependent patients [29], which is of
week, underlying disease and mechanism. However, it is course relevant when interpreting the effect of entero-
important to recognise that, at any one time and for any indi- hormonal therapies such as Teduglutide on QoL. In a similar
vidual, QoL represents a complex interplay of social, medi- fashion, the interplay between intestinal anatomy, HPS
cal and psychological issues. Nonetheless, identifying requirements and QoL likely explain the finding that patients
common influential factors in cohorts of patients with a with less than 50 cm of remnant small bowel report a poorer
specific disease can of course be informative both for
QoL compared to those with longer bowel lengths, even
research and day-to-day clinical practice. when adjusting for confounders of age, sex, body mass index
and education [16]. It must be recognised that those with
shorter remnant small bowel are likely to have greater HPS
Effect of Infusion Time/Amount requirements. However, the additional detrimental effect of a
high stoma output and voluminous diarrhoea may also play a
As noted, there is a clear correlation between frequency HPS part in impairing QoL in those with shorter bowel lengths,
requirements and duration of infusion and QoL. Patients who which may also explain the association between citrulline
require the greatest number of nights per week consistently levels and QoL reported in patients with SBS, with citrulline
report the worst QoL, as evidenced in studies using PNIQ and acting as a surrogate marker for small bowel mass and func-
HPN-QoL, which demonstrated an association between tion, as well as HPS requirements [29].
worsening QoL with an increasing number of infusion days
[13, 16, 20]. Patients have also reported an improvement in
their QoL when a reduction in PS requirements is achieved Duration of Illness and of Receiving HPS
[26], with Nordsten et al. demonstrating an improvement in
SBS-QoL with a reduction in daily PS volumes [16]. The length of time an individual has received HPS, as well as
the duration of any pre-morbid condition can also influence
QoL. Thus, it was recognised more than 20 years ago that
Effect of Peptide Growth Factors those with relatively sudden onset intestinal failure, such as
following an acute mesenteric ischaemic insult, may experi-
The associations between PS frequency and duration of infu- ence an abrupt deterioration in QoL, compared to those
sion and QoL are important since therapeutic strategies, such already suffering with long term chronic conditions such as
Fig. 1 Quality of life of HPS Variation in Quality of Life

patient secondary to Crohn’s
and mesenteric ischaemia and 1
variation with time
¬Mesenteric infarct
0.8
Quality of life
0.6
0.4
0.2
¬Start of HPN
0
Time
Mesenteri vascular disease

Crohns disease
(0 = death, 100 = best possible quality of life)
Crohn’s disease (Fig. 1). In keeping with this, Burden and QoL when directly compared to those with Crohn’s or mes-
colleagues more recently demonstrated that those suffering enteric ischaemia [20]; however, this was not the case when
from surgical complications leading to intestinal failure PNIQ was used to evaluate QoL [13]. This discrepancy may
reported a poorer PNIQ score compared to HPS-dependent reflect the fact that PNIQ solely evaluates the impact of HPS
patients with chronic inflammatory bowel disease [13]; this on QoL, while tools such as HPN-QoL also take into account
effect may be explained by the sudden onset of intestinal underlying gastro-intestinal symptoms and patients with
failure that occurs in patients with surgical complications. gastro-intestinal dysmotility receiving HPS will often con-
Indeed, patients with acute, type 2 IF resultant from surgical tinue to have very troublesome symptoms, including pain,
complications, typically present after multiple operations nausea and vomiting. Therefore, tools which assess symp-
and, after prolonged periods of in-patient stay, are discharged tom impact as well as HPS impact will likely report lower
home to recuperate on HPN [30, 31] and such patients are QoL scores.
often devastated by a relatively rapid deterioration in their
QoL [13]. Moreover, better overall HPN-QoL scores were
reported in patients with HPN duration longer than 24 months Employment
compared to patients with shorter duration [20] and other
studies have similarly demonstrated the same pattern of The ability to work and maintain a living will ultimately
improving QoL with over time [26, 32]. have a significant impact on an individual’s and families’
quality of life, as with all chronic conditions. One consis-
tent finding is the positive impact on wellbeing that
Dysmotility employment has. Ablett et al. reported patients with poor
social networks and those of working age who had ceased
The reported QoL of HPS-dependent patients resultant from employment were particularly risk of depression and anxi-
gastrointestinal dysmotility seems to vary according to the ety [33]. The number of days per week on HPN and the
tool used. While there has been a report of increased distress desire of the patient to return to employment have also
secondary to gastrointestinal symptoms and problems with been found to be significantly associated with the ability to
eating in those with underlying dysmotility compared to maintain employment [34]. When compared to HPS-
patients with SBS, this did not seem to have an impact on dependent patients receiving an above minimum wage,
overall QoL [14, 21]. Baxter et al. used HPN-QoL to demon- those paid minimum wage or below had a significantly
strate that patients with GI motility disorders had a lower lower reported QoL [13].
Quality of Life 803
Activities of Daily Living increased demands on time and perceived strain. A multina-
tional, cross-sectional survey from 2021 assessed the impact
When using a qualitative, non-interventional interview on caregivers of adult patients receiving parenteral support
approach to assess QoL in HPS-dependent patients with for short-bowel syndrome. Caregivers reported an overall
SBS-IF, novel themes and drivers can be identified. A recent negative effect, with a reduction in the ability to work full-
qualitative assessment of HPS-dependent patients with SBS time. They also reported an impact on daily activities and
and their family members, described restrictions on daily their ability to participate in recreational activities. When
life, actives of daily living and physical functioning, high- asked about the impact of caregiving on emotions, most care-
lighting that patients’ lives were dominated by their condi- givers reported worrying about the health of the patient [37].
tion. The most burdensome symptoms reported by patients The health status of the caregiver also appears to be an
was thirst. In addition, patients described the emotional important factor, with French et al. (unpublished) reporting
aspects of living with SBS, specifically with difficulties family members with a poor health status more likely to per-
socialising and maintaining relationships. Patients also ceive a moderate to very severe subjective burden when liv-
described coping mechanisms and adapting their lives ing with an individual dependent on HPS [38].
around their condition, acknowledging the life sustaining
element of the treatment. Family members also described the
impact of living with an individual on HPS, reporting that Intestinal Transplantation
they worried about their relative’s condition with some also
being affected by the obligations of HPS and the impact it Intestinal transplantation can be considered in patients with
had on QoL. Relatives also reported the importance of unique circumstances of extremely poor QoL (see chapter
achieving a night off from infusions, which is an important “Intestinal Transplantation”) but, given the risks associated
consideration for clinicians [35]. with transplantation, QoL alone should be scrutinised by a
multidisciplinary team if used as a single factor indication
for transplant [39].
Advanced Malignancy It is difficult to directly compare the QoL of patients of
patients receiving HPS with patients who have undergo an
Quantitative and qualitative evaluation of the impact of HPS intestinal transplant. However, using HPN-QoL as the
in those with advanced malignancy and palliative needs have assessment tool, Pironi et al. made comparisons between
revealed insightful results. Notably, the PNIQ score of people receiving long term HPS for benign disease and those
patients with advanced cancer was comparable to that of who had undergone intestinal transplant; notably, transplant
patients with inflammatory bowel disease in a large U.K. recipients showed a significantly better score in the domains
study, suggesting that HPS has a similar effect on the QoL of related to ability to holiday/travel, fatigue, gastrointestinal
those with benign and malignant conditions [13]. Sowerbutts symptoms, stoma management or bowel movements and the
et al. used longitudinal interviews to assess QoL of patients numerical rating scales of quality of life. Furthermore, HPS-
with ovarian cancer and malignant bowel obstruction, along dependent patients reported poorer scores for employment
with their caregivers. Patients considered HPS as an essential and for emotional function [40].
element of their condition as a whole. Although it inferred Pither et al. reported QoL scores measured using SF-36
some negative aspects, many considered it as a “lifeline” that improved in approximately half of the patients compared to
allowed them be at home. Negative aspects reported included their status at listing for transplantation, no change in around
the loss of normality and the effect it could have on the social one third, and a minority experienced a decline [41]. In a par-
aspect of mealtimes. On the whole, many felt HPS was allel paper, Pither and colleagues evaluated psychiatric disor-
worthwhile because of the extended time they had at home ders in patients pre- and post-transplantation and found that 10
with their relative [36]. of 14 patients still had a single psychiatric disorder after trans-
plantation and 3 of 14 had also acquired a second psychiatric
diagnosis with suicidal ideation in 2 cases. Notably, depres-
Impact on Family Members and Carers sion resolved in only 1 patient after transplantation and a fur-
ther patient without a history of psychiatric issues before being
More recent larger studies have further evaluated the impact transplanted, developed a double psychiatric diagnosis (anxi-
of HPS on family members and carers. Beursken-Meijerink ety with depression) during the post-operative course [42].
et al. assessed QoL and distress using the HPN-Qol and the The authors highlighted in their conclusion that the additional
Caregiver Strain Index (CSI) and found that the caregivers of stress of transplantation can impact psychological wellbeing,
those with dysmotility experienced a higher burden when detailing the importance of mental health support during reha-
compared with caregivers of patients with SBS, due to bilitation. A further study found that patient personal financial
pressures are greater following intestinal transplant which 12. Dibb M, Lal S. Home parenteral nutrition: vascular access and
related complications. Nutr Clin Pract. 2017;32(6):769–76. https://
may affect the morbidity associated with organ graft receipt
doi.org/10.1177/0884533617734788.
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whereby a number of domains improved post-transplant, but home parenteral nutrition. Clin Nutr. 2019;38:1433–8.
recipients reported worsening of levels of depression and 14. Sowerbutts AM, Jones D, Lal S, Burden S. Quality of life in
patients and in family members of those receiving home paren-
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lished in 2016 reported that post-transplant QoL improved 2021;40:3210–20.
with time since transplant and there is a need for large and 15. Persoon A, et al. Impact of long-term HPN on daily life in adults.
longitudinal studies to explore any improvements to QoL and Clin Nutr. 2005;24:304–13.
16. Nordsten CB, et al. High parenteral support volume is associ-
other areas of daily living over time in more detail [45].
ated with reduced quality of life determined by the short-bowel
When considering QoL as a sole indication for transplanta- syndrome quality of life scale in nonmalignant intestinal failure
tion, it is, of course, important to take survival into account. A patients. J Parenter Enter Nutr. 2021;45:926–32.
prospective 5-year study compared survival of patients with 17. World Health Organization. The World Health Organization Quality
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The Patient’s Requirements
Carolyn Wheatley, Monika Malickova, Joanne Shepherd,

and Steven Brown
Key Points their own homes whilst receiving artificial nutrition. Some
1. Patients prefer to have their care at home but not all will individuals are immediately dependent on it from birth,
want to self-care. whilst for others it is the failure to thrive that subsequently
2. The patient must feel part of the decision-making pro- leads to awareness that it is urgently needed. Both adults and
cesses involving their care. children may encounter medical and surgical complications
3. Many have body image issues in addition to physical that necessitate artificial feeding during their lifetimes,
weakness. which then becomes a life-saving home therapy. While many
4. While there is feed and ancillaries (equipment and con- patients are fortunate to have homecare as an option, we
sumables) delivered to the home, the home should not know through the network of patient groups, that the avail-
look like a hospital. ability of homecare varies around the world.
5. The patient/carer/parent/guardian needs to understand the Home is always the goal—it’s where people want to be,
underlying medical condition and the reasons for the type both those receiving the treatment and their parents, partners
of feeding (enteral or parenteral nutrition) and the chal- and families. For many this will be a welcome relief from
lenges (including complications) that may occur. It is long and possible frequent episodes of hospitalisation, but
helpful to have a short medical summary that includes for others it may mean a life of intense routine and isolation.
contact details. Acceptance that life is dependent upon a specialised treat-
6. The aim at home is to be able to return to doing all/most ment, aseptic procedures, complex routines and mechanical
of the activities that were previously done (includes equipment can be hard to comprehend. Those able to self-
washing/dressing, driving, sport/leisure activities and care may find adjusting a little easier, but this should not be
going on holidays. assumed. Children will naturally be dependent on their par-
7. Patient groups and associations can give very useful sup- ents/guardians for their care initially.
port and helpful advice? to common problems. During treatment, and at intervals along the way, every-
one will need the support of family and friends. Whilst they
are life-saving treatments, they can be both demanding and a
burden [1]. Patients understand these are likely to be needed
Introduction long-term, and that a desired lifestyle choice may need
changing or modifying. An adult may resent being depen-
The route to home artificial nutrition is complex and the rea- dent on others for their care and all those involved in home
sons why it is required are diverse. Navigating this route to treatment will need to place their trust in the hands of a
successful discharge and home treatment can be challenging. highly specialised medical team whose skills will allow them
Increasing numbers of patients—both adults and children, to integrate the therapy into their home and personal lives.
are now able to live with varying degrees of independence in Additionally, for those who have a homecare service and
community support, it will be necessary to determine who is
responsible and how this all fits together to provide the nec-
essary support for all concerned.
C. Wheatley (*) · J. Shepherd · S. Brown Patients, parents and carers are fully aware that home
Dorset, UK
nutritional support will not cure their underlying condition,
e-mail: [email protected]; [email protected]
but instead allow them to live with it. In the initial stages, and
M. Malickova
possibly for the duration of their therapy, both children and
Prague, Czech Republic

808 C. Wheatley et al.
adults may experience situations and emotions that are psy- rior to Insertion of Venous Access Device/
P
chologically challenging. These experiences can be difficult Feeding Tube
to explain and are partly due to the subjective effects of both
the nutritional support and the underlying illness(es). To support the patient and provide them with all relevant
There are pros and cons to having hidden conditions and information, it is important to ensure enough time is set aside
tubes. Invisibility may mean the patient is perceived as ‘nor- to discuss all aspects of the process. To facilitate the accep-
mal’, however, the need for artificial nutrition is often poorly tance of change, the patient needs to feel empowered [2].
understood by society at large, so many patients can find Where the parents or carers of a young person are making the
themselves alienated in a world that does not always compre- decisions, they need equal time and opportunity to discuss it
hend things it cannot see. and ask questions. Indeed, the parents/carers will need to
Recently, patient groups and associations worldwide have explain this to their child and it will be them who they turn to
made excellent progress in forging links. It has proved if they have questions. Everyone needs the opportunity to
invaluable to learn of the variation in treatment options and discuss any fears or concerns with the medical team. It is
homecare. We are now able to appreciate the inequity in both vital that the patient feels part of the decision-making pro-
care and services. cesses [3], as it is their body. Verbal communication needs to
Despite difficult, and possibly prolonged periods of hos- be as informal and open as possible. Educational resources,
pitalisation, homecare is a natural step for many. However, where possible, should be made available in different for-
the journey to going home can be a long one, if it’s even an mats such as film or reading material—as not everyone pro-
option. There are some patients fighting for their treatment cesses information in the same way.
options, parents advocating for their children, and carers, As soon as the need for a feeding device is identified, the
who for a variety of reasons, are also seeking appropriate preparation should begin, it should not be rushed nor over-
treatment and choices. looked. No concern or question should be belittled. Anxieties
require discussion and need to be systematically worked
through to quell any fears. The patient or carer may benefit
Care in Hospital from time spent familiarising themselves with the equip-
ment. This juncture is crucial to the acceptance of what will
Once the decision has been made to commence artificial change their life forever—not only will they have a visual
nutrition, parenteral or enteral, the patient or carers are likely and constant reminder that they are now different, but their
to experience some degree of apprehension. They will be state of mind may be altered. There are several child-friendly
aware that this treatment is only commenced when all other educational resources available, which will certainly aid
avenues have been exhausted. As the patient may have expe- acceptance for a child. These are also useful for siblings.
rienced disappointment following previous treatment failure, At this crucial point of acceptance, the patient and/or their
doubts may surface. The patient and carers may wonder ‘can family may need some psychological support to navigate the
we afford to place our trust in yet another treatment which change. Support should be provided by healthcare profes-
may not have a positive outcome?’ Often the families and sionals who have experience of intestinal failure and artifi-
carers involved are juggling work, childcare and education cial nutrition. Some intestinal failure units have acknowledged
so they want the right decision made for their loved one to the benefit of having this support integrated into their service
expedite improved nutritional status and hopefully and, as a result, have psychologists as part of the nutritional
discharge. care team [4].
Weight loss or failure to thrive, has both clinical and phys- Dependent upon the patient’s state, appropriate anaesthet-
ical impacts on the body. People may experience poor body ics should be administered to ensure equanimity during the
image in addition to the physical weaknesses this imposes. procedure. For those who have undergone many surgical pro-
Observing the body wasting away or failing to develop prop- cedures during their illness, another procedure, no matter
erly, despite all attempts to correct it, can leave the patient how minor, may cause distress. When feeding devices are
with low self-esteem, feeling worthless and defeated. In cer- being replaced, it is important to ask the patient or carer about
tain circumstances the individual may lapse into a period of previous experiences that could impede the smooth operation
denial, and this state of mind may adversely affect the out- of the next procedure. They are experts in their own health
come of their treatment. Parents and carers may feel helpless and procedures. It is important to stress that discomfort and
despite the encouragement and support they provide; their soreness may be present after the insertion. Knowing some-
desire to make things better is not always that simple. thing is normal and expected can be reassuring.
The Patient’s Requirements 809
A positive result for the patient is full acceptance and cor- For many, as they are starting to regain control of their
rect management of their feeding device. life, confidence will return and they will be heartened by
their improved appearance. A former dislike to weighing
scales may vanish as they are now displaying signs that ‘this
fter Venous Access Device/Feeding Tube
A treatment’ is working.
Insertion Conversely, there are patients who find themselves on
artificial nutrition with no time to prepare or adjust; it hap-
Patients and carers will notice that shortly after nutritional pens quickly—an accident or sudden health change. For
support has commenced the nourishment has a positive these patients, acceptance takes longer or may not happen.
impact on the body and mind. Possibly, the initial and most Additionally, not all patients feel better and have complica-
obvious sign of improvement will be a healthier looking tions that add to their medical issues; it’s not always a
patient and weight gain. It may be slow, but the much-needed blessing.
nutrition will fuel the body. It will become apparent that the A skilled medical team with carefully planned follow-up
patient is more attentive and shows a greater ability to appointments for the patient, should be in place to not only
concentrate. monitor the clinical parameters but also the psychological
Everyone will be pleased to see the improvements, and aspects of living with home artificial nutrition. They will
this will hopefully contribute to acceptance of the device and have seen the ‘unexpected’ emotions before and their exper-
the need for artificial nutrition. Patients may previously have tise can be used to address these and, if necessary, refer
been told they looked thin and unwell. Following treatment, patients, parents and carers for additional support [5].
it can be satisfying to be told how well you look. Often, it’s
not until things improve that there is recognition of how bad
things were beforehand. However, underlying conditions Training Programme
must not be forgotten during this phase. For parents of tube-
fed children weight gain will be welcome, but they will also It is essential that the patient, parents and carers understand
be keen to know if their child is progressing in other ways the training programme which has been devised for them and
too. appreciate the importance of taking one step at a time. We
For the patient the presence of a feeding device may be recognise that the training for parenteral and enteral proce-
both welcomed and feared. It will alter body-image and may dures are different and require different training programmes.
not be the only medical attachment they have. Even patients Also, there are large variations in training locations. At one
who accepted the need for the device prior to its insertion, time it was always carried out in hospital but in some coun-
may find that the physical presence alters how they feel. tries, it’s done in the patient’s home. There is also variation
They may require support from psychologists with experi- between the adult and child training.
ence of intestinal failure and artificial nutrition; ideally one A training programme should ideally be outlined in
connected to the nutrition team. advance, providing information on where it will be done and
who will be trained. Everyone concerned should be informed;
if self-caring is the goal then this should be made clear with
Equipment Management goals and clear timelines. For those who will self-care, it will
be a one-to-one training progamme. For those who are reli-
Tubes and central lines require strict care and observation to ant on parents or carers, an amended programme will be
ensure they remain patent, safe and infection free. The pres- needed. Preferably more than one person will be trained to
ence of a feeding device will bring restrictions in terms of care for the patient, particularly for children. The best laid
clothing, activities and possibly raise questions about sports plans often need to change, usually at short notice. At no
and swimming. Children may be restricted, and parents may time should day-to-day living cause issues if a sole parent or
be concerned about normal development milestones that carer became detained or delayed; feeding and the care of the
could compromise a feeding device e.g. tummy time, crawl- patient should never be compromised.
ing, rolling over and a lot of tossing and turning at night. Where children transition into adulthood and still require
All patients have personal feeding regimes, many patients artificial nutrition, transferring skills to create independence
are restricted by feeding tubes and central lines, pumps and and autonomy, should be discussed with the parents and car-
equipment—it is unrealistic to assume that all patients stay ers as soon as it’s considered appropriate. Where possible
in bed for the duration of their feed. independence should always be the goal.
Where homecare nursing services are used to train person receiving artificial feeding but to family and friends.
patients, a clear outline of the plan and timescale should be A large portion of social interaction is based around food and
apparent. Sometimes people are eager to take over their own drink, birthdays, christenings, weddings and religious events;
care; whilst others nearing the end of their training may feel life with a limited or no oral intake is challenging. Identifying
uneasy about losing visits from nursing staff. It’s essential this is important and support should be offered as part of the
that no patient, parent or carer should feel that once training clinical care. Support groups can help with empathy but
ends they are on their own. The availability of a support net- often a higher level of care is required.
work must be certain.
Everyone will learn at their own pace; it may be necessary Babies and young children: For families taking home a
to reiterate certain aspects of the procedures to ensure people baby or small child; while it’s exciting, there may be a lack
understand what they are doing and why. It can be an over- of support from the usual channels, i.e. health visitor, GP,
whelming process for some; others will pick it up easily, it’s baby clinic and the most natural network of other new fami-
about ensuring the patient is competent and capable of per- lies. Home can suddenly feel isolating and lonely. Whilst the
forming the procedures. goal is to give families the best possible quality of life, the
Individuals may form a close bond with those who are burden of care on the parents is enormous [7]. The only net-
teaching them; it’s a very personal time and during training, work they may have is medical. It’s preferable to balance
people often share their feelings and seek reassurance that medical with conventional support.
it’s all going to be okay.
Following initial training, everyone should have the Children and young adults will start or return to school,
opportunity to ask questions or express their concerns. Also, college or progress onto university. All aspects of their care
as new products are introduced, it’s preferable if everyone is and personal needs should be considered; life must go on to
taught how to use and integrate them. Often basic informa- provide normal education and development; systems need to
tion is sent out via the homecare companies and patients, but be in place to support them on this journey.
parents and carers are left wondering what to do with them.
At all times during the need for artificial nutrition, healthcare Adults at home: Adults may be returning home to find life
professionals should be vigilant to ensure patients, parents has carried on without them. How they integrate back into
and carers are continually reviewed and updated [6]. family life, work, friendships and hobbies may be over-
whelming depending on how much they are able to
participate.
Life at Home
For some people, they are returning home to be on their
Going home can be a satisfying feeling, however this may be own, this can be isolating; it’s very different to the hustle and
combined with feelings of anxiety, fear and excitement. bustle of hospital life. Those with partners or other family
Often, long periods of hospitalisation will have been members at home may find that their loved ones must give up
endured and it may take time to adjust to life on the outside. work or education to become full-time carers and the combi-
It will be challenging for all concerned; there will be so nation of the feeding, medical conditions and daily life may
much to adjust to; feeding equipment, ancillaries, routines leave little time for activities outside the home. Many people
and procedures all to be done in a completely different envi- cope extremely well with the immense changes that have
ronment. Home is not a hospital, but it will need to accom- occurred. But these coping mechanisms, which partly depend
modate all the essential elements of the home artificial upon the effects of their underlying condition and its treat-
feeding. Preferably home should not resemble a hospital but ment, are not automatic and they take time to evolve.
the amount of storage required may mean several adjust-
ments need to be made. Some people will dedicate a spare Needs of the carers at home: Consideration should be
room for this and keep it all stored centrally. Others will need given to the mental health and emotional needs of the
to use every bit of space they can find to fit it all in. The prac- patients; but let us not forget the parents and carers. Everyone
tical aspects of being at home can be a challenge. will have their own set of challenges, this will fluctuate with
Some people receiving home artificial nutrition may have health changes and day-to-day living. To make life at home
a reduced capacity for oral intake. It will vary between peo- as manageable as possible, focus needs to be on the whole
ple and for an array of reasons. Adjusting and accepting to person and not just the feeding.
this may be difficult for some people and psychological sup-
port should be offered to aid the adjustment period. Family As we know, patients often return to hospital, it’s upset-
life includes food and drink; for being unable to enjoy it or ting when it happens, people truly don’t want to be in hospi-
take part has the potential to cause distress, not only to the tal but often know it’s the best place to be. Frequently
admissions cause further emotional turmoil for everyone; Independent patients may need help with personal hygiene
once at home it’s where people want to stay. Sadly, when life or medication.
at home starts to settle, fate often dictates that it’s time to The common belief that parenteral feeding at home is
pack your bags and be re-admitted; often not knowing how administered while the patient is asleep is not necessarily
long it will be until everyone is back at home. correct. Each patient will have their own sleeping patterns
and may not wish to retire to bed early just because it is time
to commence feeding. Some patients are electing to feed
Feeding during the day to try and eliminate frequently disturbed
nights due to regular trips to the bathroom. Feeding patterns
Food is everywhere—television commercials, magazines, will not be constant and the time for connecting will fluctu-
advertising hoarding and it is also a key component in cele- ate. As part of the teaching process, the patient should be
brating any major event. Eating and drinking are accepted assured that it will be a natural occurrence for feeding time
social pastimes and exclusion from these can cause social to vary from those that they have become used to in hospital.
isolation, leading to depression, social anxieties and Patients, parents and carers should be encouraged to take
loneliness. control of the feeding regimes in terms of timings. Life must
Eating and drinking will be advised for each patient go on, families and couples need quality time together, this
depending upon their personal circumstances. Some patients may be outside the home, so feeding must be adapted to
will have upper allowances of what they can consume orally. ensure this takes place. Where possible, patients, parents and
These allowances should be monitored in the hope that they carers should ensure that the treatment does not rule their
can be increased, and, for some patients, dietitian involvement lives. The aim of the therapy should be to enable the indi-
can have key benefits. Where limits are set; self-control must vidual to live life to the fullest and to meet their personal
be steadfast. goals.
When it comes to the actual process of setting up the
feeds, how this affects family or home life will vary from one
situation to another. Being part of a normal household may Equipment
bring unexpected pressures, particularly with timings.
Initially, accommodating the feeding into other people’s life- There are various aspects of equipment management that
styles may be problematic and adjustments will be required. need to be considered for home artificial feeding.
Those who can self-care will determine how best to accom-
modate it. If the patient needs a carer to set the feed up, then Ancillaries and storage: Initial deliveries of ancillaries
the timing and availability of their support network will need may be overwhelming. Patients, parents and carers may not
careful consideration and planning. In some countries, where fully appreciate the number of essential items they will be
patients cannot carry out their own procedures, a nursing ser- receiving. It may be mentioned that a lot of boxes will be
vice may be available. While this is good as the patient can sent but it’s not until you see it in the home environment that
go home, it can be restrictive in terms of rotas and the capac- reality dawns. Storage space may be a significant issue.
ity of the nurses. For example, up to a 2-h window may be Ancillaries need to be stored safely yet easily accessible for
given—the nurse will be arriving at some point during that use, as well as being rotated and used in date order. Keeping
slot. If nursing support is required, sometimes twice a day, curious people out of medical fridges or little people away
then the patient and family may have restricted freedom of from interesting medical supplies may be a challenge.
movements and feeding time options.
Feeding the patient is the priority; in practice how this
works while people juggle their daily commitments can Type of pumps and equipment used in the home: Despite
mean a major impact on day-to-day living. In some instances, increased awareness of ambulatory feeding pumps, some
a child may need more than one parent or an additional carer patients are using hospital-style static pumps in the home
to assist for logistical reasons; their playfulness, feeling tired environment. These pumps need to be attached to heavy
or unwell may hamper the parent or carers from being able to hospital-style cumbersome drip stands. This is across both
perform the procedures safely. feeding treatments; enteral and parenteral. However, sadly
Some people, both adults and children, will need supervi- there are many patients who do not even have a static pump
sion or assistance during the night both in terms of practical to infuse their feeds. Gravity feeding is still favoured by
help—toilet needs, responding to pump alarms, changing some countries and healthcare professionals. Mobility is
feeding containers/topping up feeds as well as safety needs— improved where ambulatory equipment is available. This
for example, failure of equipment, such as tubing leaks, or applies within the home—being able to go up and down
symptoms of infection requiring immediate hospitalisation. stairs independently or move freely is a huge confidence
booster. Pumps are evolving which enhance the patient’s quency should be tailored to local resources in conjunction
quality of life; allowing them to feed outside the home and with the instructions from healthcare professionals as they
not be dependent upon a power supply to power the pump. arrange these services for their patients. A desirable goal
would be for a homecare company to supply all relevant
All options should be discussed with the patient, parents medical items related to the patient’s needs. Centralising
and carers. Pumps should be reviewed in line with lifestyles. contact and distribution would make life much easier for
While we advocate that ambulatory pumps should be consid- patients, parents and carers. One call, one delivery, one mon-
ered, backpacks may not be viable for all patients. It will be itoring and checking process.
dependent upon their personal well-being. The development Where homecare companies operate, there should be a
of wheel rucksacks should be welcomed to meet the chang- good relationship between the prescribing hospital, the com-
ing needs of patients, whether that is adults or babies and pany and the patient. It should be clear how the service will
toddler patients who are learning to crawl or walk and need operate, who to contact and how and where the lines of
to be given confidence from an early age [8]. responsibility rest. Where the patient, parent or carer has
been given a homecare service, it should meet their expecta-
Dedicated parenteral nutrition fridge: There are large tions and enhance their home feeding regime. They should
variations in how parenteral nutrition is supplied and subse- deliver what’s promised, when it’s promised and in good
quently stored by the patient. Some feeds are supplied as condition and be fit for purpose [9]. Ancillaries and fluids
multi-chamber bags while others are cold-chain bespoke should be supplied as expected; any omissions or replace-
compounded solutions. For those who have cold-chain feeds, ment should be made known to the patient in advance of the
the storage facilities should be between 2 and 8° and a delivery. For some patients, it’s a struggle to determine what
dedicated fridge is desirable. Some patients are not given they can have and how many. The lines of approval for ancil-
fridges, some need to purchase their own while others have laries is often unclear and the importance of a consistent ser-
access to anything between domestic fridges and pharmacy vice cannot be underestimated.
quality fridges. Some patients will struggle to accommodate This is an area where the patient, carer or parent can feel
a large fridge and it may need to be ‘squeezed’ into the home ‘out of control’ of the means to sustain their life. They put
somehow. Ensuring it’s not tampered with is also vital, the huge trust in the homecare company and it can be a source of
internal temperature must be maintained to ensure the safety anxiety if errors and mix-ups occur. Whilst a consumer can
of the parenteral nutrition. look at a food and drink item and use their senses of vision,
smell, taste etc. to assess the quality, freshness and safety;
Patients, parents and carers should be asked about their with medicinal products and ancillaries the consumer is
lifestyles and the most appropriate equipment supplied. This trusting the provider. When errors occur, thoughts as to what
should also be reviewed, as they may not necessarily know other undetectable errors have occurred can be a source of
what the alternatives are. Healthcare professionals need to anxiety. Due to the lines of responsibility between the hospi-
ensure they support their patients with choices, while being tal, homecare company and patient, follow-up of errors and
clinically safe, about equipment and ancillaries that could ensuring appropriate action is taken can be difficult for the
either hamper or enhance their feeding experience. patient themselves to facilitate.
During the COVID 19 pandemic many homecare services
were under as much pressure as the hospital services around
Deliveries/Supplies to the Home the world. Homecare services need to be protected and safe-
guarded to ensure the supply of essential medical nutrition
For the patient to carry out their essential medical treatments during usual and unexpected crises. Communication with
they need the relevant ancillaries, and prescribed medication/ patients/families/careers is vital for reassurance. Information
solutions. There may be various options available to the needs to be given to those dependent on homecare deliveries
patient, but some may be time consuming and difficult, espe- and supplies. Homecare enables people to remain at home
cially if we consider that patients are unwell and have vary- unless clinical care is specifically needed in a hospital.
ing levels of mobility, particularly when attached to their
feed. Gathering supplies from local pharmacies or surgeries
and collecting nutritional fluids from hospitals, for example, Hospital Follow-Up
is less than ideal.
Although homecare companies do not operate in all coun- All patients, parents and carers understand the need for fol-
tries; in an ideal world, all patients should have a reliable low-up and clinic appointments at the hospital. Not only is it
service that will minimise stress by delivering complete sup- necessary to review and monitor their nutritional status but
plies directly to their home [9]. The delivery times and fre- also their on-going underlying condition(s). The frequency
will vary depending on the needs of the individual patient. In and when transitioning careful attention must be paid to the
addition to follow-up and clinics, some patients may be fre- emotional and psychological support, not only for the patient
quently admitted to hospital to manage various aspects of but the parents.
their needs. While necessary, this is very disruptive to family
life, work life, schooling and education. It’s upsetting when
loved ones are re-admitted, often with no knowledge of how Relationships
long they will be an in-patient. While the patient is in hospi-
tal, life at home doesn’t stop; school, work and social occa- The need for home artificial nutrition can start at any point in
sions continue regardless. Each admission brings familiar someone’s life; unexpectedly—following a trauma or acci-
emotions, often difficult and painful. dent or because of a long-term illness which may change
At home, the patient, parent and carer assume the roles of over time. As there are various types of artificial nutrition,
some of the healthcare professionals as they need to monitor oral supplements, enteral and parenteral feeding, it is not
and respond to the changing situations at home. Ill-health, unusual for some patients to have progressed from one to
raised temperatures, pain, sickness—each need appropriate another based on their personal needs. No matter when arti-
action. When do you stop trying at home and decide to con- ficial nutrition is introduced into a family unit it will have
tact the hospital? Self-diagnosis is common and accepted for profound effects. If we consider the numerous types of rela-
those with long-term illness and treatments but knowing tionships we have in our lives starting from an early age—
when to seek help can be confusing and worrying. parents and children, children and siblings/school friends,
Continual support must be given to the patient, parents friends we socialise with, work colleagues, personal rela-
and carers, and they must feel secure in the knowledge that tionships—long-term relationships: life evolves as do
advice is available 24 h a day just as it was in the hospital. relationships.
Contact numbers must be given, but more importantly, where Children should be encouraged to ask questions about
there is an answer machine, they should be checked regularly relationships as they develop. Altered body image, along
or provide clear and precise instruction on how to gain access with peer pressure, may leave them confused with potential
to a person able to provide support. The nurse is generally for low self-esteem. As a child approaches puberty and then
the team member that the patient turns to in a crisis, therefore transitions to adulthood, it can be extremely daunting with-
their availability and accessibility is paramount to the out the right support.
patient’s sense of security. New personal relationships may be hard to contemplate—
Unfortunately, many of the problems faced by patients at long-term ones may be just as difficult to re-establish.
home appear to occur late in the evening or at weekends. Consideration and understanding for all concerned should
Most patients prefer to deal with their own team members ease people through these testing times. It often helps to dis-
who have knowledge and an understanding about them, cuss these emotions with either the hospital team or other
which eliminates the need to go over old ground before any patients, people who have faced these challenges many times
help can be offered. Hopefully, the hospital supervising the before. Partners and parents often need to adopt the role of
care will have someone known to the patient on call or at the carer, even if this would not be a natural fit for them,
least they can be contacted for expert advice. It’s important which can alter previous relationship frameworks. It’s imper-
to realise that most people on home artificial nutrition are ative that personal relationships are maintained, but in prac-
experts in their own conditions and care. Many are more than tice, marriages and partnerships may be put under
happy to discuss this and work with healthcare professionals considerable strain. Other family members will be affected,
to ensure the right treatment options are planned and admin- and their needs may be overlooked. Child and sibling carers’
istered. Patients, parents and carers will be fully aware of all needs are not always met.
the complications that can arise. Established relationships may be already strained during
Large units with specialised knowledge in intestinal fail- the diagnosis, admission and treatment phases. Bearing in
ure care for many patients receiving home parenteral nutri- mind, always, that the underlying condition may still be
tion. This may pose problems as the distance between home present and active, the treatment may feel like another set of
and the hospital may be considerable; requiring the need for issues to contend with. All aspects of the need for artificial
a car, for example. However, this does not deter many nutrition will fluctuate and need careful understanding along
patients and they elect to stay under their care despite the the way.
distance involved. For some a shared care policy can add a In an ideal world we would hope that other people would
reassuring back up for unexpected events. be more accepting of illness and medical treatments, but
When a child needs to transition to adult services, there is sadly we know that this is not always the case. Whilst family
usually a clear pathway already defined. It’s essential that and friends may find they can accommodate additional needs
children are not seen as small adults, they have specific needs such as the use of a wheelchair easily, planning for unseen
conditions and disabilities may not be so easy. For example, must be discussed and agreed prior to the child returning to
strain may be placed on relationships with family and friends school. Obviously, this should be reviewed at frequent inter-
who don’t make allowances for the need to be home in time vals. Mainstream school and education should be encour-
to commence feeding. There may be time when activities are aged unless they have specific needs that cannot be met in
planned which the patient finds it difficult to participate in. these environments.
Feeding regimes can make spontaneity difficult, thereby
excluding the patient or adding stress to their life.
When the patient is in hospital, friends and family realise Work
that attendance at social events such as weddings and cele-
brations is impossible. However, once home, expectations of For those on artificial feeding who will hopefully embark on
family and friends might exceed the patient’s ability to orga- a career when completing education, their chosen pathway
nise their healthcare needs to attend such events. It might be may be already influenced based on their health and feeding.
very difficult for the patient to attend, especially if the event Young adults should be encouraged to grow and prosper and
is organised without the patient’s needs in mind, but family venture into the world with confidence; it goes without say-
and friends may not see these difficulties and may view it as ing that support networks should be in place throughout their
the patient being difficult or unreasonable. adventure in life.
Self-confidence can be easily knocked by thoughtlessness For an adult patient, depending upon the type of career
or when constant rejections are made, leading to friendship/ the patient has, it may be possible to return with minor or no
relationship breakdown. The treatment becomes the obvious modifications. For some, the prospect of returning to full-
obstacle, which can lead to diminished enthusiasm for trying time employment or an established career may not be possi-
again. Negotiating the relationship maze may be tricky for ble; every effort should be made to ensure the patient has an
some, easier for others and it may change throughout the life opportunity to consider all options.
of the patient. In some instances, partners and parents become a carer
Talking about sex and relationships should be part of the for the patient—personal careers and ambitions are set aside
overall care of the patient, it should be managed by the right to support their loved one. While they often do this freely and
people and support offered to those who need it. Sadly, unconditionally; it frequently leaves people feeling burdened
access to psychologists may be patchy. In many places men- with the routine and responsibility of home artificial nutri-
tal health services are not established or funded sufficiently tion and the medical needs of the patient.
to enable this. However, the mind should be supported as The perception that ambulatory equipment is a given to
much as the body is; we should never assume patients will easier employment is misleading. We need to consider the
just cope [4]. many ‘health and safety’ aspects of offices and compa-
It is assumed that there are fewer psychosocial and sexual nies; they will accommodate medical and special needs
problems where low level or implanted feeding devices are much more widely nowadays, but these should not be
used [10]. However, this will vary from patient to patient. Let assumed, just like a child at school, they should be dis-
us not forget that the feeding device may not be the only cussed and planned. A recent survey by PINNT showed
medical attachment they have, stomas are often present for that adult patients on home artificial nutrition reported
many, along with scars and dressings. that their ability to work was moderately to severely
affected [11].
Education and Work

Travelling and Holidays
It can take several weeks, if not months before usual routines
or lifestyles can be re-established. The prospect of starting/ Planning is key—any time away from home on artificial
returning to school or work may need to be reconsidered and nutrition requires close attention to detail! Where patients
based upon feeding regimes and health, adjustments may be are visiting other countries, it’s good to try and establish
required. links for added support, even determining if there is any help
in terms of fluids, compounding or healthcare, where
possible.
School/Education Most patients want to travel, if not for themselves then for
the benefit of their friends and family, it’s something most
The safety of the patient, in any setting, must be the priority. people take for granted. Often, it’s not the distance you travel
For a child at school or in education determining what help but the personal journey you take.
they may need, what information needs to be shared and Travelling and holidays are enjoyable and fun; for exam-
whether any special arrangements need to be put in place, ple, it is often during a holiday that the thought of a fun pas-
time such as swimming is considered. Patients will have at groups and associations have been established in many coun-
least one feeding device. Currently there is no consensus on tries, and often it’s a case of locating them and providing
swimming. information to the patients as part of their discharge plan-
Travel is also necessary in many aspects of life. For ning. For many patients a large proportion of their energy is
patients who have lifelong artificial nutrition, travel does not channelled into maintaining an image of expected well-
just mean a ‘week in the sun’ but may be required in employ- being. It becomes a natural part of being ill to maintain an
ment and to visit friends and relatives. At times, travel may outwardly positive facade.
be required at short notice, such as the sudden illness or Some groups and associations have been established for
death of a member of the family and the perceived barrier to many years, others are in the early stages of becoming estab-
travel, the artificial nutrition can be especially difficult. lished. Their remits may vary but fundamentally they all pro-
Ensuring patients and their parents and carers can travel is vide a vital support network to patients in their own country
crucial to quality of life. or locality as well as setting up International networks.
Patients travel via various modes of transport, some find Almost all problems experienced by a new patient have been
packing the car easier and less stressful, others want to fly. encountered and resolved by a previous patient. It is reassur-
Cruising is becoming increasingly popular with patients, ing to know that there are others in similar situations who
especially no-fly cruises. Several destinations can be enjoyed can frequently offer support.
in one trip, there are medical facilities on-board and storage— Advice and assistance are tailored to the needs of patients,
especially for parenteral nutrition, and it may be easier to family and carers. Each group will provide the support and
arrange. advice they know their members need. Many will campaign
Due to heightened security around the world, especially for products and services that, if available, would enhance
in airports, navigating the strict security systems may be the quality of life for the patient.
worrying for many. It comes back to planning; making all the Via the patient groups network, we can identify that there
right pre-travel arrangements and having the right paperwork is a distinct inequity in both services and products for those
should ease the stress and aid a swift and safe transition on home artificial nutrition. Some patients are fighting for
through the airport. basic care and services, while others don’t realise the wealth
Where patients have a homecare provider, it’s useful to of choice they have available to them.
find out what help and assistance they provide with arrang- In the UK, the patient group PINNT, is a core group and
ing travel or a holiday. There are variations in services, it’s founder member of the British Association for Parenteral and
always good to ask well in advance of travelling. Some Enteral Nutrition (BAPEN); this well-established relation-
homecare companies have a deadline for requests. ship has been beneficial for all concerned. If we truly believe
The first trip away can be the most daunting. It is best for all aspects of home artificial nutrition should be managed by
the patient to start by talking to their usual healthcare profes- multi-professional teams then surely the patients and carers
sionals to seek advice. Deciding where to go and when are should be part of that. We hope to see this model adopted in
possibly the most important issues to address. If the chosen more countries.
destination is warm, the patient may need to consider extra In addition to groups and associations, modern communi-
fluids to ensure they do not suffer any effects from dehydra- cation methods provide different models of support via social
tion. If the patient is staying in their own country access to media. Most are very useful and credible, but caution should
their usual support networks should be available to them. always be applied when using social media due to its faceless
However, if they elect to go further afield, there are different nature.
aspects to consider. While the basic planning will be the same
for both enteral and parenteral patients, for those transporting
cold-chain parenteral nutrition it may be more complex. Conclusions
Patients, parents and carers need to take great caution
when travelling, make lists, check and re-check, never forget Home artificial nutrition provides patients with an essential
the basic principles that have been learnt, always take safety treatment that can be carried out in their own homes. Often
stock too. Feeding can be done anywhere providing the pro- these treatments have saved lives and brought individuals
cedures and safety aspects are maintained. back from the depths of illness, but not provided a cure. All
age groups, who receive home artificial nutrition, have been
through some very challenging times and no doubt will face
Support Groups/Patient Associations further difficulties in the years ahead [12].
Feeds and formulations are continually evolving and
The best support for patients, parents and carers in terms of feeding lines and tubes are improving all the time. These
adapting to life and facing the future on home artificial nutri- changes contribute to better outcomes for those receiving the
tion, is to meet and talk to others in similar positions. Patient treatments, meaning that many patients are thriving on artifi-
cial nutrition. These improvements also mean that the num- References
ber of adults who have been on artificial nutrition all their
life and have a prognosis of lifelong artificial nutrition is 1. Smith CE. Quality of life in long term TPN patients and their family
caregivers. J Parenter Enter Nutr. 1993;17:501–6.
growing. This provides new challenges for healthcare, for 2. Patient empowerment – a patient-Centre approach to improve care.
example, in a patient with parenteral nutrition, this might Hong Kong Med J. 2002;8(5):372.
mean taking a very conservative approach to preserving 3. Liberating the NHS: No decision about me, without me’. 1st edn.
venous access, given that the patient will need lifelong London. 2012. https://www.gov.uk/government/uploads/sys-
tem/uploads/attachment_data/file/216980/Liberating-the-NHS-
access. Many patients, parents and carers develop an inner No-d ecision-a bout-m e-w ithout-m e-G overnment-r esponse.pdf.
strength and good coping mechanisms. Life presents its ups Accessed 29 Sept 2018.
and downs and they continually endeavour to overcome each 4. Klek S, Forbes A, Gabe S. Management of acute intestinal failure.
of them in their own unique way. Don’t ever assume it’s A position paper from the European Society for Clinical Nutrition
and Metabolism (ESPEN) Special Interest Group. Clin Nutr.
easy; it’s an emotional rollercoaster. 2006;35:1209–18.
Homecare is growing, and we would like to see greater 5. Staun M, Peroni L, Bozzetti F, et al. ESPEN guidelines on paren-
equity for all patients who need these life-saving treatments teral nutrition: home parenteral nutrition (HPN) in adult patients.
at home. When faced with illness or trauma, they should not Clin Nutr. 2009;28(4):467–79.
6. Prioni L, Arends J, Bozzetti F, et al. ESPEN guidelines on chronic
be using their energy to fight for the right to live but channel intestinal failure in adults. Clin Nutr. 2016;35:247–307.
their energy and personal resources into achieving improved 7. Koletzko B, Agonstoni C, Ball P. ESPEN/ESPGHAN guide-
health and an acceptable quality of life. lines on paediatric parenteral nutrition. J Gastroenterol Nutr.
Patients constantly face the problem of projecting a posi- 2006;41:S70–5.
8. Boutin J, Hagan E. Patients’ preference regarding portable pumps.
tive and healthy exterior with no visible signs of the pain and J Intravenous Nurs. 1992;15(4):230–2.
suffering they may be experiencing from their underlying 9. PINNT. Home parenteral nutrition services in England Patient
condition(s). Artificial nutrition has enabled patients to man- Charter, 2016. https://pinnt.com/Support/HPN-Patient-Services-
age this, along with their lives to an acceptable standard. The in-E ngland-Patient-C harter/Patient-C harter-2 016-F inal.aspx.
Accessed 9 July 2018.
permanent links with hospitals and healthcare professionals 10. Magnay S, Wheatley C, Wood S, Forbes A. Comparison of
are accepted as part of their normal life and the patient implanted ports with Broviac/Hickman-style tunnelled catheters for
becomes an active member of any healthcare team. Their long term home parenteral nutrition: the patient’s view. Proc Nutr
continued support in addition to that of the homecare pro- Soc. 1995;54:103A.
11. PINNT. Short bowel syndrome survey. 2017. https://pinnt.com/
vider, partners, friends and family is essential to maintain the getattachment/1862b5f8-7adf-4a5b-94a2-058d7a4002c7/PINNT-
status quo and it is important for them to remember that each Short-Bowel-Syndrome-Survey-2016.pdf.aspx. Accessed 1 July
patient is an individual who must be treated accordingly. 2018.
Everyone should have access to appropriate healthcare 12. Farrer K, Cawley C, Page A, Taylor M, and the BIFA Committee.
Top tips for discharging a patient on home parenteral support in
and support that treats them holistically rather than as a sum England. www.bapen.org.uk/pdfs/bifa/bifa-top-tips-series-8.pdf.
of their parts.
Nutritional Support Services
Simon Lal, Simon Gabe, and Jeremy M.D. Nightingale
Key Points 5. IF/IRUs should continuously collect data and undertake

quality improvement activity on type 2 and 3 IF out-
1. Patients with type 1 (short term) intestinal failure (IF) are comes, including mortality, surgical and catheter/meta-
managed by a hospital multidisciplinary nutrition support bolic complication rates, unplanned re-admissions,
team (NST). By keeping careful data a NST should be waiting times for admission, length of stay and patient
able to justify itself in terms of quality of care and cost quality of life.
savings. 6. IF/IRUs should work to national and international guide-
2. Patients with type 2 (medium term) IF and those re- lines and audit their outcomes.
admitted to hospital with complications associated with 7. There should be close working relationships between IF/
type 3 (long term) IF should be managed by a specialised IRUs and intestinal transplant services with regular MDT
multidisciplinary team on a dedicated Intestinal Failure/ meetings to overview patient selection and follow-up.
Rehabilitation Unit (IF/IRU) in order to achieve an opti- 8. The organisation of hospitals specialising in IF/rehabili-
mal outcome. tation care in a country can be developed into a formal
3. Core members of the IF multidisciplinary team (MDT) network to harmonise patient care.
should include gastroenterologists, IF surgeons, special-
ist nurses, dietitians, pharmacists, interventional radiolo-
gists, microbiologists and psychologists/psychiatrists.
4. A ward dedicated solely to the management of patients Introduction
with type 2 and 3 IF concentrates clinical expertise and
can obtain the lowest central venous catheter-related There are three types of IF [1, 2]. Type I IF (short term) is a
complication rates, while also promoting patient, family common, short-lived and usually self-limiting condition,
and carer support. occurring in approximately 15% of patients in the periopera-
tive setting after abdominal surgery and comprising the vast
majority of all cases of IF on general hospital wards [2].
Indeed, more than 90% of patients requiring PN following
surgery do so for less than 30 days [3]. Such patients should
be managed by hospital NSTs to ensure appropriateness of
PN and minimise their risk of PN-related complications [4].
S. Lal (*) Types 2 (medium term) and 3 (long-term) IF are rarer and
Salford National Intestinal Failure Reference Centre, Northern more complex conditions [1, 2]. Type 2 IF is a prolonged
Care Alliance, Salford, UK
acute condition, characterised by metabolic instability,
whereby patients require intravenous nutrition for weeks or
S. Gabe
months [1, 2]. Type 3 IF is a chronic condition occurring in
Lennard-Jones Intestinal Failure Unit, St Mark’s Hospital,
Harrow, Middlesex, UK metabolically stable patients who require long term, some-
times lifelong, PN; type 3 IF may be reversible or irrevers-
Imperial College, London, UK
e-mail: [email protected] ible [1, 2]. Patients with type 2 IF and those re-admitted to
hospital with complications associated with type 3 IF should
J. M.D. Nightingale
St Mark’s Hospital, Harrow, Middlesex, UK be managed by specialised MDTs on a dedicated IF/IRU in
e-mail: [email protected] order to achieve optimal outcomes [5, 6].

818 S. Lal et al.
Nutrition Support Team hospital, attention can be directed to the nutritional/fluid

requirements with the dietitian and to the composition/com-
If healthcare staff are not skilled and experienced in giving pounding of the PN bags with a pharmacist. Thus the tradi-
clinically assisted nutrition and hydration (CANH) serious tional NST core membership consists of a clinician, NNS,
life threatening complications can occur; with enteral nutri- dietitian and pharmacist though other specialists may be
tion (EN) aspiration pneumonia and local gastrostomy prob- involved particularly when the team works with type 2 and 3
lems; with PN catheter-related blood stream infection patients (e.g. chemical pathologist, microbiologist, radiolo-
(CRBSI), central vein thrombosis and IF associated liver dis- gist) (Table 1). A NST improves the quality of patient care
ease (IFALD). largely though education that improves nutritional assess-
Many disciplines with different, but essential skills ment, appropriate nutrient delivery and reduces mechanical,
(Table 1), are involved in the safe administration of CANH infective and metabolic complications [9, 14]. The rate of
particularly parenteral support (PS) and these staff need to CRBSI should fall to much less than 10/1000 catheter days
communicate regularly with each other to give co-ordinated (ideally nearer to 5/1000 days) after an NST had been formed
planned care. This is most commonly and effectively done by [13, 15].
combining the specialist skills of different disciplines into
one NST that works closely together. The composition of a
NST team is variable in different hospitals but core members ther Staff in the Extended NST and Needed
O
are a clinician, nutrition nurse specialist (NNS), dietitian and for IF/IRUs [10, 16, 17]
pharmacist [7, 8, 11] and they will do a NST inpatient round
2–5 times a week. Gastroenterologists have largely taken on
the role of leading an NST because they can achieve access to Stoma care/tissue viability nurses.
the gut via endoscopic techniques and they manage patients Upper or lower intestinal surgeons (± plastic surgeon).
with intestinal problems. However, some teams are run effec- Social worker.
tively by a non-gastroenterologist such as a general surgeon, Physiotherapist.
chemical pathologist, anaesthetist or endocrinologist. The Occupational therapist.
most important starting member of a new NST is the NNS Psychiatrist/psychologist.
who allows safe PN using aseptic techniques [12, 13]. The Interventional radiologist.
NNS achieves the administration of safe PN with a low rate of Microbiologist.
CRBSI initially by personally caring for the central feeding Speech and language therapist.
catheters and later by teaching others to put up and take down Other specialists as necessary (e.g. haematologist, urologist,
a PN bag [9]. The techniques used to do this involve strict gynaecologist etc).
asepsis (non-touching of key parts) and may be different to Community workers (e.g. dietitians and nurses).
the clean techniques used by other disciplines to care for
Hickman-type lines. Once PN can be administered safely in a Most hospitals in the UK have a NST [18]. While they may
be involved with seeing all types of patient needing nutri-
tional support, they are likely to manage many with type 1
Table 1 Members of a nutrition support team [7–10] IF. Table 2 gives an example of the types of patient referred
Essential to the NST for PN.
member Roles The overall aim of a multidisciplinary NST team is to pro-
Clinician Overall responsibility, co-ordinated care, may insert vide safe up-to date appropriate nutritional and fluid support
enteral and intravenous feeding tubes. Liaises with
the patient’s primary team. Prescribes the parenteral to an individual patient, who is malnourished or at risk of
feeding solution
Nutrition Teaches and supervises care of tubes and catheters
nurse and recognises and manages complications. Places or Table 2 Reasons for 117 patients being given PN by an NST in its first
specialist assists in placement of enteral and parenteral feeding year after formation [19]
catheters. Acts as the patient’s advocate, who also n (%)
trains patients/carers to manage at home Short term—type 1
Dietitian Nutritional assessment, calculates requirements, Ileus 17 (15)
designs feeding regimen and monitors nutritional and
Chemotherapy/GVHD 12 (10)
fluid status. Can also act as a patient advocate
HIV 4 (3)
Pharmacist Responsible for providing enteral feeds and sterile
Medium term—type 2
PN nutrition solutions (may include compounding).
Optimises composition and advises on compatibility/ Fistula/anastomotic leak 35 (30)
stability issues and drug/nutrient interactions Small bowel obstruction 28 (24)
Long term—type 3
NB: the roles may overlap and all are involved in monitoring progress
High output stoma/short bowel 18 (15)
All the core personnel need cover for all their roles in of case time away
(courses, holiday, sickness, etc.) Other 3 (3)
Nutritional Support Services 819
malnutrition, in a co-ordinated fashion. In many of the ing line is inserted relates to the subsequent occurrence of
patients the care also will involve treating over hydration CRBSI providing the insertion is performed using an aseptic
(usually due to excess intravenous saline) or dehydration technique. Most enteral tubes will be inserted by the gastro-
(often due to a high output stoma or fistula). enterologists (naso-jejunal (NJ), percutaneous endoscopic
The NST can be “totally responsible (complete auton- gastrostomy (PEG), PEG with a jejunal extension (PEGJ), or
omy)” in which the team assesses the nutritional and fluid percutaneous endoscopic jejunostomy (PEJ)), some will be
requirements of the patient, established the access for feed- inserted in a radiology department and others in theatres by
ing, writes the prescription, monitors progress and manages surgeons.
any complications. It is easier if the team is also responsible An NST needs to establish good links with the local com-
for the medical management of the patient but this is not munity staff who will care for patients needing enteral feed-
always practical. An alternative way of working is to be ing. There needs to be clear information/guidelines about the
“consultative (or supervisory)” and to see patients and advise care and contact details if there are problems. When this
upon their management. This is more difficult and less effi- works well patients will be discharged home more quickly
cient as it relies upon good communication with the primary and emergency admissions can be prevented.
medical team, who need to act upon the advice offered. Often The NST is likely to undertake a large educational role
a team will work in a totally responsible way on some wards both teaching (undergraduates and postgraduates in medi-
(e.g. medical gastrointestinal and surgical wards) and in a cine and nursing, all healthcare workers and many carers/
consultative capacity on others (e.g. ITU, haematology and patients) and writing guidelines/policies and setting stan-
oncology). At least one member of an NST must see all dards. These are likely to be about nutritional assessment,
patients needing PN daily. indications and management of EN and PN. The NNS may
The team may perform some procedures itself. Some teach and establish link nurses on the relevant wards.
teams insert all central parenteral lines themselves with or The UK NICE guidelines recommend that all hospital
without ultrasound and/or X-ray guidance. Others may insert trusts have a nutrition steering committee (NSC) to co-
the peripherally inserted central catheters (PICC) themselves ordinate the nutritional care within a hospital and in addition
and ask radiologists, surgeons or anaethetists to do other cen- to the NST this includes catering and dietetic services [8]
tral lines. There is no evidence that the place a central feed- (Fig. 1). In the UK, a freedom of information request in 2017
Fig. 1 Organisation of Organisation of nutritional support within a hospital

nutritional support within a
hospital
820 S. Lal et al.
showed that 80% of Trusts have a NSC [18]. Core members about wasted PN bags, central vein thrombosis and IFALD,
of the NST are members of and will report to the NSC which and PEGs not inserted and PS not deemed appropriate.
oversees their actions and reports directly to the Trust Board While the employment of a NST involves costs these can
(see Fig. 1). Some members of the NST may become be offset by showing quality benefits and cost savings. In
involved in the hospital catering. terms of PS, the savings come in avoiding giving PS (using
EN instead) and in reducing complications especially CRBSI
[13]. Additional cost savings can be made by an NST reduc-
he Setting Up and the Continuation
T ing the number of PEGs that are inserted [23] and preventing
of a Hospital NST PN bags from being wasted.
The NST must have plans for backup staff to cover holi-
The process of setting up a team is slow and involves chang- day, study leave and sick leave.
ing the culture of an organisation to one that realises the
importance of such a team and questions why it does not
have one. This process involves making many presentations I ntestinal Failure or Intestinal
to management and healthcare workers. This can be done Rehabilitation?
simply using three questions; where are we now, where do
we want to be and how do we get there? In addition a As described in this book, IF occurs in patients who require
strengths, weaknesses, opportunities and threats analysis nutritional support to survive and there are established types
may be used (SWOT analysis). In making a business case of IF (types 1–3). However, for patients/relatives the feeling
alternatives need to be proposed and these include doing that they have a failing organ is not a helpful perception
nothing, having a fully functioning salaried team with especially if this is a long term or indefinite situation (type 3
backup, or in-between situations (e.g. employing a nutrition IF). Being treated in an IRU by specialists in intestinal reha-
support nurse only). bilitation implies both hope and specialism. Consequently,
In a hospital with no NST, there is likely to be a problem some units around the world (England, North America,
of unrecognised malnutrition which may be poorly treated Columbia and the Middle East) are adopting this terminol-
with high complication rates and high rates of PS bags being ogy that includes rehabilitation (rather than failure) within
wasted. There may be no or few policies / guidelines and their names to become an IRU with doctors and other health-
care is likely to be fragmented and uncoordinated. To dem- care professionals specialising in the various elements of
onstrate the poor current situation background local data intestinal rehabilitation. Small changes like this can make a
needs to be collected; this may include looking at the preva- big difference to patients and relatives.
lence of in-patients who are undernourished or at risk of
becoming undernourished and determining how many of
these are unrecognised [20] and the staff knowledge of Referral to a Specialised IF/IRU
undernutrition and its treatment [21]. The rate of CRS, wait-
ing time for venous access for PN, waiting time for NJ or Specialised units caring for patients with IF are usually
PEG tube placement, and the number of wasted parenteral called intestinal failure units (IFU). However, the teams offer
feeding bags is relatively easy to obtain. The number of positive ways of helping patients manage with a life threat-
PEGs inserted, their appropriateness and the 30 day mortal- ing condition.
ity rate following placement may also be audited. In the U.K., a service specifications outlined referral rec-
The two key steps in setting up a NST are to establish a ommendations for specialised IF care [24] (Table 3). Patients
Nutrition Steering Committee (NSC) which reports directly with type 2 IF include those requiring prolonged PN support;
to the Trust board and to appoint a NNS who can perform the duration of support can vary but, in general, patients
and teach the aseptic techniques to safely set up and take needing more than 28 days of PN tend to cross the threshold
down a parenteral feeding bag. from having type 1 to 2 IF. However, if the referring team
The continuation of the NST at first will depend upon it have difficulties managing the patient’s medical and/or sur-
keeping good audit data. As a minimum it must record details gical IF needs prior to 28 days, then earlier referral is appro-
of all patients seen and data about every episode of CRBSI priate. Intestinal rehabilitation teams should proactively
and every other complications of parenteral support (PS) manage patients referred on any waiting list through regular
[22]. It should present infection data per 1000 catheter days; contact with referring teams in order to optimise the patient’s
percentage of infections is not such a good indicator as it condition prior to transfer and to make pre-emptive admis-
gives no indication of the duration of the feeding before an sion and discharge plans. This may include multidisciplinary
infection occurred. There should be a clear definition of what contact by a nurse, dietitian and/or physician/surgeon and
a CRBSI is (definite and probable). It may also have data can involve the use of telemedicine. Any urgent non-IF
Table 3 Referral indications for specialised intestinal rehabilitation ment and care should take into account the patients’ needs
care [24]
and preferences.
PN with complications or PN whose duration is causing concern . Depending on the patient’s individual requirements, the
• More than two episodes of catheter related blood stream core MDT may require access to additional specialised ser-
infection
• Uncontrolled high output stoma despite standard management
vices, such as urologists, gynaecologists, pain management
• Central venous thrombosis with associated access problems teams, plastic surgeons, physiotherapists, clinical biochem-
• Persistent metabolic complications (e.g. liver or renal ists, occupational therapists and social services [1, 5].
dysfunction, diabetes) Adoption of a cohesive multidisciplinary approach to
• Significant associated psychiatric co-morbidity intestinal rehabilitation care is integral to successful intesti-
IF with intra-abdominal sepsis, fistulation and/or open abdomen
nal rehabilitation outcomes. The ‘Sepsis-Nutrition-Anatomy-
• Recurrent/persistent severe abdominal sepsis
Plan’ approach is a tried and tested means to manage the
• Complex fistulation requiring surgical reconstruction
• Dehisced abdominal wound or open abdomen needing patient with complex IF needs and can form part of the
reconstruction MDT’s core standard of care [1, 5].
• High output enterocutaneous fistula despite standard
management
• Need for distal limb feeding
IFU/IRU Environment
• Surgery in a patient with radiation enteritis or inherited
connective tissue disorder
• Persistent IF with significant comorbidity There is a learning curve for the MDT managing patients
IF occurring in patients requiring intestinal reconstruction requiring long term PN, and this affects patient outcomes
• Surgery for severe intestinal dysmotility [26]. Indeed, since then, evidence has confirmed that lack of
• Intestinal lengthening team experience can have an adverse experience on the sur-
Surgical re-appraisal vival of patients with type 3 IF [27]. For example, it is clear
• Severe intra-abdominal adhesions/potentially hostile abdomen
that the reported incidence of CRBSI rates varies hugely
• IF due to encapsulating peritoneal sclerosis
Establishment on HPN between different centres and that experienced teams with
• Short bowel syndrome established CVC care protocols achieve the lowest CRBSI
• Uncontrolled high output stoma or fistula rates for both outpatients and inpatients [28, 29]. This was
• Severe intestinal dysmotility or mucosal disease leading to recently further evidence based in a large multinational study
malabsorption unable to meet needs via enteral nutrition of 2194 HPN-dependent patients from 65 centres which
• Advanced malignancy with loss of intestinal function
demonstrated that the risk of death on HPN and the occur-
rence of a CVC infection were both negatively associated
related confounding medical issues should be optimised with the number of patients included in the study by the indi-
prior to transfer, where it is safe and appropriate to defer vidual HPN centre; again, the implication of these findings is
transfer to the IF/IRU. If required, direct transfer to the that centres managing larger cohorts, with therefore likely
intensive care may be needed in exceptional circumstances greater IF experience, can achieve better outcomes [30]. A
for clinical stabilisation prior to admission to the IF/IRU challenge now is to share best practice between established
ward. It is incumbent on the intestinal rehabilitation service IFUs and emerging teams in the same and other countries in
to minimise waiting times for transfer where possible; such order to standardise the care delivered so that optimal out-
an approach can mitigate the risk of IF-related morbidity and comes can be achieved in all centres.
mortality prior to transfer [25]. In the U.K., dedicated IFUs were established in Salford
and London in the late 1970s. Both services and the teams’
experience have grown over time; the IFUs commenced as
IF/IRU Multidisciplinary Team small, 4–5 bedded units and have grown to current estab-
lishments housing more than 20 beds each. These units
A broad and experienced MDT (Table 1) is required to man- have ring-fenced beds within the hospital solely for patients
age the complex needs of patients with types 2 and 3 IF. Core with type 2 or those readmitted with type 3 IF. A clear
clinical members involved in day-to-day patient care include advantage of such dedicated units includes the ability to
specialist gastroenterologists (with experience in nutrition concentrate multidisciplinary expertise into one area within
support), IF surgeons (usually with a colorectal background), the hospital. A key component to day-to-day patient care
specialist nurses, specialist dietitians, specialist pharmacists, includes nursing expertise to manage large laparostomy
interventional radiologists, microbiologists and psycholo- wounds and long term central venous catheters (CVC).
gists/psychiatrists. Patients should be given every opportu- Meticulous care is required to achieve wound healing and
nity to make informed decisions about their care and optimal surgical outcomes, while maintaining a low CVC
treatment, in partnership with their MDT. Subsequent treat- infection rate, so as not to add to the patient’s metabolic
822 S. Lal et al.
instability with an additional focus of infection. Thus, by chology review where necessary with positive feedback from
concentrating intestinal rehabilitation nursing expertise on patients, particularly through avoiding the need to travel
one ward within a hospital allows teams to achieve very [31]. Following the recent Covid-19 pandemic this has
low in-patient catheter infection rates on such units as com- become much easier to perform for both the healthcare staff
pared to patients receiving PN on general hospital wards. and patients.
While quality improvement measures, including the intro- It is also, of course, vital that all intestinal rehabilitation
duction of a nutrition support team, were shown to reduce teams offer 24-h access to specialist advice and admission to
the catheter-related infection rates in patients with type 1 IF the dedicated IF/IRU when required. Patient guided self-
receiving PN on general hospitals ward to a low level of management using appropriate education material reduces
around 0.7 per 1000 [4], this figure was still greater than complication rates and anxieties related to HPN complica-
17-fold higher than the 0.04 in-patient catheter- related tions; both U.K. units have also found that the use of novel
infection rate reported for patients with type 2 and type 3 IF personal health records or e-portal systems supports this
cared for on a dedicated IFU in the same hospital in Salford approach by allowing patients and other hospital teams
[29]. access to clinical records as well as secure ways of patients
Beyond very tangible clinical outcomes such as cathe- interacting with their clinical team while at home [32]. Using
ter infection rates, dedicated IF/IRUs also benefit patients these systems patients can ask questions from the team as
and families by providing an environment for patient-to- well as upload images, results or correspondence. In addi-
patient peer support. Patients can stay in hospital for a tion, some personal health record systems enable easier com-
number of months, often a significant distance from home munication between different healthcare professionals,
and, therefore, appropriate facilities also need to be especially when transferring information between multiple
offered on the IF/IRU to improve patient outcomes and care providers [33].
enhance patients’ and families’ experiences. Access to As survival improves, an increasing requirement for tran-
social areas, overnight accommodation for families and sition from paediatric to adult centres has been recognised in
catering facilities help patients and their visitors interact, most countries. Again, considered and early outpatient MDT
so promoting the peer support that is fundamental in help- involvement in these processes is mandatory to manage
ing individuals live with chronic and rare conditions. A patient and parent expectation, minimise risk and also, ulti-
quiet area or room that allows psychological counselling, mately, achieve autonomy for the patient in managing his/her
along with more specialised facilities such as cold storage own long term healthcare needs.
for PN and bioelectrical impedance equipment for dietetic
assessment, can also help focussed delivery of care by the
MDT. In the past, both U.K. units dedicated an area for Quality Outcomes
training patients to administer PN while in-hospital.
However, with an increasing service demand and associ- It is the responsibility of all IF/IRUs to collect data on out-
ated pressure on in-patient beds, patients are now trained comes of type 2 and 3 IF, including mortality, re-fistulation
at home by home care nursing teams with no detriment rates, CRBSI rates, CVC thrombosis rates, unplanned re-
noted to CRBSI rates [28]. admissions, waiting times for admission and length of stay.
Progressive teams are also encouraged to embrace quality
improvement methodology to address any issues that may
Out-Patient Follow-Up arise; examples of successes of this approach include prac-
tice changes to reduce admission waiting times and in-
Patients with type 3 IF require regular review in the outpatient lengths of stay [34], as well as PN wastage [25]. It is
patient setting by the MDT, not only to ensure safe and tai- now equally incumbent on intestinal rehabilitation teams to
lored delivery of PN support, but also to optimise patient and evaluate the quality of life of patients with IF. We aim that
family psychological wellbeing. Thus, the outpatient MDT completion of a needs-based QoL tool that takes patients
largely mirrors that delivering inpatient care, with dietetic minutes to complete, will now be routine practice for
and pharmacy review, physician and surgical input, as well patients with type 3 IF in the U.K. [35]. While established
as nursing and psychological support. While patients may tools such as the hospital anxiety and depression scale can
require regular hospital attendance for physical examination, currently be used for in-patients, a more dedicated patient-
there has been an increasing desire by patients to avoid long reported outcome measure is required for patients with type
distance travel, such that established IFU MDTs now offer 2 IF. Ultimately, all recorded clinical and quality of life out-
the option of telemedicine (with telephone or video consulta- come measures should be part of a national IF registry,
tions) [31]. Notably, this approach has not only been offered allowing continued monitoring of intestinal rehabilitation
for medical review, but also for dietetic, nursing and psy- service provision.
Home HPS Care Providers Consequently, in 2007 a national review was undertaken
by the NHS which resulted in the publication in 2008 of ‘A
In the UK there is a PN framework contract with commer- Strategic Framework for Intestinal Failure and Home
cial companies that compound, dispense, and deliver the Parenteral Nutrition Services for Adults in England’ [10].
PS bags. They are responsible for supplying all equipment There was significant geographical variation seen in the
(fridge, pumps, drip stands, working surface etc) and management and prevalence of both type 2 and type 3 IF. In
ancillaries (dressing packs, flushes etc). They have to addition, there was no consistent coding to identify patients
ensure they meet quality, time, cost and professional stan- with type 2 IF and the costs were high to manage these
dards. In addition, an increasing number of patients have patients. It was proposed that a network of specialist hospi-
the feed set up and taken down by the companies trained tals differentiated by their skill sets would be best to cater for
nursing staff. the population of patients with IF in England. A specialised
definition set was also developed which included standards
that should be met by the service [24].
Intestinal Transplantation Recently, in England a network comprising HPN centres
(predominantly care of type 3 IF), Integrated Care (IC) centres
Around the world there are very different approaches to the (caring for patients with both types 2 and 3 IF) and National
timing and position of intestinal transplantation in the man- Reference Centres has been developed. In 2021 the IC and
agement of patients with IF. This can relate to the availability National Reference Centres were appointed with the HPN cen-
and success of HPN and transplant services in different tres appointed later in 2021. The whole network (HIFNET—
countries and healthcare systems. Both services are costly Home parenteral nutrition & Intestinal Failure NETwork) will
for any healthcare service and some countries do not offer work to common protocols and standards to help to unify prac-
either service. In countries that offer both long term HPN tice across the country to the overall benefit of patients.
and intestinal transplantation, there will be established crite- This approach to develop a network of units or hospitals
ria that need to be met for intestinal transplantation (chapter within a country by the NHS is unique and we believe that it
“Intestinal Transplantation”). will help to set a standard globally as well. There is very
Unlike heart, lung and kidney transplantation, there is significant geographical variation in both the prevalence of
much less awareness of the possibility of intestinal trans- IF and the management of the condition, which would ben-
plantation in the general public, patients and even healthcare efit from harmonisation.
workers [36]. The staff working in an IFU/IRU need to be Networks between countries are more difficult to organise
aware of the indications for transplantation and should also but the European Society of Enteral and Parenteral Nutrition
be aware of the patient journey undergoing an intestinal (European Society of Clinical Nutrition and Metabolism)
transplant in order to start this conversation. At a practical (ESPEN) and the American Society for Parenteral and
level, this may be easier where an IF/IRU is co-located in the Enteral Nutrition (ASPEN) have been instrumental in help-
same hospital as an intestinal transplant centre. For IF/IRUs ing to facilitate this by developing guidelines for these condi-
that are not co-located with an intestinal transplant centre, it tions [5, 6, 37–40]. In addition, ESPEN developed special
is important that there are close working relationships with interest groups in both acute and chronic IF enabling interna-
the regional or national transplant service that involves sys- tional cooperation, surveys and studies. The BAPEN special
tems for regular MDT meetings to overview patient selection interest group (BIFA, the British Intestinal Failure Alliance)
and follow-up. has also developed guidance and top tips that have been
widely disseminated (www.bapen.org.uk/about-bapen/
bapen-special-interest-groups/bifa).
IF Networks Within and Between Countries
In 2001 a patient survey in the UK by the patient advocacy Appendix

group PINNT suggested that patients appreciated expert care
in specialised centres with high reputations, but found the Key Education Topics for Members of a NST [41]
distances involved in attending these units for routine care,
unforeseen problems or emergencies excessive. Patients 1. Understand the role of a hospital nutrition support team
want care that leads to an improved quality of life. However, (NST) in giving good quality, safe nutritional care.
in view of the fact that severe IF is a rare condition, there has • Consists at least of a clinician, nutrition nurse special-
to be a balance between centralising the expertise required ist, registered dietitian and pharmacist.
for specialised services and providing more accessible ser- • Advises and manages the care of patients needing clin-
vices with potentially less expertise. ically assisted nutrition and hydration.
824 S. Lal et al.
2. Include nutritional/fluid status into every patient’s clinical complications and the duration of the hospital
notes and state where appropriate a nutritional/fluid care admission.
plan.
Recognition/Detection of Patients Who Are Malnourished or
Basic Physiology at Risk of Becoming So
3. Understand how appetite/food intake is regulated. This 12. Appreciate the methods and importance of formally
includes neurological, hormonal and psychological assessing nutritional status and the limitations of relying
mechanisms. on the initial clinical impression alone. The assessments
4. Understand the processes of digestion and absorption (for include:
macronutrients, water, minerals and vitamins), including • Detecting those currently malnourished from the cal-
the importance of colonic fermentation. Know the vol- culation of BMI, percentage weight loss and mid arm
umes of the gastrointestinal secretions in health. Know muscle circumference. A measure of muscle function
the variable length of the ‘normal’ small intestine. (e.g. grip strength or sit up to squat (SUSS) test) may
5. Know how the estimated daily requirements are derived help. Other tools may be used and include subjective
and appreciate that they vary with rest, physical activity, global assessment (SGA), malnutrition universal
illness and during life. screening tool (MUST) and the global leadership ini-
6. The essential components of a diet are macronutrients tiative on malnutrition (GLIM).
(carbohydrate, fat and protein), water, minerals (includes • Detecting those at risk of becoming malnourished
those often referred to as electrolytes (Na, K, Cl, Mg, P) from the current nutrient intake and the illnesses’ pre-
and trace elements (e.g. Se and Zn)) and vitamins. Know dicted course.
the daily requirements for water and key minerals in 13. Recognise intake (oral) failure (inability to get food into
health and in illness (including post-operatively). the gut) due to poor dentition, poor appetite, head/neck
7. Understand how inflammation and specific diseases cancer/trauma, neurological disease (e.g. stroke, cere-
(including sepsis, trauma, burns and cancer) and their bral palsy, motor neurone disease, multiple sclerosis)
treatments influence nutritional status and needs by and psychological disorders (e.g. dementia, depression
affecting: and anorexia nervosa).
• intake, digestion and absorption 14. Recognise the symptoms and signs of typical and atypi-
• requirements cal eating disorders (and other psychological problems)
• losses of water and electrolytes (e.g. from the gut or and know how/when to obtain help from eating disorder
urine) specialists.
8. Know the effects of acute and chronic malnutrition on 15. Recognise digestive and absorptive (intestinal) failures.
physiological (especially muscle), biochemical, immuno- Digestive failure is due to gastric or pancreatic disease
logical and mental processes. and absorptive (intestinal) failure due to short gut, intes-
9. Understand the processes of adaptation (hyperphagia, tinal fistula, obstruction, dysfunction or mucosal
structural and functional adaptation) that may occur in disease.
patients with a short bowel (especially when the colon 16. Identify patients at risk of developing refeeding prob-
remains in continuity). lems (e.g. low phosphate) when food (especially carbo-
hydrate) is introduced to a malnourished patient. Know
Problems of Malnutrition the principles to prevent and treat this.
10. Be aware of the effect of malnutrition on clinical out- Recognition of Patients Who Are Dehydrated or Overhydrated
comes (including complications, length of stay and read-
mission rate) via mechanisms including: 17. Recognise the clinical symptoms, signs and observa-
• muscle strength (thus mobility and respiratory reserve), tions (e.g. weight, fluid balance, postural blood pressure,
• wound healing and the risk of pressure ulcers urine sodium concentration) of over and under
• resistance to infection hydration.
Problems of Under and Over Hydration Treatment (Nutrition and Fluid)
11. Dehydration may cause acute and chronic kidney injury 18. Appreciate that giving nutritional support to malnour-
and death. Over hydration (especially saline excess in ished patients improves the quality of life, morbidity and
surgical patients) delays recovery, increases mortality, mortality. Some diseases (e.g. COPD, CCF, IBD and
cancer) and surgical procedures have a better outcome if teral feeding in hospital and at home. London: Kings Fund Centre;
1992.
nutritional status is improved or normalised.
8. Nutrition support for adults: oral nutrition support, enteral tube
19. Know how to calculate fluid requirements (including an feeding and intestinal failure. Clinical guideline [CG32]; 22 Feb
intravenous infusion regimen for a patient taking noth- 2006. Last updated August 2017.
ing by mouth) and know how to take into account losses 9. Nightingale JN. Nutrition support teams: how they work, are set up
and maintained. Frontline Gastroenterol. 2010;1:171–7.
(e.g. nasogastric aspirate, small bowel stoma/fistula out-
10. A Strategic Framework for Intestinal Failure and Home Parenteral
put). Be able to monitor fluid balance with daily weight Nutrition Services for Adults in England. April 2008.
and fluid balance charts; and sodium balance with a uri- 11. Powell-Tuck J. Organisation of food and nutritional support in
nary sodium concentration (especially important in hospitals. Redditch: British Association for Parenteral and Enteral
Nutrition; 2007.
patients’ with a small bowel stoma/fistula).
12. Keohane PP, Jones BJ, Attrill H, Cribb A, Northover J, Frost P, Silk
20. Know the indications and goals for nutritional/fluid sup- DB. Effect of catheter tunnelling and a nutrition nurse on cath-
port. Have knowledge of the routes (oral, enteral and eter sepsis during parenteral nutrition. A controlled trial. Lancet.
parenteral) of giving nutritional support and the advan- 1983;ii:1388–90.
13. Kennedy JFR, Nightingale JMD. Cost savings of an Adult Hospital
tages and disadvantages of the different forms of nutri-
Nutrition Support Team. Nutrition. 2005;21:1127–33.
tion/fluid support. 14. Vlug LE, Nagelkerke SCJ, Jonkers-Schuitema CF, Rings EHHM,
Tabbers MM. The role of a nutrition support team in the manage-
Problems of Treatment ment of intestinal failure patients. Nutrients. 2020;12(1):172.
15. Mughal MM. Complications of intravenous feeding catheters. Br J
Surg. 1989;76:15–21.
21. Have knowledge of the problems that can occur with 16. A strategic framework for intestinal failure and home parenteral
enteral nutrition (e.g. mal-positioned enteral tube, leak- nutrition Services for Adults in England. Implementation plan; Feb
age, blockage or associated diarrhoea) and with paren- 2009. www.ncg.nhs.uk/?dl_id=330.
17. Puntis J, Beath S, Beattie M et al. Intestinal failure: recommenda-
teral nutrition (e.g. catheter-related blood stream
tions for tertiary management of infants and children. A Report by
infection, central vein thrombosis/stenosis, intestinal the Intestinal Failure Working Group, British Society of Paediatric
failure associated liver disease and metabolic bone Gastroenterology, Hepatology and Nutrition, and the British
disease). Association of Paediatric Surgeons. 2007.
18. Hollingworth T, Akbar T, Oke S, McKee R, Smith T, Gabe
S. Nutrition Support Teams & Committee’s in the UK: the current
Ethics picture. Gut. 2018;67(Suppl):A174–5.
19. Kennedy JF, Baker ML, Nightingale JMD. Appropriate parenteral
22. Know and understand how to apply the principles of the nutrition – the role of the hospital nutrition support team. Clin Nutr.
2002;21(Suppl 1):35.
ethical and legal aspects of providing, withholding or
20. Nightingale JMD, Walsh N, Bullock ME, Wicks AC. Three simple
withdrawing nutrition and hydration treatment. This methods of detecting malnutrition on medical wards. J Roy Soc
includes autonomy, beneficence, non-maleficence, jus- Med. 1996;89:144–8.
tice and mental capacity. 21. Nightingale JMD, Reeves J. Knowledge about the assessment and
management of undernutrition: a pilot questionnaire in a UK teach-
ing hospital. Clin Nutr. 1996;18:23–7.
22. Austin P, Stroud M. Prescribing adult intravenous nutrition.
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et al. Improving quality in a National Intestinal Failure Unit:
Ethical and Legal Aspects of Nutritional
Support
Andrew Rochford
Key Points health) is declining with increasing incidence and prevalence

of conditions such as cancer and dementia. For example, in
1. Artificial nutrition and hydration constitute medical the United Kingdom (UK) it has been estimated that 1.3 mil-
treatment. lion people aged over 65 are malnourished or at risk of mal-
2. Nutrition support should be considered in people who are nutrition. One third of people in this age group are found to
malnourished or at risk of malnutrition. be at risk of malnutrition when they are admitted to hospital,
3. The first question should be ‘what are we trying to and the same proportion are discovered to be at risk on
achieve’? If in doubt, a trial of clinically assisted nutrition admittance to a care home [2]. The use of a validated nutri-
and hydration with clearly agreed objectives may be tion screening tool such as the Malnutrition Universal
appropriate. Screening Tool (‘MUST’) is essential to identify nutritional
4. It is essential to consider the pre-existing wishes of the risk and enable action to be taken at the earliest opportunity
patient and adhere to the core ethical principles of auton- to reverse or delay the progress of malnutrition. There is also
omy, non-maleficence, beneficence and justice. an increasing drive to encourage patients to self-screen with
5. Decisions should be made as a multi-professional team clinically validated tools such as the Patients Association
and clearly communicated and documented. Nutrition Checklist [3].
However, it is not simply ageing that challenges the legal
and ethical provision of Clinically Assisted Nutrition and
Hydration (CANH). The number of patients living with
Introduction chronic disease and long-term conditions that compromise
their nutritional intake is also increasing. The number of
The number and proportion of people aged 60 years and patients on home enteral tube feeding (HETF) is on the
older in the world population is increasing. In 2019, the increase worldwide due to advances in technology, develop-
number of people aged 60 years and older was one billion. ment of percutaneous endoscopic gastrostomy (PEG) tech-
This number will increase to 1.4 billion by 2030 and 2.1 bil- niques, and the shift in care provisions from acute to
lion by 2050. This increase is occurring at an unprecedented community settings. For example, in the UK in 2015 72% of
pace and will accelerate in coming decades, particularly in HETF patients registered as part of the British Artificial
developing countries [1]. It is important to acknowledge that Nutrition Survey (BANS) were living in their own home [4].
millions of people globally are malnourished and face food While the significance of home enteral nutrition in meeting
insecurity on a daily basis. This represents its own ethical the nutritional requirements of patients with poor swallow-
and social challenge but is beyond the scope of this chapter. ing reflexes and those with poor nutritional status is not in
Although life expectancy is rising, healthy life expec- doubt, differences exist in terms of funding, standards, man-
tancy (i.e., the number of years we can expect to live in good agement approaches and the level of infrastructural develop-
ment across the world [5].
The provision of CANH often presents an ethical chal-
lenge to many clinicians; in the context of changing health
and social demographics, this challenge is set to increase.
A. Rochford (*) The subject is incredibly emotive for patients, relatives and
Royal Free London Hospitals NHS Foundation Trust, London, UK carers, and staff as the provision of food and water represent
the most basic requirements for life.

828 A. Rochford
Ethical Position When making decisions about the appropriateness of a

medical intervention clinicians must balance the benefits
Biomedical ethics is underpinned by four main tenets: (beneficence) and risks of harm (non-maleficence) from the
intervention. It is important to note that potential harm may
1. Autonomy—respecting and supporting autonomous not only be physical but can also be psychological or involve
decisions infringement on a patient’s privacy or liberty. In some cases,
2. Non-maleficence—avoiding the causation of harm there will be a conclusion that treatment will not yield or
3. Beneficence—a group of norms pertaining to relieving, may no longer yield any benefits and/or the risks of harm
lessening, or preventing harm and providing benefits and outweigh the anticipated benefits. In other words, the medi-
balancing benefits against risk and costs cal intervention is inappropriate or disproportionate. This
4. Justice—ensuring fair distribution of benefits, risks and situation is described as “therapeutic obstinacy” (or unrea-
costs [6]. sonable obstinacy). In such cases, the clinician may legiti-
mately decide, in their dialogue with the patient, not to
These should not be seen as a set of rules but rather perspec- implement the treatment or to withdraw it [9].
tives that should be used to frame and facilitate discussion in There is no obvious means of measuring whether medical
order to reach consensus (Fig. 1). Important principles to interventions to provide CANH are disproportionate. Even
help guide these discussions are the sanctity of life and the though there are medical criteria from evidence-based medi-
preservation of dignity. The sanctity of life means that the cine, which can be used to evaluate risks and benefits,
life of a patient is valuable in itself and does not depend on whether or not treatment is proportionate will be assessed in
their social or economic achievements. However, the princi- the light of the patient’s situation as a whole. Clinical deci-
ple of the sanctity of life does not mean that life should be sions are the result of a reconciliation between the will of the
preserved at all costs. For instance, it need not oppose with- patient and the assessment of the situation by a healthcare
drawal or withholding of treatment in particular cases. professional taking into account all the ethical tenets.
Neither does the principle of the sanctity of life mean that a
patient’s autonomous wish to refuse treatment may be over-
ridden. The preservation of dignity means that, at all times, Religious and Cultural Context
the patient should be treated with respect [7]. These princi-
ples are internationally recognised and underpin all aspects Eating and drinking are not simply essential for maintaining
of clinical practice. Furthermore, these principles are inter- nutrition and hydration. They are important for pleasure and
related, and this should be taken into account when consider- social interactions – food and mealtimes are a way we con-
ing their application. nect with others and can often be an expression of our cul-
The principle of autonomy recognises the right and the tural identity.
capacity of a person to make a personal choice. People may The provision of oral nutritional support should therefore
refuse support even if the refusal is difficult to understand by be the preferred method of choice for any patient with inad-
others and may change their mind at any time with regard to equate food and fluid intake to meet requirements, unless
consent [8]. Autonomy does not mean that a patient has the they cannot swallow safely, have inadequate gastrointestinal
right to obtain every treatment they wish or request, if this function or if no benefit is anticipated, for example in the last
particular treatment would not be medically indicated. days of end-of-life care [7].
Fig. 1 Ethical considerations

for clinical care
Ethical and Legal Aspects of Nutritional Support 829
Modern society is an amalgam of different religious, eth- Table 1 Factors encouraging CANH [11]
nic and cultural backgrounds, and beliefs. Attitudes to end- Party
of-life care and the sanctity of life vary widely between involved Factors encouraging CANH
different groups. Additionally, medical staff will inevitably Relatives • Unwillingness to accept terminal prognosis
• Belief in cruelty of dying process if ANH not
judge patients according to their own morals and beliefs. It is administered
beholden on all those involved to respect these views and • Need to demand interventions to avoid guilt
wherever possible take account of them in a sympathetic and Clinicians • Lack of familiarity with palliative care techniques
understanding manner [8]. and evidence
• Length of time needed to educate families
The ethics of refusing or withdrawing nutrition and hydra- • Desire to avoid controversial decisions
tion from sick or dying patients has a substantial history with • Fears of litigation
theological discussions dating back more than 400 years; Others • Fear of regulatory sanctions if ANH not provided
this suggests that there has always been a significant ethical (nursing homes)
• Extra time and staff needed to assist with oral
dilemma to the provision of CANH.
feeding
Legal and Regulatory Position

In the acute setting, the ethical challenges around provid-
Generally, in law, the term ‘child’ is used to refer to people ing CANH frequently involve patients who lack capacity
under the age of 18. The law treats a child’s consent to treatment with increasing pressure for clinicians to prescribe CANH
differently from a refusal of consent. This is because it assumes for a number of reasons (see Table 1). However, healthcare
that healthcare professionals who propose treatment do so for professionals should not be tempted to underestimate the
good reasons [7]. The provision of nutrition and hydration to patient’s capacity to make a decision and should make every
children and adolescents may differ from adults; in this section attempt to assist this process.
we will focus on the legal and regulatory position in adults. The legal and regulatory position on the provision of
The provision of food and drink by mouth is seen legally as CANH varies in different countries and often within differ-
basic care whereas the provision of CANH is considered a ent states. It. Is therefore paramount that appropriate advice
medical treatment in many, but not all countries. The compe- is sought where there may be doubt or confusion.
tent patient has the right to participate in decision making and
to refuse treatment although a doctor is not obliged to give
treatment which they consider futile or against the patient’s Patients Who Lack Capacity
interests. There is often a delicate balance between professional
judgement and patients’ rights which on occasion has been The provision of nutrition and hydration is a basic human
legally challenged. The ethical principle of autonomy under- right. It is only in circumstances where a person is unable to
pins the legal process of consent as it is the patient’s consent eat and drink for themselves or adequately maintain their
that makes invasive medical treatment lawful. Clear guidance required nutrition and hydration where medical intervention
has been provided by the British Medical Association and the may need to be considered and the principles of biomedical
Law Society regarding gaining consent in the UK (see Box 1). ethics applied.
Someone’s capacity may be affected by cognitive impair-
ment which may be permanent (e.g. dementia) or temporary
Box 1 Best practice guide for gaining consent [10] (e.g. delirium), a learning disability, or a mental health prob-
A person should be able to: lem. There may be other clinical reasons which affect peo-
ple’s capacity, for example sedation or anaesthesia. It is
• Understand in simple language what the medical important to recognise therefore that decisions regarding the
treatment (or research intervention) is, its purpose provision of CANH may need to be assessed over a period of
and why it is proposed. time.
• Understand its principle benefits, risks and The Mental Capacity Act 2005 (MCA) is a statute in force
alternatives. in England and Wales [11]. It sets out a legal framework for
• Understand in broad terms what will be the conse- determining mental capacity and making decisions on behalf
quences of not receiving the proposed treatment. of people aged 16 and over who lack the capacity to decide
• Retain the information for long enough to make an for themselves and provides a good reference with which to
effective decision. frame discussion in this section.
• Make a free choice without pressure. The MCA specifies that any act done, or decision made,
for a patient who lacks capacity, and does not have a valid
830 A. Rochford
and applicable advance decision to refuse treatment, must be it is medically justified. Patients may have capacity to make
done or made in their best interests. This means that a some decisions but not others and so the standard of practice
decision-maker must consider all relevant circumstances, around informed consent still applies. Equally, patients with
including any wishes, feelings, beliefs and values of the mental health disorders may lack capacity in the same way
patient. The MCA provides very useful guidance on how to as anyone else in which case treatment will be deemed legal
determine capacity (summarised in Box 2). if it is in the patient’s best interest.
Under carefully specified circumstances, CANH may be
considered a medical treatment for a mental health disorder.
Box 2 Best Practice Guide for Assessing Capacity For example, in eating disorders such as Anorexia Nervosa,
malnutrition contributes to the psychiatric burden of the ill-
The MCA says that a person has capacity if they are ness and in extreme cases CANH may need to be enforced to
able to: support treatment of the underlying mental health disorder.
However, in all situations the ethical principles of providing
• Understand the information relevant to the CANH should be carefully considered and applied.
decision.
• Retain that information.
• Use or weigh that information as part of the process Best Interests
of making the decision.
• Communicate their decision (by talking, using sign In making a best interests decision about giving or continu-
language or any other means). ing life-sustaining treatment, there is always a strong legal
presumption that it will be in the patient’s best interests to
prolong their life. This presumption can be nullified if there
The MCA requires that the decision should be that which, is sufficient evidence to suggest that the patient would not
objectively, is in the best interests of the patient [12]. want to have the treatment proposed in the given circum-
Decision-makers must start from the strong presumption that stance, the treatment itself would be overly burdensome for
it is in a patient’s best interests to receive life-sustaining the patient, or the treatment would not provide the patient
treatment, but that presumption can be rebutted if there is with an acceptable quality of life. However, it is imperative
clear evidence that a patient would not want CANH provided to highlight that these judgements must be made from the
in the circumstances that have arisen. patient’s perspective and not those of healthcare
If the patient does not have capacity and cannot make professionals.
their own decisions about what to do, then their voice will There have been a number of high profile cases relating to
have to be relayed by others. It is imperative that the collec- CANH (see Table 2) that provide insight into the legal chal-
tion of information and opinions should be respectful, unhur- lenges that exist around best interest decisions.
ried and comprehensive, as well as carefully documented. Legal proceedings in England have highlighted that best
Legally, family members cannot give consent to or refuse interests means more than ‘best medical interests.’ Healthcare
treatment on the patient’s behalf unless they have been for- professionals making decisions must look at a patient’s wel-
mally appointed as a health and welfare attorney. Although fare in the widest sense—not just medical but social and psy-
not the decision-maker, they do have a crucial role in provid- chological. They must consider the nature of the medical
ing information about the patient as part of the best interest’s treatment, what it involves and its prospects of success. They
assessment [7]. must ask what the patient’s attitude to the treatment is or
would be likely to be; and they must consult others for their
view of what his or her attitude would be. 1
Mental Health
Patients with mental health disorders cannot have treatment

imposed on them simply because the treating clinicians think
1
Aintree University Hospitals NHS Foundation Trust v James [2013]
UKSC 67 at paragraph 39.
Table 2 Examples of high profile court cases relating to CANH

Legal case (country) Background Outcome
Tony Bland (England)a Tony Bland was a football supporter who was crushed in the The court ruled that there was no duty to treat if
Hillsborough disaster which reduced him to a persistent treatment was not in the best interests of the
vegetative state. He had been in this state for three years. His patient. Since there was no prospect of the
brain stem was still functioning, so technically he was still alive treatment improving the patient’s condition the
but he was not conscious and had no hope of recovery treatment was deemed futile and there was no
The hospital with the consent of his parents applied to the interest for Tony Bland in continuing the process
courts to discontinue all life-sustaining treatment and medical of artificially feeding him upon which the
support measures, including the termination of CANH prolongation of his life depended
Vincent Lambert Vincent Lambert sustained serious head injuries in a road- The Grand Chamber of the Strasbourg Court
(France)b traffic accident in 2008, which left him tetraplegic and in a state upheld the right of to die with dignity by ruling
of complete dependency that there would be no violation of Article 2 (right
In 2011 his condition was characterised as minimally conscious to life) of the European Convention on Human
and in 2014 as vegetative Rights if artificial nutrition and hydration were to
He received CANH via a gastrostomy be withdrawn from a patient in a persistent
In 2012 his carers observed increasing signs of what they vegetative state
believed to be resistance on his part to daily care
In early 2013 the medical team initiated a procedure provided
for by French law on patients’ rights and end-of-life issues
(known as the “Leonetti Act”). The patient’s wife Rachel
Lambert was involved in the procedure, which resulted in a
decision by his doctor to withdraw CANH. The courts ruled
this as appropriate in April 2013. However, the parents and
other family members appealed and won an injunction ordering
the hospital to resume CANH
In January 2014, there was a further application to discontinue
CANH which was upheld but family members appealed to the
European Court of Human Rights in Strasbourg
Terri Schiavo (USA)c At the age of 26 Terri Schiavo had an out of hospital cardiac The “Terri Schiavo case” actually refers to a series
arrest and suffered a hypoxic brain injury. After almost three of cases. Fundamentally, the case involved a
months without recovery, she was declared to be in a permanent dispute between family members over what the
vegetative state. Her clinical condition remained unchanged patient’s wishes would have been for such a
despite intensive rehabilitation effort over the next two years situation
Schiavo’s husband and legal guardian argued that Schiavo The Schiavo case involved 14 appeals and
would not have wanted prolonged artificial life support without numerous motions, petitions, and hearings in the
the prospect of recovery, and in 1998 elected to remove the Florida courts; five suits in federal district court;
gastrostomy tube. Schiavo’s parents disputed her husband’s extensive political intervention at the levels of the
assertions and challenged Schiavo’s medical diagnosis, arguing Florida state legislature, Governor Jeb Bush, the
in favour of continuing CANH U.S. Congress, and President George W. Bush;
There then followed a prolonged series of legal challenges and four judicial reviews in the Supreme Court of
presented by her parents, which ultimately involved state and the United States
federal politicians up to the level of President George W. Bush
After a a seven-year (1998 to 2005) period Schiavo’s
gastrostomy tube was finally removed
a
Airedale N.H.S. Trust v Bland [1993] A.C. 789 House of Lords (see also All Engl Law Rep 1993;1:821–96)
b
Lambert and Others v. France (application no. 46043/14) http://hudoc.echr.coe.int/eng?i=001-155352
c
See Caplan AL Ed. (2006) The case of Terri Schiavo: Ethics at the End of Life. Amherst, NY: Prometheus books
832 A. Rochford
The MCA has outlined a helpful checklist (see Box 3) that make decisions relating to personal health, financial and
can be used to help decision making when determining best property matters when the patient becomes incapacitated. If
interests. the patient has no relatives and lacks capacity, consideration
should be given to appointing an Independent Mental
Capacity Advocate, particularly if Deprivation of Liberty
Box 3 A Proposed Checklist for Determining Best Safeguards are being considered [13].
Interests [13]
• Do not discriminate or make assumptions on the Oral Feeding Dilemmas

basis of the person’s age, appearance, condition or
behaviour If possible, the provision of adequate food and water taken
• Consider whether the person will at some time by mouth should be the aim for all patients. When consider-
regain capacity, and if this is likely, whether the ing the provision of CANH the first question should be ‘what
decision could be postponed are we trying to achieve?’ If there is any doubt it is recom-
• Encourage participation by doing whatever is pos- mended that a trial of treatment is provided. A good example
sible to permit or encourage the person to take part would be in the case of an acute stroke where the prognosis
• Cannot be motivated by a desire to bring about the may be uncertain in the short term; however, without the pro-
person’s death where the decision relates to life- vision of CANH the recovery and outcomes would be poorer.
sustaining treatment In contrast, for patients in an advanced stage of a progressive
• Consider all the relevant circumstances by trying to neurological disease such as Alzheimer’s dementia it has
identify the things the person lacking capacity been shown that tube feeding does not prolong life and
would take into account if they were making the causes more complications than benefits.
decision themselves For many patients maintaining independence with eating
• Find out the person’s views, including their past and and drinking for as long as possible remains important; and
present wishes and feelings, and any beliefs or val- mealtimes continue to provide a key opportunity for social
ues that might influence their decision if they had interaction and enjoyment as well as nutritional intake.
capacity. This should include consulting family, Unintentional weight loss in the frail elderly is associated
carers and anyone granted a lasting power of with higher rates of mortality, institutionalisation, adverse
attorney. health outcomes, decline in functional status, and overall
poorer quality of life. A careful weight history is therefore
paramount when considering the provision of CANH. The
mechanisms of weight loss are multi-factorial, but the preva-
Advance Decisions lence of malnutrition often increases with disease progres-
sion; for example, in the later stages of dementia more than
An advance decision is a decision by a person to refuse par- two thirds of all those living with dementia are likely to be at
ticular medical treatments at a time in the future when they risk of malnutrition [14]. There is evidence that meal-time
may be unable to make such a decision. It is sometimes adaptations such as providing assistance and an appropriate
referred to as a living will or advance directive. It might say, environment for eating can slow the rate of unintentional
for example, that an individual would not want to be given weight loss, however, as disease progresses it is unlikely that
CANH if they were ever in a permanent vegetative state. malnutrition can be reversed and simply slowing nutritional
An advance decision is legally binding in English law and deterioration through adapted oral intake should be seen as a
can be applied to adults who wish to refuse life-sustaining positive outcome.
treatment. It is therefore considered a surrogate for the Many patients with oral feeding difficulties have commu-
patient’s autonomy should they not be able to express their nication or cognitive disabilities which affect understanding,
own wish. An advance decision only applies where it is in retention and processing of verbal and written information
writing, witnessed, and verified by a statement by the person and communication of needs. It is therefore imperative that
to the effect that it is to apply to that treatment even if life is appropriate measures have been taken to enable participation
at risk [7]. However, even if not all the legal criteria are fol- in discussions and decision making around long term nutri-
lowed, an advanced decision can be considered as an expres- tion and hydration. Ideally, discussions and decisions about
sion of a patient’s feelings and should be taken into the provision of CANH for patients with progressive condi-
consideration when making best interest decisions. tions should be made in advance of the point of clinical dete-
In England the MCA recognises that some patients may rioration where CANH is being considered. It is recommended
also have appointed a Lasting Power of Attorney, who can that decisions to provide CANH should be reviewed every
6 months (or every 12 months where the patient has been in PEG. There was also no significant difference in outcomes
a stable condition over a long period of time) and more often relating quality of life, patient satisfaction, inconvenience of
if the clinical situation has changed significantly [7]. maintaining the intervention by nurses, and functional ability
The term ‘feeding at risk’ or ‘risk-feeding’ is currently [18].
used to refer to oral feeding when people continue to eat and Decision making in these circumstances is often complex
drink despite a perceived risk of aspiration. This approach is and involves many steps; decisions may evolve as the
appropriate for patients unsuitable for tube feeding who have patient’s condition changes requiring re-referral and re-
an unsafe swallow that is unlikely to improve and is often assessment. It is often appropriate to seek a second opinion
seen as a strategy that affords comfort, dignity and autonomy from members of the nutrition support team regarding the
for patients [15]. most appropriate long-term course of action.
Many patients will require assistance to eat and drink. It is important that clinicians consider all the ethical per-
The majority of carers prepare all the meals for the person spectives outlined in Fig. 1 for each individual patient. There
that they care for and 60% of carers express worry about the may well be conflicting views held within the multi-
nutrition of the person they support [16]. Carers may need professional team as well as between patients, relatives and
training and support to ensure that they are using the correct care givers. Particular care needs to be taken for patients with
techniques and are complying with guidance regarding prep- functional gastrointestinal disorders where additional psy-
aration of consistency and the modification of food and fluid. chological and/or psychiatric evaluation may be required to
If an individual is ‘feeding at risk’ then this decision needs to explore the principles of non-maleficence and beneficence in
be documented with clear guidance for carers and healthcare more detail. Similarly care should be taken for patients with
professionals on how to assist the person with eating and learning disabilities. It has been estimated that approxi-
drinking. mately 36% of patients with learning disabilities in the UK
living in community settings have swallowing difficulties
[19]. In many countries it is illegal to discriminate against
Enteral Nutrition patients with learning disabilities on the basis of that disabil-
ity. It would also be considered ethically inappropriate to
All clinicians have a morale and professional duty to monitor insert a gastrostomy tube for the convenience of the care-
and review the nutrition and hydration needs of their patients. giver. Where there is doubt about clinical outcome and/or
For example, in the UK the General Medical Council states: long-term nutrition and hydration requirements a trial period
Malnutrition and dehydration can be both a cause and conse- of feeding via NGT is recommended.
quence of ill health, so maintaining a healthy level of nutrition When tube feeding is continued outside hospital there is
and hydration can help to prevent or treat illness and symptoms an ethical duty to ensure that the patient, carergivers and the
and improve treatment outcomes for patients. You must keep the community health team are adequately instructed in the tech-
nutrition and hydration status of your patients under review…..
If you are concerned that a patient is not receiving adequate nique and possible complications.
nutrition or hydration by mouth, even with support, you must
carry out an assessment of their condition and their individual
requirements. You must assess their needs for nutrition and Parenteral Nutrition
hydration separately and consider what forms of clinically
assisted nutrition or hydration may be required to meet their
needs [17]. Home parenteral support (HPS) is arguably more accessible
than ever before. For example, the National Framework
When patients fail to meet or maintain their nutrition and Agreement for Home Parenteral Nutrition in England allows
hydration needs orally other routes of administration should suitable patients to be discharged within 5 working days
be considered. Enteral nutrition is commonly provided tem- once they are stable on their HPS regime; acknowledging
porarily via Nasogastric tubes (NGT) and over a longer that gaining clinical stability may take several weeks in hos-
period via gastrostomy tubes placed either endoscopically pital. Over the last 5 years there has been a greater than 200%
(PEG) or radiologically (RIG). The placement of a gastros- increase in new HPS patients. In 2015, the major underlying
tomy tube has recognised risks of mortality and morbidity diagnosis for new patients with ‘gastrointestinal obstruction’
but there is a lack of high quality clinical evidence in the treated with HPS was malignancy (69%) [20].
benefit of gastrostomy feeding in certain population groups. For most patients requiring HPS the ethical consider-
A Cochrane Systematic Review of PEG versus NGT feeding ations are identical to other forms of clinical nutrition sup-
demonstrated no significant difference in mortality rates port and the decision making process should be similarly
between the two groups. Furthermore, there was no signifi- robust. Although it should be highlighted that HPS is an
cant difference between risk of aspiration although there was expensive healthcare intervention, and its provision may
a lower risk of reflux oesophagitis in patients with a place a significant economic burden on healthcare services
834 A. Rochford
where resources are limited. This does, therefore, raise a Withholding and Withdrawing Treatment
question surrounding the ethical position of justice and
resource allocation in such cases. People with preserved cognitive function who are unable to
It is generally accepted that the significant risks and eat or drink must be involved in decision making (with all the
burdens of HPS outweigh the benefits in patients who have necessary support). Their perception of the process resulting
an expected survival of less than 2 months. However, it is from absence of food will be different from those with
often extremely difficult to predict the length of survival impaired cognitive function. It is commonly believed that
and quality of life for patients being considered for HPS death from lack of nutrition or hydration is distressing or
and there may be palliative benefits in providing HPS to painful for the patient. This may be true for some, especially
patients with a shorter prognosis but with a good perfor- those with better cognitive function. However, appetite is
mance status. It is therefore paramount that informed deci- often severely reduced in terminal disease and the sensations
sions are made regarding prognosis and performance of hunger and thirst are suppressed. For those who are
status. It is recommended that a recognised measure such severely cognitively impaired, there is little evidence that
as the Eastern Cooperative Oncology Group (ECOG)/ hunger or thirst are perceived significantly. Indeed, patients
World Health Organisation (WHO) performance status is may resist efforts by carers to offer food or fluids. These
used. rejections may be no more than reflex responses. The
dilemma of whether to ‘force feed’ such patients by mouth
or with clinical assistance then arises [7].
Feeding at the End of Life In England the law regards withholding and withdrawing
treatment as the same. There is no requirement for decisions
There is limited evidence for recommendations regarding to withdraw CANH to be approved by the court, as long as
nutrition in end-of-life care due to the challenges in under- there is agreement upon what is in the best interests of the
taking intervention studies in this population. However, in patient, the provisions of the Mental Capacity Act 2005 have
the terminal phase of illness the inability or unwillingness to been followed, and the relevant professional guidance has
eat often creates significant anxieties for relatives and carers. been observed [23]. There are, however, certain situations
It is important for healthcare professionals to support under- e.g. persistent vegetative state or when there is conflict
standing that both the social significance of eating and the between professional judgement and the wishes of legal
atmosphere created around eating may be more important at guardian or family, when the courts need to be involved
the end of life than the nutritional content of the food itself before any action is taken (see Table 2 for some examples).
[21]. There is legal guidance that can be helpful in supporting
In the dying phase, a patient’s desire for food and drink decision making about the provision of CANH in patients
lessens. Good mouth care rather than attempting to feed a who are not imminently dying (see Box 4).
patient becomes a more appropriate intervention. It is
important at this stage to consider the appropriateness of
Box 4 Suggested Questions to Support Decision Making
continuing either enteral or parenteral nutrition and atten-
Regarding the Provision of CANH [24]
tion to patient comfort and dignity should take precedence.
The discontinuation of intravenous fluids must also be con-
sidered, as at this late stage it may only serve to exacerbate • What is his/her current condition?
pulmonary oedema, peripheral oedema and increase secre- • What is the quality of his/her life at present (from
tions, which the semi-conscious patient is unable to man- his or her perspective)?
age. Clear reasons should be identified and recorded for • What is his/her awareness of the world around him/
withdrawal of nutrition and hydration and good communi- her?
cation between healthcare staff, relatives and carers is • Is there any (or any significant) enjoyment in his/
essential. her life? If so, how can this be maximised?
In end-of-life situations, the assessment of “overall bene- • Does he/she experience pain and/or distress and if
fit” plays a particularly important role in determining the so, is it appropriately managed?
suitability of a treatment whose purpose may change (shift- • What is his/her prognosis, if CANH were to be
ing from a curative to a palliative purpose for example). In continued?
these situations, the prolonging of life must not in itself be • Is there any real prospect of recovery of any func-
the sole aim of medical practice, which should attempt just tions or improvement to a quality of life that he/she
as much to relieve suffering. The difficulty of any medical would value?
decision at the end of life is to ensure that the patient’s auton- • What is the prognosis if CANH were to be
omy and dignity are respected and that a balance is struck discontinued?
between the protection of life and the person’s right to be • What end-of-life care would be provided?
relieved of suffering if possible [22].
The General Medical Council’s guidance states that a • Respect for patients
second clinical opinion should be sought where it is pro- • Duty of care
posed, in the patient’s best interests, to stop or not start • Equity of care
CANH and the patient is not within hours or days of death • Accountability and transparency
[25]. There is sufficient evidence that the provision of par- • Inclusivity
enteral nutrition is best provided by specialist nutrition • Reasonableness
teams and there is some evidence that the provision of
enteral tube feeding support has less complications and bet- Furthermore, the guidance recommends a stepwise, question-
ter outcomes if managed through a specialist nutrition team. based approach to ethical decision making that is founded on
It is therefore appropriate that the opinion of nutrition sup- the work of Jonsen, Siegler and Winslade [28] (shown in
port teams may be sought to assist in decision making Fig. 3).
around the provision of CANH. For more complex situations, the RCP recommends using
It is important to highlight that in some countries the Ethical Care Decision-Making Record (ECDMR) which
CANH does not constitute treatment but is considered a is available to download at https://www.rcplondon.ac.uk/
form of care meeting the patient’s basic needs, which can- projects/outputs/conversations-ethically-complex-care. This
not be withdrawn unless the patient, in the terminal phase provides an excellent framework that will ensure robust and
of an end-of-life situation, has expressed a wish to that appropriate documentation of the decisions made.
effect.
Multi-Professional Working and Best Practice
Communication and decision making surrounding CANH

often takes time and requires considerable skill. A multi-
professional approach is essential but within a multi-
professional team there may well be differing moral,
ethical, religious and cultural opinions and beliefs. A study
of the dynamic challenges facing a multi-professional team
discussing the provision of CANH has shown that decision
making is not a singular decision but frequently involves
many steps with the potential for anonymity of decision-
making to emerge [26]. Decisions are rarely made in a sin-
gle meeting and are constantly evaluated in different
settings and clinical situations. Decisions are frequently
made across at least four inter-dependent axes (as shown in
Fig. 2).
The Royal College of Physicians (RCP) has published
guidance to support conversations for ethically complex care
[27]. The College recommends six guiding principles for Fig. 2 An illustrative model of the decision-making axes upon which
ethical decision making which are: clinical information can be weighted to make decisions [26]
Fig. 3 A four-question approach to facilitate and support conversations for ethically complex care
836 A. Rochford
Conclusions and Recommendations 10. The British Medical Association and the Law Society. Assessment
of mental capacity. 4th ed. London: General Editor Alex Ruck
Keene. Law Society; 2015.
In many countries CANH is regarded in law as medical treat- 11. The Mental Capacity Act 2005. https://www.legislation.gov.uk/
ment and should therefore be considered in the same way as ukpga/2005/9/contents. Accessed 5 Jun 2021.
any other medical intervention. The application of the prin- 12. Salford Royal NHS Foundation Trust v Mrs P [2017] EWCOP 23.
https://www.bailii.org/ew/cases/EWCOP/2017/23.html.
ciples of biomedical ethics is paramount. Patients, relatives 13. Mental Capacity Act Code of Practice. www.gov.uk. Published
and carers cannot demand treatment, but patients can refuse 2007 ISBN 9780117037465. Updated 2016.
treatment. For patients who lack capacity there is clear guid- 14. Franx BA, Arnoldussen IA, Kiliaan AJ, et al. Weight loss in patients
ance for healthcare professionals to support best interest with dementia: considering the potential impact of pharmacother-
apy. Drugs Aging. 2017;34(6):425–36.
decision making. There is a lack of high-quality clinical evi- 15. Palecek EJ, Teno JM, Casarett DJ, et al. Comfort feeding only: a
dence, but it is recommended that decisions are made on a proposal to bring clarity to decision-making regarding difficulty
case-by-case basis involving a multi-professional team with with eating for persons with advanced dementia. J Am Geriatr Soc.
experience of providing CANH. As patients approach the 2010;58:580–4.
16. Carers UK. Malnutrition and caring. London: Carers UK; 2012.
end-of-life priority should be given to supporting quality of 17. General Medical Council. Treatment and care towards the end of
life over and above nutritional intake and may involve sup- life: good practice in decision making. Manchester: The General
porting patients, relatives and carers to ‘feed at risk’ in pref- Medical Council; 2020.
erence to the provision of CANH. 18. Gomes CAR Jr, Andriolo RB, Bennett C, et al. Percutaneous
endoscopic gastrostomy versus nasogastric tube feeding for adults
with swallowing disturbances. Cochrane Database Syst Rev.
2015;2015(5):CD008096.
References 19. Leslie P, Crawford H, Wilkinson H. People with a learning dis-
ability and dysphagia: a Cinderella population? Dysphagia.
1. https://www.who.int/health-topics/ageing#tab=tab_1. Accessed 3 2009;24(1):103–4.
Apr 2021. 20. Smith T, Ngabi M. Artificial nutrition support in the UK 2005–
2. Stratton R, Smith T, Gabe S. Managing malnutrition to improve 2015. Adult home parenteral nutrition & home intravenous fluids.
lives and save money. BAPEN October 2018. https://www.bapen. BAPEN BANS Report 2016. https://www.bapen.org.uk/images/
org.uk/pdfs/reports/mag/managing-malnutrition.pdf. pdfs/reports/bans-report-2016.pdf.
3. Murphy JL, Burrow A, Guestinin R, et al. Identifying older people 21. Hopkinson JB, Wright D, Foster CL. The emotional aspects of can-
at risk of malnutrition and treatment in the community: prevalence cer anorexia. Curr Opin Support Palliat Care. 2010;4(4):4254–8.
and concurrent validation of the Patients Association Nutrition 22. Council of Europe Issues Guide to End-of-Life Care. http://www.
Checklist with ‘MIUST’. J Hum Nutr Diet. 2019;33(1):31–7. coe.int/en/web/bioethics/end-of-life. Accessed 4 Apr 2021.
4. Stratton R, Evill R, Smith T. Home Enteral Tube Feeding (HETF) 23. An NHS Trust v Y [2018] UKSC 46. https://www.bailii.org/uk/
in Adults (2010-2015). BAPEN BANS Report 2018. https://www. cases/UKSC/2018/46.html.
bapen.org.uk/pdfs/reports/bans/bans-report-2018.pdf. 24. PL v Sutton Clinical Commissioning Group & Anor [2017] EWCOP
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978e0195143324. ventions for people at risk of lacking decision-making capacity:
7. Royal College of Physicians. Supporting people who have eat- who decides and how? BMC Med Ethics. 2005;16:41.
ing and drinking difficulties. A guide to practical care and clinical 27. Royal College of Physicians. Conversations for ethically complex
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party. London: RCP; 2021. sion making for levels of care in clinical practice. London: RCP;
8. Druml C, Ballmer P, Druml W, et al. ESPEN guideline on ethical 2021. www.rcplondon.ac.uk/ethically-complex-care
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Part VII
Problems of Treatment
Enteral Nutrition
Timothy Bowling

1. Enteral nutrition is most commonly given to patients with
“intake (oral) failure” (inability to get food into the gut) Undernutrition is common in the hospitalized patient, as has
due to poor dentition, poor appetite, head/neck cancer/ been described elsewhere. When a patient is unable to meet
trauma, neurological disease (e.g. stroke, cerebral palsy, their nutritional requirements by oral intake with or without
motor neurone disease, multiple sclerosis) and psycho- oral nutritional supplements, enteral feeding will be required,
logical disorders (e.g. dementia, depression and anorexia providing there is a functioning and accessible gastrointesti-
nervosa). nal tract. The management should be by a multi-professional
2. Enteral tubes are used for patients with inadequate or nutrition team, including (as a minimum) a doctor, dietitian
unsafe oral intake, and a functional, accessible gastroin- and nutrition nurse specialist. Indications for enteral tube
testinal tract. feeding are listed in Table 1. Access to the gastrointestinal
3. Complications of enteral tube feeding may be mechanical tract can either be via a nasogastric or nasojejunal tube or by
(tube insertion, the tube blockage/displacement etc), feed an enterostomy. This chapter will mention the routes and
delivery, metabolic/biochemical or gastrointestinal feed delivery; but mainly deals with the complications of
related. enteral feeding.
4. The risk of aspiration of the feed from an enteral feeding
tube may be reduced by elevating the head of the bed to
30° or more, feeding for less than 24 h a day, using a Table 1 Indication for enteral feeding
lower osmolality feed and considering a tube with its tip Patients with a functioning stomach and/or intestine
beyond the duodeno-jejunal flexure. • Impaired swallow, e.g. stroke, motor neurone disease, Parkinson’s
5. There is always a risk of a naso-gastric feeding tube being disease
inserted inadvertently into the lung. In patients with • Altered level of consciousness, making oral feeding impossible
reduced conscious level or reduced oro-pharyngeal sen- • Ventilated patients
• Dysphagia with oro-pharyngeal/oesophageal obstruction, i.e.
sation a post procedure chest X-ray may be done in addi- head and neck and oesophageal cancer
tion to testing the pH of aspirate. • Gastric outlet obstruction: Mechanical (tumour, pyloric stricture)
6. Diarrhoea with enteral tube feeding is most commonly or functional (stasis). These situations will require jejunal feeding
due to medication (especially anti-biotics). (see below)
• Severe pancreatitis (gastric or jejunal)
Supplement inadequate oral intake
• Cystic fibrosis
• Hyper-catabolic states, e.g. burn injury, decompensated liver
disease
• Facial injury
• HIV wasting
T. Bowling (*) • Psychological/psychiatric reasons, e.g. anorexia nervosa
Clinical Nutrition and Gastroenterology, Nottingham University
Hospitals NHS Trust, Nottingham, UK

840 T. Bowling
Routes for Enteral Feeding Nasojejunal Tubes
The following options are available: These are most commonly placed endoscopically. However,
specifically designed self-propelling nasojejunal tubes will
1. Nasogastric tube (NGT) spontaneously cross the pylorus in 70–80% of patients with
2. Nasojejunal tube (NJT) normal gastroduodenal motility, especially with a concurrent
3. Gastrostomy intravenous bolus of metoclopramide [4]. If the stomach is
(a) Percutaneous Endoscopic Gastrostomy (PEG) atonic, nasojejunal tubes usually require endoscopic place-
(b) Radiological Inserted Gastrostomy (RIG) ment. The distal end must be placed beyond the duodeno-
(c) Surgical jejunal flexure or it will invariably pass retrogradely back into
4. Jejunostomy the stomach. There are other systems that can facilitate trans-
(a) Endoscopic (PEJ or PEGJ) pyloric passage, for example an electromagnetic device on the
(b) Radiological (RIGJ) end of the tube can be tracked by a bedside imaging system to
(c) Surgical help ensure correct placement [5]. Plain abdominal X-ray is
required to verify placement, unless placed under screening.
NJT come as single, double or triple lumen. Double or triple
lumen tubes are recommended for patients who require simul-
Nasogastric Tubes taneous gastric decompression and small bowel feeding.
NGT are recommended for those requiring tube feeding for

no longer than 4–6 weeks. They are safe, cost effective and Gastrostomy
less invasive than alternatives. There are two types of NGT:
Fine bore tubes designed for administration of feed; and A gastrostomy is usually preferred if tube feeding is likely to
wide bore tubes (e.g. Ryles) designed for aspiration. The lat- be required for greater than 4–6 weeks. It can be placed
ter can cause oesophageal damage, such as ulceration and endoscopically (PEG); radiologically (RIG); or occasionally
stricture, if left in for a prolonged period, and should not surgically. There are a number of different types of PEG/RIG
normally be used for feeding. Fine bore tubes are usually tubes in terms of size (9 FG–30 FG); internal fixator (flange,
easy to insert and safe, even in patients with oesophageal balloon) and material, including more cosmetically accept-
varices. They should not be inserted in patients with obstruc- able “button” gastrostomies. If the anatomy prevents inser-
tive pathology in the nasopharynx or oesophagus, or in tion by one method then other methods will often be limited
patients with basal skull fractures. by the same problem.
NHS Improvement issued guidance in 2016 for safe PEG insertion is usually straightforward. Although not a
placement and position checking of nasogastric tubes [1]. sterile procedure, antibiotic prophylaxis 30 min prior to the
The guidance highlighted the unreliability of certain tests— procedure is recommended [6]. Table 2 lists the contraindi-
such as the “whoosh” test and testing for acidity with lit- cations to PEG insertion. It should be noted that many of
mus paper - and instead recommended testing with pH
indicator paper as the first line check (pH ≤ 5.5). Higher pH Table 2 Contraindications to PEG insertion
suggests either the position could be wrong, i.e. in the Absolute Relative
respiratory tract, or the patient could be on acid suppress- • Inability to pass endoscope due • Severe obesity (due to
ing therapies, such as a proton pump inhibitor. It recom- to obstructing pathology in technical difficulties accessing
mended checking X-ray images as the second line test, oro-pharynx or oesophagusa the stomach)a
• Obstructing gastric outflow • Uncorrected coagulopathy
although not for routine use. The single greatest cause of pathology • Portal hypertension/ascites
harm resulted from misinterpretation of X-ray images. The • Significant ascites • Active gastric ulceration/
National Patient Safety Agency (NPSA) issued a safety • Gastric varices malignancy
alert in March 2011 focusing on safe interpretation of X-ray • Gastroparesis
• Gastrectomy (total or
images [2]. Tube placements should be checked at least partial)a
once daily and before administering each feed or medica- • Severe kyphoscoliosis (may
tion. However, there has to be an element of pragmatism in be difficult to access stomach)a
this. Provided that the initial placement was appropriately • Impaired respiratory
reserve, e.g. motor neurone
confirmed and no other signs of dislodgement (such as disease
retching or coughing) are present, repeat radiography • Current peritoneal dialysis
would not usually be needed as long as the external length a
May be achievable if done under radiological guidance to locate
of tube remains unchanged [3]. stomach
Enteral Nutrition 841
the “relative contraindications” to endoscopic placement

can be overcome if insertion is done under radiological Delivery of Enteral Feed
guidance.
PEG’s and RIG’s can be easily taken out, but care is Feed can be administered as a bolus or continuously.
required. If removed within 2–3 weeks of insertion a formal Continuous feeding is usually over 16–18 h; bolus feeds are
tract may not have formed, with consequent risk of spillage typically 100-500mls of feed over 15–60 min at 3–6 h inter-
of gastric contents into the peritoneal cavity leading to peri- vals. Bolus feeding into the stomach is more physiological.
tonitis. This also means that it is not possible to re-insert a Although there is a perception that it predisposes to aspira-
feeding tube down the same track, as it will not find its way tion, diarrhoea, bloating and dumping syndrome compared
into the gastric lumen. Therefore if the PEG/RIG does come to continuous feeding, there is no clinical evidence to indi-
out in the first few weeks of insertion the stoma site should cate that this is the case. With jejunal feeding, the loss of the
be covered, antibiotic cover instituted and, if nutritional sup- stomach reservoir means patients with post pyloric tubes
port is still required, an alternative, e.g. NGT, used until the should be fed continuously. Further detail on delivery and
wound has healed. After 2–3 weeks removal presents little formulation of enteral feeds is dealt with elsewhere.
risk of peritonitis or sepsis. However, closure is rapid, so if
replacement is required this must be done within 4–6 h using
a fresh PEG/RIG or, temporarily, a balloon gastrostomy or Complications of Enteral Feeding
Foley catheter. Elective removal is usually undertaken endo-
scopically. Alternatively, the tube can be cut close to the skin Complications of enteral feeding can be divided into
allowing the internal fixator to pass spontaneously through mechanical, ie related to the tube; gastrointestinal, ie related
the gastrointestinal tract. There are a few reported incidents to the delivery of the feed; and biochemical/metabolic, ie
of obstruction, e.g. at the ileocaecal junction, and therefore related to the content of the feed. Table 3 lists these.
some experts are wary of this method of removal [7]. This
should not be undertaken if there is known small intestinal
pathology, such as strictures. Mechanical Complications
Naso-Enteric Feeding Tubes

Jejunostomy
Inadvertent Removal
Percutaneous endoscopic gastrojejunostomy (PEGJ) are The most commonly encountered problem with NGT is
“extensions” that attach to a PEG and can be passed endo- inadvertent removal, either by the patient or by accident, e.g.
scopically beyond the duodeno-jejunal flexure. PEJ is simi- snagged on clothing, vomiting. If this is a recurring problem
lar to PEG but requires a direct puncture into the small and feeding is still required, either a PEG can be considered
intestine. Insertion techniques are not straightforward, but in
expert hands successful placement can be achieved in Table 3 Complications of enteral tube feeding
70–80% [8]. For most hospitals, where such expertise may Mechanical Insertion Nasoenteral—nasal damage,
not be available, and where post-pyloric feeding is required, intra-cranial insertion, pharyngeal/
a surgically-placed jejunostomy for post-pyloric feeding is oesophageal pouch perforation,
often preferred, except in a patient too unfit for a general bronchial placement
Enterostomy—bleeding, pain,
anaesthetic.
peritonitis, pneumoperitoneum,
Removal of PEGJ/PEJ’s have similar cautions as those intestinal/colonic perforation,
described for PEGs. gastrocolic fistula
Surgical jejunostomies are most commonly needle cathe- Post-insertion Nasoenteral—tube displacement/
ter jejunostomies inserted subserosally to reduce the risk of removal, blockage, bronchial
administration of feed, erosions,
leakage, but tend to be fine bore, and prone to block if poorly strictures
managed. Other tubes such as Foley catheters can be used Enterostomy—stoma infection,
but are not recommended because of leakage and difficulties blockage, displacement, leakage,
in connecting with feeding equipment. Increasingly, jejunos- over-granulation, buried bumper
Feed Gastrointestinal Nausea, fullness, diarrhoea,
tomies are inserted per-operatively to allow for early post- delivery constipation
operative feeding, especially in those whose nutritional Pulmonary Aspiration, pneumonia
status is sub-optimal at the time of surgery. Although compli- Metabolic Refeeding syndrome,
cations can occur, the advantages of improved post-operative hyperglycaemia, fluid overload,
nutrition usually out-weigh the risks [9]. electrolyte disturbance
842 T. Bowling
or a “nasal loop” or bridle can be attached, thereby making mucous membranes. Simple measures such as mouthwashes,
accidental removal far less likely—18% for bridled tubes sucking ice cubes or using artificial saliva may help alleviate
compared to 63% for non-bridled tubes in one study—with discomfort. Nasal erosions and occasionally an abscess can
the bridled group more likely to meet their recommended occur from pressure of the naso-enteric tube on the nasal
nutritional requirements [10]. Bridle systems are commer- alae. If the sinus tracts or Eustachian tubes are blocked by
cially available and although their unit cost is relatively high, the naso-enteric tube, acute sinusitis or secondary otitis
this is more than offset by the avoidance of repeated NGT media infection respectively may occur. The mucous mem-
placements +/− X-rays to verify placement. branes of the larynx can be irritated causing hoarseness.
Excessive pressure against the oesophageal wall may cause
Tube Blockage ulceration with subsequent stenosis. The risk of oesophageal
Tube blockage may occur if crushed medication is inserted ulceration is increased in the presence of severe gastro-
into fine-bore tubes, if the tube is not flushed adequately, or oesophageal reflux and oesophagitis. Fine bore tubes do not
if there is precipitation of protein in the enteral feed. appear to jeopardise the integrity of oesophageal varices.
Precipitation of enteral feed occurs because the iso-electric However, large bore tubes should be avoided where varices
point of protein is between pH 4.5 and 5.3, and at this pH, are known to exist. Rarely, tracheo-oesophageal fistula may
protein precipitates causing tube blockage [11]. Many elixir develop with large-bore naso-enteric tubes as a result of
medications have a pH of 5 or less [12] and thus may cause pressure necrosis of the oesophagus and trachea.
protein precipitation and tube blockage.
To prevent tube blockage a feeding tube should be flushed Enterostomy Feeding Tubes
with sterile or boiled water at least before and after a feed or Complications can arise from the insertion procedure itself
medication. Obstructed tubes may be unblocked with water, or related to the enterostomy. A more detailed review can be
a variety of solutions including fizzy drinks, pineapple or found elsewhere [15].
cranberry juice, alcohol or powdered pancreatic enzymes. If
enteric-coated pancreatic enzymes are used they need to be Insertion Related Complications
dissolved in a sodium bicarbonate solution before being
administered (e.g. the contents of one Creon® capsule can be • Complications of endoscopy, such as cardiopulmonary
dissolved in 10 ml of 8.4% sodium bicarbonate). compromise resulting from sedation, hypoxia, arrhyth-
mias and hypotension; upper gastrointestinal haemor-
Malposition rhage and oesophageal perforation all have similar rates
Malposition of a naso-enteric feeding tube, especially when of occurrence as with other diagnostic and therapeutic
inserted blind, occurs in about 2% of insertions. When placed endoscopies. The risk of pulmonary aspiration and subse-
into the airways, with subsequent intrapulmonary infusion of quent chest infection is greater, as a result of the case mix
an enteral diet, this can be fatal if not recognized. Intracranial of those requiring a PEG, who are often older, more frail
placement has also been reported. Other complications aris- and have, by the definition of needing a PEG, significant
ing from tube malposition include pneumothorax, intrapleu- co-morbidity, usually affecting the ability to swallow and
ral infusion of enteral diet and oesophageal perforation [13]. gag. Further detail of endoscopic complications can be
found elsewhere [16].
Localised Trauma • Pain: This is common within the first 24 h. If severe, it is
Physical complications of naso-enteric tubes may be due to important to exclude peritonitis or tube displacement into
the size, material and pliability of the tube used. Polyurethane the anterior abdominal wall.
naso-enteric feeding tubes are preferable to polyvinylchlo- • Haemorrhage: This is unusual if the clotting screen is
ride naso-enteric feeding tubes, as they are softer, less trau- within normal limits. As malnutrition can lead to vitamin
matic and easier to aspirate the gastric contents. Intubation K deficiency, the prothrombin time/INR should always be
with a naso-enteric tube can cause discomfort for patients, checked prior to procedure, and corrected if necessary.
and depends to some extent on the type and size of tube used. • Peritonitis: This can develop from infection introduced
In general, the larger the tube the greater the discomfort [14]. during the insertion process. Pre-procedure antibiotics
Although many problems are less common with the mitigate against this complication [6].
softer, more flexible fine-bore tubes, complications due to • Pneumoperitoneum: There will always be some free air
the physical presence of the feeding tube can occur. after PEG insertion Pneumoperitoneum is usually self-
Nasopharyngeal discomfort persisting after intubation may limiting. It only needs to be a cause of concern when intra-
be due to reduced saliva production, due to mouth breathing abdominal air is worsening or when it is found in the
and absence of chewing. Patients can develop a sore mouth, presence of signs of peritonitis, portal and/or mesenteric
difficulty with swallowing, and a sensation of thirst and dry venous gas, systemic inflammatory response and/or sepsis.
• Gastrocolic fistula due to the interposition of the colon checked either radiologically or endoscopically, and cor-
between the anterior abdominal wall and stomach is a rare rected if necessary. There should not be excessive traction
complication. It is often not clinically apparent and can be on the external bolster compressing the abdominal wall
found by chance, for example during a colonoscopy. too tightly, and this should be loosened if necessary.
Measurement of the anterior abdominal wall thickness on Barrier creams and skin protectants should be applied.
the PEG after insertion can be an indicator. For example Antisecretory therapy, such as proton pump inhibitors, to
measurements over 3 cm in a thin individual should raise reduce gastric acid secretion can help. Replacing the orig-
concern of interposed tissue between the stomach and inal PEG tube with a larger one should be avoided as this
anterior abdominal wall. may cause the tract to enlarge and exacerbate the leakage.
• Injuries to small and large intestine, spleen and liver have If leakage persists, it is often necessary to remove the
all been documented. They are rare, but should be consid- PEG and resite a new one elsewhere.
ered when there is otherwise unexplained haemodynamic • Displacement of a PEJ or PEGJ back into the stomach is
compromise or signs of peritonitis following insertion. a common problem, and this should be suspected if the
• Surgical or anaesthetic complications need to be consid- patient complains of the symptoms that led to the need for
ered in surgically placed enterostomies or those placed post-pyloric feeding in the first place, including fullness
under a general anaesthetic. Further discussion on these and vomiting with feed.
issues is beyond the remit of this chapter. • Buried bumper: This is migration of the internal fixator
into the gastric/anterior abdominal wall leading to tube
blockage. It is a late complication, usually months or years
Tube-Related Complications after placement, and diagnosed when the enterostomy can-
not be rotated or pushed inwards. Removal can often be
• Stoma infection: This is a common complication, and done endoscopically, but on occasions requires surgery.
even with prophylactic antibiotics occurs in up to 5% in • Tumour tract seeding: There are some case reports of
the first 30 days after insertion [6]. The risk is increased PEG’s inserted where there are oesophageal or oro-
both from insertion factors, eg excessive traction on the pharyngeal tumours, with neoplastic seeding in stoma
internal bumper, and host factors such as diabetes, malnu- tracks [18]. Where the PEG is inserted as part of palliative
trition and underlying malignancy. It usually resolves care, this is unlikely to be of relevance in the patient’s life-
with appropriate antibiotics and proper stoma care. It is time. Where an enterostomy is required as a bridge for
not usually necessary to remove the enterostomy or stop definitive treatment, a radiological procedure avoids the
feeding unless severe ulceration or wound breakdown risk of tract seeding, and some experts advocate this.
occurs. • Overgranuation: Can occur at the stoma site and bleed
• Less commonly an abscess in the anterior abdominal wall and/or become painful. This is treated with steroid cream
can develop, especially if there is spillage of feed and gas- or silver nitrate.
tric contents through an immature stoma tract. This will • Mortality: There is a 30 day mortality of about 10% fol-
cause localized pain. The management is usually to stop lowing PEG insertion, and 40% following a RIG. The dif-
the feed and give antibiotics. ference is explained by the case mix for the two
• Necrotising fasciitis is a very rare complication, and more procedures, with the sicker and more co-morbid individu-
likely when there is systemic compromise, for example als more likely to have a RIG [19]. Careful case selection
poorly controlled diabetes. This usually requires surgical can minimise these figures.
debridement.
• Tube blockage: This is a common problem, and arises
either because of thick consistency of feed or medication.
It can be minimized if flushed with water before and after Complications Relating to Feed Delivery
each feed/medication. The management is the same as for
a blocked nasoenteral tube (see above). Gastrointestinal Problems
• Peristomal leakage and tube displacement: Although
the reported incidence of peristomal leakage is 1–2% Nausea and Fullness
[17], this complication is probably much more common, Nausea and fullness can occur in 10–20% of patients, with
especially early after PEG placement. Tube displacement the pathogenesis being multifactorial, including smell, diet
through the gastric wall in the immature stoma tract is a osmolality, altered gastric emptying, rapid infusion of feed
common precipitant to peristomal leakage. This is more and psychological factors [20]. Management has to be indi-
likely to occur in a confused patient who may pull on the vidualised, depending on the circumstances of the particular
enterostomy. Correct siting of the internal end should be patient.
844 T. Bowling
Diarrhoea medication, prescription and otherwise, should be consid-

Diarrhoea occurring in the enterally-fed patient is a common ered and, if appropriate, stopped [24].
problem, with a reported incidence ranging from 6–60%, Other aetiological factors have been proposed as relevant
more frequent in the critical care setting. This huge variabil- to enteral feeding related diarrhoea [25]. Hypo-albuminaemia
ity is a reflection of the heterogeneity of patients and case- has been associated but is probably only as a surrogate for a
mix in the various studies and of the definitions used for sick patient with a sick and leaky gut. There is no evidence to
diarrhoea. Patients range from critical care to community- implicate lactose intolerance or diet osmolality, both of
based elderly, all with varying degrees of comorbidity and which have been proposed in the literature. It has been sug-
polypharmacy. The definitions of diarrhoea are even more gested from healthy volunteer studies that intragastric feed-
variable—at least 33 quoted in the literature [21]. Many ing is more likely to lead to diarrhoea than post-pyloric
studies utilise consistency, frequency, stool volume and stool feeding, because of different neurohumoral responses result-
weights either alone or in many different combinations. ing from the two methods of feeding, with consequent effects
Some studies have developed diarrhoea scores; others just on colonic water flows [26]. However, no clinical studies
cite “inconvenient” bowel activity and several have no defi- have been undertaken to test this hypothesis.
nition at all. What this all means is that it is difficult to truly Diarrhoea is distressing for patients and their relatives,
determine from the literature how much of a problem there is time-consuming for nursing staff and can add to potential
with diarrhoea in the enterally-fed patient. problems such as infected pressure sores and altered fluid
Contaminated feeds and feeding equipment can lead to and electrolyte balance. It may also delay patient discharge
the introduction of exogenous pathogens into the gastroin- and increase hospital costs. Loperamide at standard dosage
testinal tract. Enteral feed provides an excellent growth (2-4 mg once to three times daily) is often very effective. The
medium for bacteria, and once contaminated bacteria will addition of codeine phosphate (30–60 mg up to four times
rapidly multiply. A variety of micro-organisms have been daily) can also be of benefit [27].
cultured from enteral feeds including Enterobacter spp., E. The role of colonic flora, short chain fatty acids, fibre and
coli, Klebsiella spp., Proteus mirabilis, Salmonella enteridi- pre/probiotics in relation to enteral feeding diarrhoea remains
tis, Pseudomonas spp., Staphylococcus aureus and epidermi- unclear. There are a lot of interesting data on the analysis of
dis, Streptococcus faecalis, Acinobacter spp., Citrobacter colonic flora and the changes observed during enteral feed-
spp. and yeasts. Although enteral feeds are sterilized, as soon ing. However, the true clinical relevance of such manipula-
as the bottles or cans are opened, there is a risk of bacterial tions remains unresolved [26]. There are some clinical data
colonization of the feed, through a variety of routes, which is to suggest that including fibre in enteral diets reduces diar-
exacerbated by handling, type of delivery system, prolonged rhoea [28]. Therefore, a trial of a fibre-containing feed is
hanging time and ascending spread of bacteria up the giving worth trying, especially when enteral feeding related diar-
set [22]. Contaminated feeds reportedly cause not only diarrhoea is not responding to anti-diarrhoeal medication [29].
rhoea, but also sepsis, pneumonia and urinary tract infections Enteral feeding is unphysiological. Bolus feeding is better
[23]. Gastric acid is an important protection against infused in this regard than continuous feeding for gastric feeding, but
exogenous pathogens, and therefore inhibiting gastric acid unless the bolus is substantial (more than 500 kcals over
secretion allows bacterial overgrowth. Those on antacid 20–30 min) the normal post-prandial neurohumoral
medication are therefore at an increased risk of infected responses do not get activated, and this may be of relevance
enteral feeds and the clinical consequences that can follow. to enteral feeding diarrhoea [30]. There are practical argu-
To mitigate risk, containers and giving sets should be ments for and against these two forms of feeding, such as
changed at least every 24 h [23]. ease of administration, patient comfort and convenience and
Many gastrointestinal diseases may cause diarrhoea, and staffing input, which often take precedence over clinical
these need to be considered, investigated for and dealt with applications. If diarrhoea is a significant problem and is not
where appropriate. Also to be considered are metabolic responding to anti-diarrhoeal medication, then a critical look
causes, such diabetes and thyroid dysfunction. Medications at the method of feeding is advised. Post-pyloric continuous
are frequently implicated in causing diarrhoea. The most feeding is more physiological and could be considered,
common are antibiotics, probably due to their effects on although there are no clinical studies comparing this with
colonic flora and short chain fatty acids. Antibiotic usage gastric feeding and the incidence of diarrhoea. Very occa-
therefore should be scrutinised and stopped if possible. Other sionally, when diarrhoea is incapacitating and cannot be
drugs include osmotically-active medications, primarily eased by any of the above, parenteral feeding can be started.
relating to sorbitol, which is present in many elixirs, and
which is frequently given to many patients on enteral feeding Constipation
for ease of swallowing. There are many other medications Constipation, often with resulting overflow diarrhoea, can
which list diarrhoea as a potential side effect. Therefore all be a problem with enteral feeding, although is much less
common that enteral feeding related diarrhoea. It has been As with gastric residuals it has also been presumed that
suggested that constipation is due to a lack of dietary fibre bolus feeding increases the risk of aspiration compared to
in many enteral feeds. There is currently, however, little continuous pump feeding. Studies have given mixed results,
conclusive evidence that using fibre-enriched enteral feeds with some demonstrating benefit with pump feeding [36]
increase stool frequency and weight. The lack of improve- and others showing no difference [37].
ment in constipation by adding fibre to enteral diets may There is no evidence that enterostomy feeding has any
be partly due to the manufacturing process which alters the less risk than nasoenteral feeding. There have been a number
physicochemical properties of the added fibre. The viscos- of controlled trials comparing postpyloric to pre-pyloric
ity of the feed is kept low by using fine rather than coarse feeding, with meta-analyses giving conflicting results [38–
fibre. However this reduces the water holding and bulking 40]. It is commonly the case that nasoduodenal tubes can
properties of the feed. Furthermore, due to the requirement reflux back into the stomach, so to minimise risk of retro-
of having a small particle size renders the fibre highly fer- grade displacement and aspiration risk, postpyloric tubes
mentable, reducing the amount of fibre available to bulk should be placed beyond the duodenojejunal flexure
faeces. A recent meta- analysis has not demonstrated a (Ligament of Treitz). Pro-motility drugs (e.g. metoclo-
clear benefit of fibre supplementation in the treatment of pramide or erythromycin) can be tried to reduce the chances
either constipation or diarrhoea [29]. However, given the of aspiration in those patients most at risk, although evidence
theoretical benefits of fibre and the intuitive view that it of benefit from meta-analysis is weak [41].
should be part of a nutritional regime, many experts would In terms of evidence, the only strategy clearly demon-
use a fibre-enriched enteral feed in patients with strated to improve aspiration risk is feeding for no more than
constipation. 20 h per day and with patients propped up by 30° or more
[31].
Pulmonary Complications
Metabolic/Biochemical Complications
Reflux of feed is almost invariable. Many studies have iden-
tified evidence of this, for example pepsin in alveolar aspi- Artificial feeding of patients may cause a variety of meta-
rates is found in more than 90% of patients being nasoenterally bolic problems, including deficiencies or excess of fluid,
fed [31]. The development of aspiration pneumonia is there- electrolytes, vitamins and trace elements. Over-hydration
fore a potential complication in all patients being tube fed occurs frequently, particularly if enterally-fed patients are
into the stomach or small bowel. Aspiration of feed can occur also receiving supplementary intravenous nutrition or fluids.
without obvious evidence of vomiting, particularly in those Hyponatraemia is a common problem when enteral nutri-
patients with poor mental status and an absent swallow tion is given to sick patients. It is often accompanied by the
reflex. Such regurgitation is often a clinically silent event development of oedema and is usually due to a combination
until signs of pneumonia develop. Those at particular risk are of enteral tube feeding and excessive use of IV fluids along
the elderly, those with dementia or neurological disease with the adverse effects from malnutrition and severe illness.
affecting their swallow and gag reflux, and those in critical Patients end up with excess body water and a very high total
care on ventilators and with impaired consciousness. body sodium (the low plasma levels being due to dilution
To reducing the risk of pulmonary aspiration, elevating effect). As a consequence, rather than administering further
the head of the bed to 30° or more, to help aboral progression sodium in feeds or IV fluids, treatment should usually entail
of feed by gravity, and feeding for less than 24 h a day, for fluid restriction. Generous amounts of potassium to encour-
example over 18–20 h, have been shown to improve aspira- age cell membrane sodium exchange may be helpful.
tion risk [32]. High osmolality feeds of 560 milliosmoles or Hypernatraemia can also occur but is usually due to dehydra-
greater can significantly delay gastric emptying, and so it is tion and/or excess water loss, e.g. through diuresis, rather
probably preferable to use iso-osmotic feeds in patients at than as a direct consequence of enteral tube feeding.
risk from aspiration. Between 10–30% of tube fed patients are hyperglycaemic
There has been much interest in gastric residual volumes and may need oral anti-diabetic agents or insulin, before and
for patients primarily in the critical care setting and a pre- during feeding. Rebound hypoglycaemia may also occur in
sumed association with risk of aspiration. On critical evalua- tube-fed patients if feeding is stopped abruptly, especially if
tion, there is no clear link between amount of residual and they are on anti-diabetic therapy.
aspiration risk, and 500 mL residuals appear to be no more Deficiencies or excesses of many other electrolytes, vita-
hazardous than smaller amounts [33, 34]. Current evidence mins and trace elements can occur but which can usually be
would therefore not support review of residuals only if these avoided by careful monitoring. Basic haematological and bio-
are less than 500 mL per 6 h [35]. chemical parameters should be measured before starting
846 T. Bowling
nutritional support, and then monitored regularly during such Although phosphate is just one of the components affected,
support, with appropriate supplementation given when neces- hypophosphataemia has far reaching consequences on the
sary, especially for those on prolonged enteral feeding. functioning of various organ systems. During starvation,
phosphate and potassium are lost from the cell in proportion
Refeeding Syndrome to the breakdown of glycogen and protein, potassium being
The refeeding syndrome was reported among those released the main intracellular cation balancing the negative charges
from concentration camps following the Second World War. on proteins. There is, therefore, no clinical deficiency of these
Oral feeding of these grossly malnourished individuals often electrolytes until catabolism is abruptly reversed and resyn-
resulted in fatal diarrhoea, heart failure and neurological com- thesis of glycogen and protein begins, creating a sudden
plications including coma and convulsions. Milder symptoms demand for inorganic phosphate for phosphorylation and ATP
were later reported by Keys et al. during the refeeding of healthy synthesis and for potassium to balance the negative charges
volunteers with a mean weight loss of 23% after starvation [42]. on protein and glycogen. Magnesium, being involved in ATP
Severely malnourished patients appear to be at particular synthesis, is also taken up by the cells. Upon the introduction
risk of developing the refeeding syndrome (chapter of carbohydrate, insulin is released into the blood stream and
“Refeeding Problems”), who’s features include: there is a shift of metabolism from fat to carbohydrate. Acute
thiamine deficiency may be precipitated, especially in patients
• Salt and water retention leading to oedema and heart fail- suffering from chronic alcoholism, since diminished thiamine
ure, which may be exacerbated by cardiac atrophy, reserves are rapidly used up, as carbohydrate metabolism is
• Hypokalaemia due to rapid cellular uptake of potassium accelerated. Excessive infusion of glucose may also cause
as glucose and amino acids are taken up during cellular hyperglycaemia leading to osmotic diuresis, dehydratation
synthesis of glycogen and protein, and hyperosmolar non-ketotic coma. The production of fat
• Hypophosphataemia due to increased phosphorylation of from glucose due to lipogenesis can result in hypertriglyceri-
glucose, daemia and/or a fatty liver.
• Rapid depletion of thiamine, a cofactor in glycolysis, Refeeding problems primarily occur after feeding com-
leading to Wernicke’s encephalopathy and/or cardiomy- mences, and can be regarded as an iatrogenic condition. With
opathy, and awareness of its existence and careful management, its
• Hypomagnesaemia due to cellular uptake of this mineral. development is usually preventable. NICE and other authori-
ties recommend that generous amounts of potassium, mag-
In severe nutritional depletion, atrophy of the gut mucosa nesium and phosphate supplements should be given alongside
and impairment of pancreatic function may predispose to initiation of feeding, which should start at around 10 kcal/kg/
severe diarrhoea following oral or enteral refeeding, precipi- day in very high risk groups [42, 43]. Thiamine and other B
tating further electrolyte and mineral imbalance. vitamins must also be given intravenously starting before
It is difficult to give a precise definition for the refeeding any feed is commenced, and continuing for at least the first
syndrome since many otherwise well-nourished patients, refed 3 days of feeding. Feeding rates can then be gradually
after only a few days starvation, will show a modest change in increased over the next few days to full calorie requirements
biochemical values, e.g. a fall in serum potassium and phos- by day 8. Thereafter, regular monitoring, especially of the
phate concentrations, without displaying any symptoms. refeeding electrolytes (phosphate, potassium and magne-
There is a spectrum or gradation in the features of this condi- sium) is essential, although the frequency required will
tion from such asymptomatic cases to those with severe mal- depend on the stability of the patient. A more in depth
nutrition who are at risk of overt and even life-threatening description of the management of refeeding syndrome can be
symptoms. The cut-off point at which the ‘refeeding syn- found in reference [43] and chapter “Refeeding Problems”.
drome’ can be said to be present is, therefore, somewhat arbi-
trary. The full blown syndrome should be defined by the
presence of symptoms, but that biochemical changes of suffi-
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Prevention, Diagnosis and Management
of Catheter-Related Blood Stream
Infections
Simon Lal, P. Chadwick, M. Gompelman, and G. Wanten
Key Points 6. When central blood cultures are positive and no periph-
1. Catheter-related bloodstream infections (CRBSI) repre- eral cultures can be taken (or vice versa), this can be
sent the most common serious and life-threatening com- classified as a probable CRBSI providing the symptoms
plication for patients receiving home parenteral support and clinical picture is suggestive of a CRBSI.
(HPS). 7. For uncomplicated CRBSIs it is recommended that an
2. Development of CRBSIs occurs mostly following attempt to salvage the CVC is made, by means of treat-
microbial migration along the contaminated or colo- ment with antibiotics since repeated catheter loss ulti-
nized central venous catheter (CVC) surface into the mately will lead to a failure to obtain adequate and
bloodstream (usually from the hub). reliable central venous access. Catheter salvage is not
3. Skin-derived flora causes most catheter related infec- recommended for candida infection.
tions; therefore adequate hand hygiene and aseptic cath- 8. Once a CRBSI is suspected and while blood cultures
eter handling techniques are most important for CRBSI results are awaited, empirical therapy should be com-
prevention. menced with a CVC antibiotic lock plus a systemic antibi-
4. CRBSI should be suspected when patients receiving HPS otic, adjusted thereafter according to microbial sensitivity.
present with fever (especially if within an hour of setting 9. If salvage fails or the patient has recurrent CRBSI, the
up an infusion), are unwell or have been involved in CVC should be removed and other sources of infection
events that may be associated with a catheter infection should be considered.
(e.g. catheter fracture, attempts at restoring patency, etc.). 10. Fluid (or parenteral nutrition) during salvage is given by
5. Paired qualitative (using differential time to positivity a different catheter (often into a peripheral vein).
(DTP) or paired quantitative (using pour plates)) blood 11. After a CRBSI the aseptic techniques in setting up/tak-
cultures from a peripheral vein and from the catheter are ing down an infusion should be reassessed, and possible
required for the diagnosis of a definite CRBSI. environmental contributors identified.
12. Central blood cultures should be taken at least 48 h after
completion of therapy to confirm successful treatment.
S. Lal (*)
Salford Royal and University of Manchester, Manchester, UK
Introduction
P. Chadwick
Department of Microbiology, Salford Royal Foundation Trust,
Salford, UK Patients with chronic intestinal failure depend on paren-
e-mail: [email protected] teral nutrition to maintain health and preserve life. Catheter
M. Gompelman related complications, particularly blood stream infec-
Department of Gastroenterology and Hepatology, Radboudumc, tions, are a significant cause of morbidity and mortality in
Nijmegen, The Netherlands patients on HPS. Dedicated intravenous catheters managed
with rigorous aseptic protocols are vital in preventing
G. Wanten complications and obtaining good long-term outcomes in
Intestinal Failure Unit, Department of Gastroenterology and
Hepatology, Radboud University Medical Center,
patients dependent on HPS. Similarly, robust arrangements
Nijmegen, The Netherlands for the early recognition and treatment of catheter-related
e-mail: [email protected] complications, including catheter-related blood stream

850 S. Lal et al.
infection (CRBSI), help to prevent progressive loss of is a potential for dispersion through detachment, allowing for
venous access. an enduring bacterial source population [5]. When harbored
within a biofilm, pathogenic bacteria are, to some degree,
protected against host defenses and antimicrobial compounds.
Pathogenesis of CRBSI The stability of this environment allows the bacteria to grow
on the surfaces of indwelling medical implants or devices
The use of a central venous catheter (CVC) is associated such as catheters or infusion ports [3, 6]. Since these devices
with the risk for microbial colonization and subsequent seri- are in direct contact with the bloodstream, the surface
ous infections, including CRBSI. Several factors have been becomes coated with bloodstream components that act as a
implicated in the pathogenesis of CRBSI: conditioning film to which microbes can attach [7]. Within
days of adherence to the catheter cell wall, multiple bacterial
layers are usually formed and microcolony aggregation
olonization and Contamination of the Central
C occurs. An extracellular matrix of exopolysaccharide (EPS)
Venous Catheter forms an antimicrobial glycocalyx or “slime” layer [8].
Bacteria in a biofilm communicate cell-to-cell through
The catheter itself can be involved through several potential molecular signals, a phenomenon that is termed ‘quorum
routes [1]: sensing’ (QS) [9]. Many proteins and virulence factors are
produced by bacteria in response to QS and thereby create a
• Colonization of the catheter tip and/or extraluminal sub- chronic, low-grade immune response [8]. A substantial pro-
cutaneous tract by skin-derived flora portion of the intimately connected microbial population
• Colonization of the catheter lumen through microbial lives in a down-regulated state because of the low nutrient and
contamination oxygen content within the biofilm. In addition, host responses
• Hematogenous spread of microbes onto the catheter sur- that comprise the actions of granulocytes, immunoglobulins
face from other foci of infection and antimicrobial therapy will likely have diminished effects
• Colonization of the catheter lumen through contaminated since they fail to penetrate the biofilm [10].
infusate.
The most common routes for contamination of CVCs are Infection Prevention
migration of skin-derived flora from the insertion or exit-site
of the catheter into the cutaneous catheter tract, and along the ype, Choice and Site of Central Venous Access
T
extraluminal surface of the catheter with subsequent coloni- Device
zation of the catheter tip, or via direct contamination of the
catheter hub by contact with hands, contaminated fluids or The choice, type and exit-site location of the central venous
devices. Less common causes of CRBSI are hematogenous catheter (CVC) plays an important role in occurrence of
seeding or infusate contamination [2]. Microbial contamina- catheter colonization and the risk for developing CRBSI and
tion, colonization and subsequently biofilm formation on is best determined by a multidisciplinary HPS team, where
catheter surfaces can occur within 24 h after insertion [3]. the opinion of the patient or his/her caregiver should also be
taken into consideration [11]. The first choice for placing the
CVC is in the upper caval vein with the tip placed as near as
Biofilm Formation possible to the level of the right atrial-superior vena cava
junction, via the internal jugular or subclavian vein and pref-
Microbial contamination of the catheter leads to the develop- erably on the right side. A left-sided approach, with a more
ment of microbial consortia associated with the CVC surface intimate contact between the venous vascular lining and the
and surrounded by a self-produced polymer matrix, termed a catheter, is associated with a higher risk for thrombotic com-
‘biofilm’. Biofilms typically consist of 3 components: the plications [12]. Femoral vein access routes potentially have
biofilm-growing microorganisms, the planktonically (nonag- more risk for catheter colonization, bloodstream infections
gregated) growing organisms and the integrated host compo- and symptomatic thrombosis, though this has only been
nent, such as fibrin, platelets or immunoglobulins [4]. proven in the case of short-term and non-tunnelled catheter-
Biofilms have the capability to seize and concentrate a num- ization [13, 14]. Subcutaneously tunnelled or totally
ber of environmental nutrients in their extracellular matrix. In implanted devices are preferred above non-tunnelled devices
addition, biofilms facilitate the resistance to antimicrobial because of the lower rate of infections due to the specific
factors by several mechanisms, such as down-regulation of protection from extraluminal contamination and fewer com-
cell division and by acting as a diffusion barrier. Finally, there plications related to self-administration of HPS [15]. If pos-
Prevention, Diagnosis and Management of Catheter-Related Blood Stream Infections 851
sible, a single lumen is device is preferred over a multiple Dental Care

lumen catheter because of the lower infection rate. Also,
infection treatment itself is more complicated in the multi- The various medications and therapies that are being used by
lumen situation [16, 17]. In selected patients, for example for patients with intestinal failure receiving HPN may affect
those with recurrent CRBSI, the creation of an arteriovenous their oral health status. Concerns exist that some CRBSIs
fistula has been proposed as a valuable alternative [18]. arise from poor oral health or recent dental treatment and for
this reason some experts recommend parenteral antibiotic
prophylaxis prior to dental care according to the infective
HPS Training endocarditis (IE) dental prophylaxis guidelines [27].
However, further study is needed to establish whether there
Careful management of CVCs, that are dedicated solely for is a true relation between dental treatment and CRBSI and
HPS administration according to a well-established protocol, clear guidelines on appropriate prescription of antibiotic pro-
is key for the prevention of CRBSI. As such, CRBSI rates are phylaxis specific for patients on HPN are required.
the main quality indicator for any HPS support program. To
establish this optimal care, the patient and caregiver need to
be well trained and educated in all fields of CVC care. Since Catheter Lock Solutions
adequate training in this respect is of major importance for
the prevention of CRBSI, training programs in many centres Catheter lock therapy is a technique for disinfecting the cath-
have been intensified in recent years. Attention is more eter lumen and involves the dispension of locking solutions
focused on the teaching of patients and their caregivers on in the catheter lumen for extended periods of time while the
how to manage their CVC themselves and encompasses catheter is not in use. Several lock-solutions have been devel-
more rigorous aseptic protocols that are performed at the oped and are being used for the prevention of CRBSIs, while
patients’ home instead of in the hospital environment, thus others primarily serve to prevent occlusions. Unfortunately,
reducing length of hospital stay [19–21]. However, so far, although this strategy may seem promising, several of these
CRBSI rates remain the lowest whenever the care is under catheter lock-solutions carry some associated risks and spe-
control of a highly trained nurse [21]. More modern forms of cial attention should be given to problems that can arise,
training programs that include video education of both staff such as the development of side effects based on toxicity and
and patients may be another measure that lowers catheter allergies, as well as antimicrobial resistance. An overview of
related infection rates and improves problem-solving capaci- the most commonly researched or used catheter lock solu-
ties and quality of life [22]. On the other hand, a recent study tions is provided below:
was more pessimistic and suggested that, when compared
with usual care, video education may lead to an increased nticoagulant and Fibrinolytic Lock Solutions
A
number of patient calls without improvements in CRBSI These types of catheter-lock solutions are especially rele-
rates [23]. vant in the setting of haemodialysis, since in these patients
blood is aspirated through the catheter and anticoagulants
are required to prevent catheter clotting and occlusion.
and Hygiene, Antiseptics and Central
H However, this does not apply to the HPS setting, since blood
Line Care is only withdrawn from the catheter in cases of a severe
infection. There is some evidence that heparin and citrate
Adequate hand hygiene with appropriate use of disinfectants may promote catheter colonization and biofilm formation
before and after touching the CVC (and non-touching of any [28]. Therefore, the use of anticoagulants as a catheter lock
key parts) by those who perform the HPS care is the corner- therapy to prevent CRBSI is not advised in the HPS
stone for preventing healthcare related infections in general setting.
[24]. The preferred antiseptic for catheter exit site and cer-
tain parts of the catheter (hubs, stopcocks and sampling Ethanol
ports) is chlorhexidine 2% [25]. Intravenous administration Although ethanol lock therapy (ELT) is relatively inexpen-
sets should be changed every 24 h when parenteral nutrition sive, readily available and seems to reduce the rate of CRBSI
(PN) is used [15]. In general, the use of in-line filters, needle in high-risk HPN patients (i.e. patients with a history of prior
free connectors and routine replacement of catheters are not CRBSI), the reduced CRBSI rate cannot be generalized to all
advised as infection prevention measures since there is no HPS patients [29–31]. Therefore, and due to the concerns
definitive proof that these measures reduce the incidence of that exist, particularly the effect of ethanol on catheter struc-
CRBSI [26]. Antimicrobial-coated access devices only seem ture, integrity and systemic toxicity, use of ELT is currently
a valuable option in short-term PN care [15]. not advised [26, 32].
852 S. Lal et al.
Antibiotic Locks ers results in a statistically significant reduction in S. aureus

Results from in vitro studies demonstrate stability of antibi- infections (RR 0.55, 95% CI 0.43–0.70). Nevertheless, there
otic locks while maintaining high concentrations for pro- is a wide variety between centers and the prevalence and
longed periods of time [33–35]. However, evidence is lacking clinical outcomes of CRBSIs caused by S. aureus in the HPN
that prophylactic use of such antibiotic locks reduce the inci- population appears in some centers not as poor as in other
dence of CRBSIs in HPS patients, while this strategy is asso- patient groups [21, 42–45]. Hopefully, in the near future it
ciated with an increased risk for the development of microbial will become clearer if the benefits also outweigh the poten-
resistance, especially in the case of long-term HPS require- tial risks for eradicating S. aureus in the HPN population.
ment [15]. Additionally, the biofilm that develops on the
intravascular catheter is relative resistant to antibiotic pene- ovel Catheter Lock Solutions
N
tration and this necessitates much higher blood levels of anti- The inhibition of biofilm formation still appears the most
biotics to reach sufficient therapeutic efficacy than can be attractive strategy to prevent catheter-associated infections.
achieved by antibiotic lock therapy [36]. In recent years, the emphasis has been on the development of
non-toxic and preferably antibiotic-free antiseptic agents
Taurolidine that disrupt the biofilm, like taurolidine; these rely on matrix
Taurolidine, a derivative of the amino acid taurine, is non- degradation, destabilization or anti-virulence compounds
toxic for humans and is rapidly metabolized into the amino that target the most tolerant microbes inside the biofilm. For
acid taurine, water and carbon oxide. An irreversible reaction example, a recently developed novel non-antibiotic, heparin-
of its downstream methylol metabolites with the bacterial free solution containing nitroglycerin (NTG) demonstrated
cell wall leads to diminished microbial adhesion to catheter in vitro activity against a broad spectrum of microbes with
surfaces, and hence, biofilm formation. Taurolidine displays high efficacy and ability to eradicate biofilm formation, with
a broad spectrum of antimicrobial activity against Gram pos- a potency similar to that of heparin. This compound appeared
itive and Gram negative microbes as well as yeasts and also safe and well-tolerated when administered in cancer patients
neutralizes bacterial endo- and exotoxins [37, 38]. Experience who had peripherally inserted central catheters (PICCs) [46–
with taurolidine as a catheter lock therapy is growing and the 48]. Altogether, a better understanding of biofilm formation
use of this compound as part of diverse available formula- at the molecular level may help to develop novel approaches
tions has become common practice in several centres over for the prevention of CRBSI.
the last years. Several randomized controlled trials (RCTs)
have been conducted and all of them showed that the use of
taurolidine locks is significantly associated with a lower inci- Diagnosis
dence of CRBSIs without obvious adverse effects and devel-
opment of bacterial resistance when compared to heparin There is a wide variation in the incidence of reported CBRSI
locks [39]. Since the previous trials cold not discriminate rates, even amongst internationally-recognised HPN centres,
between the beneficial effects of taurolidine and/or detrimen- with a systematic review published in 2013 reporting a range
tal effects of heparin, more recently a European multicenter of 0.38–4.58 per 1000 catheter days amongst 39 studies
RCT was conducted that compared taurolidine 2% to sodium reviewed [44]. Since the publication of this systematic review,
chloride 0.9% as a catheter lock solution in HPS patients. In a case series from the U.S.A. reported a much higher CRBSI
this study, use of taurolidine resulted in a decreased CRBSI rate of 11.5 per 1000 catheter days occurring in 101 adults
risk by more than four times with a favourable safety profile newly discharged home on PN [49], while a much larger series
as compared to saline, without adversely influencing micro- from the U.K. published in 2017 reported the lowest published
bial susceptibility [40]. Whether taurolidine as a catheter- CRBSI rate of 0.22 per 1000 catheter days in 279 patients
lock solution should be considered in all patients or only newly discharged on home parenteral nutrition (HPN) [21].
those with a high infection risk is still a matter of debate, not This variation in CRBSI rates between different international
least because of the financial implications of this strategy. centres may, to a limited degree, reflect differences in patient
cohorts studied since a number of patient-related factors, such
as the presence of a stoma and/or opiate use, have been associ-
Novel Preventive Strategies ated with CRBSI occurrence [45]; however, differences in
catheter care protocols between centres is likely the most sig-
Staphylococcus aureus Eradication nificant factor accounting for the extremes in CRBSI rates.
Although not new, strategies focussing on the eradication of Another factor that may influence reported CRBSI rates
the skin bacterium Staphylococcus aureus are currently is the criteria used for CRBSI diagnosis. A number of organ-
under research in the HPN population [41]. It is known that isations have proposed criteria for the diagnosis of bacte-
eradicating S. aureus with mupirocin ointment in nasal carri- remia affecting patients with indwelling venous catheters,
including the Centre for Disease Control and Prevention bacterial febrile illnesses and CRBSIs in a small study of
(CDC), Infectious Disease Society of America (IDSA) and children with intestinal failure [59] while other methods
the European Society of Enteral and Parenteral Nutrition aimed at making a rapid diagnosis, including real time PCR,
(European Society of Clinical Nutrition and Metabolism) have been explored but currently do not appear to be ade-
(ESPEN) [15, 50, 51]. The current ESPEN guidelines are quately sensitive to be used in this setting [60]. Further work
based upon the CDC criteria and recommend that a CRBSI is is required to develop and evaluate the role of novel tech-
diagnosed by a ‘positive culture of the catheter (on removal), niques aimed at rapidly diagnosing CRBSIs, while ensuring
or paired blood cultures from a peripheral vein and the cath- consistent methodology so that meaningful comparisons of
eter (when left in place) with isolation of identical organisms CRBSI rates can be made between different IF centres.
(both species and antibiograms) from cultures of catheter seg-
ments and blood drawn from a peripheral vein in a patient with
clinical symptoms of sepsis and the absence of another source Management
of infection.’ Once drawn, international guidelines further rec-
ommend that blood samples from central and peripheral veins Current international guidelines recommend that infected
undergo quantitative and/or qualitative analysis in the labora- CVCs are salvaged wherever possible because repeated cath-
tory. Quantitative methods, such as pour plates, are thought to eter loss can ultimately lead to failed venous access which,
have the best diagnostic accuracy and are recommended by currently, can be an indication for a small bowel transplant
international organisations, but may not be widely used [50, [26]. Thus, once diagnosed, attempts should be considered to
52–55]; if quantitative methods are used, then the diagnosis treat the CRBSI with antibiotics without resorting to CVC
of a CRBSI should be made if the colony count of microbes removal. Of course, salvage should be only attempted if
grown from the catheter hub blood sample is at least three- deemed clinically appropriate such that immediate CVC
fold greater than the colony count from the peripheral blood removal is recommended if the patient is at clinical risk with
[50]. Qualitative methods include assessment of differential septic shock, where any attempt at CVC salvage may be felt
time to positivity (DTP), which has reasonable accuracy and to compromise the safety of the patient [21, 26, 45]. In addi-
is more widely available in most hospitals; a positive CRBSI tion, if patients have a CVC tunnel infection, a metastatic
is diagnosed if the growth of microbes from the catheter hub infection (e.g. endocarditis, osteomyelitis) or a septic throm-
blood sample occurs at least 2 h before any microbial growth bosis associated with the CRBSI, salvage is also not gener-
is detected in the peripheral blood sample [56]. Quantitative ally recommended because of the relatively low chance of
and qualitative blood cultures rely upon careful sample label- success and, in these circumstances, CVC removal is advised
ling, with equal volumes of blood instilled into blood culture [26, 45]. While tunnelled catheters can be readily salvaged,
bottles (within 10 min) and that the samples are then handled some experts also describe successful salvage of infected
identically. The samples require prompt transport to and pro- implanted ports; however, in the authors’ experience and
cessing within the laboratory (within 4 h of being collected). according to European guidelines [26], successful salvage of
Failure to follow standardised guidelines utilising quanti- these devices is rare and most implanted ports have to be
tative or qualitative paired cultures can lead to CRBSI misdi- removed if infected [16, 26]. If removed, reinsertion of any
agnosis, inappropriate antibiotic usage and potentially long term CVC should not take place until after completion
unnecessary catheter removal. Indeed, a retrospective study of a course of appropriate systemic antibiotics and, thereaf-
from Denmark demonstrated that simply adopting a ter, once repeat blood cultures are negative [26].
clinically-based approach to diagnose CRBSI (for example, For uncomplicated CRBSIs, current guidelines advise
based on the presence of clinical symptoms, elevation of bio- that systemic antibiotics with appropriate microbial sensitiv-
chemical blood tests and a positive peripheral or central ity based on blood culture results, alongside antibiotic CVC
blood culture) rather than using quantitative or qualitative lock therapy, should be used for 2 weeks [26]. Two recent
methods may lead to significant over-diagnosis by 46% [57]. papers evaluating very large series since the 1990s, from
Thus, consistent approaches to the CRBSI diagnosis are Salford in the U.K. and the Mayo Clinic in the U.S.A., have
clearly important to allow meaningful comparisons between demonstrated high CVC salvage rates of HPS-associated
different centres, not least because CRBSI rate is deemed a CRBSIs of 72.5% (180 CVCs salvaged of 248 CRBSIs) and
surrogate marker of the quality of care provided by HPS cen- 70% (325 CVCs salvaged of 465 CRBSIs) respectively, with
tres and the outcome indicator considered to be the most low associated mortality (U.K. 1.7% inpatient episodes of
important by HPN-dependent patients [58]. CRBSI and U.S.A. 3.5% overall mortality from CRBSI in
New methods to diagnose CRBSI have been evaluated but the HPN population) [45, 61]. Coagulase negative staphylo-
have not yet proven to be of clinical benefit. For example, cocci were the most frequent isolate in both series and had
plasma immunoglobulin levels against flagellin and lipo- the greatest successful salvage rate of 79.8% in the U.K.
polysaccharide were not found to differentiate between non- paper and 77.8% in the U.S.A. paper [45, 61]. CVCs infected
854 S. Lal et al.
with Gram negative or polymicrobial bacteria could also be cohort after antibiotic therapy and the subsequent in-patient
salvaged at high rates [45, 61]. Notably both papers demon- catheter-related BSI rate for those admitted with a CVC on
strated that more than half of all CVCs infected with poten- the IFU was very low at 0.042 per 1000 catheter days, over a
tially highly pathogenic organisms, such as S. aureus, could total of 23,548 in-patient catheter days [21]. Thus, since
also be safely salvaged [45, 61]. This is despite guidance there is a risk that continued PN infusion may serve as an
from the Infectious Disease Society of America (IDSA) rec- infective milieu, identification of central venous catheter
ommending that CVCs infected with S. aureus should be infection or colonisation is clearly important in patients with
removed [62]. Most international authorities recommend acute IF to attempt to reduce the risk of the associated mor-
that CVCs infected with fungi should be removed [15, 26, bidity resultant from subsequent CRBSI development in
50, 51] and this was the practice in recently published papers already metabolically-unstable individuals [21].
from the U.K. [21, 45]; the Mayo group actually reported After a CRBSI the patient/carer’s aseptic technique in
successful treatment of fungal CRBSIs, albeit at a very low handling should be reassessed. If recurrent CRBSI another
rate (14.2%) [61]. An ECHO should be performed if there is source of infection should be sought (e.g. teeth, wounds,
a prosthetic heart valve, pacemaker/ICD, persistent bacterae- nails, urine etc). 70% Isopropyl alcohol port protectors may
mia and/or pyrexia 72 h after initiation of appropriate antibi- be used. The prophylactic use of antimicrobial locks (e.g.
otic therapy and/or with S aureus infection. taurolidine) can be used for recurrent CRBSI, but ethanol
There remain some methodological differences between locks are not recommended. For all (especially nursed)
institutions in CVC salvage protocols. For example, some patients a root cause analysis is recommended to try and
[21, 45] but not all [61] centres advocate routine use of identify possible contributory factors.
thrombolytics within the CVC salvage protocol theoretically
to remove any associated intraluminal thrombus, although
the evidence-base for this approach is limited [26].
Furthermore, the duration of antibiotic therapy has varied References
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Central Vein Thrombosis
Cristina Cuerda and Yaser Naji
Key Points Incidence and Etiology
1. Acute central vein thrombosis is a medical emergency Thrombotic complications of the catheter are a dynamic pro-
requiring an urgent Doppler ultrasound and/or cess with varying severity from the appearance of the fibrin
venogram. sheath at the tip of the catheter, intraluminal blood clot,
2. Thrombolysis can be given directly into the clot. mural thrombosis to venous thrombosis [1].
3. Early treatment may prevent later venous stenosis/ The fibrin sheath does not usually affect catheter function
occlusion. and can occur within 24 h after catheter placement and often
4. Chronic venous stenosis can be treated with angioplasty develops within two weeks. Intraluminal clots usually cause
and stenting. catheter occlusion. Mural thrombosis is a blood clot that
5. The cause of the thrombosis should be determined. adheres to the vessel wall and can occlude the tip of the cath-
6. When 2 of the 4 major supra-diaphragmatic veins have eter but does not completely occlude the vein. Central venous
been lost there should be consideration for a small bowel thrombosis (CVT) occludes the vein and is the most signifi-
transplant. cant thrombotic complication.
CVT is a severe complication that is responsible for the
loss of central venous accesses in patients on home paren-
teral support (HPS) and may be an indication for small bowel
Introduction transplantation if it affects two or more of the central venous
vessels (subclavian, jugular or femoral) [2].
Home parenteral support (HPS) is administered through cen- The pathogenesis of CVT is multifactorial and includes
tral catheters of different type (tunneled, ports, peripheral the following: (a) vessel injury during the procedure of inser-
inserted central catheters (PICCs)). Even though thrombotic tion, (b) venous stasis due to indwelling of the device and
complications of the catheter are less frequent than catheter- damage to the endothelium caused by infusion of parenteral
related infections, they cause a significant burden in these nutrition with a high osmolality, and (c) mechanical rubbing
patients and may lead to catheter replacement and loss of of the catheter against the vessel wall.
venous access that may compromise the administration of Venous thrombosis can develop soon after catheter inser-
parenteral nutrition in the long-term. tion or delayed in patients with long-term catheterization.
In this chapter we will review the incidence, etiology, The former cause is probably related to the damage to the
diagnosis and the strategies for the prevention and treatment endothelium of the vein during the insertion and may be
of this complication. decreased using ultrasound guidance [3]. Other important
factors are the proper selection of the vein (the right internal
jugular vein is the preferred one due to its direct direction to
the right atrium vs. the left-sided catheters), the catheter (less
C. Cuerda (*) thrombogenic material, lowest calibre and single-lumen),
Department of Medicine, Universidad Complutense, Madrid, Spain and the correct location of the tip of the catheter (in the lower
Nutrition Unit, Hospital General Universitario Gregorio Marañón, third of the superior vena cava, at the atrio-caval junction, or
Madrid, Spain in the upper portion of the right atrium) [3–6]. PICCs are
Y. Naji associated with a higher risk of CVT than tunneled or chest
London North West Hospitals, London, UK ports in some studies [7, 8], but not in others [9, 10]. The risk

858 C. Cuerda and Y. Naji
Table 1 Risk factors for venous thrombosis However, in a recent prospective study of the HAN-CIF
Catheter ESPEN group in 62 patients, the incidence of CVT with
• Material (polyvinylchloride and polyethylene are more serial Color Doppler Duplex Sonography evaluations for
thrombogenic than silicone and polyurethane)
• Number of lumens
12 months after catheter insertion was 0.045/catheter/year,
• Diameter of the catheter quite like that referred in retrospective studies [27]. In this
• Location of the tip of the catheter study all the catheters were inserted with ultrasound guide or
• Traumatic insertion (previous catheterizations) radiologic control and the catheter tip was in the atrio-caval
• Infection
• Ethanol lock (pediatric patients)
junction or in the lower third of the superior cava vein in all
• Type of catheter (PICC associated with more thrombosis than the subjects.
tunneled or chest ports)
Patient
• Underlying disease (cancer) Diagnosis
• Thrombotic diathesis
• Previous thrombosis
• HPS, chemotherapy, thoracic radiation The diagnosis of venous thrombosis may be suspected in
• Immobilization patients with symptoms due to interrupted venous return
(pain, swelling, erythema, positional headache; patients
often say they have a sensation of having a swollen head and
for thrombosis is also higher in patients with cancer, throm- neck) and signs (oedema, non-pulsatile raised jugular venous
botic diathesis, previous thrombosis, multiple catheteriza- pulse and if chronic visible collateral vessels usually on the
tions, catheter infection, or treatment with chemotherapy upper anterior chest wall) in the territory drained by the vein
[11, 12]. In recent studies it has been described an increased in which the catheter is located. Due to its low specificity
risk for thrombosis associated with ethanol lock therapy in (14%), the d-dimer test is not a useful method in screening
the pediatric HPN population [13, 14]. In children with intes- for deep vein thrombosis of upper extremities [11]. The gold
tinal failure on long-term HPS low levels of anticoagulant standard method for diagnosis is venography, but it is inva-
proteins (antithrombin, protein C and S) and elevated factor sive and requires exposure to intravenous contrast and radia-
FVIII activity have been described, likely reflecting liver tion (Fig. 1). The preferred method for screening is Doppler
insufficiency and chronic inflammation [15]. The main risk ultrasonography, which may be employed in both symptom-
factors for venous thrombosis are summarized in (Table 1). atic and asymptomatic thrombosis as it is a non-invasive
CVT may be clinically manifest or subclinical. Most of method with high sensitivity (97%) and specificity (96%)
the data on the incidence of CVT in patients receiving home
parenteral nutrition (HPN) comes from retrospective series
with large patient numbers but only report clinically mani-
fest thrombosis. In these studies, the incidence of CVT is
around 0.02–0.09 cases/catheter/yr. or 0.06–0.12/1000 cath-
eter-days [16–23]. Some retrospective cohort studies have
shown a decrease in the incidence of this complication over
the years, probably due to changes in the catheter manage-
ment and patient selection [12]. Paediatric patients seem to
have higher incidence of CVT than adults [15, 24].
The incidence of subclinical CVT with a routine diagnos-
tic imaging in patients on HPS is much more unknown. In a
cross-sectional study in 42 adult patients on HPN with a
mean dwelling time of 37 weeks, the authors reported 26%
of clinical obstruction of the upper venous system, 51% of
radiologic thrombotic changes of the vessels wall and/or
catheter tip and 66% of catheter dislocation from the original
place, although this study is quite old and probably does not
reflect the current practise [25]. In a prospective study includ-
ing 30 consecutive patients receiving intravenous feeding
(16 of whom had cancer), venography was performed in the
24-h period prior to catheter removal. The percentage of
thrombosis found was 33%, but only one patient had symp- Fig. 1 Right upper limb venography showing occluded right brachio-
toms [26]. cephalic vein with extensive collaterals
Central Vein Thrombosis 859
compared to venography in upper extremity deep venous summarized in several meta-analysis and systematic reviews,
thrombosis [4]. Duplex ultrasound can accurately detect but the results are difficult to analyze as they often include a
CVT involving the jugular, axillary, distal subclavian and the mixed population (cancer and benign disease), hospitalized
arm veins. Constrast venographic imaging is required for and at home, different types of catheters, and there are differ-
indeterminate duplex findings and to evaluate the deep cen- ences in the diagnosis of thrombotic complications (with rou-
tral veins and pulmonary arteries. tine diagnostic imaging or with clinical endpoints) [30–38].
Alternative strategies such as serially performed ultra- Based on the current evidence the use of routine prophylactic
sound, spiral CT or MRI may be useful and of potential anticoagulation is not recommended in patients with central
interest, but are not yet validated [28]. catheters in different guidelines [39, 40]. In the same direction,
ESPEN guidelines do not recommend routine thrombopro-
phylaxis with drugs (heparin, warfarin) for all adults on HPS
Complications based on the risk/benefit balance (grade of evidence low) [5].
At least 5 old, randomized studies in patients receiving
The main complications of venous thrombosis are infection, parenteral nutrition (none receiving HPN) used unfraction-
pulmonary thromboembolism and post-thrombotic syn- ated heparin in various doses added in the bag or intrave-
drome [1, 11]. Also, intracardiac thrombus has been described nously and found a trend through less thrombotic events in
in patients on HPS [29]. the venogram [41–45]. However, the safety of heparin pro-
The infection of the thrombus leads to a septic thrombo- phylaxis due to the risk of bleeding, thrombocytopenia, bone
phlebitis that is a serious complication that requires catheter disease, among others, presumably outweighs the risk of
removal. On the other hand, catheter infection facilitates the thrombosis in many cases.
development of thrombosis due to the adherence of the com- Regarding HPS adult patients, there are only retrospective
ponents of the thrombus to the biofilm. Pulmonary thrombo- and prospective studies, but no large, randomized, controlled
embolism is symptomatic in 4–14% of patients with venous clinical trial that evaluates the role of thromboprophylaxis.
thrombosis of the upper limbs and is asymptomatic in Studies on the effectiveness of warfarin in preventing
15–36%, sometimes delayed months or years after catheter thrombosis in HPN patients are limited and most have used
withdrawal. Although the post-thrombotic syndrome has low-dose warfarin (1 or 2 mg/day), which does not increase
been described only in 5% of patients with deep thrombosis the INR. One of the factors that may influence the effective-
of the upper limbs, it may be more frequent in patients on ness of warfarin prophylaxis is vitamin K intake in these
HPN. In the study of Barco et al., 20.7% of the HPN patients patients [46]. Three studies evaluated warfarin prophylaxis
with venous thrombosis developed vena cava syndrome [12]. in HPN adults. In a prospective non-randomized trial of 2 mg
In a retrospective study of 527 patients, including 138 chil- of warfarin given to 23 HPN patients, the incidence of venous
dren found an incidence of superior vena cava or inferior thrombosis was 1 in 1617 catheter days compared with 1 in
vena cava syndrome of 0.02/catheter/year [16]. Moreover, 251 days prior to the study [47]. In a retrospective review of
CVT causes loss of central venous accesses and may com- 47 HPN patients with HIV/AIDS, the thrombosis rate was
promise the administration of HPS in the long-term in these 0.016 per patient per month in 9 patients receiving 1 mg/day
patients. warfarin compared with a rate of 0.09 thromboses per patient
per month in 38 patients on no prophylaxis [48]. Finally, in a
retrospective review of HPN patients who already had 1
Prevention thrombotic event, the use of therapeutic warfarin resulted in
a significantly decreased thrombosis rate (1 in 18 patient
To prevent CVT it is very important to minimize the damage months vs. 1 in 184 patient months) [49].
to the vein wall during catheter insertion, recommending In a retrospective study in children on HPN, prophylactic
using ultrasound guided catheterization, choosing a catheter anticoagulation with low molecular weight heparin or warfa-
with the smallest caliber compatible with the infusion ther- rin significantly decreased catheter-related thrombosis and
apy, and placing the tip of the catheter at or near to the atrio- occlusion [50].
caval junction [3, 5]. All the risk factors relating to the patient In general, therapeutic warfarin has been associated with a
and catheter, previously discussed, should be considered. A 0.4%–2% annual risk of non-intracranial hemorrhage and an
thrombophilia screen may be done. annual intracranial hemorrhage risk of 0.1–0.9%, depending
Several drugs have been used in the prevention of CVT, on the INR target range [51]. In a study with patients on HPN
including heparin (in the catheter lock, inside the HPN bag, or the annual incidence of major bleeding was 4.3% for patients
administered subcutaneously) and oral anticoagulation (vita- on anticoagulants versus 1.8% for those off anticoagulants,
min K antagonists). Also, these studies may be done in pri- heparin-induced thrombocytopenia occurred in 0.6% and
mary and secondary prevention of CVT. They have been heparin hypersensitivity in 2.5% of the patients [12].
In two recent surveys on the current practice of experi- Anticoagulation

enced centers on HPN (one in UK, and the other one in the
HAN-CIF ESPEN group) most of the centers used warfarin This is the mainstay of treatment for acute CVT in addition
for the prevention of CVT only in patients with previous to endovascular procedures as catheter-directed thromboly-
CVT or other venous thrombotic events [52, 53]. sis (CDT), pharmacomechanical catheter-directed throm-
Based on current evidence, the decision to use anticoagu- bolysis (PCDT), or percutaneous mechanical thrombectomy
lation therapy to prevent venous thrombosis requires an (PMT). Endovascular procedures have proven to be effective
assessment of the risk of thrombosis, bleeding risk with in improving patient’s outcomes [57].
anticoagulation therapy and patient compliance, on an indi- Anticoagulation will prevent progression of the thrombus
vidual basis. and preserve patency of the collaterals. Unfractionated hepa-
rin is used initially as a bridge until full anticoagulation with
warfarin is achieved, with a target INR between 2.0 and 3.0.
Treatment Unfractionated heparin can be replaced with low molecular
weight heparin which is helpful for those patients who can
Treatment of CVT depends on the chronicity of the condi- be managed in an outpatient setting [58].
tion, the underlying cause, and the clinical presentation [54]. Anticoagulation does not lyse an already existing clot that
Acute CVT is a medical emergency and its adequate treat- has formed after CVT. The residual thrombus will impede
ment can prevent loss of venous access. BAPEN has recently blood flow and the inflammatory reaction to the thrombus
pubished guidance papers for the appropriate treatment of can cause significant narrowing or occlusion [59].
this relevant catheter complication [55, 56]. The time on anticoagulant treatment should be individual-
The treatment will include thrombolysis if within ized, and long-term anticoagulation must be considered,
14 days of onset of symptoms followed by anticoagulation; with any decision to cease determined on a case-by-case
otherwise anticoagulation only will be used. There should basis involving discussions with an expert in intestinal fail-
be an early discussion of the patient with the vascular ure/parenteral support.
radiological team. It is important not to remove CVC
immediately, as it may be dangerous. However, it may be
necessary if thrombolysis is not successful. If there is a Thrombolysis
residual central venous stenosis then balloon venoplasty
can be considered (with or without stenting) and subse- Systemic thrombolysis has been proven to cause partial clot
quently antiplatelet therapy should be given for 3–6 months, removal in randomized clinical trials but is associated with
with anticoagulation after this. Figure 2 summarizes the 3–4 times increased risk of major bleeding when compared
treatment of acute CVT. with anticoagulation alone [60–62].
Fig. 2 Algorithm of acute

central venous thrombosis
treatment. (Modified from
[56])
Catheter-directed thrombolysis (CDT) is a procedure nolytic drug, when compared with systemic administration
where a fibrinolytic drug is infused, over 6–24 h, directly of the drug. This will result in reduced treatment time and
into the thrombus using a catheter with many side holes, that hospital stay as well as less bleeding complications.
is positioned directly into the clot under fluoroscopy guid- Underlying venous strictures, which might be the precipitat-
ance. This ensures that a smaller dose of the fibrinolytic drug ing factor for CVT, can be identified and treated at the same
achieves a higher intra-thrombus concentration of the fibri- time after dissolving the clot [63, 64] (Fig. 3a–d). Heparin is
a b
c d
Fig. 3 (a) Right upper limb venography showing a thrombus in the Thrombolysis check venography 24 h post initiation of catheter-
form of filling defect in the right brachiocephalic vein (arrow). (b) directed thrombolysis shows complete resolution of the thrombus and
Catheter-directed thrombolysis. A catheter with multiple side holes an underlying significant stenosis at upper SVC (arrow). (d) Self
(identified by two radio-opaque markers on the catheter “arrows”) is expanding metal stent deployed at site of stenosis
introduced so that the holes are present within the thrombus. (c)
infused at the same time, through the side arm of the vascular ies for PTA demonstrated a cumulative patency rate of 76%
sheath, to prevent venous thrombosis around the sheath and at 3 months, 62% at 6 months, and 53% at 12 months [84].
the catheter [58]. Repeated interventions with PTA might be needed for
A successful rate of clot lysis is expected in 80–90% of central venous disease to maintain patency for a long dura-
patients after 1–3 days of the thrombolytic treatment if the tion [82, 83].
thrombus is less than 2 weeks old [64].
Cases should be individually assessed to address the fac-
tors that might increase the risk of bleeding, which is a Stenting
potential serious side effect of CDT. Those factors include
active or recent bleeding, recent major surgery or trauma, Bare metal stents (BMS) will provide mechanical support and
recent haemorrhagic stroke, or bleeding-prone lesions in are indicated if the following conditions: (1) significant resid-
critical areas like the central nervous system, and uncon- ual stenosis (>30%) after PTA (2) dissections or circumscribed
trolled hypertension [65, 66]. perforations after PTA (3) post recanalization of venous occlu-
The incidence of major bleeding is estimated to be 2–4% sions. Stents can migrate, shorten, fracture, or get luminal in-
only with infusions of recombinant tissue plasminogen acti- stent narrowing due to intimal hyperplasia, which will require
vator at low doses (0.5–1.0 mg/h) [67–69]. frequent ballooning. As no proven advantage has been noticed
The addition of a mechanical thrombectomy device to in BMS over PTA, stent deployment should be restricted to the
intrathrombus administration of the fibrinolytic drug is above-mentioned indications [82–84]. Primary and cumula-
called pharmacomechanical CDT (PCDT). Devices like tive patency rates of BMS at 3 months are 63–100% and
AngioJet (Possis Medical Inc) and Aspirex (Straub Medical) 72–100% respectively, 42–89% and 55–100% at 6 months,
have been widely used. Retrospective studies have sug- and 14–73% and 31–91% at 12 months [78, 79, 82–93].
gested that PCDT can further reduce the dose of fibrinolytic Flexible, self-expandable bare-metal stents are preferred as
therapy needed to lyse the clot as well as treatment time [70, they can conform with the tortuosity of the veins and enough
71]. radial strength for most venous occlusions [94]. In patients
Thrombolysis restores venous flow early on, prevent with Paget-Schroetter syndrome (venous thoracic outlet syn-
endothelial damage and subsequent long-term complications drome), stent insertion across the first rib/clavicle is a contra-
like stenosis and occlusions which are detrimental to patients indicated due to high rate of stent fracture and occlusion [95].
on parenteral nutrition [72–74]. Covered stents (CSs) might have the advantage of reduced
When thrombolysis restores venous patency, and if there endothelialisation and in-stent stenosis while still provide
is an underlying significant venous narrowing, endovascular the mechanical effect of the BMS. The disadvantages of CSc
treatment options include percutaneous transluminal angio- are occlusion of collateral veins, accidental cover of nearby
plasty (PTA) and bare metal stents (BMS). Several studies veins like the internal jugular or the contralateral brachioce-
have demonstrated variable success rates for all these proce- phalic vein and the high cost [96].
dures [75–79]. In cases with chronic occlusion of the central veins, the
The most common complication of thrombolysis is punc- combination of catheters and glide wires is tried first to cross
ture site oozing or bleeding. This is usually responsive to the occlusion. This is followed by prolonged ballooning with
manual compression or extrinsic compression using ban- or with stent insertion. If conventional wire manipulation was
dages. Allergic reaction to the fibrinolytic drug can occur and unsuccessful in crossing the lesion, sharp recanalization using
is more likely to happen with Streptokinase. the back of a stiff wire, or a thin-gauge needle can be attempted
[95]. If the occlusion could not be crossed with this technique,
a longer sheath is advanced as close as possible to the occlu-
Balloon Angioplasty sion and angled or straight glide wires (Terumo) with glide
catheters are usually successful in crossing the occlusion
Balloon angioplasty is usually performed for chronic venous [96]. If not, a second venous access in performed from the
narrowing/occlusion. Noncompliant high-pressure balloons right common femoral vein under US guidance and a glide
with diameters from 8–16 are needed to dilate the narrowing catheter and wire are used to negotiate the occlusion from
or occlusion in the central veins. These balloons have a below. More aggressive techniques like using the back end of
higher rated bursting pressure (up to 18 atm.) compared with a stiff wire or a thin trocar needle and trocar cannula can be
the standard balloons. If a significant residual narrowing used to cross tough and fibrotic lesions [58] (Fig. 4a–e).
(>30%) is still present post balloon angioplasty with persis- Cases with complete occlusion of the central veins,
tent filling of the collaterals, insertion of a bare metal stent is including those who will require access from brachial / sub-
advised to prevent recurrence of CVT [80]. clavian and femoral veins, and even those in whom thin nee-
PTA for central venous disease has a technical success dles are needed to cross the occlusions are not associated
rate of 70–90% [75, 78, 79, 81–83]. One of the largest stud- with higher complication rates [97].
a b
c d e
Fig. 4 (a) Left upper limb venography confirms an occluded left bra- crossed, and an 8 mm diameter balloon is used to dilate the track before
chiocephalic vein (arrow) with multiple bridging collaterals. Crossing stent deployment. (d) Two self-expanding metal stents deployed at site
the lesion with an angled glide wire was unsuccessful. (b) A long sheath of occlusion and dilated using a 10 mm diameter balloon. (e) A feeding
with an angled glide wire were advanced form the left upper limb line was inserted from a separate left subclavian vein puncture and
venography puncture site (straight arrow) and a curved catheter (curved through the stents. Note that the tip of the feeding line was kept at lower
arrow) was introduced into the upper SVC for a right common femoral SVC / upper part of right atrium to reduce the risk of catheter-induced
vein puncture to help in crossing the occlusion. (c) The occlusion was venous narrowing (arrow)
omplications of Balloon Dilatation

C ment is needed. Most of the cases will be performed under
and Stenting general anaesthesia but the pain might persist for few days
after stent insertion [82, 83].
PTA and stent insertion for venous narrowing or occlusions Stent can migrate especially if under-sized. If they migrate
are considered safe procedures [83, 97–100]. Puncture site to the heart or the pulmonary circulation, they should be
bleeding, which is usually mild even in patients who are anti- removed as soon as possible [100]. Increased venous return
coagulated, can be easily managed with manual compres- that can occur after venous recanalization of major central
sion. Venous perforation, which can happen during sharp veins has been reported to cause pulmonary oedema [101].
recanalization is not associated with serious comorbidities Stent thrombosis can happen, which can be treated with throm-
and serious bleeding is rate, as there is low or zero flow at the bolysis or anticoagulation. In stent stenosis, due to endothelial
site of perforation [82, 83, 100]. hyperplasia can be treated with repeated balloon angioplasty
Recanalization and stenting for chronic venous occlusion rather than an additional stent insertion [100]. Over dilatation
is associated with severe pain and adequate pain manage- of the SVC can cause arrhythmia or even cardiac arrest [102].
Surgery 13. Wong T, Clifford V, McCallum Z, Shalley H, Peterkin M, Paxton

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J Radiol. 2004;49:81–5.
Part VIII
Surgical Treatment of Chronic Intestinal Failure
Surgery for Patients with a Short Bowel
and Tissue Engineering
Mattias Soop, Laween Meran, Jeremy M.D. Nightingale,

and Jon S. Thompson
Key Points 6. The serial transverse enteroplasty (STEP) procedure is

technically less challenging than the LILT procedure, and
1. Surgery for patients with a short bowel is either to man- is now more used in both children and adults.
age the complications resulting from the resection (e.g. 7. Small bowel mucosa may be grown and placed in a syn-
abdominal wound, gallstones or renal stones) or to use thetic or biological scaffold; however, work continues to
surgical procedures to maximize the function of the exist- form a neural network. In future a tissue engineered graft
ing intestine. may be an option to small bowel transplantation.
2. The vast majority of surgical procedures to improve
absorption involve standard techniques such as recruiting
additional intestine into continuity, relieving obstruction
or tapering massively dilated segments. Introduction
3. Less common surgical techniques involve lengthening
and tapering the bowel or slowing the passage of chyme There are two important roles for surgical procedures in the
through the small intestine. management of patients with a short bowel. One is the man-
4. Various procedures to slow intestinal transit have been agement of complications related to the massive intestinal
attempted but long term efficacy and benefit have not resection and the resulting pathophysiology. The other is to
been demonstrated. employ surgical procedures therapeutically to maximize the
5. The longitudinal intestinal lengthening and tapering function of existing intestine.
(LILT or Bianchi) procedure may increase the absorption
surface of the remnant bowel, but can only be performed
on a dilated small bowel and is rarely technically possible Surgical Management of Complications
in adults.
Approximately 50% of patients with a short bowel will
require re-operation after their initial time in hospital [1].
These procedures are most frequently required for intestinal
M. Soop (*) problems and cholelithiasis. Gastric acid hypersecretion is
Department of Inflammatory Bowel Disease and Intestinal Failure
no longer a commonly encountered, probably [2] as most
Surgery, Karolinska University Hospital and Karolinska Institutet,
Stockholm, Sweden patients are given proton pump inhibitors. The important
e-mail: [email protected] aspects of management are shown in Table 1.
L. Meran
John Radcliffe, The Hospital, Oxford, England, UK Table 1 Surgical management of complications
University of Oxford, Oxford, England, UK Intestinal problems
e-mail: [email protected] • Preserve intestinal remnant length
J. M.D. Nightingale Cholelithiasis
St Mark’s Hospital, Harrow, Middlesex, UK • Early diagnosis
e-mail: [email protected]; [email protected] • Prophylactic cholecystectomy
Abdominal wall protection
J. S. Thompson
• Convert enterocutaneous and enteroatmospheric fistulas to
Department of Surgery, University of Nebraska Medical Center,
conventional stoma
Omaha, NE, USA
• Reduce chronic abdominal wall sepsis

870 M. Soop et al.
Intestinal Problems develops [11, 14]. This is particularly appropriate in patients

with benign conditions and anticipated long-term survival.
Two-thirds of re-operations in patients with a short bowel are While cholecystectomy may not be advisable at the time of
for intestinal problems. Many are related to the underlying the initial massive resection, it should be considered at the
intestinal disease or to mechanical challenges to the intestine time of other abdominal operations in those patients who
from adhesions or hernias, requiring further resection or have developed gallstones [15].
management of obstruction or fistula. During these proce-
dures an important goal is to preserve as much of the intesti-
nal remnant as possible. There are several strategies that can Abdominal Wall Protection
be used to preserve intestinal length when further intestinal
disease occurs in patients with short intestinal remnants. Many enterocutaneous and, even more so, enteroatmo-
These include employing intestinal tapering for dilated seg- spheric, fistulas severely worsen a patient’s quality of life
ments, stricturoplasty for strictures and serosal patches for [16] by causing frequent leakages under the skin appliance
strictures and perforations to avoid resection [3] (Fig. 1). If of the fistula bag, destruction of the surrounding skin with
resection is necessary, minimal resections should be per- associated chronic pain, and the requirement for very lengthy
formed whenever possible. An end-to-end anastomosis is and frequent procedures for fistula dressings. Resection of
preferred when maintaining length is the goal. the fistula is sometimes indicated on the basis of this indica-
Whereas normally a surgeon might discard a few inches tion alone, even in cases where there is no scope for a signifi-
of intestine to avoid another anastomosis, this should be cant increase in absorptive capacity. A clinical observation is
given careful consideration in patients with a short bowel that the improvement in quality of life when such a fistula is
where each additional centimetre of bowel becomes impor- resected and converted into a conventional stoma, even if
tant. Such consideration will take into account the length of high-volume, is very significant.
bowel already in continuity, the relative gain of the addi- Occasionally, patients with fistulas develop chronic cavi-
tional segment(s) as well as the type of bowel under consid- ties in the abdominal wall, resulting in accumulation of
eration: jejunum, ileum or colon. The colon is often thought infected fluid. When it is not possible to control such cavities
of as an organ absorbing only water and sodium. However, by drainage procedures, the patient may need to stay nil by
the colon and rectum also absorb energy in the form of short- mouth. Resecting such fistulas, or diverting them proximally,
chain fatty acids resulting from the microbial metabolism of will often resolve the chronic abdominal wall sepsis and
polysaccharides [5]. allow patients to resume an oral diet.
Cholelithiasis urgical Therapy for Patients with a Short

S
Bowel
As discussed in chapter “Gallstones in Intestinal Failure”
cholelithiasis eventually occurs in approximately half of The goal of surgical therapy is to increase intestinal absorp-
patients (adults and children) with a short bowel requiring tive capacity by either improving absorption by existing
parenteral support [3, 5–15]. These patients have a signifi- intestine or by increasing the area of absorption (Table 2).
cantly increased risk of developing cholelithiasis (about Absorption can often be improved by recruiting additional
75%) when the remnant length is less than 120 cm, total par- intestine into continuity, relieving obstruction, or slowing
enteral nutrition (TPN) is required and the terminal ileum is intestinal transit. Intestinal lengthening is feasible in selected
resected [14, 15]. Furthermore, these patients have more patients but obviously the most significant increase in length
complicated biliary tract disease and increased postoperative is achieved by intestinal transplantation (chapter “Intestinal
morbidity and mortality rates [11, 14]. In one study, 40% of Transplantation”).
these procedures were performed as an emergency, with a Adjunctive procedures for surgical therapy of patients
complication rate of 54% and mortality of 11% [11]. Delay with a short bowel should not be performed at the time of
in diagnosis may contribute to this poor outcome, particu- initial resection [17, 18]. They add potential morbidity in
larly because of the confounding effect of Intestinal failure patients who are already quite ill. Furthermore, intestinal
associated liver disease (IFALD). Thus, the diagnosis should adaptation, in patients with retained ileum and/or colon, will
be suspected and ultrasonography performed liberally to per- often result in sufficient improvement in absorption to obvi-
mit early diagnosis. The significant morbidity of symptom- ate the need for additional therapy. This is particularly true in
atic cholelithiasis in these patients has led to recommendation children, where additional growth occurs. Adaptation may
of prophylactic cholecystectomy, even before cholelithiasis avoid the need for PN in almost half of patients [19, 20].
Surgery for Patients with a Short Bowel and Tissue Engineering 871
Fig. 1 Techniques for preserving intestinal length include tapering of dilated segments rather than resection (a), stricturoplasty for strictures (b),
and serosal patches for strictures and perforations (c). (Reproduced with permission from Thompson [4])
Such adaptation may take longer than previously thought; a Moreover, there is evidence to suggest that performing
substantial proportion of patients continue the adaptive pro- such procedures (e.g. colon interposition and serosal patch-
cess beyond 10 years [20]. ing), at the initial resection may diminish the degree of adap-
872 M. Soop et al.
Table 2 Surgical therapy for patients with a short bowel at initial resection had a satisfactory long-term outcome. In
Optimize intestinal function addition to improving absorption, maintaining intestinal con-
• Restore continuity tinuity eliminates the inconvenience of the stoma. This has
• Relieve obstruction more than psychological advantages since patients with a
• Taper dilated bowel
stoma are more likely to have catheter-related blood stream
Slow intestinal transit
• Reversed intestinal segment
infections (CRBSI) [25]. Furthermore, malabsorbed carbohy-
• Artificial valve drates that reach the colon are metabolized to short-chain
• Colon interposition fatty acids by colonic bacteria [26]. Short-chain fatty acids
Increase intestinal length improve fluid and electrolyte absorption, are absorbed as
• Intestinal lengthening additional energy and may be trophic to the intestinal remnant
[26, 27].
There are also a number of potential risks inherent in
tation that occurs [19, 21]. Thus, surgical therapy for patients restoring intestinal continuity. Bile acids cause secretion of
with a short bowel should only be undertaken after the initial fluid in the colon and may exacerbate diarrhea. Thus, there
adaptive period and even then with specific objectives. may be more perianal complications and resultant dietary
The nature of nutritional support is the primary factor to restrictions. 60% of patients in one study had dietary restric-
be considered when surgical therapy for patients with a short tions with intestinal continuity compared to 33% with a
bowel is contemplated. Patients supported by enteral nutri- stoma [23]. Also, calcium oxalate kidney stones occur more
tion (EN) alone should be considered for operation only if frequently because of absorption of unbound oxalate from
they demonstrate worsening malabsorption, are at risk for the colon (chapter “Nephrolithiasis and Nephrocalcinosis”).
receiving parenteral nutrition (PN) or have other symptoms In another study no patients with a jejunostomy had nephro-
related to malabsorption. Patients who are stable on PN lithiasis compared to one-fourth of patients with a short
should undergo surgical therapy only if this would permit bowel and an intact colon [13].
them to discontinue or significantly reduce PN. Patients who Predicting the functional outcome after restoring intesti-
develop significant complications from PN will eventually nal continuity in individual patients with short remnants is
require either combined liver–intestine or solitary intestine difficult. In general, Carbonnel et al. [28], found that a
transplantation. jejuno-ileal anastomosis is equivalent to adding 80 cm of
small bowel and a jejuno-colic anastomosis equivalent to
25 cm of small bowel in terms of improved energy absorp-
Optimising Intestinal Function tive function compared to a jejunostomy. Patients with a
marked increase in stomal output in response to feeding
Recruiting any additional intestine into continuity with the will not do well unless a significant amount of small intes-
gastrointestinal tract is an important objective in managing tine is recruited distally. As adaptation to a short bowel is a
patients with a short bowel. Intestinal absorptive capacity process that continues for several years, sometimes beyond
can be increased and transit time prolonged. Recruiting a decade [20], it is not necessary to await completion of this
downstream intestine may simply entail exchanging a more process until surgery to restore intestinal continuity is
proximal jejunostomy for a more distal colostomy or actu- undertaken.
ally closing a stoma. However, occasionally other intestinal Assessing the effect of the distal bowel on absorption has
segments are available. For example, continuity has been been evaluated by using an external reinfusion apparatus [29]
restored using an ileal segment previously used as a urinary (chapter “Distal Feeding and Hydration”). This technique is
conduit in a patient with a short bowel; this ameliorated diar- somewhat cumbersome and requires access to the distal rem-
rhoea and steatorrhoea [22]. nant. A smaller reinfusion device that resides in the stoma bag
Many patients have stomas created at the time of massive itself has been introduced with favorable results [30]. The
resection [23]. Whether or not intestinal continuity should be potential roles of chyme reinfusion are in evolution, and
restored at a later time will depend on several factors, includ- include evaluation of the effects of restoration of continuity on
ing length of intestinal remnant, status of the ileocaecal valve bowel absorption and function; trophic feeding of the distal
and colon and the overall condition of the patient. While gut to prepare this for re-anastomosis and improved recovery;
some patients function well with very short intestinal rem- and in some cases a replacement of parenteral support
nants, generally at least a metre of small intestine is required altogether.
to prevent severe diarrhoea and perianal complications [23, The proximal intestine may become markedly dilated sec-
24]. Only 20% of the patients with an initial stoma had intes- ondary to chronic obstruction and/or structural adaptation in
tinal continuity restored at a later time [23]. Moreover, only patients with a short bowel. In adults this is usually due to
one-third of the patients in whom continuity was maintained obstruction secondary to stenosis. A useful approach in these
patients is simply to relieve the obstruction. Stricturoplasty on the antimesenteric border. Tapering can be accomplished
may be efficacious [19]. Dilated bowel is less frequently due by either resection or simply turning in the redundant tissue.
to obstruction in children and may be a variant of intestinal Overlapping the redundant intestine results in more normal
pseudo-obstruction. The resultant stasis and bacterial over- intestinal structure and function than tapering by longitudi-
growth further aggravates malabsorption. These large diam- nal transection and is the preferred approach [33].
eter segments of intestine have low contraction pressures that
result in poor propulsion [31]. Therefore, tapering dilated
segments should improve motility in these patients. Slowing Intestinal Transit
The earliest surgical therapeutic attempts for patients with a

Intestinal Tapering short bowel involved using techniques to retard intestinal tran-
sit [34]. These have included antiperistaltic segments, artificial
Intestinal tapering has been reported in at least 27 children valves, colon interposition and other approaches (Fig. 2). These
with a short bowel and dilated intestine [19, 31, 32]. procedures are most appropriate in patients with sufficient
Absorptive function, growth and development improved in intestinal surface area but rapid intestinal transit. Massive intes-
all cases. Patients had bacterial overgrowth but only one- tinal resection results in markedly shortened intestinal transit
fourth had an associated mechanical obstruction [19]. All time, which contributes to malabsorption and diarrhoea. The
had transient functional improvement but 2 of 11 required evolution of pharmacological agents that slow gastrointestinal
further procedures for recurrent malabsorption. Many transit, including glucagon- like peptide analogues (chapter
patients experienced a prolonged postoperative ileus. “Pro-adaptive Hormones in the Rehabilitation of Adult SBS
Segments ranging from 15 to 35 cm in length were tapered Patients”), has reduced the role of these operations.
Fig. 2 Techniques for slowing intestinal transit: intestinal valve (upper left), antiperistaltic segment (upper right), recirculating loop (lower left)
and intestinal pacing (lower right). (Reproduced with permission from Thompson [4])
874 M. Soop et al.
Antiperistaltic Segments Intestinal valves and sphincters have been created by a

variety of different techniques. These include constricting
Reversing segments of intestine to slow intestinal transit has the intestine externally, denervating segments of intestine
been studied extensively. The antiperistaltic segment acts as and increasing intraluminal pressure by intussuscepting
a ‘physiologic valve’ by causing retrograde peristalsis and intestinal segments [48–55]. Thompson et al. generally cre-
disrupting the motility of the proximal intestine. The disrup- ates a sphincter similar to that employed in the continent
tion of the intrinsic nerve plexus slows distal myoelectrical ileostomy procedure but only 2 cm in length [19]. The effect
activity [35]. Although retrograde peristalsis has been dem- of valves and sphincters on intestinal motility is complex,
onstrated radiologically, this finding does not always corre- involving several different mechanisms. They create a partial
late with improved function [36]. Antiperistaltic segments mechanical obstruction, prevent retrograde reflux of colonic
slow intestinal transit, improve absorption, reduce weight contents and disrupt the normal motor pattern of the small
loss and prolong survival after intestinal resection in some intestine, converting jejunal motor activity to a pattern more
experimental studies but others report no beneficial effect similar to the ileum [51, 54, 55]. While intestinal valves and
[37–39]. sphincters have been shown to lengthen transit time, increase
These conflicting results may be partly explained by the absorptive capacity and prolong survival in several experi-
different lengths of antiperistaltic segments used. While the mental studies, results have been inconsistent [49, 50, 52, 54,
ideal length of the antiperistaltic segment is not clear, lengthy 55]. Effective valves usually cause some dilation of the prox-
segments may produce significant obstruction and short seg- imal intestine and may result in obstructive symptoms.
ments may be ineffective. In one study an intestinal valve Necrosis of the valve, complete obstruction and intussuscep-
was more effective than an antiperistaltic segment in pro- tion are potential complications. Valves may lose the sphinc-
longing transit time after resection, but neither procedure ter function with time [49].
improved absorption [40]. Clinical experience with intestinal valves and sphincters
Antiperistaltic segments have been used clinically in has been limited with approximately 25 cases reported [19,
more than 80 patients, the majority being adults [19, 41–46]. 48, 51, 56]. Intussuscepted valves have been reported in six
Slowed intestinal transit and increased absorption occurs patients with a short bowel [19, 48, 51]. Four patients
[45]. They benefit half of the selected patients with a short improved markedly, one remained unchanged and the other
bowel who have rapid transit but adequate remnant length. had an obstruction necessitating take down of the valve.
The outcome in individual patients is difficult to predict and However, in one long-term study ileocolic nipple valves
subsequent surgery was frequently required [44]. Transient were lost in one-third of patients followed for more than
obstructive symptoms and anastomotic leak are potential 5 years [56]. As described below, nipple valves have recently
problems [39, 42]. While the length of the segment has var- been utilized to cause dilation of the intestine to permit sub-
ied from 5 to 15 cm in these reports, the ideal length of the sequent intestinal lengthening [57].
reversed segment seems to be approximately 10 cm in adults
and 3 cm in children. In one study a reversed segment that Colon Interposition
initially increased absorption could not be demonstrated Isoperistaltic and antiperistaltic colon interposition will
radiologically 6 months later [45]. Furthermore, initial retard intestinal transit. Isoperistaltic transposition is per-
manometric abnormalities in the proximal intestine may formed proximally and functions by slowing down the rate at
resolve with time which may explain loss of function over which nutrients are delivered to the distal small intestine [21,
the long term this procedure [46]. Another limitation of this 58]. The antiperistaltic colon interposition is placed distally,
procedure is that patients with shorter intestinal remnants similar to the reversed small intestinal segment, but has the
may not be able to afford to sacrifice a 10-cm segment for advantage that none of the small intestine remnant is used. In
reversal. addition to the effect on transit time, interposed segments
absorb water, electrolytes and nutrients [59]. Experimental
Intestinal Valves and Sphincters studies demonstrate that isoperistaltic colon interposition,
The terminal ileum and ileocaecal valve may be important either proximal or distal to the small intestinal remnant,
in retarding intestinal transit of nutrients and preventing resulted in slower transit time, less weight loss and increased
reflux of colonic contents. The presence of colonic con- survival without producing intestinal obstruction [58–60].
tents in the small intestine may alter motility and may con- While one investigator also demonstrated prolonged transit
tribute to bacterial colonization of the small intestine and time with isoperistaltic colon interposition, no significant
further malabsorption. An intact ileocaecal valve permits improvement in body weight or intestinal absorption was
survival in children with only 11 cm of small intestine found [21]. The length of colon interposed seems to be less
remaining, whereas those who lost their ileocaecal valve critical than with reversed segments. However, results with
required at least 25 cm of small intestine for survival with- antiperistaltic colon interposition have been less consistent
out PN [47]. [61, 62].
The use of colon interposition has been reported in ten etrograde Electrical Pacing
R
patients. Isoperistaltic interposition was performed in nine of Retrograde electrical pacing has also been investigated as a
these patients, of whom eight were infants less than 1 year of means of prolonging transit time [76–78]. This promotes
age [63–67]. The length of colon interposed varied between peristalsis in a reverse direction and also alters the motility of
8 and 24 cm. All patients were dependent on PN and had non-paced intestine, presumably through a hormonal mecha-
intestinal remnants ranging from 15 to 63 cm in length. Four nism [78]. In experimental studies, postcibal retrograde pac-
infants were weaned off PN within 4 months and survived. ing improved absorption of water and minerals after intestinal
Diarrhoea improved in one infant who subsequently died of resection [76, 77]. In addition, weight loss and faecal fat and
pneumonia. Three patients did not improve and subsequently nitrogen excretion were decreased. Intestinal pacing has
died of sepsis or hepatic failure. An adult patient had transit been used clinically in only one patient with a short bowel,
time prolonged from 10 to 25 min and a 50% reduction in PN but the pacemaker failed to stimulate the intestine [79]. In
[65]. Thus, isoperistaltic colon interposition has shown some humans, the natural pacemaker potential frequency is similar
promise as a therapeutic alternative. In a single report of anti- throughout the length of the small intestine. Intestinal tran-
peristaltic colon interposition, an infant eventually died after section does not alter the pacemaker frequency of the distal
initial increase in weight and slowing of intestinal transit intestine [80]. Because the pacemaker frequency cannot be
time [67]. increased above the natural rate in the intact intestine, it may
not, in fact, be feasible to entrain the intestine to achieve ret-
Recirculating Loops rograde pacing in humans [81].
Theoretically, intestinal pouches and recirculating loops would
prolong transit time by permitting repeated or prolonged expo-
sure of luminal nutrients to the intestinal absorptive surface Increasing Intestinal Length
[68, 69]. However, these procedures have been associated with
high morbidity and mortality rates in experimental studies and Longitudinal intestinal tapering and lengthening (LILT),
do not clearly improve absorption or survival rates after mas- which has the attraction of not only tapering the dilated
sive resection [70, 71]. The results of few anecdotal clinical intestine but also using the redundant intestine for additional
reports using recirculating loops have not demonstrated clear length, was initially described by Bianchi in 1984 [82].
benefit [72–74]. The three adults were followed for 7, 10 and Dissection is performed longitudinally between the blood
24 months. Two died and increased absorption was not clearly vessels on the mesenteric border of the intestine, allocating
demonstrated. Cywes [75] previously created a proximal jeju- vessels to either side of the intestinal wall (Fig. 3). A rela-
nal pouch with a distal 4-cm antiperistaltic segment in an tively avascular plane can be developed because these ves-
infant. After 3 months transit time was prolonged, but improved sels enter the intestine from either side of midline. The
absorption was not demonstrated. intestine is then transected longitudinally with clamps or a
Fig. 3 Longitudinal intestinal

tapering and lengthening
a b
(LILT). Dissection
longitudinally between the
blood vessels on the
mesenteric border (a) permits
the stapler to be used to divide
the bowel longitudinally (b,
c). The two parallel segments
are then anastomosed
end-to-end (d). (Reproduced
with permission from
Thompson [4])
c d
876 M. Soop et al.
stapler. The resultant parallel intestinal segments are then require separation of the leaves of the mesentery, and can
anastomosed end-to-end so that the initial dilated segment therefore also be applied to adults. Instead, the dilated intes-
becomes a segment of one-half the diameter and twice the tine is lengthened by partially dividing the bowel from alter-
length. In the short-term this procedure disrupts motor activ- nate sides with a cutting stapler instrument (Fig. 4), leaving
ity and alters the hormonal response to resection [83]. a channel 2.5 cm in diameter and some 70% longer than the
However, long-term patency and function of divided seg- original segment.
ments has been demonstrated with resultant improved At least 111 children have undergone the STEP procedure
absorption. [87]. Of 97 children with long-term follow-up, 11 died and 5
The Bianchi procedure has been reported in more than 50 had an intestinal transplant. Thirty-seven achieved nutri-
children ranging in age from 1 day to 19 years [57, 83–85]. tional autonomy [88].
Bacterial overgrowth and complications of TPN were pres- Data on outcomes of STEP in adults are scarce. The Nebraska
ent frequently. Significant improvement in nutritional status group published a detailed case series in 2010, reporting out-
occurred in approximately 90% of patients in these reports. comes in 20 adults who had bowel lengthening, of whom 15 had
Segments as long as 55 cm have been tapered and length- the STEP procedure [87]. Overall, mortality was nil and four
ened. Complications have been reported in 20% of cases. In patients (20%) required a reoperation, in all cases for obstruc-
one patient in whom a 25-cm segment of proximal intestine tion. At long-term follow-up, 59% had regained nutritional
was divided longitudinally, one-half of the divided segment autonomy. Cleveland Clinic reported overall outcomes of 420
became ischaemic and required resection. Intestinal motility cases of autologous gastrointestinal reconstruction for intestinal
is slow to return in these patients and gastrostomy tubes are failure, 14 of whom were children [89]. Among the 420, 68
frequently used. Death is rare but has occurred in the young- underwent the STEP procedure. Interestingly, 12 of those also
est (days/weeks old) and may be due to sepsis related to an underwent STEP on their colon. Nutritional autonomy was
anastomotic leak. Thus, although intestinal lengthening is regained by 44 (72%) of 61 long-term survivors [89].
beneficial in selected patients with a short bowel, the proce- At present intestinal lengthening can only be applied to a
dure should be applied cautiously because there is the risk of fairly select group of patients. They must have a short
jeopardizing the divided segments. The vascular anatomy remnant and an intestinal diameter greater than 4 cm. Thus,
must be favourable and the intestinal diameter of the seg- there has been recent interest in sequential procedures, first
ment to be tapered should be at least 4 cm. employing a distal valve or sphincter to dilate the proximal
The serial transverse enteroplasty (STEP) procedure was bowel and then performing the lengthening procedure [57].
described by Kim et al. in 2003 [86]. This procedure does not Alternative methods to increase blood supply to isolated seg-
Fig. 4 Serial transverse

enteroplasty procedure
(STEP). Direction of insertion
of the cutting stapler
instrument indicated by
smaller arrows. (Reproduced
by permission from Kim et al.
[86])
ments (e.g. from liver or omentum) and thus, permit repeated this approach. Clinical experience with intestinal patching to
lengthening have also been investigated [90]. increase absorptive surface in patients with a short bowel has
The STEP and LILT procedures are both accepted proce- not been reported. This remains a useful technique, however,
dures for non-transplant surgical management of children for managing intestinal defects and strictures when it is
with a short bowel, and the outcome of the STEP procedure desirable to avoid resection.
may be more favourable [91, 92]. Long-term outcomes were
recently compared in a systematic review of studies includ-
ing 782 children, reporting nutritional autonomy in 52% of Intestinal Tissue Engineering
patients following LILT, and 48% following STEP [93].
Spiral intestinal lengthening and tailoring (SILT) is a Introduction
novel technique described in children by Morabito, which
requires less manipulation of the mesentery than the LILT Tissue engineering is an evolving scientific discipline that
procedure, and does not alter the orientation of the muscle combines stem cell biology and biomaterials science to con-
fibers as with the STEP procedure [94–96]. In brief, inci- struct human organs. The unifying philosophy within the
sions are made in the dilated bowel at 45–60° to the longitu- field of tissue engineering is that the human body’s innate
dinal axis. The bowel segment is then stretched longitudinally regenerative responses can be applied and induced in the
over a wide catheter with the same diameter as the desired laboratory, to reconstruct functional human tissue for trans-
new lumen. The incisions are now closed with bowel in its plantation. Bioengineering of tissues with simpler functions
new, narrowed configuration. This promising technique such as the skin and cornea are established in clinical prac-
awaits validation in other centres. tice [97, 98]. Successful clinical applications of more com-
plex organs have also been demonstrated in a few case
reports of trachea and bladder reconstruction [99, 100].
Other Techniques There have been great advances in pre-clinical studies of bio-
engineering organs including oesophagus, skeletal muscle,
While the surgical techniques are summarised in Table 3, liver and lung [101–106]. Tissue engineering of small bowel
there are other potential techniques for expanding the intesti- is particularly relevant for patients with a short bowel. Here
nal surface area take advantage of the regenerative capability we discuss the recent advances and strategies in development
of the intestine. for intestinal tissue engineering solutions in short bowel
Intestinal regeneration will occur in full thickness intesti- syndrome.
nal defects patched with a variety of surfaces, including adja-
cent serosal surfaces. Whether or not sufficient mucosa can
be produced by intestinal patching to significantly increase Intestinal Stem Cells
intestinal absorption remains unclear [18]. Further experi-
mental study is necessary to assess the safety and efficacy of The intestinal mucosa has one of the fastest self-regenerating
rates of all mammalian tissues. Self-renewal is driven by
Table 3 Surgical options for patients with a short bowel intestinal stem cells (ISCs), positioned at the base of intesti-
Remnant
nal crypts. As ISCs divide, they give rise to daughter cells
length Clinical condition Surgical options which then proliferate and migrate upwards towards the
Remnant Normal diameter Optimize intestinal crypt-villus junction. Here, they terminally differentiate into
>120 cm function the absorptive or secretory lineages before reaching the vil-
Enteral nutrition lus tip, where they are shed into the lumen [107].
Dilated bowel with bacterial Treat obstruction
Early attempts to establish the in vitro expansion of ISCs
overgrowth, stasis
Intestinal tapering were extremely difficult without first inducing genetic trans-
Remnant Rapid transit Recruit additional formations, which limited their clinical translation potential.
>90 cm length In 1992, Evans et al., first demonstrated primary adult intes-
Need for PN Reversed intestinal tinal crypt cultures that consisted of both epithelial and
segment mesenchymal cells [108]. However, only short-term cultures
Artificial valve
lasting up to 2 weeks were possible using this method and
Colon interposition
Remnant Normal diameter Optimize intestinal multipotency was somewhat variable. In 2007, Barker et al.,
60–90 cm function made the landmark discovery that ISCs were marked by the
Dilated bowel Intestinal Wnt target gene Lgr5 [107]. The increasing knowledge in
lengthening ISC biology paved the way for the establishment of intestinal
Need for PN
organoids in vitro (Fig. 5) [109]. Sato et al., showed that both
Remnant Complications of PN Intestinal
<60 cm transplantation mouse and human intestinal organoids could be cultured in a
878 M. Soop et al.
Scaffold Biomaterials
Scaffolds are an essential component in tissue engineering as

they act as a physical platform and support network, guiding
three-dimensional cell growth. Scaffold composition should
ideally mimic the natural extracellular matrix (ECM) that
exists in vivo as closely as possible [103, 118–120].
Biodegradability of the scaffold is also an important consid-
eration to ensure structural competence once anastomosed to
native structures. Both synthetic and biological scaffolds
have shown promising results in pre-clinical animal studies.
Synthetic intestinal scaffolds have been derived from bio-
degradable polymers and are moulded or printed into the
intestinal shape. The great advantage of synthetic scaffolds is
the potential to develop an “off the shelf” product that is
widely available and can be manufactured in large scale pro-
duction lines. However, these polymers do not retain any of
the natural nanotopography of the native intestine, nor any
bioactivity, which in turn affects cell behaviour such as loss
of pluripotency [120].
Fig. 5 Whole mount immunofluorescence staining of a human jejunal Biological scaffolds are derived directly from the ECM of
organoid. Proliferative cells are marked in magenta by 5-ethynyl-2′- native organs through a process of decellularization, which
deoxyuridine (EdU), whilst non-proliferating cells are marked in blue describes the process whereby an organ is perfused with a
by 4,6-diamidino-2-phenylindole (DAPI)
series of chemical and biological solutions to remove all cel-
lular and immunogenic material [112, 118]. Bioactivity of
three-dimensional matrix with an unlimited expansion important growth factors (such as vascular endothelial
potential whilst maintaining multipotency of all differenti- growth factor) is maintained after decellularization [121].
ated intestinal epithelial cell types [109, 110]. This was a key Most promisingly, human intestinal decellularized scaffolds
milestone in the field with significant research applications, (Fig. 6) have been formed and are shown to have preserved
particularly for intestinal tissue engineering [111, 112]. microarchitecture of the crypt-villus axis and retained bio-
Sources of intestinal cells include induced pluripotent logical activity, therefore offering the most biomimetic sub-
stem cells (iPSCs) and embryonic derived stem cells (ESCs). strate for intestinal tissue engineering [112]. Whilst this
iPSCs are generated by forced expression of genes in differ-
entiated adult cells such as fibroblasts [113], and have been
used to generate intestinal epithelium of all lineages in vitro
[114, 115]. Furthermore, they have been used in pre-clinical
intestinal tissue engineering studies where human iPSCs
grafts were transplanted in rats to demonstrate both struc-
tural and digestive functional competence in vivo [116]. An
advantage is that donor cells can be non-invasively obtained
from autologous sources such as skin biopsies, rather than
requiring endoscopy.
In contrast, ESCs are derived from totipotent cells of the
blastocyst stage of the early mammalian embryo (i.e. less
than 8 weeks after fertilization) and are capable of unlimited,
undifferentiated proliferation in vitro [117]. Human ES cell
lines (commercially available) have also been used to form
intestinal tissue when engrafted in the kidney capsule of
NSG mice. After 6 weeks in vivo, the cellular grafts con-
tained most of the intestinal epithelial, mesenchymal and
smooth muscle cell types found in the developing gut [115]. Fig. 6 False coloured scanning electron micrograph of human small
intestinal decellularized scaffold. Epithelial cells have been stripped off
However, the derivation of ESCs from human embryos is
to reveal the underlying extracellular matrix. Crypts are present as
associated with substantial ethical impediments, which may depressions on the mucosal surface, whilst villi protrude upwards
hinder their translation into clinical studies. (coloured in violet/grey at their tips)
strategy still relies on the availability of donor organs, the 8. Roslyn JJ, Berquist WE, Pitt HA, Mann LL, Kangarloo H,
DenBesten L, Ament ME. Increased risk of gallstones in children
study also showed it was possible to use colon scaffolds as
on total parenteral nutrition. Paediatrics. 1983;71:784–9.
substrates for jejunal mucosal reconstruction which would 9. Messing B, Bories C, Kunstlinger F, Bernier J. Does total paren-
provide an alternative source of tissue [112]. teral nutrition induce gallbladder sludge formation and lithiasis?
10. Pitt HA, King W, Mann LL, Roslyn JJ, Berquist WE, Ament ME,
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Bioengineering Human Intestinal Grafts parenteral nutrition. Am J Surg. 1983;145:106–12.
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optimal combination of human intestinal cells and scaffolds
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for transplantation studies [116, 119, 122–126]. Most GL. Gallstone disease in patients with severe short bowel syn-
recently, patient derived jejunal ISCs were expanded and drome dependent on parenteral nutrition. J Parenter Enter Nutr.
combined with human decellularized small intestine and 1989;12:461–4.
13. Nightingale JMD, Lennard-Jones JE, Gertner DJ, Wood SR,
colon scaffolds to form intestinal grafts which demonstrated
Bartram CI. Colonic preservation reduces need of parenteral
digestive and absorptive function in vitro. When transplanted therapy, increases incidence of renal stones, but does not change
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biological scaffolds. A second evolving unique strategy nal failure: a longitudinal cohort study from a National Specialized
Centre. J Gastrointest Surg. 2019;23(10):2002–6.
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Intestinal Transplantation
Lisa M. Sharkey, Stephen J. Middleton, Irum Amin,

and Andrew J. Butler
Key Points is accepted to be the first example of a successful small

bowel transplant [1]. This group made the observation that
1. There are 4 types of intestine-containing transplant (often this success was associated with the presence of a chimeric
these are all grouped under the umbrella term of ‘intestinal population of immunocompetent cells in this patient which
transplant’)—isolated intestinal graft, liver plus intestine, led to the proposal that engagement of the host and donor
modified multivisceral (stomach, pancreaticoduodenal immune systems promotes a degree of tolerance by the
complex and intestine) and Multivisceral (includes stom- recipient for the graft. Other centres have reported evidence
ach, pancreaticoduodenal complex, liver and intestine). of graft tolerance such as the observation of regulatory T
2. An intestinal transplant is considered for the complica- cells in the transplanted intestinal lamina propria [2].
tions of intestinal failure/parenteral nutrition (e.g. liver Under normal circumstances, lymphocytes circulate
disease), or in the context of extensive evisceration for between the peripheral lymphatic tissues such as the spleen,
desmoid or other benign abdominal tumours. lymph nodes and the gut. This process continues after small
3. For an isolated small bowel graft the 5 year patient sur- bowel transplantation but there is interplay between host and
vival is as high as 80% in some centres and the chance of transplanted lymphocytes which cycle through the trans-
these patients being off parenteral support is 93%. planted and host trafficking sites [3–5]. Under suitable
4. Problems of immunosuppression include increased risk immunosuppression this can be a benign process where tol-
of infection, nephrotoxicity, neurological side effects and erance prevails. However, inadequate immunosuppression
increased risk of malignancy can lead to proinflammatory lymphocyte behaviour and graft
5. Rejection occurs in 30% and graft-versus-host-disease rejection or less commonly GVHD [6, 7]. Efficacy of
in 10%. lymphocyte-depleting agents may arise at least in part from
the generation of “prope-tolerance” encouraged by the
replacement of depleted host immunocytes with a new popu-
lation that emerges in the environment consisting of both
Historical Perspective host and donor tissues such that there is an enhanced degree
of tolerance of donor tissues as self. In 1995 Campath 1H, a
Transplantation of the small intestine, either alone or as part monoclonal anti-CD 52 antibody, was first used for a multi-
of a cluster of organs has been undertaken for more than a visceral transplantation in Cambridge, UK. This depletes
century, but patient survival for more than a few days was not both T and B lymphocytes and seems to promote a greater
achieved until the late 1980s when Grant et al. reported what degree of tolerance which, together with the advent of the
more potent calcineurin inhibitors such as Tacrolimus in the
early 1990s, led to a decade when the use of intestinal trans-
L. M. Sharkey (*) · S. J. Middleton
plantation became exponential. An increase in serious infec-
Department of Gastroenterology, Cambridge University Hospitals,
Cambridge, UK tions tempered enthusiasm and highlighted the delicate
e-mail: [email protected]; balance between preventing rejection and avoiding infection.
[email protected] Attempts to improve tolerance and reduce infections by con-
I. Amin · A. J. Butler current splenic transplantation gained some traction for a
University Department of Surgery, Cambridge University brief period but has not stood the test of time.
Hospitals, Cambridge, UK
Over the last decade there has been a more cautious pol-
e-mail: [email protected];
[email protected] icy in most transplant centres and in general survival figures

884 L. M. Sharkey et al.
are now reasonable with a few centres still achieving results Table 1 Current indications for intestinal transplantation in the UK
(Source: NHS blood and transplant, https://www.odt.nhs.uk/transplan-
similar to those of liver transplantation. The incorporation of
tation/small-bowel/
a liver in the cluster of transplanted organs was initially
Irreversible intestinal failure, plus
believed to be largely responsible for inducing graft toler-
1. Life-threatening complications of parenteral nutrition
ance. It is now clear that it greatly increases the overall risk (a) Progressive intestinal failure-associated liver disease
of the procedure and is associated with a reduced survival (IFALD) or non-IFALD
compared with that associated with procedures that do not • Assessed by biochemistry and biopsy
contain a liver. Consequently, patients on parenteral nutri- • Combined intestinal and liver transplant is best
considered in the presence of advanced liver disease
tion, particularly if they have a very short small bowel rem- (portal hypertension or advanced fibrosis)
nant, should be carefully monitored and referred early to a (b) Severe sepsis
transplant centre before significant liver disease develops. • More than one life-threatening episode of catheter-
related sepsis for which no remediable cause can be
identified
• Endocarditis or other metastatic infection
I ndications and When to Refer for Intestinal (c) Limited central venous access
Transplantation • Venous access limited to three major conventional
sites in adults (above and below the diaphragm) and
two major conventional sites above the diaphragm in
The current indications for intestinal transplantation in the
children
UK as published by NHS blood transfusion and transplanta- • Conventional central venous sites are defined as
tion are summarized in Table 1. These have gradually broad- internal jugular, subclavian and femoral veins
ened over the last 15 years as the risks and benefits of these 2. Very poor quality of life thought likely to be correctable by
procedures have become more understood and the survival transplantation
Patients with indications for extensive surgery involving partial or
chance a little more predictable. However, there remains a complete evisceration
need for a fully validated system to estimate survival chance 1. Surgery to remove a large proportion of the abdominal viscera
of patients who are considered as candidates, both with their considered untenable without associated multi-visceral
existing problems and in the event of transplantation. The transplantation (e.g. extensive desmoid disease, extensive
critical mesenteric arterial disease)
same applies to the effect of transplantation on quality of life.
2. Localised malignancy considered amenable to curative
Some patients find their quality of life enhanced after intesti- resection requiring extensive evisceration (e.g. localised
nal transplantation, but others do not, and may even find a neuroendocrine tumours). Particular caution should be
reduction. Currently it is not possible to predict which patients exercised in this group and patients should be discussed in a
will do well from this perspective. Attention should be given multidisciplinary multicentre forum (e.g. National adult small
intestinal transplant forum, NASIT)
to the likely impact of transplantation on aspects of life that
Patients requiring transplantation of other organs where exclusion of
the patient considers of greatest importance to them, but simultaneous intestinal transplantation would adversely affect
always in the context of the other effects of their likely post- patient survival
transplant condition. This area remains very challenging. 1. Where the transplantation procedure is expected to preclude
As seen in Table 1, loss of central access sites for paren- the possibility of future intestinal transplantation (e.g. loss of
venous access or further human leukocyte antigen
teral nutrition is an indication for IT. However, it is critical sensitisation)
that the patient has sufficient venous access to allow ade- 2. Where the need for subsequent intestinal transplantation is
quate operative and post-operative support. For example, considered likely and the risk of death is increased by
many patients will require temporary renal replacement ther- excluding the intestine from the graft
Examples include predictable problems related to administering
apy, intravenous nutrition, management of complex sepsis, immunosuppression (e.g. line sepsis), or continuing severe intestinal
multiple surgical procedures and other invasive procedures disease such as diabetic visceral neuropathy, or ultra-short bowel
during their post-operative recovery. They will therefore syndrome, which may cause fluid, electrolyte and acid base balance
require suitable venous access sites to be available over a problems that would damage an existing or planned renal graft
Special considerations
long period of time and continued attrition of these is to be
Transplantation of additional organs for feasibility reasons
expected. Even after hospital discharge it is usual for patients Renal transplantation
to require intermittent re-admission [8], over the long term, Adults and children with corrected GFR of <45 mL/min/m2 are
with serious intercurrent illness when they require good cen- evaluated for the possibility of simultaneous renal transplantation
tral access to receive appropriate treatment.
Others may have recurrent sepsis or inadequate nutri-
tional support resulting in a steady decline, and slow grow- to be more advanced than indicated on cross sectional
ing tumours such as desmoids can present a particular timing imaging.
difficulty due to their unpredictable growth rate and tendency
Intestinal Transplantation 885
In addition to these factors, consideration should be given identified these patients should be considered as functionally
to the escalation of surgical complexity. If transplanted early pro-thrombotic.
enough, liver disease associated with intestinal failure often Some patients will have developed anti-human leucocyte
resolves. The requirement of a liver as part of the cluster of antigen (HLA) antibodies, as a consequence of pregnancies,
transplanted organs is associated with a much lower survival blood transfusions or previous transplants and are described
rate than non-liver containing grafts. Unfortunately, intesti- as “sensitised”. Knowledge of previous of sensitising events
nal failure associated liver disease can develop insidiously is mandatory and a full tissue type and HLA antibody screen
and reach an advanced stage with few if any signs for the performed. If there are anti HLA antibodies this will influ-
attending clinician to become alerted to its presence (see ence waiting time for organs [9] and may preclude transplan-
below). tation. Once listed it is important to avoid unnecessary
Therefore, it is necessary to avoid premature listing for sensitising events (e.g. blood transfusions).
transplantation when the patient does not fulfil criteria and Details of the immune status of the host to infections such
would be exposed to the risks of transplantation unnecessar- as Cytomegalovirus, Epstein Barr Virus, Toxoplasmosis,
ily, but also avoid undue delay when the patient’s condition Varicella Zoster, Herpes simplex, HIV, Hepatitis B, C and E
has deteriorated to a point which significantly reduces his/ and Mycobacterium tuberculosis are important for the heav-
her chances of survival. ily immunosuppressed post-operative environment.
Knowledge of previous infections particularly if multi-drug
resistant will allow better selection of anti-microbial therapy
Assessing the Potential Transplant Recipient and patients should receive appropriate vaccination against
the endemic infections they are likely to be exposed to dur-
The importance of the patients’ pre-operative condition and ing and after transplantation. Knowledge of the immune sta-
the adverse effect of comorbidity on operative and post- tus to CMV and EBV can influence donor and recipient
operative survival are now well established. Not only must matching and prophylaxis after transplantation.
patients be in a suitable physical condition but their mental Assessment of liver pathology in patients with IF is critical.
state is also of critical importance. Many patients already Normal liver function tests do not exclude underlying fibrosis
have mental illness arising in the context of their protracted or cirrhosis, and features of portal hypertension can be absent
physical morbidity and the additional burden of the trans- even in the presence of cirrhosis, due to reduced splanchnic
plant process often deepens any existing tendency toward blood flow. Patients at particular risk for advanced fibrosis are
depression and anxiety. Patients frequently spend several those who are ‘ultra-short’ [10] (residual SB length less than
months in hospital after the transplant and have long periods 20 cm), or those with a second hepatic insult (alcohol, viral
on the intensive care unit. These stresses are often associated hepatitis, previous non-alcoholic fatty liver disease). Transient
with loss or reduction in their support network of friends and Elastography (Fibroscan®) has not been validated in this group
family, due to geographical constraints. of patients and may be misleading. Liver biopsy is currently
There needs to be careful multi-disciplinary consideration the gold standard for liver assessment in this context. It is
as to the suitability of each patient in the broader context of important that the biopsy is of sufficient size and length and is
their general condition and likelihood of surviving what is interpreted by an experienced liver pathologist.
one of the most challenging medical procedures performed Patients with moderate or moderate to severe fibrosis would
in the modern era. Some centres achieve this with multidis- not necessarily require a liver as part of their graft. Patients
ciplinary meetings, and in the UK there is a National Adult with established cirrhosis will usually require a combined
Small Intestinal Transplantation forum (NASIT) at which all intestine/liver graft, even in the absence of portal hypertension
potential candidates are reviewed prior to listing for trans- as patients often do not manifest the clinical or radiological
plantation. This has also proven to be a valuable opportunity stigmata of chronic liver disease. Timing of transplantation
for the exchange of ideas and experiences between centres may be informed by the patient’s United Kingdom model for
and is attended by representatives from intestinal failure end stage liver disease (UKELD) or model for end stage liver
units as well as transplant centres. disease (MELD) scores but these have not been validated in
IFALD. In any case with IFALD, careful and nuanced judge-
ment by an experienced transplant centre is required.
Medical Assessment
The majority of candidates have experienced multiple throm- Surgical Assessment

botic events, either causing bowel loss or complications of
vascular access. A comprehensive thrombophilia screen is At referral, knowledge of the current anatomy including a
necessary but even if no defined pro-coagulant condition is detailed appraisal of the vasculature and previous surgical
history is needed. Previous histopathology can be helpful, morbidity and mortality and the projected long-term survival
particularly if liver pathology (e.g. IFALD) or dysmotility is is fundamental [12].
expected. Many candidates are considered for transplant because of
Examination focuses on stomata, enterocutaneous fistu- impaired vascular access. For liver containing grafts vascular
lae, surgical incisions, drain sites and anthropometrics. access above and below the diaphragm is required. For non-
Abdominal wall scarring results in reduced compliance and liver containing grafts two central veins are adequate.
abdominal domain, limiting the size of potential donors. Limitation of access to a single central vein considerably
Ascites increases the size of the abdominal cavity and there- increases the peri and post-operative risk, but does not neces-
fore the availability of potential donors. sarily exclude the patient from consideration.
Assessment for peripheral vascular disease is essential in The functional status of the patient is of great importance
any transplant; if present it is a marker of reduced long-term as many are deconditioned. A program of prehabilitation is
survival. desirable to improve post-transplant morbidity.
Radiological Assessment Psychological Assessment
Interpretation of current and previous images with a dedi- The pre-operative psychiatric and psychological assess-
cated radiologist experienced in the challenges of intestinal ment of patients deserves special mention. A number of
transplantation is essential. patients have died as a consequence of the development or
The corner stone of radiological assessment is triple phase deterioration of mental health disorders. The engagement
CT. This is the most useful modality to assess gastrointesti- of patients with the appropriate mental health support in the
nal and vascular anatomy. Assessment of the arterial supply preoperative period is of critical importance. Not only for
to the remaining abdominal organs, degree of aortic calcifi- post-operative management but to be as certain as possible
cation and patency of venous structures within and outside that patients have the mental capacity to provide fully
the abdomen are essential. informed consent. Institutionalised behaviour including
Many patients will have compromised central venous chronic opiate use and poor social support impact on out-
access which impacts per-i and post-operative care. comes and in extreme cases may preclude listing. A super-
Ultrasound, CT, MRI and/or conventional venography are vised pretransplant opiate reduction plan will have a
used for venous mapping. Venous reconstruction (using positive effect on post-operative pain management and
interventional radiology or surgery) may be required to allow graft function.
transplantation.
Nuclear medicine EDTA GFR (nGFR) can be performed
to determine the need for simultaneous kidney transplanta- Nutritional Assessment
tion in borderline cases [11]. DEXA scanning is necessary
given the high incidence of pre-existing metabolic bone dis- Weight loss (and loss of lean body mass) is frequently seen
ease in this cohort. in the first 3–6 months post-operatively. In our series 90%
These are the minimum tests that all potential candidates of patients lost weight, which was ≥20% of their pre-trans-
require, individual circumstances may dictate further testing plant weight in one third [13]. In paediatric recipients,
such as MRCP, CT chest and head. height and weight parameters improve over the first year
post transplant [14, 15]. Therefore, attention should be
given to the optimization of both the lean body mass and
Anaesthetic Assessment energy stores of the patients with appropriate involvement
of the nutrition team. The presence of sarcopenia can be
Cardiopulmonary testing in our institution involves ECG, judged by CT scans of the abdomen, from measurements of
lung function test, trans-thoracic echocardiography and psoas muscle mass, or total abdominal muscle mass.
some form of cardiac stress test in higher risk patients (those Bedside anthropometric measurements (including mid-arm
with 1 or more cardiac risk factors). muscle circumference, triceps skinfold thickness and hand-
Assessment by an anaesthetist experienced with the oper- grip strength) are useful as they can be performed serially
ation is essential. Consideration of the peri and post-operative to monitor progress.
Table 2 Example assessment checklist

System being Additional testing/intervention
assessed Minimum measurement tools needed in some Cut off criteriaa
Cardiac 12 lead ECG, echocardiogram, stress testing Angiography – Inducible ischaemia not
(dobutamine stress echo or MPS scan) correctable by intervention
– Moderate to severe impairment of
LV systolic function
Respiratory Pulmonary function tests including transfer CPEX – FEV1 < 1.5 L
factor – TLCO <50% predicted
– AT <8 mL/kg/min
Renal eGFR MAG3 renogram (split function) GFR <45 requires consideration for
If eGFR <60 mL/min for Nuclear medicine concurrent renal graft
EDTA GFR
Psychiatric At least one assessment by a psychiatry Intervention with CBT or other Psychiatric opinion regarding suitability
consultant experienced in transplant therapy and reassessment for Tx
assessment
Drug and Active use of recreational drugs – Equivalent total morphine dose
alcohol per day <100 mg
– Any alcohol intake (for liver-
containing grafts) in past 6 months
Dietetic Basic anthropometrics (BMI, MAMC, TSF, BMI <18
HGS)
Anaesthetic At least one assessment by an anaesthetic Prehabilitation plan (strength,
consultant experienced in transplant aerobic and respiratory capacity)
assessment
MPS myocardial perfusion scan, CPEX cardio-pulmonary exercise testing, FEV1 forced expiratory volume in 1 s, TLCO total lung transfer factor
measured by carbon monoxide exchange, AT anaerobic threshold, CBT cognitive behavioural therapy, BMI body mass index, MAMC mid-arm
muscle circumference, TSF triceps skinfold thickness, HGS handgrip strength
a
Not prohibitive, requires MDT discussion of overall risk
Treatment for reduced bone density should be promptly Even minor disorders that would under normal circum-
initiated and managed by a metabolic bone disease stances pose little risk to patients or challenge for clinicians
specialist. can develop into serious life-threatening complications
during the operative and post-operative period. An example
checklist for listing is shown in Table 2.
Summary of the Assessment Process The death of patients can often be traced back, with root
cause analysis, to a relatively minor disorder which led to a
Patients who are selected as candidates for transplantation sequence of ever increasing morbidity. The under apprecia-
will in most cases have already undergone a rigorous multi- tion of this phenomenon is probably the commonest mistake
disciplinary review as part of the selection process. The sub- made by clinicians when assessing patients for intestinal and
sequent preparation for transplantation should be thorough in particular multi-visceral transplantation.
and provide a convenient summary of all comorbidity which
should be quantified and monitored. This involves a compre-
hensive and sequential evaluation of each body system and Types of Intestinal Containing Grafts
should include a careful psychiatric and psychological
review. Any abnormality should be fully investigated and There are a variety of different intestinal containing grafts
corrected if possible and irreversible comorbidity or other and the most commonly performed examples are described
risk factors these should be detailed in a special preoperative below and in further detail in Table 3 and Figs. 1, 2, 3 and 4:
summary to allow them to be appropriately factored into the Any transplant that contains a transplant intestine meets the
management of the patients during and after transplantation. definition of ‘intestinal transplant’.
Table 3 Types of intestine-containing grafts

Proximal enteric
Type of graft Organs transplanted anastomosis Advantages/disadvantages Impact of graft failure
Isolated small Small bowel (+/− pancreatico- Jejuno-jejunal Limited exenteration Return to PN, potential
bowel transplant duodenal complex, colon) Duodeno-jejunal Splenic preservation retransplant at a later
date
Modified Stomach, pancreatico-duodenal Gastro-gastric More extensive evisceration including Urgent re-transplant
multivisceral complex, small bowel Oesophago- splenectomy
(+/−colon) gastric Stomach inclusion with increased risk
of aspiration, gastroparesis and
anastomotic leak
Liver small bowel Liver, pancreatico-duodenal Jejuno-jejunal Splenic and gastric preservation Urgent re-transplant
complex, small bowel Duodeno-jejunal
(+/−colon)
Multivisceral Liver, Stomach, pancreatico- Gastro-gastric Extensive evisceration with loss of Urgent re-transplant
duodenal complex, small bowel Oesophago- stomach and spleen
(+/− colon) gastric
Liver small bowel transplant Small bowel, pancreas & colon transplant
Fig. 2 ‘Isolated’ intestinal transplant (which usually includes small

bowel, pancreas and colon)
Fig. 1 Combined liver/intestinal transplant (native stomach and

pancreatico-duodeno-splenic complex left in situ)
Modified multi-visceral transplant Full multi-visceral transplant
Fig. 4 ‘Full’ multivisceral transplant: replacement of stomach,

pancreatico-duodenal complex, small bowel, colon and liver
Fig. 3 Modified multivisceral transplant (graft includes stomach, pan-

creaticoduodenal complex, small bowel and colon with native liver left using donor blood group blood when transfusion is neces-
in situ) sary post-op. HLA matching is not routinely undertaken, as
there is not yet good published evidence to suggest it affects
graft survival, but avoidance of donors to which recipients
The Transplant Procedure have pre-existing high level anti HLA antibodies is desirable.
In some centres donors and recipients are matched according
The intestine is particularly sensitive to ischaemia reperfu- to CMV and EBV serological status to attempt to reduce
sion injury. In order to minimise the cold ischaemia time CMV disease [17] and possibly EBV driven PTLD.
(<6 hours) the donor and recipient procedures are performed
simultaneously.
Organ Retrieval (Procurement) Procedure
Donor Selection After an appropriate organ donor has been identified and
prior to arrival of the retrieval team the donor bowel is pre-
Most donors are DBD (donation after brain death) and are treated with anti-fungal and anti-bacterial agents to reduce
selected on the basis of blood group, HLA type, size, viral the number of resident luminal micro-organisms It is not cur-
status and logistics. A small number of living donor intesti- rent practice to pre-treat the donor with lymphocyte depleting
nal transplants have been performed. agents although this has been undertaken by some centres in
Blood group compatibility is necessary. If the donor and the past, with no obvious benefit observed.
recipient blood groups are compatible but not identical there After the donor procedure has started the organs are
may be a period of passenger lymphocyte syndrome with assessed for anatomical anomalies and other pathology that
haemolysis for up to 6 months [16]. This is addressed by would make the organs unsuitable. Once the organs are
deemed appropriate this is communicated to the implanting collections and various stomata. Explanting desmoid
team and the recipient is anaesthetised and the explant proce- tumours and other slow growing neoplasms present a par-
dure is started. ticular set of issues including involvement of the abdominal
The specific extent of dissection is dictated by the nature wall and other organs (including the liver and ureters). The
of the graft required [18]. In the situation where a full multi- involvement of neighbouring organs may require complex
visceral graft is required then the liver, stomach, pancreas, strategies (e.g. ureteric reconstruction or auto-transplantation
small bowel and colon are prepared in such a way that the of the native kidney).
donor organs can be removed en bloc with a common vascu- Once the necessary native organs have been explanted the
lar pedicle. In circumstances where the liver is not required vascular inflow and outflow for the graft are prepared.
as part of the graft then the block is dissected in such a way Usually this involves dissection of the infra renal aorta in
that it can be split readily and quickly after cross clamp, thus preparation either for suturing of the Carrel patch or aortic
minimising the cold ischaemia time involved [19]. When no conduit. The venous outflow is either via the IVC or native
further dissection is necessary this is communicated to the portal vein or Superior mesenteric vein (SMV).
implanting team. If the implanting team are not sufficiently
advanced the donor team will delay cross clamp until the
recipient operation has progressed further. For this reason Isolated Intestinal Transplant (IT)
the duration of the donor procedure is very unpredictable. It
is critical that the other transplanting teams (thoracic and An isolated small intestinal transplant (not including pan-
abdominal) need to be aware that there may be delays. creas or colon) allows the donor pancreas to be utilised as
At cross clamp the organs are flushed with preservation part of a simultaneous pancreas and kidney transplant or
solution at 4 °C and rapidly removed and packed in more of pancreas alone transplant. In this situation the arterial inflow
this solution. Removal of the thoracic and abdominal organs is via the SMA and venous drainage is via the superior mes-
is undertaken simultaneously. As a result of the extensive enteric vein (SMV). This may necessitate vascular recon-
dissection prior to cross clamp in these retrievals the intesti- struction (often using donor iliac vessels) with a potential
nal block is often the first to be explanted. increased risk of vascular complications. For this reason
At this point the organs are transported to the recipient many units favour inclusion of the pancreas in intestinal
centre. grafts.
This facilitates colon inclusion and often negates the need
for vascular reconstruction.
The Recipient Procedure Under these circumstances, arterial inflow is via the CA
and SMA on a single Carrel patch. This is either sutured
The recipient procedure involves the removal of the diseased directly to the abdominal aorta of the recipient or via an aor-
native organs, preparation for implantation of the graft, graft tic conduit (donor thoracic aorta). Venous outflow is via the
implantation and reperfusion and abdominal closure. portal vein (PV), anastomosed to the recipient PV or SMV
Once the recipient is anaesthetised, central venous access (portal drainage) or recipient IVC (systemic drainage).
is established to facilitate anaesthesia, for veno-venous Pancreas inclusion preserves the middle colic vessels and
bypass (to allow inferior vena cava (IVC) cross clamping or may reduce vascular complications. The proximal enteric
reduce haemorrhage) and allow intra-operative haemofiltra- anastomosis is to the most distal part of the native foregut.
tion (for metabolic stability). For patients with severe portal Many units routinely include the colon as part of the graft in
hypertension requiring a liver containing graft, very substan- order to improve fluid balance and potentially minimise
tial blood loss is expected. Embolisation of the recipient deterioration in renal function [22, 23].
superior mesenteric artery (SMA) and or the coeliac artery
(CA) prior to starting the explant procedure results in reduced
blood loss and improved haemodynamic stability [20, 21]. Modified Multivisceral Transplant
The technical challenges of the explant procedure can be
very variable. In rare circumstances there is little dissection A modified multivisceral (MMV) graft requires a larger
required to prepare for implantation, most of the native explant procedure and includes resection of residual small
organs having been previously explanted. In most circum- bowel, pancreas, spleen, duodenum and part or all of the
stances the recipient will have had multiple previous lapa- stomach. It is essential that the hepatic artery is preserved
rotomies resulting in unclear intra-abdominal anatomy, and if possible, the left gastric artery (allowing a pouch of
dense adhesions, enterocutaneous fistulae, intra-abdominal native stomach to remain). This allows a gastric-to-gastric
proximal anastomosis (a lower risk anastomosis than se of Prosthetic Materials

U
oesophago-gastric). Biological and non-biological meshes have been used. They
As part of the implant procedure a pyloroplasty is neces- are readily available but have a number of disadvantages.
sary to allow gastric emptying. Some transplant centres per-
form simultaneous gastric fundoplication to reduce the risks Abdominal Wall Transplantation (Composite
of reflux and aspiration pneumonia. Arterial inflow and Tissue Allograft)
venous outflow is as for IT. These are vascularised composite allografts with a number
of important considerations in their use [25, 26].
iver Small Bowel Transplant and Full

L • At implantation the graft is vascularised using microsur-
Multivisceral Transplant gical techniques either directly to the recipient inferior
epigastric vessels or indirectly to the arm vessels in a tem-
Liver containing grafts include either a full multi-visceral porary manner
transplant (including a stomach) (MVT) or a liver small • The teams using this technique have suggested that the
bowel transplant (LSB). donor skin can act as a marker for rejection (a rash) which
If there are concerns that either the arterial supply/venous may help with patient management.
drainage of the native stomach (before or after explant) is
inadequate or there is compromised gastric motility then a
full MVT will be required. ectus Abdominus Fascial Grafts
R
Preservation of the native stomach reduces the magni- Some centres have used rectus abdominus fascia as a non-
tude of the explant procedure and also facilitates splenic vascularised graft [27, 28] (Fig. 1).
preservation This is associated with a reduction in sepsis
and (anecdotally) the risk of GVHD. For both LSB and Tissue Expansion
MVT the arterial inflow is via the CA and SMA on a single Pre-operative insertion of tissue expanders has been
Carrel patch and venous outflow via the hepatic veins. described. There are a number of issues that have limited
Where the native stomach and native pancreatico-duodenal their use.
complex are preserved, the venous outflow from these
organs is achieved by a portocaval shunt (either spontane-
ous, e.g. lienorenal shunt, or constructed at the time of The Postoperative Course
transplant).
At reperfusion extreme fluxes in potassium (from the Post-operative care is frequented by medical and surgical
preservation solution) may cause cardiac arrhythmias and challenges. Some of these are common to all solid organ
even cardiac arrest. This is usually reversible with CPR. transplant recipients, however many of these occur with
After completion of the implant and immediately prior to greater frequency in recipients of intestinal transplants. In
closure most units form a stoma to facilitate graft monitor- addition, these patients can present/demonstrate almost
ing. The type of stoma used is variable (and some units unique pathologies that challenge diagnosis and manage-
choose to avoid a stoma [24]). Our preferred option is a ment. The resolution of these conditions, which occur in
Bishop Koop stoma. This allows access to the graft ileum most areas of specialist medicine, usually require resort to
and colon for surveillance biopsies and keeps the transplant basic principles of the underpinning medical sciences
colon in continuity to improve fluid balance. It allows stoma [29].
reversal avoiding a full laparotomy. Induction immunosuppression is given at the time of
reperfusion of the graft and may consists of a lymphocyte-
depleting antibody and methylprednisolone. Our practice is
Abdominal Closure to give Alemtuzumab (Campath-1H), but some centres use
anti-thymocyte globulin, a polyclonal preparation of lytic
Abdominal closure must be achieved without causing anti-lymphocyte antibodies or IL-2 receptor blocking anti-
abdominal compartment syndrome. This is particularly bodies, such as Basiliximab. Maintenance immunosuppres-
important immediately after transplant because of graft sion is initially with tacrolimus and a reducing course of
oedema from ischaemia reperfusion injury. If the abdominal steroids, with the introduction of an antimetabolite (usually
domain of the recipient is adequate primary closure is under- Mycophenolate mofetil) within the first 2–3 months, depend-
taken, if not other techniques may be required: ing on individual circumstances.
a b
Fig. 5 Donor abdominal wall fascia—pre- (a) and post-implantation (b)
Mucosal integrity can be compromised in the early phase patients had received an intestine-containing graft world-
by ischaemia-reperfusion injury, so broad spectrum antibi- wide. Patient survival curves for adult and paediatric trans-
otic cover is given for at least the first week, then as neces- plant recipients are depicted in Fig. 5. UK-specific results are
sary for infectious complications. Antifungal and antiviral published annually at https://www.odt.nhs.uk/statistics-and-
prophylaxis are given for variable durations post-transplant, reports/organ-specific-reports/
depending on the transplanting centre and patient’s overall
risk.
Most intestinal transplant units have their own protocols Post Transplant Complications: Surgical
for monitoring and management. Key aspects of this include
graft surveillance for rejection, monitoring and treatment of The usual range of surgical complications occur after trans-
infections, nutritional rehabilitation, psychological care and plantation but in addition there are some that require particu-
a supported discharge. A wide range of team members are lar consideration.
involved, but the transplant specialist nurses are vital for
patient support. It is a mistake to try and operate this type of
facility without adequate staffing and it is often difficult for Vascular Complications
those not directly involved to appreciate the number of staff
required to provide adequate care for such a brittle and com- Some patients have a history of arterial or venous thrombo-
plex group of patients. ses [30] and will have an ongoing need for anticoagulation
The median length of stay in Cambridge is 57 days, the post-op. Despite this, some still develop thrombotic compli-
US transplant centres report an overall median length of stay cations, in the most severe circumstances this can results in
of 49 days (adults and paediatrics). Initially patients are on graft loss or the need for retransplant.
ICU or high-dependency units and may need to return to a Management of thrombosis may be surgical (thrombec-
level 2 or 1 unit if complications develop. It is important that tomy) or conservative.
patients are advised of this possibility; to avoid feeling this is The balance between bleeding and thrombosis in these
a ‘backwards step’. patients is challenging. From a surgical perspective, bleeding
All patients will be on parenteral nutrition immediately is preferable to graft thrombosis and loss but it can have cata-
post-transplant. Nutritional requirements at this stage are strophic consequences e.g. intracerebral haemorrhage. In
very high due to an intense catabolic state and the PN script intestinal transplantation the vascular anastomoses are wide
will reflect this. A feeding jejunostomy tube is often placed with limited risk of stenosis. Vessel ‘kinking’ and extrinsic
at the time of surgery, and this can be used for feeding once compression occur more frequently. In our series this par-
the stoma starts working (usually within the first week). Over ticularly affects the donor SMA presenting with ischaemic
90% of patients are weaned off PN by the time of discharge enteritis [31].
and over 95% are free of this long term. The development of a mycotic aneurysm is a very unusual
The international intestinal transplant registry (ITR) last but potentially catastrophic vascular complication [32]
presented their data in 2019. In this report, just over 4100 (Fig. 6). The patient usually exhibits a fever with no obvious
care is needed to avoid the pleural cavity as this may result in

empyema and the potentiation of an enteric fistula.
‘Spontaneous’ entereocutaneous fistulae may also occur.
These have been associated with intraperitoneal sepsis (often
fungal) and graft ischaemia.
Volvulus
The transplanted small bowel has relatively few peritoneal
attachments to the retroperitoneum and this may result in
internal herniation and the potential for volvulus and subse-
quent infarction.
Stoma Complications
Endoscopic graft surveillance early after transplant may con-

tribute to the development of stomal prolapse. Parastomal
hernias are common. Immunosuppression and poor nutrition
Fig. 6 Mycotic aneurysm of donor aortic conduit (arrow) result in poor wound healing. The transplanted bowel is
oedematous at the time of stoma formation and this may
cause and a contrast enhanced CT demonstrates an aneu- require the use of a larger fascial defect. Stoma reversal is
rysm. Management is difficult and involves appropriate anti- usually undertaken at 6 months to 1 year but may not be pos-
microbial agents, interventional radiology [33] and may sible if there is insufficient distal colon or the patient has a
require surgery to excise the infected tissue and replacement history of anorectal dysfunction [35].
with a vascular homograft.
Chyle Leaks
Chyle leaks may present following commencement of
Enteric Complications enteral feeding. Diagnosis is made by inspection of drain
contents and confirmed by measurement of triglyceride con-
Enteric Leaks centration. Resolution is achieved with conversion to a
Enteric leaks can be either anastomotic or non-anastomotic. medium chain triglyceride (MCT) diet as MCTs are
Diagnosis can be difficult in immunosuppressed patients. absorbed directly into the portal bloodstream, rather than
Prompt diagnosis relies upon a high index of suspicion and via the (disrupted) lymphatics [36], and/or bowel rest with
appropriate use of imaging (oral and iv contrast enhanced parenteral nutrition.
CT).
The oesophago-gastric anastomosis is at particular risk of
leak and may be associated with Candidal infection. Post Transplant Complications: Medical
Management has traditionally been surgical (revision of the
anastomosis) but successful use of endoscopic ‘vac sponge’ Whilst most of the medical complications occurring in the
has been recently described [34]. post-transplant period are not unique to these types of grafts,
The aetiology of spontaneous perforations is less clear. many occur at higher rates than in other solid organ trans-
They happen relatively early after the transplant and may be plants. Of particular concern due to the morbidity and mor-
associated with unrecognised ischaemic reperfusion injury. tality incurred, and therefore discussed in detail here, are
acute cellular rejection, graft versus host disease, post-
Enterocutaneous Fistulae transplant lymphoproliferative disorder (PTLD) and infec-
These may be either iatrogenic (associated with surgical or tions. Other significant complications including
radiological interventions) or ‘spontaneous’. Iatrogenic fis- haematological, neurological and psychiatric, are outlined in
tulae may follow enterotomies at laparotomy. Surgical inter- brief. The typical medication list of a post-transplant patient
vention early after transplantation is extremely challenging. is seen in Table 4.
The transplanted bowel is oedematous and friable and Overall graft and patient survival has been improving
densely adherent to itself and the surrounding tissues. over time. Data is collected from all centres for an interna-
Radiological placement of drains to treat post-operative tional registry and the latest output from this registry is
collections is helpful but may result in perforation. Particular shown in Fig. 7.
Table 4 List of typical medication a post-transplant patient will be taking

Medication Reason for taking Duration
Tacrolimusa Immunosuppression Lifelong
Mycophenolate mofetil Immunosuppression Lifelong
Prednisolone Immunosuppression Reducing course, some may need to continue low dose lifelong
PPI Gastric protection 6 months
Magnesium supplement Manage hypomagnesaemia Often only for 6–12 months
Fluconazole Fungal prophylaxis 1 year
Valganciclovir/Aciclovirb Viral prophyalxis 12 months/3 months
Penicillin Splenectomy prophylaxis for some patients Lifelong
Co-trimoxazolec PCP prophyalxis Lifelong
Anticoagulation If pre or post-transplant thrombosis Lifelong
Loperamide, codeine Reduce stomal output According to symptoms
PPI proton pump inhibitor, PCP Pneumocystis jirovecii pneumonia
a
May be converted to ciclosporin or sirolimus
b
Aciclovir if both donor and recipient CMV seronegative, otherwise valganciclovir given
c
Alternatives are atovaquone, dapsone or pentamidine
Fig. 7 Adult and paediatric Adult Graft Survival by Transplant Type (2009-2015) Adult Patient Survival by Transplant Type (2009-2015)
patient and graft survival. 100% 100%
Reproduced from the
International intestinal 75% 75%
transplant registry with
Graft Survival
Patient Survival
permission
50% 50%
25% SBT 25% SBT

p = 0.00024 MVT p < 0.0001 MVT
MMVT MMVT
SB+Liv SB+Liv
0% 0%
0 2 4 6 0 2 4 6
Years Years
Pediatric Graft Survival by Transplant Type (2009-2015) Pediatric Patient Survival by Transplant Type (2009-2015)
100% 100%
75% 75%
Graft Survival
Patient Survival
50% 50%
SBT SBT
MVT MVT
25% MMVT 25% MMVT
p = 0.3 p = 0.55
SB+Liv SB+Liv
0% 0%
0 2 4 6 0 2 4 6
Years Years
Acute Cellular Rejection dendritic cells and macrophages in mucosal layer). The clas-
sical presentation is with abdominal pain, fever and increased
This is the most common type of rejection in intestinal trans- stomal output. However, it can rapidly progress to bacterae-
plant recipients and affects 30–40% in the first year [37]. In mia and septic shock as the damage to the mucosal layer
brief, the mechanisms involve donor antigen presentation to disrupts the usual barrier function. Bacterial translocation
recipient CD4+ T cells, with co-stimulatory signals, result- can readily occur from the gut lumen into the bloodstream so
ing in activation of the CD4+ T cells. This results in IL-2 concurrent broad-spectrum antimicrobials are usually given
secretion which activates CD8+ (cytotoxic) T cells. These in addition to augmented immunosuppression.
infiltrate the graft and cause tissue damage. Diagnosis is by endoscopic evaluation of the graft and
The intestine is more likely to reject, due to the increased histopathology. The early endoscopic findings are mucosal
numbers of antigen-presenting cells in the gut (intestinal epi- oedema (leading to loss of normal vascular pattern), pro-
thelial cells express MHC Class II molecules, in addition to gressing to ulceration and areas of mucosal/villous loss
gut-resident ‘professional’ antigen-presenting cells such as (Fig. 8). The histological criteria for diagnosis were defined
Fig. 9 Typical skin rash of graft versus host disease (plaster depicts
biopsy site)
o pposite process to graft rejection, but again occurs more

frequently in patients receiving intestine-containing grafts,
affecting around 10% of patients [40–42]. This is due to the
Fig. 8 Endoscopic appearance of severe rejection of the ileum, with large burden of reactive lymphocytes in the mucosa-
mucosal loss, contact bleeding and reduced motility associated lymphoid tissue and mesenteric lymph nodes.
Any native organ is potentially a target for GVHD, though
the most common site is the skin. A maculopapular rash usu-
at the VIII International Small Bowel Transplant Symposium ally starts on the trunk (Fig. 9). Biopsy may show interface
in 2003 [38]. Histologically the early findings are of an dermatitis. If there is a sex-mismatch between the donor and
increase in the number of apoptotic bodies in the crypts recipient, then fluorescence in-situ hybridisation (FISH) can
(expressed as the number of bodies per 10 adjacent crypts). demonstrate the presence of donor lymphocytes within the
With increasing severity, lamina propria inflammation is inflammatory infiltrate.
seen, then architectural distortion and mucosal ulceration. Other target organs can include lung, eyes, native GI tract
Infections can mimic the symptoms and early histological or bone marrow. Involvement of the bone marrow leads to
findings of ACR so it is important to screen all patients for cytopenias and unfortunately the prognosis with bone mar-
bacterial pathogens and viruses (particularly adenovirus, row involvement is especially poor. An adjunct method for
rotavirus, CMV). diagnosis and monitoring of GVHD uses the detection of
First line treatment of ACR is with pulsed methylpred- peripheral T cell chimerism, the detection of reactive donor
nisolone (500 mg–1 g per day for 3–5 days). Following this T cells within the circulating blood. This can be quantified as
it can be difficult to determine the patient’s trajectory. a percentage of total circulating lymphocytes and used to
Endoscopic and histological features can take 2–3 weeks to guide response to treatment.
improve. It is critical that escalation to second line treatment Management approaches to GVHD differ between units.
is timed appropriately. The authors’ view is that if a patient Some advocate an increase in immunosuppression, initially
is clinically well and a repeat endoscopy 1 week after the with pulsed methylprednisolone, to suppress the graft
index scope does not appear to be worsening, then first line response. If this approach is used, the risk is of increased
care should be continued. If the patient is deteriorating or the infectious complications. Others propose that reducing the
endoscopic appearances are clearly worsening, escalation to immunosuppression (cessation of tacrolimus and antimetab-
a second line agent is needed (Alemtuzumab, Anti-thymocyte olite) may allow the host immune system to counteract that
globulin, Basiliximab). Graft removal may be necessary in of the graft. Using this latter approach mandates very careful
refractory cases, followed by immediate or delayed relisting graft monitoring for rejection and reintroduction of immuno-
depending on the patient’s clinical state and graft type [39]. suppression at the earliest signs of graft dysfunction.
Graft Versus Host Disease ost-Transplant Lymphoproliferative Disorder

P
(and Other Cancers)
Graft versus host disease (GVHD) after solid organ trans-
plant is mediated by immunocompetent donor T lympho- Post-transplant Lymphoproliferative disorders (PTLD) is the
cytes moving out of the graft and mounting an immune most common de novo malignancy occurring after transplan-
response against native tissue. It can be considered the tation of the intestine, in both adults and children. It occurs
in around 15% [43, 44] usually within the first 12 months failure of clinical response within the first 2–3 weeks.
post-transplant. The site (s) affected are often the intestinal Alternatives include foscarnet and cidofovir and newer agents
graft or mesenteric nodes, but can be extra-intestinal. PTLD include maribavir and letermovir. Adjunctive therapies are
is associated with EBV infection in the majority of cases and used variably, and include CMV immunoglobulin, lefluon-
the development of an EBV viraemia should prompt investi- amide and adoptive transfer of CMV-specific T cells.
gation for possible PTLD.
13
FDG-PET CT scanning can be very useful in the work-
up of possible PTLD, by identifying sites and giving a guide Neurological Complications
as to the burden of disease. However, definitive diagnosis
requires a biopsy of affected tissue. The histology can vary, Calcineurin inhibitors (CNI’s) such as tacrolimus cause
from polymorphic lymphoid proliferations, to aggressive tremor and myoclonic jerks. This is usually dose-related and
monomorphic PTLD or Hodgkin’s-like tumours. responds to a lowering of the blood level. CNI’s can also
Management of PTLD is with a cautious reduction in cause Posterior Reversible Encephalopathy Syndrome
immunosuppression and Rituximab, a chimeric antibody to (PRES) which presents in a variable way, with symptoms
CD20, a B cell surface marker. There is some evidence that including headache, visual disturbance, confusion and sei-
Ganciclovir has activity against EBV in vitro, but not in vivo. zures. Underlying mechanisms are not fully understood, but
EBV-specific Cytotoxic T cells are available commercially possibly include cerebral auto-regulation failure.
in some areas and have been used for PTLD following hae- Characteristic imaging features are of vasogenic oedema in
matopoietic stem cell transplant and PTLD after intestinal the occipital and parietal lobes, best seen on T2-weighted
transplant. For refractory cases, chemotherapy is necessary. FLAIR MRI head sequences. Patients respond to a change
In general, the outlook is good, with reported survival after in immunosuppression and the prognosis for recovery is
PTLD at 1 year of 91% and 75% at 5 years [44] of those good [46].
affected. In patients who have received an isolated intestinal graft,
All solid-organ recipients are counseled about increased the donor portal vein that accompanies the graft, is usually
risk of other malignancies, particularly non-melanoma skin anastomosed directly onto the inferior vena cava, effectively
cancer. 50–75% of Caucasian transplant recipients will be forming a porto-systemic shunt. If there is moderate liver
affected by skin cancer within 20 years of transplant. Risk fibrosis (perhaps the indication for transplant), then a hepatic-
factors include fair skin, UV exposure, older age and cumu- like encephalopathy can occur, with asterixis, confusion and
lative exposure to immunosuppression. Patients are therefore raised ammonia. Management is with laxatives and non-
advised to adhere rigidly to guidance recommending high absorbable antibiotics such as Rifaximin. Occasionally this
factor sunblock and protective clothing. can occur in the context of essentially normal liver function
if there is a high burden of small bowel bacterial overgrowth
due to stasis. It is of value to exclude reversible causes of
Cytomegalovirus stasis such as anastomotic strictures [47].
Cytomegalovirus (CMV) is the most common viral infection

after intestinal transplant. Rates are highest in recipients who Haematological Complications
are naïve to CMV themselves but receive organs from sero-
positive donors [45]. Intestinal transplant centres may use Many of these patients have pro-thrombotic tendencies
universal prophylaxis or a pre-emptive strategy to manage which have led to their needing an intestinal or multivisceral
risk of CMV infection. Some centres will also list CMV transplant (mesenteric arterial thrombosis leading to short
seronegative recipients for matched (also CMV negative) bowel, venous thrombosis associated with central venous
donors. catheters for parenteral nutrition, extensive porto-mesenteric
Manifestations of CMV infection include asymptomatic thrombosis associated with cirrhosis). The transplant itself
viraemia, CMV syndrome (fever, malaise and cytopenias) or involves the addition of new vascular anastomoses, there-
tissue-invasive disease. Diagnosis is by quantitative PCR- fore, for most patients anticoagulation is continued, even in
based detection of viral DNA and histological examination the early post-operative period.
of suspected end-organs involved. Drug-induced leucopenia or myelosuppression is com-
Universal prophylaxis is usually with ganciclovir (intrave- mon [48], as many of the necessary drugs have this side
nous) or valganciclovir (oral). Treatment of confirmed disease effect. In particular, the antimetabolites such as azathioprine
is also with one of these agents, at higher doses. Dose adjust- and mycophenolate, and antimicrobial agents ganciclovir
ment is required for renal dysfunction. Ganciclovir resistance and co-trimoxazole are common culprits. Minimising the
is an emerging problem and should be suspected if there is a doses, using alternative agents, or supporting counts with
Granulocyte colony stimulating factor (GCSF), are strategies disparate results [54], which likely reflects the heterogeneity
for overcoming this problem depending on the clinical con- of the patients. The need for ongoing nutrition support, fre-
dition of the patient. quency of hospital admissions and need for interventions
Transplant-Associated Thrombotic Microangiopathy strongly influence the self-reported quality of life outcomes
(TA-TMA) is a multisystem disorder characterized by a for patients. The neuropsychiatric side effects of corticoste-
microangiopathic haemolytic anaemia (MAHA), thrombo- roids are well known. Patients who have been dependent on
cytopenia and end-organ damage affecting the kidneys and/ opiates pretransplant may need continued support with this
or brain. There are no absolute diagnostic criteria but sup- and involvement of a multidisciplinary pain team is extremely
portive findings include red cell fragments, thrombocytope- helpful. Recent data from the team in Oxford showed lower
nia and raised lactate dehydrogenase. In the transplant quality of life metrics in patients being assessed for trans-
population, the most common causes are calcineurin inhibi- plantation compared to patients stable on home parenteral
tors and sirolimus [49]. Management involves a change in nutrition, but improvement following transplant to levels
immunosuppression and plasma exchange or eculizumab, a comparable to this stable HPN cohort [55]. The effect was
complement-blocking antibody, for refractory cases. seen using generic and disease specific measurement tools.
In the UK, two recipients of intestinal transplant set up a
support group for all adult and paediatric patients. They pro-
Renal Complications vide valuable emotional support to patients and families on
every step of their journey, supply care packages to patients
Intestinal transplant recipients are at particular risk of devel- who are in hospital and are actively involved in raising
oping chronic renal failure (CRF) and this must be taken into awareness and fundraising.
account during the assessment and listing process. In a large Transition of patients transplanted as children who are
US study of almost 70,000 transplant recipients (but only now entering adolescence must be carried out in a meticu-
228 intestinal grafts), the cumulative incidence of develop- lous, planned way. This time is associated with graft loss and
ing CRF (defined as an estimated glomerular filtration rate of significant morbidity if not conducted properly. The key
≤29 mL/min/1.73m2 body surface area), was 14.2% at requirements are a staged handover and multiple joint clinics
3 years and 21.3% at 5 years [50]. A more recent analysis of between the paediatric and adult teams.
all adult intestinal transplant recipients in the US included
843 patients and showed alarming 1, 5 and 10-year cumula-
tive incidence of CRF (defined as eGFR <29 mL/min, Conclusions
chronic dialysis or need for renal transplant) was 3.2%,
25.1%, and 54.1% respectively [51]. A smaller case series Significant advances have been made in the medical and
from the UK showed a median decline in GFR of 40% in the surgical management of patients receiving an intestine-
first 3 months after transplant [11]. The mortality rate for containing transplant. Survival rates are now similar to
those developing CRF after transplant was sixfold higher those on home parenteral nutrition (HPN), thus intestinal
than those who maintained renal function. transplant should be at least considered for all patients with
It is critical to preserve renal function pre transplant, as permanent intestinal failure, particularly for those HPN
this study also showed that each 10 mL/min/1.73 m2 increase patients in higher risk groups. The development of end-
in GFR pre transplant was associated with a reduced risk of stage IFALD severely disadvantages patients and Intestinal
CKD by 7.6%. This is especially important in patients with Rehabilitation teams need to develop processes that are
short bowel who may have high stomal fluid losses. In the more proactive in diagnosing and monitoring IFALD so
UK it is recommended that all patients referred for intestinal that timely referral for transplantation can be considered. It
transplant assessment are also considered for simultaneous is also crucial that patients who are losing vascular access
renal transplant [52] if their baseline GFR is <45 mL/ are referred early enough to still be candidates for
min/1.73m2. Although it increases the time and complexity transplantation.
of the transplant procedure, short term outcomes for those Aside from Intestinal Failure, the indications for trans-
who receive combined grafts are similar to those without plant are expanding and with this it is crucial that multidisci-
[53]. plinary decision-making continues and there are robust
reporting systems to the appropriate body for the evolving
indications (for example, the advisory groups of NHS Blood
Psychological Considerations and Transplant in the UK and the international Intestinal
Transplant Registry https://www.odt.nhs.uk/odt-structures-
There are no studies evaluating mental health in intestinal and-standards/clinical-leadership/advisory-groups/; https://
transplant recipients. Studies on quality of life have reported tts.org/irta-resources/irta-resources-main).
As patient and graft survival rates improve, surgical tech- Acknowledgements The authors would like to thank all members of
the transplant team, colleagues in referring centres, our patients and
niques are advanced and medical prevention and manage-
their families.
ment of complications continue to improve, the time is
approaching when intestinal transplant can be offered as an
Glossary1
alternative to HPN. All clinicians caring for patients with Allograft Transplant between two genetically different
intestinal failure should be aware of the possibility of intesti- members of the same species.
nal transplant and be able to discuss this with their patients. Allogeneic Of different genetic make up and therefore capa-
Local teams will also need to be involved in the acute man- ble of inducing rejection.
agement of sick transplant recipients (Box 1). Referring and Antigen A protein molecule that is capable of inducing an
transplant centres must continue to work cooperatively to immune reaction. In transplantation antigens on the sur-
optimize outcomes for all patients with intestinal failure. face of graft cells are the trigger to the immune system of
Establishing a dedicated forum for clinicians to present and the recipient-inducing rejection.
discuss their patients and learn from each other’s experiences Carrel patch Full thickness cuff of aorta incorporating the
in a cooperative and supportive environment is of particular orifices of the coeliac and superior mesenteric arteries to
value. facilitate the arterial anastomosis.
Cell surface markers Antigenic determinants on the surface
of cells. In some circumstances these act as binding sites
Box 1 Actions to be Taken When an Intestinal Transplant and linkage with a matching determinant is important to
Recipient Is Admitted Unwell to a Non-Transplantation allow an immune reaction to proceed. Cell surface anti-
Hospital gens have been defined by a number of international work-
shops that have generated the Cluster of Differentiation
1. Contact the appropriate transplant centre without delay (CD) nomenclature.
for advice and possible transfer CD3 The CD3 antigen is composed of five invariable chains
2. Undertake a full infection screen, including culture (and
microscopy) of blood, urine, sputum, stoma effluent/
and is closely associated with the T-cell antigen recep-
stool, EBV/CMV–PCR, chest and/or abdominal imaging tor. It is expressed on 70–80% of normal peripheral blood
as guided by symptoms. Common seasonal viral lymphocytes and plays a significant role in signal trans-
infections can present as a severe illness in these patients duction during antigen recognition.
and trigger graft rejection
CD4 The CD4 antigen is transmembrane glycoprotein
3. If infection is suspected (usual) commence broad-
spectrum antimicrobial therapy without delay, with expressed on T helper/inducer cell populations. It is
advice from microbiologists. This usually includes: expressed on approximately 45% of peripheral blood lym-
meropenem, vancomycin, AmBisome®, ganciclovir. If phocytes and it is involved in the co-recognition of MHC
there is evidence of pulmonary infection, consider class II antigens in association with the T-cell receptor.
high-dose co-trimoxazole, which is active against
Pneumocystis jirovecii. Advice should be sought from CD8 The CD8 antigen is a two-chain complex expressed on
the transplant centre (24/7 on call service available). T cytotoxic/suppressor cell populations. It is expressed
Many of these patients are colonised with multi-resistant on 13–48% of peripheral blood lymphocytes and it is
micro-organisms, details of which can be obtained from involved in the co-recognition of MHC class I antigens in
their transplant centre
4. Be aware of the possibility of tacrolimus nephrotoxicity
association with the T-cell receptor.
and neutropenia associated with valganciclovir and CD25 The CD25 antigen is the low affinity inter-leukin-2
co-trimoxazole (patients may already be taking these) receptor. It associates with the common (CD132) and
5. Fluid balance: patients will be prone to salt and water high affinity (CD122) chains to form the high affinity
depletion. They should be aware of their normal body
IL-2 receptor complex. CD25 is expressed on activated
weight, assess sodium and water balance with spot
urinary sodium and osmolarity respectively (urine dip T and B lymphocytes and activated macrophages and its
stick for specific gravity is a helpful initial guide) expression on lymphocytes is upregulated on activation.
6. Graft rejection is difficult to diagnose so patients should Interleukin-2 receptor antagonists are used as induction
be transferred to an appropriate transplantation centre as immunosuppression in certain patients.
soon as possible. Suspect rejection if there is a change in
stoma output, abdominal pain, fever and/or vomiting CD28 The CD28 antigen is expressed on most mature
7. These patients are likely to develop unexpected T-cells and antibody-producing B-cells (plasma cells).
complications which often present in an unusual manner It is involved in signal transduction and cell activation
and transfer back to the transplant centre is usually the events.
best option
1
This glossary provides definitions of immunological and transplant-
related terms, which may be unfamiliar to some readers.
CD44 The CD44 antigen is expressed on leucocytes, eryth- 5. Webster GA, Wood RF, Pockley AG. Identification of migratory
graft and host cell populations after allogeneic rat small bowel
rocytes and weakly on platelets. The molecule has a
transplantation. Immunol Invest. 1996;25(5–6):435–46. https://doi.
functional role in cell migration, leucocyte homing and org/10.3109/08820139609055733.
adhesion during lymphocyte activation. 6. Clark CL, Price BA, Malcolm P, Lear PA, Wood RF. Graft ver-
CD52 The CD52 antigen is present on mature T and B lym- sus host disease in small bowel transplantation. Br J Surg.
1991;78(9):1077–9. https://doi.org/10.1002/bjs.1800780915.
phocytes and is the target for Alemtuzumab induction
7. Starzl TE, Demetris AJ, Murase N, Thomson AW, Trucco M, Ricordi
immunosuppression. C. Donor cell chimerism permitted by immunosuppressive drugs: a
Chimerism The presence of donor cells in recipient tissues new view of organ transplantation. Immunol Today. 1993;14(6):326–
or bloodstream. 32. https://doi.org/10.1016/0167-5699(93)90054-o.
8. Kwon YK, Etesami K, Sharp AL, Matsumoto CS, Fishbein TM,
Graft-versus-host disease A reaction in which lymphoid
Girlanda R. Hospital readmissions after intestinal and multivisceral
cells in a graft are capable of migrating to recipient tissues transplantation. Transplant Proc. 2016;48(6):2186–91. https://doi.
and stimulating an inflammatory immune reaction. This is org/10.1016/j.transproceed.2016.03.036.
an important feature in bone marrow transplantation but 9. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous
immune globulin for desensitization during renal transplanta-
can also occur in intestinal transplantation because the
tion. N Engl J Med. 2008;359(3):242–51. https://doi.org/10.1056/
gut contains large numbers of lymphoid cells capable of NEJMoa0707894.
migrating. 10. Cazals-Hatem D, Billiauws L, Rautou P-E, et al. Ultra-short bowel
Haplotype A set of genetic determinants located on a single is an independent risk factor for liver fibrosis in adults with home
parenteral nutrition. Liver Int. 2018;38(1):174–82. https://doi.
chromosome.
org/10.1111/liv.13545.
Heterotopic A graft placed in an abnormal anatomical 11. Rutter CS, Russell NK, Sharkey LM, Amin I, Butler AJ. Decline
position. in renal function following intestinal transplant: is the die cast at 3
HLA Cell surface proteins encoded by the highly polymor- months? Clin Transpl. 2021;35(5):e14249. https://doi.org/10.1111/
ctr.14249.
phic major histocompatibility gene in humans. The HLA/
12. Zerillo J, Kim S, Hill B, et al. Anesthetic management for intestinal
MHC proteins are highly involved in antigen presention transplantation: a decade of experience. Clin Transpl. 2017;31:10.
to T cells. https://doi.org/10.1111/ctr.13085.
Natural killer cells Cells capable of reacting against foreign 13. Sharkey L, Kratzing C, Rutter C, et al. PTH-127 nutri-
tional status after intestinal and multivisceral transplant. Gut.
proteins without undergoing prior sensitization. They act
2014;63(Suppl 1):A267.1–A267. https://doi.org/10.1136/
as immune scavengers and are important in both cancer gutjnl-2014-307263.573.
(in eliminating abnormal cells) and in transplantation 14. Venick RS, Farmer DG, Saikali D, et al. Nutritional out-
where they may be able to initiate rejection. comes following pediatric intestinal transplantation.
Transplant Proc. 2006;38(6):1718–9. https://doi.org/10.1016/j.
Orthotopic A graft placed in its normal anatomical position.
transproceed.2006.05.051.
In intestinal transplantation the proximal end of the small 15. Venick RS, Wozniak LJ, Colangelo J, et al. Long-term nutrition and
bowel would therefore be connected to the duodenum and predictors of growth and weight gain following pediatric intestinal
the distal end to the ilio-caecal junction. transplantation. Transplantation. 2011;92(9):1058–62. https://doi.
org/10.1097/TP.0b013e31822f2b1b.
Tolerance The specific absence of a destructive immune
16. Foell D, Glasmeyer S, Senninger N, Wolters H, Palmes D, Bahde
response to a transplanted tissue in the absence of R. Successful management of passenger lymphocyte syndrome
immunosuppression. in an ABO-compatible, nonidentical isolated bowel transplant:
a case report and review of the literature. Transfusion (Paris).
2017;57(6):1396–400. https://doi.org/10.1111/trf.14086.
17. Sharkey L, Amin I, Russell N, et al. P-74: change in
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22. Ewald C, Swanson BJ, Vargas L, et al. Including colon i

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Jeremy M.D.

ISBN 978-3-031-22264-1 ISBN 978-3-031-22265-8 (eBook)

© Springer Nature Switzerland AG 2001, 2023

May, 2023 Kishore R. Iyer

ECHO Institute, Albuquerque, NM, USA

Emeritus Professor at the University of Manchester, Sir Miles Irving

St Mark’s Hospital, Harrow, UK Jeremy M.D. Nightingale

Part II Acute (Short and Medium Term Reversible) Intestinal Failure

Part III Chronic (Long-Term) Intestinal Failure

Part IV Consequences of Intestinal Failure

Part V Assessment and Treatment of Intestinal Failure

Part VI Outcome of Intestinal Failure

Part VII Problems of Treatment

Part VIII Surgical Treatment of Chronic Intestinal Failure

A&E Accident and emergency

BMS Bare metal stents

DIT Diet-induced thermogenesis

FXR Farnesoid X receptor

IHD Intermittent haemodialysis

MRP Multidrug resistance-associated protein

PEGJ Percutaneous endoscopic gastro-jejunostomy

John E. Lennard-Jones, Gil Hardy,

© Springer Nature Switzerland AG 2023 3

 daptation of the Residual Small Intestine

whole small bowel for a condition such as desmoid tumour

The first resection in humans of more than 200 cm of small

Jeremy M.D. Nightingale and Robin Spiller

J. M.D. Nightingale (*)

© Springer Nature Switzerland AG 2023 13

Macronutrients brush border immediately before absorption (Table 3).

Table 3 Content and function of most upper gastrointestinal secretions

fundus undergoing digestion and dilution by gastric secre- Gastrointestinal Tract

Table 4 Gastrointestinal hormones

and intestine, while CCK-B predominates in the stomach Motilin

Neurotensin Glucagon-Like Peptides

 lucagon-Like Peptide-1 (GLP-1)

Ingested bacteria, viruses and other dietary antigens are

Jeremy M.D. Nightingale

Key Points Introduction

Fig. 1 Reasons for Nutritional support

Intake (Oral) failure Digestive failure Absorptive (Intestinal) failure

J. M.D. Nightingale (*)

© Springer Nature Switzerland AG 2023 35

Definition of Intestinal failure

Fig. 2 Classification of IF INTESTINAL FAILURE

Short term Medium term Long term

Jejunostomy Jejunum-colon Jejunum-ileum

Table 1 Common underlying diseases causing IF

Fig. 3 Diagram to show the Intestinal Nutrition Water / electrolyte

Moderate Enteral Enteral Intestinal

Severe) Parenteral* Parenteral*

References Daniels J, Serlie MJ, Cooper SC, Poullenot F, Rasmussen HH,

Ian Bissett and Dileep N. Lobo

Key Points lack of passage of flatus or stool and abdominal distension

© Springer Nature Switzerland AG 2023 43

Fig. 1 A 57 year old man a b

The aetiology of PPOI is multifactorial. Its initiation is asso-

Table 1 Risk factors and possible mechanisms for postoperative ileus

A systematic review that identified 10 RCTs comparing non-

St Mark’s Hospital, Harrow, UK Jeremy M.D. Nightingale

Part II Acute (Short and Medium Term Reversible) Intestinal Failure

Part III Chronic (Long-Term) Intestinal Failure

Part IV Consequences of Intestinal Failure

Part V Assessment and Treatment of Intestinal Failure

Part VI Outcome of Intestinal Failure

Part VII Problems of Treatment

Part VIII Surgical Treatment of Chronic Intestinal Failure

daptation of the Residual Small Intestine

Macronutrients brush border immediately before absorption (Table 3).

fundus undergoing digestion and dilution by gastric secre- Gastrointestinal Tract

and intestine, while CCK-B predominates in the stomach Motilin

Neurotensin Glucagon-Like Peptides

lucagon-Like Peptide-1 (GLP-1)

Key Points Introduction

Definition of Intestinal failure

Nutritional Support and Optimisation

to translocate, along with the production of pro-inflammatory

SMA Embolectomy taken to avoid damage or rupture to fragile collaterals of the

on-invasive Predictors of Transmural Necrosis

ost to Healthcare Services

Prevention Table 1 Adhesion prevention strategies

Histologic Features of EPS

Surgery for EPS [119, 121]. Surgical intervention is planned depending on

ietary Therapy (to Avoid Obstructive

he Management of Advanced Cases Where

Fibre Containing Enteral Nutrition

complications including slow immunological reconstitu- Umbilical Cord Blood

Table 1 Principles of HSCT procedure Gastrointestinal Complications

Pre-engraftment Complications common toxicity criteria for grading of stomatitis’, which

Key Points Introduction