Challenging Concepts in Critical Care

Foreword
Challenging Concepts in Critical Care:

Cases with Expert Commentary
Edited by Christopher Gough, Justine Barnett, Tim Cook,
and Jerry Nolan
Publisher: Oxford University Press Print Publication Date: Dec 2019

Print ISBN-13: 9780198814924 Published online: Mar 2020
DOI: 10.1093/med/
9780198814924.001.0001
Foreword
Author(s): Mervyn Singer
‘Challenging Concepts in Critical Care’ moves away from the traditional

and somewhat dry format of didactic chapters. It offers a refreshing new
take on educating doctors and allied healthcare practitioners working in
critical care by using a detailed case-based approach for each section
with a succession of key learning points, expert commentary, and lots of
valuable references. This is a neat way of contextualizing everyday
problems, and offers a reasonable management pathway to follow, based
on current knowledge and recommended practices. A broad gamut of
topics are covered from sepsis and respiratory failure through to organ
donation, burns, and pandemic planning. The editors, authors, and expert
commentators should be congratulated on an enjoyable, original, and
highly informative read.
Mervyn Singer MB BS MD FRCP(Lon) FRCP(Edin) FFICM
Professor of Intensive Care Medicine
University College London
London, UK
Page 1 of 2
Foreword
Page 2 of 2
PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

University Press, 2021. All Rights Reserved. Under the terms of the licence agreement, an
individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for
personal use (for details see Privacy Policy and Legal Notice).
Acknowledgements

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Acknowledgements
With thanks to our families and colleagues for their considerable support
throughout this project.
Page 1 of 1
Contributors

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Contributors
Justine Barnett
Consultant in Anaesthesia and ICM, Royal United Hospitals, Bath, UK
Catherine Bryant
Consultant Anaesthetist and Intensivist, Gloucestershire Hospitals
NHS Foundation Trust, Great Western Road, Gloucester, UK
Jamie Cooper
Professor in Intensive Care Medicine, The Alfred Hospital, Melbourne,
Australia
Ron Daniels
CEO, UK Sepsis Trust; Consultant in Critical Care and Anaesthesia,
Heart of England NHS Foundation Trust, Solihull, UK
Nishita Desai
Specialty Registrar in Intensive Care Medicine, London North West
Healthcare Trust, London, UK
Jeremy Farrar
Professor, Director, Wellcome Trust, London, UK
Lucinda Gabriel
Clinical Fellow in Critical Care, Guy’s and St Thomas’ Hospital NHS
Foundation Trust, London, UK
Kim Gupta
Consultant in ICM and Anaesthesia, Royal United Hospitals, Bath, UK
Nicholas Hart
Page 1 of 4
Contributors
Clinical Director, Professor of Respiratory and Critical Care Medicine,

Director of Research Delivery, Lane Fox Respiratory Service, St
Thomas’ Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London,
UK
Richard Hunt
Advanced Trainee in Intensive Care Medicine and Anaesthesia,
Derriford Hospital, Plymouth, UK
Martin Huntley
Consultant in Anaesthesia and Intensive Care Medicine, Harrogate
and District NHS Foundation Trust, Harrogate, UK
Matthew A. Kirkman
Specialty Registrar in Neurosurgery and Honorary Fellow in
Neurocritical Care, Neurocritical Care Unit, The National Hospital for
Neurology and Neurosurgery, University College London Hospitals,
London, UK
Amy Krepska
Consultant Anaesthetist, Royal Brisbane and Women’s Hospital,
Brisbane, Australia
Clinton Lobo
Consultant in Anaesthesia and Intensive Care Medicine, Southmead
Hospital, North Bristol NHS Trust, Bristol, UK
David J. Lockey
Consultant Anaesthetist and Intensivist, North Bristol NHS Trust, Hon
Professor, University of Bristol, UK
Peter MacNaughton
Clinical director Critical Care, Derriford Hospital, Plymouth, UK
Laith Malhas
Consultant Anaesthetist, University Hospitals Coventry and
Warwickshire NHS Trust, Coventry, UK
Alex Manara
Consultant in Anaesthesia and Intensive Care Medicine, Southmead
Hospital, North Bristol NHS Trust, Bristol, UK
Ramani Moonesinghe
Consultant in Anaesthesia and ICM, University College London
Hospitals, London, UK
Sian Alys Moxham
Specialty Registrar in Anaesthesia and Intensive Care Medicine,
Bristol School of Anaesthesia, Bristol, UK
Deirdre Murphy
Senior Consultant Intensivist, Cabrini Health, Malvern, Melbourne,
Australia
Patrick B. Murphy
Consultant Physician, Lane Fox Respiratory Unit, St Thomas’ Hospital,
Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Dave Murray
Consultant Anaesthetist, James Cook University Hospital,
Middlesbrough, UK
Virginia Newcombe
Page 2 of 4

Contributors
Consultant in Intensive Care and Emergency Medicine, Addenbrooke’s

Hospital, Cambridge, UK
Paul Nixon
Consultant Intensivist, The Alfred Hospital, Melbourne, Australia
Jerry Nolan
Consultant in ICM and Anaesthesia, Royal United Hospitals Bath,
Bath; Professor of Resuscitation Medicine, University of Bristol,
Bristol, UK
Matt Oliver
NIHR UCL Clinical Lecturer in Anaesthesia, NELA Research Advisor,
London North Central Anaesthetic Registrar, London, UK
Nim Pathmanathan
Consultant in ICM and Anaesthesia, Royal Devon and Exeter NHS
Foundation Trust, Exeter, UK
Tasneem Pirani
Consultant in General Intensive Care and Liver Intensive Care, King’s
College Hospital, London, UK
Andrew Ray
Specialty Registrar in Anaesthesia and Intensive Care Medicine,
Bristol School of Anaesthesia, Bristol, UK
Marius Rehn
Consultant Anaesthesiologist, Division of Prehospital Services, Air
Ambulance Department, Oslo University Hospital, Oslo; Norwegian Air
Ambulance Foundation, Oslo; University of Stavanger, Faculty of
Health Sciences, Stavanger, Norway
Sanjoy Shah
Consultant Intensivist, University Hospitals Bristol, Bristol, UK
Martin Smith
Consultant and Honorary Professor in Neuroanaesthesia and
Neurocritical Care, Neurocritical Care Unit, The National Hospital for
Neurology and Neurosurgery, University College London Hospitals,
London, UK
Matt Thomas
Consultant in Anaesthesia and ICM, University Hospitals Bristol,
Bristol, UK
Gary Wares
Consultant in ICM and Anaesthesia, The Royal Marsden Hospital,
London, UK
Julia Wendon
Professor of Hepatology and Consultant Intensivist, King’s College
London, London, UK
Amber E. Young
Consultant Paediatric Anaesthetist and Lead Children’s Burns
Research Centre, University Hospitals Bristol NHS Foundation Trust;
Senior Research and NIHR Doctoral Fellow, Bristol Centre for Surgical
Research, Population Health Sciences, Bristol Medical School,
University of Bristol, Bristol, UK
Page 3 of 4

Contributors
Page 4 of 4

Abbreviations

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Abbreviations
ABG
arterial blood gas
ACE
angiotensin-converting enzyme
ACLF
acute-on-chronic liver failure
ACS
acute coronary syndrome
AD
acute decompensation
ADH
antidiuretic hormone
AECOPD
acute exacerbation of chronic obstructive pulmonary disease
AH
alcoholic hepatitis
AKI
acute kidney injury
ALF
acute liver failure
ALP
alkaline phosphatase
Page 1 of 8
Abbreviations
APTT
activated partial thromboplastin time
ARDS
acute respiratory distress syndrome
ASA
American Society of Anesthesiologists
AST
aspartate transaminase
BE
base excess
BIS
bispectral index
BMI
body mass index
BNP
beta-type natriuretic peptide
bpm
beats per minute
CAM
Confusion Assessment Method
CAM-ICU
Confusion Assessment Method for the Intensive Care Unit
CLD
chronic liver disease
CMV
cytomegalovirus
CO
carbon monoxide
COHb
carboxyhaemoglobin
COPD
chronic obstructive pulmonary disease
CPAP
continuous positive airway pressure
CPC
cerebral performance category
CPP
cerebral perfusion pressure
CRP
C-reactive protein
CRRT
continuous renal replacement therapy
CSF
cerebrospinal fluid
CSW
cerebral salt wasting
CTA
computed tomography angiogram
cTnI
Page 2 of 8

Abbreviations
cardiac troponin I
CVC
central venous catheter
CVP
central venous pressure
CVVHDF
continuous venovenous haemodiafiltration
CXR
chest X-ray
DBD
donation after brain death
DCD
donation after circulatory death
DCI
delayed cerebral ischaemia
DVT
deep vein thrombosis
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
ED
emergency department
EEG
electroencephalogram
EGDT
early goal-directed therapy
eGOS
extended Glasgow Outcome Scale
EMS
emergency medical services
EPAP
expiratory positive airway pressure
ERC
European Resuscitation Council
ERCP
endoscopic retrograde cholangiopancreatography
ESICM
European Society of Intensive Care Medicine
ETCO2
end-tidal carbon dioxide
EVD
external ventricular drain
FFP
fresh frozen plasma
FiO2
fraction of inspired oxygen
FLAIR
fluid-attenuated inversion recovery
Page 3 of 8

Abbreviations
GABA
gamma-aminobutyric acid
GCS
Glasgow Coma Scale
G-CSF
granulocyte-colony stimulating factor
GDFT
goal-directed fluid therapy
GMC
General Medical Council
GvHD
graft-versus-host disease
HD
haemodialysis
HE
hepatic encephalopathy
HES
hydroxyethyl starch
HF
haemofiltration
HFNO
high-flow nasal oxygenation
HLA
human leucocyte antigen
HRS
hepatorenal syndrome
HSCT
haematopoietic stem cell transplantation
IABP
intra-aortic balloon pump
ICP
intracranial pressure
ICU
intensive care unit
IMCA
Independent Mental Capacity Advocate
INR
international normalized ratio
IPAP
inspiratory positive airway pressure
LOLA
L-ornithinine L-aspartate
LPA
lasting power of attorney
MAP
mean arterial pressure
MARS
molecular adsorbent recirculating system
mcg
Page 4 of 8

Abbreviations
microgram(s)
MELD
Model for End-stage Liver Disease
MERS
Middle Eastern respiratory syndrome
MIE
mechanical insufflation–exsufflation
min
minute(s)
MMM
multimodality monitoring
MRC
Medical Research Council
MRI
magnetic resonance imaging
MTC
major trauma centre
NAI
non-accidental injury
NELA
National Emergency Laparotomy Audit
NEWS
National Early Warning Score
NG
nasogastric
NHS
National Health Service
NICE
National Institute for Health and Care Excellence
NIV
non-invasive ventilation
NMBD
neuromuscular blocking drug
NMD
neuromuscular disease
NSE
neuron-specific enolase
NSM
neurogenic stunned myocardium
OHCA
out-of-hospital cardiac arrest
OR
operating room
PaCO2
partial pressure of carbon dioxide
PaO2
partial pressure of oxygen
PbtO2
brain tissue oxygen tension
Page 5 of 8

Abbreviations
PCI
percutaneous coronary intervention
PCR
polymerase chain reaction
PCT
procalcitonin
PD
peritoneal dialysis
PEEP
positive end-expiratory pressure
PICC
peripherally inserted central catheter
PIP
peak inspiratory pressure
PJP
Pneumocystis jirovecii pneumonia
PLR
passive leg raise
PPE
personal protective equipment
PPI
proton pump inhibitor
P-POSSUM
Portsmouth Physiological and Operative Severity Score for the
Enumeration of Mortality and Morbidity
PRN
as required
PRx
pressure reactivity index
PT
prothrombin time
qSOFA
quick Sequential (Sepsis-Related) Organ Failure Assessment
RASS
Richmond Agitation–Sedation Scale
RCT
randomized controlled trial
REE
resting energy expenditure
ROSC
return of spontaneous circulation
RRT
renal replacement therapy
RSBI
rapid shallow breathing index
SAH
subarachnoid haemorrhage
SARS
severe acute respiratory syndrome
Page 6 of 8

Abbreviations
SBP
spontaneous bacterial peritonitis
SBT
spontaneous breathing trial
ScvO2
central venous oxygen saturation
SIADH
syndrome of inappropriate antidiuretic hormone
SIR
systemic inflammatory response
SIRS
systemic inflammatory response syndrome
SN-OD
specialist nurse in organ donation
SOFA
Sequential [Sepsis-Related] Organ Failure Assessment
SORT
Surgical Outcomes Risk Tool
SpO2
oxygen saturation by pulse oximetry
SSC
Surviving Sepsis Campaign
SSEP
somatosensory evoked potential
SvO2
mixed venous blood oxygen saturation
TBI
traumatic brain injury
TBSA
total body surface area
TCD
transcranial Doppler
TTM
targeted temperature management
UK
United Kingdom
US
United States
V/Q
ventilation/perfusion
VA
venoarterial
VF
ventricular fibrillation
VOD
veno-occlusive disease
WFNS
World Federation of Neurological Societies
WLST
Page 7 of 8

Abbreviations
withdrawal of life-sustaining treatment
Page 8 of 8

Sepsis

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Sepsis
Chapter: Sepsis
Author(s): Laith Malhas
DOI: 10.1093/med/9780198814924.003.0001
Expert commentary by Ron Daniels
Case history
A 68-year-old man was brought into the emergency department

(ED) at 19:00 by his son, having been found at home generally unwell.
The patient was not able to answer any questions himself, but the son
reported that he tried to call his father in the day with no answer, and on
visiting found him confused. He last spoke to him 4 days previously, when
his father had seemed well. His only past medical history was recently
diagnosed hypertension for which he had just started lisinopril 10 mg
once daily prescribed by his general practitioner.
On initial assessment in the ED, his lungs were clear on auscultation,

heart sounds normal, central capillary refill time was 4 seconds, and his
peripheries were cool with no oedema. He had a soft abdomen with no
palpable masses or organomegaly but grimaced on palpation of the left
side. Bowel sounds were absent. He answered only direct questions and
Page 1 of 36
Sepsis
was confused, although no focal neurology was found and his pupils were
equal and responsive to light.
His observations were as follows:
A. Oxygen saturation by pulse oximetry (SpO2) 99% on room air.

B. Respiratory rate 18 breaths/min.
C. Heart rate 99 beats/min (bpm).
D. Blood pressure (BP) 96/40 mmHg.
E. Glasgow Coma Scale (GCS) score 13 (E3, V4, M6).
F. Temperature 35.8°C.
He had not passed any urine since being found. His National Early
Warning Score (NEWS) was 7 (Table 1.1).
Page 2 of 36

Sepsis
Table 1.1 National Early Warning Score (NEWS), developed by the Royal College of Physicians. Each variable is allocated a score and each of these is added
to give a total NEWS score
Physiological 3 2 1 0 1 2 3
parameters
Respiratory rate ≤8 9–11 12–20 21–24 ≥25

(breaths/min)
Oxygen ≤91 92–93 94–95 ≥96

saturations (%)
Any extra Yes No

oxygen
Temperature ≤35.0 35.1–36.0 36.1–38.0 38.1–39.0 ≥39.1

(°C)
Systolic blood ≤90 91–100 101–110 111–219 ≥220

pressure
(mmHg)
Heart rate ≤40 41–50 51–90 91–110 111–130 ≥131

(bpm)
Level of A V, P, or U
consciousness
A, alert; P, pain; U, unresponsive; V, voice.
Page 3 of 36
PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2021. All Rights Reserved. Under the terms of the
licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy
and Legal Notice).
Sepsis
Initial management involved placement of an 18-gauge peripheral venous

cannula with venous blood samples sent for full blood count, urea and
electrolytes, liver function tests, clotting studies, and gas analysis, and
starting an intravenous (IV) infusion of 1 L of 0.9% sodium chloride.
His results returned at 20:00 and were as follows:
Venous blood gas
pH 7.28 (7.35–7.45)
PaCO2 (kPa) 6.6 (4.7–6)
PaO2 (kPa) 3.9 (>10)
HCO3− (mmol/L) 18.8 (22–28)
BE (mmol/L) −6.7 (±2)
Lactate (mmol/L) 5.5 (0.5–2)
Full blood count
Hb (g/L) 98 (130–180)
Plat (×109/L) 118 (150–400)
WCC (×109/L) 18.2 (4–11)
Liver function and clotting
Bili (μmol/L) 8 (3–20)
Alk Phos (U/L) 131 (30–130)
ALT (U/L) 27 (10–40)
INR 1.6
Urea and electrolytes
Na (mmol/L) 148 (135–145)
K (mmol/L) 4.7 (3.5–5)
Page 4 of 36

Sepsis
Urea (mmol/L) 22 (2.5–6.7)
Cr (μmol/L) 380 (60–110)
Alb (g/L) 22 (35–50)
CRP (mg/L) 183 (<10)
Glucose (mmol/L) 15.0 (6–10)
Alb, albumin; Alk Phos, alkaline phosphatase, ALT, alanine

aminotransferase; BE, base excess; Bili, bilirubin; Cr, creatinine; CRP,
C-reactive protein; Hb, haemoglobin; INR, international normalized
ratio; K, potassium; Na, sodium; Plat, platelets; U, units; WCC, white
cell count.
After being reviewed by the ED doctor, his acute kidney injury (AKI) was
identified and attributed to dehydration, and his mild hypothermia was
noted.
EXPERT COMMENT
A reliance on laboratory investigations to identify many of the organ

dysfunction criteria means, in a resource-challenged busy clinical
environment, that patients without obvious shock or hypoxia are
missed. Patients get one opportunity to present their illness to a
health professional—it is not always possible to review the patient in
a timely manner with laboratory results as soon as they become
available. qSOFA, and proposed alternatives such as the NEWS, move
away from reliance on laboratory criteria.
LEARNING POINT Defining and identifying sepsis
The first consensus definitions were determined by the American

College of Chest Physicians and the Society of Critical Care Medicine
in 1992, which formally defined the systemic inflammatory response
syndrome (SIRS), sepsis, and other clinical classifications. This was
updated in 2001 in conjunction with the European Society of
Intensive Care Medicine [1], a collaboration which resulted in a
widening of the original list of four SIRS criteria to over 20 signs and
symptoms of infection to improve specificity. This was later
condensed into a more pragmatic set of six criteria by the Surviving
Sepsis Campaign (SSC) [2]. However, it was widely recognized that
the consensus definitions continued to be imperfect, as the SIRS
Page 5 of 36

Sepsis
criteria as a tool for detecting sepsis tended to be oversensitive and

poorly specific to either critical illness in general or sepsis in
particular.
A third revision was published in 2016 by the European Society of

Intensive Care Medicine and Society of Critical Care Medicine, coined
Sepsis-3, which abandoned the term severe sepsis and attempted to
simplify recognition [3]. Sepsis is now described as organ dysfunction
secondary to infection. Organ dysfunction can be tracked with the
Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score,
a clinical scoring system already used for identifying organ
dysfunction in intensive care units (ICUs). SIRS was still described as
a useful tool to identify possible infection, but no longer formed part
of the formal diagnosis of sepsis. The authors instead recommended
the use of bedside clinical scoring systems to improve reliability of
recognition, and proposed ‘quick SOFA’ (qSOFA) as a bedside test.
The qSOFA comprises:
● alteration in mental status

● systolic blood pressure less than or equal to 100 mmHg, or
● respiratory rate at least 22/min.
with any two indicating a high risk of sepsis.
qSOFA was derived by a retrospective analysis of large (primarily US

derived) datasets as a method of clinically identifying patients who
were likely to have a poor outcome, defined as an ICU stay of 3 days
or more, or death.
Sepsis-3: terms and definitions
● Sepsis is defined as life-threatening organ dysfunction caused by

a dysregulated host response to infection.
● Organ dysfunction can be identified as an acute change in total
SOFA score of 2 points or more due to the infection.
● The baseline SOFA score can be assumed to be zero in patients
not known to have pre-existing organ dysfunction.
● A SOFA score of 2 or greater reflects an overall mortality risk of
approximately 10% in a general hospital population with suspected
infection.
● Patients with suspected infection who are likely to have a
prolonged ICU stay or to die in the hospital can be promptly
identified at the bedside with qSOFA.
● Septic shock is a subset of sepsis in which underlying circulatory
and cellular/metabolic abnormalities are profound enough to
substantially increase mortality.
Page 6 of 36

Sepsis
Patients with septic shock can be identified by the presence of sepsis

with persisting hypotension requiring vasopressors to maintain mean
arterial pressure (MAP) at 65 mmHg or higher and a serum lactate
level greater than 2 mmol/L despite adequate volume resuscitation.
With these criteria, hospital mortality is greater than 40%.
This patient presented with an elevated white blood cell count which
leads to a suspicion of infection, along with a qSOFA score of 2 which
identifies him as more likely to have a poor outcome.
qSOFA has not been universally embraced. Organizations such as the

Latin American Sepsis Institute and the UK National Institute for
Health and Care Excellence (NICE) have gone as far as to
intentionally avoid recommending its use. In 2016, a large
prospective validation exercise in over 30,000 patients found qSOFA
to be inferior to existing early warning scores (EWS) in identifying
patients with sepsis at risk of adverse outcome [4].
Other groups have also developed diagnostic approaches to increase

the reliability of suspecting sepsis and initiating treatment pathways.
NICE offers guidance with age-specific risk stratification tools for
anyone presenting with possible sepsis. These stratify elements of
history and examination into categories indicating low, moderate–
high, and high risk of severe illness/death (Table 1.2) [5].
Table 1.2 Risk stratification tool for adults, children, and young
people aged 12 years and older with suspected sepsis
Category High-risk criteria Moderate- to high-

risk criteria
History Evidence of new History of new

altered mental state alteration in
behaviour or mental
state
History of acute
deterioration of
functional ability
Immune impairment
(including oral
steroids)
Recent (within 6
weeks) history of
trauma, surgery, or
invasive procedure
Respiratory Elevated respiratory Elevated respiratory

rate: ≥25 breaths/min rate: 21–24 breaths/
min
Page 7 of 36

Sepsis
Acquired oxygen
requirement >FiO2
0.4, to maintain SpO2
>92% (or >88% in
known COPD)
Blood SBP ≤90 mmHg or at SBP 91–100 mmHg

pressure least 40 mmHg below
normal
Circulation HR >130 bpm HR 91–130 bpm or

and Not passed urine for new arrhythmia
hydration at least 18 hours Not passed urine for
If catheterized, urine 12–18 hours
output <0.5 mL/kg/ For catheterized
hour patients, urine output
0.5–1 mL/kg/hour
Temperature Tympanic
temperature <36°C
Skin Mottled or ashen Any signs of potential

appearance infection e.g.
Central or peripheral discharge at surgical
cyanosis site
Non-blanching rash
bpm, beats per minute, COPD, chronic obstructive pulmonary

disease; HR, heart rate; SBP, systolic blood pressure.
Source: data from The National Institute for Health and Care
Excellence (NICE). (2016) Sepsis: recognition, diagnosis and early
management [NG51]. Copyright © 2016 NICE. Available at https://
www.nice.org.uk
These remain included in operational tools such as the UK Sepsis

Trust’s Red Flag Sepsis system (Figure 1.1) [6].
EXPERT COMMENT
There are concerns that, while valid in hospital, the new definitions
used in Sepsis-3 may not be sensitive enough for use outside hospital,
for example, when considering hospital referral. As serum lactate has
been validated as a predictor of mortality, including identifying
‘cryptic shock’ (hypoperfusion with normotension) [7], organizations
not already using track-and-trigger EWS might usefully include
Page 8 of 36

Sepsis
qSOFA as a screening tool, adding lactate where necessary. Until

there is further prospective validation of qSOFA, those already using
NEWS/modified EWS can reasonably continue using a combination of
a high index of suspicion of sepsis and the EWS to trigger
consideration of sepsis. In the UK, NICE will be issuing a Quality
Standard which is likely to reinforce the use of its risk stratification
system described previously, which the UK Sepsis Trust has
operationalized into Red Flag and Amber Flag Sepsis criteria (Figure
1.1).
The formal identification of sepsis using a change in SOFA score is

more widely accepted, but in low- and middle-income countries needs
careful interpretation, for example, to identify the criteria for septic
shock.
Page 9 of 36

Sepsis
Figure 1.1
Extract from the UK Sepsis Trust clinical toolkit for emergency
departments made with formal arrangement with NICE.
Reproduced with permission from UK Sepsis Trust, registered charity no.
1158843.
Noting the high lactate, the ED junior doctor suspected high-risk (‘Red
Flag’) sepsis (likely septic shock) according to NICE guidelines and
initiated treatment. Supplemental oxygen was given and a further litre of
0.9% saline started. A urinary catheter was inserted, draining 280 mL of
Page 10 of 36

Sepsis
residual urine, which was clear but concentrated, with dipstick testing
showing no evidence of leucocytes.
A venous blood culture sample was sent and antibiotics started according
to hospital protocols (IV amoxicillin 1 g, metronidazole 500 mg, and
gentamicin 320 mg for sepsis with a suspected intraabdominal cause).
Although a 5-day course was anticipated, the antibiotics were prescribed
for an initial 48-hour period with a plan to review the drug, indication,
and duration at this point. The chest X-ray was unremarkable.
After discussion with the ED middle-grade doctor, the patient was

referred to the surgical team and to the ICU team for review, due to his
clinical deterioration as shown by his elevated NEWS score.
LEARNING POINT Initial management
Prompt early initiation of treatment has consistently been shown to

reduce mortality from sepsis [8, 9, 10]. For this reason, there has
been much effort to ensure that, once the diagnosis of sepsis is made,
evidence-based care bundles are implemented.
The SSC divides the initial management into two care bundles, the
first to be completed by 3 hours from the diagnosis being made:
1. Measure serum lactate level.

2. Obtain blood cultures prior to administration of antibiotics.
3. Administer broad-spectrum antibiotics.
4. Administer 30 mL/kg crystalloid in divided aliquots for
management of hypotension or if lactate is 4 mmol/L or greater.
The ideal time of administration of antibiotics is immediately before

sepsis develops from the underlying infection, but attempting to
predict this risks overtreatment.
Once sepsis does develop, any delay is linked to increasing

progression of the septic process to multiorgan failure. Empiric
antibiotics should be administered within 1 hour of the identification
of sepsis. When possible, blood cultures should be obtained before
administering antibiotics, but this should not delay initiation of
antibiotics.
As with the diagnostic criteria, keeping therapeutic protocols simple

improves uptake and ultimately patient outcomes. The value of early
treatment has been shown by several care bundles which reduce the
time to completion of all tasks to 1 hour. For this reason, the UK
Sepsis Trust’s ‘Sepsis Six’ has become widely popular as an effective
1-hour bundle for when sepsis is suspected and has been shown to
Page 11 of 36

Sepsis
reduce sepsis-associated mortality rates by up to 50% [11, 12]. The

Sepsis Six can be remembered as ‘take three, give three’.
The Sepsis Six:

Take 3
1. Take blood cultures.

2. Measure serial serum lactates.
3. Measure accurate hourly urine output.
Give 3
4. Administer oxygen to maintain saturations at greater than

94% (88–92% in chronic obstructive pulmonary disease).
5. Give broad-spectrum antibiotics.
6. Give IV fluid challenges if the patient is hypotensive or their
lactate is elevated.
EXPERT COMMENT
The inclusion of high-flow oxygen was slightly contentious given that

cautious oxygen therapy is recommended in other acute conditions.
The harmful effects of hyperoxia have been demonstrated in healthy
individuals, and growing evidence highlights the deleterious effects of
high inspired oxygen concentrations in treating patients with acute
myocardial infarction, ischaemic stroke, neonatal resuscitation, and
adult resuscitation following cardiac arrest [13]. The recent
Hyperoxia and Hypertonic Saline in Patients with Septic Shock
(HYPERS2S) trial documented significantly more serious adverse
events in patients with sepsis treated for 24 hours with 100% oxygen
versus those treated to achieve normoxia (SpO2 88–95%) [14]. While
hyperoxia is potentially harmful, significant hypoxia is undeniably
harmful and must be avoided or treated.
The patient was reviewed by the surgical team who did not consider the
patient to have peritonitis but arranged an abdominal computed
tomography scan.
On review by the intensive care senior trainee at 20:35, an arterial line

was inserted, and on examination the patient was found to have cool
peripheries. Based on clinical judgement and the presence of suspected
sepsis, a fluid bolus of 500 mL Hartmann’s solution was infused IV.
The patient’s NEWS score subsequently deteriorated to 9 with minimal

urine output.
Page 12 of 36

Sepsis
EXPERT COMMENT
The value of fluid resuscitation has always been unclear, and recently
the routine use of liberal fluid resuscitation has been called into
question [15]. Until further evidence becomes available, even
considering recent evidence, we recommend that fluid be given
rapidly to correct hypovolaemia in the early stages following
presentation, but relatively restricted compared with historical
practice once the patient has stabilized.
LEARNING POINT Fluid resuscitation
Fluid resuscitation remains one of the mainstays of early treatment

for patients with sepsis and septic shock, working by increasing
intravascular volume, venous return, and hence cardiac output to
improve blood pressure and organ/tissue perfusion. However, the
type and quantity of fluid to use is contentious and studies have
produced conflicting results. Problems arise from the complex and
variable pathophysiological changes in sepsis, and interpretation of
trials is complicated by the inclusion of heterogeneous patients at
different stages in their clinical course.
Fluid type
The two main groups are crystalloid and colloid, with further division
between balanced and non-balanced solutions.
Crystalloids
Crystalloid solutions can either be balanced solutions (e.g.
Hartmann’s solution and Plasma-Lyte 148), which are designed to
mimic plasma and buffer against pH changes, or unbalanced 0.9%
sodium chloride (commonly known as normal saline). Normal saline
has been used historically because it is a cheap, stable, and easily
manufactured isotonic solution; however, in studies comparing it with
balanced solutions [16] it has been shown to:
● increase metabolic and dilution acidosis

● decrease renal blood flow
● increase risk of renal failure [17]
● create a coagulopathy
● increase inflammation
● be associated with an increased risk of death.
Page 13 of 36

Sepsis
Although these perceived attributes have generated a move towards

use of balanced solutions and away from ‘abnormal’ saline, in the
0.9% Saline versus Plasma-Lyte 148 for ICU fluid Therapy (SPLIT
trial), use of a buffered crystalloid compared with saline did not
reduce the risk of AKI in a heterogeneous group of critically ill
patients [18].
Colloids
Colloidal solutions became popular because of the theoretical
physiological advantage of being retained in the intravascular space
for longer than crystalloids. The three main colloids are albumin,
gelatin, and hydroxyethyl starch (HES).
Research has identified side effects and worsening outcomes

(including higher mortality rates) associated with the use of some
colloids, particularly in the setting of sepsis. The US Food and Drug
Administration and the European Medicines Agency issued warnings
after a proven increased risk of renal failure and death when HES
was used in septic patients in the ICU [19]. The use of HES is
contraindicated in critically ill patients.
These adverse effects of HES are thought to be from the colloid

molecule accumulating in the interstitial tissues, exacerbated by the
endothelial dysfunction brought about by the septic process. Within
the kidney, this causes an osmotic nephrosis and a renal compartment
syndrome within the capsule. There are observational data suggesting
that use of gelatin is also associated with an increase in AKI.
Albumin, a natural colloid, has theoretical advantages over synthetic

colloids: it maintains endothelial function as well as having
antioxidant and anti-inflammatory properties. A subgroup analysis of
septic patients in the Saline versus Albumin Fluid Evaluation (SAFE)
trial, and a larger meta-analysis [20], suggested an association with
reduced mortality. However, a more recent meta-analysis that
included subsequent trials from the Early Albumin Resuscitation for
Sepsis and Septic Shock (EARSS) study group and the Albumin Italian
Outcomes Study (ALBIOS) trial found that albumin, when included in
a fluid regimen for septic patients, showed no benefit in reducing
mortality, though neither did it cause harm [21].
Given the additional expense of colloids over crystalloids, there

should be evidence of benefit to justify their use. The SSC guidance
currently recommends crystalloids as the initial fluid of choice and
recommends albumin when patients require substantial amounts of
crystalloids.
How much fluid?

The complex pathophysiology of sepsis necessitates caution: give too
little fluid and circulatory function will not be restored, give too much
Page 14 of 36

Sepsis
and excess fluid quickly leads to tissue oedema increasing organ

dysfunction, morbidity, and mortality. Tissue oedema manifests
clinically as peripheral oedema, increased extravascular lung water
and, in some patients, acute respiratory distress syndrome. Multiple
studies have shown an association between mortality and excessively
positive fluid balance [22, 23, 24, 25] and increased extravascular
lung water [26].
The goal is to identify those patients whose cardiac output will

improve with fluid—those who are fluid responsive. Patients can be
divided into fluid responders, who may benefit from more fluid, or
fluid non-responders in whom further fluid may be detrimental: these
patients will require other support. Approximately 50% of all patients
—with and without sepsis—in ICU are fluid responders [27].
Several variables have been used to predict fluid responsiveness with

variable success, either as static measurements or dynamically in
response to a fluid challenge or passive leg raise (PLR) (Table 1.3).
From a basic science perspective, this is a clinical intervention to
attempt to identify the patient’s position on the Frank–Starling curve.
Table 1.3 Methods of monitoring fluid responsiveness
Static monitors Dynamic monitors
Central venous pressure Stroke volume variation (SVV)

(CVP)
Pulmonary artery Pulse pressure variation (PPV)

occlusion pressure
(PAOP)
Heart rate (HR) Pleth variability index (PVI)
Mean arterial pressure Doppler and ultrasound measured

(MAP) changes (oesophageal Doppler
monitor (ODM)/echocardiography)
Flow time corrected Inferior vena cava distensibility/

(FTc) collapsibility index on
ultrasonography
Static measurements have generally been found to be unhelpful in

identifying fluid responders. The central venous pressure (CVP) or
CVP responsiveness is now considered to be of little or no value. In
conjunction with a PLR, the pulse pressure is useful [28]. The flow
time corrected has mainly been used in perioperative patients, but is
Page 15 of 36

Sepsis
determined by systemic vascular resistance as well as intravascular

volume [29].
Dynamic monitors rely on measurement of haemodynamic responses

to variations in cardiac filling (e.g. caused by natural variation in
heart rate during respiration). In patients undergoing positive
pressure ventilation, the intermittent rise and fall of intrathoracic
pressure leads to alterations in venous return and reflex responses in
heart rate. These affect cardiac filling and the resulting
haemodynamic changes can be used to assess the likelihood of fluid
responsiveness. Dynamic monitors perform better in stable situations
such as a patient who is undergoing pressure control ventilation and
who has a normal heart rate and rhythm. Minimally invasive monitors
are grouped into uncalibrated and calibrated devices, the latter being
the more accurate. Other cardiac output monitors estimate cardiac
output based on detection of a change in concentration of a dye
(LiDCO), cold (PICCO), thoracic bioimpedance (CCO, Edwards
Lifesciences), or analysis of the arterial line waveform (LiDCO rapid,
FloTrac) and may rely on fluid administration or PLR to predict fluid
responsiveness [30].
Bedside echocardiography is used routinely on many ICUs and is

increasingly being undertaken by intensive care clinicians.
Echocardiography enables assessment of right and left cardiac
function, regional wall movement abnormalities (pre-existing or new
ischaemic heart disease), valvular function, and, importantly, fluid
status. While static measurements give some information, dynamic
measures are more useful to determine fluid volume status. Variations
in vena cava diameter (distensibility index) with the respiratory cycle
provide good predictive information: visualization of the superior
vena cava with transoesophageal echocardiography and the inferior
vena cava with transthoracic echocardiography or transabdominal
ultrasonography are possible, the latter requiring less extensive
training. The main advantage of these methods is that the patient
does not have to be in sinus rhythm—atrial fibrillation is common in
the critically ill [31].
EXPERT COMMENT
The SSC recommends initial fluid challenges in patients with

hypoperfusion with suspicion of hypovolaemia up to a maximum of 30
mL/kg; further fluid challenges are based on haemodynamic
improvement of static or dynamic variables. Little controversy
surrounds the rationale behind initial restoration of circulating
volume; however, too much fluid beyond the initial correction of
hypovolaemia will worsen tissue oedema and oxygen delivery.
Adequate initial fluid resuscitation should be followed by conservative
Page 16 of 36

Sepsis
late fluid management, defined as even or negative fluid balance

measured on at least two consecutive days during the first 7 days
after the onset of septic shock [32].
CLINICAL TIP Passive leg raise
The PLR is a clinical tool to determine fluid responsiveness and is a

simple, non-invasive, and accurate bedside test which can be
performed by nursing staff in conjunction with monitoring of dynamic
variables [33]. Leg elevation induces an autotransfusion roughly
equivalent to a 500 mL fluid challenge but is in effect reversible so
that the non-responder is not given fluid that could be harmful.
A PLR requires positioning of the patient head up at 45° and then

tilting the bed back in a Trendelenburg position until the head of the
bed is horizontal (Figure 1.2). This provides a greater autotransfusion
volume than simply elevating the legs with the trunk in a supine
position. Any response occurs in the first minute and therefore
requires a dynamic flow measurement (or flow derivation) device with
sufficiently fast response time. It has been studied with a variety of
minimally invasive cardiac output monitors: an increase in cardiac
output or stroke volume of 10% is taken to indicate a fluid-responsive
patient. Intra-abdominal hypertension may impair venous drainage
and invalidate the results.
Figure 1.2
Performing a passive leg raise test.
Given the patient’s lack of response to an initial 3 L of fluid resuscitation

(the patient weighed approximately 80 kg), he was admitted to the ICU
for invasive monitoring and early goal-directed therapy (EGDT). On
arrival in the ICU at 21:30, a central venous catheter was inserted.
Vital signs at this time were:
Heart rate 92 bpm
Average BP (MAP) 99/43 (62) mmHg
Page 17 of 36

Sepsis
SpO2 99%
GCS score 14
Urine output 35 mL/hour
Central venous oxygen saturation 56%
Arterial blood gas values, breathing 80% oxygen were:
Arterial blood gas FiO2 0.8
pH 7.35 (7.35–7.45)
PaCO2 (kPa) 7.35 (4.7–6)
PaO2 (kPa) 25.6 (>10)
HCO3− (mmol/L) 28.1 (22–28)
BE (mmol/L) −4.7 (±2)
Na (mmol/L) 144 (135–145)
K (mmol/L) 3.4 (3.5–5)
Cl− (mmol/L) 106 (97–107)
An insulin infusion was started to normalize the blood glucose values; a

nasogastric feeding tube was inserted, its position confirmed, and enteral
feeding started.
LEARNING POINT
The second SSC care bundle, to be completed within the first 6 hours,
gives physiological end points to be met as an indication of adequate
organ perfusion and oxygen delivery.
1. Infuse vasopressors for hypotension that does not respond to

initial fluid resuscitation to maintain a MAP of at least 65 mmHg.
Page 18 of 36

Sepsis
2. In the event of persistent arterial hypotension despite volume

resuscitation (septic shock) or an initial lactate level greater
than or equal to 4 mmol/L (36 mg/dL):
◦ Measure central venous oxygen saturation (ScvO2).
◦ Measure cardiac output if available.
◦ Consider inotropic support.
3. Remeasure lactate if initial lactate was elevated.
Earlier recommendations with rigid physiological end points had been

taken from an initial study of EGDT [34] but this approach has been
overturned by three more recent studies. The US ProCESS, the
Australian ARISE, and the UK ProMISe studies have all failed to show
a difference in outcome when EGDT was compared with usual care
[35, 36, 37]. The SSC now advises that measurement of CVP and
ScvO2 are not routinely necessary for patients with septic shock. The
SSC is revising the haemodynamic bundle in accordance with the
latest evidence [38].
EXPERT COMMENT
In addition to source control and antimicrobial therapy, fluid

resuscitation to correct hypovolaemia remains the central tenet of
resuscitation in septic shock. The failure of ProCESS, ARISE and
ProMISe to show treatment benefit in the intervention groups may
reflect that basic care has improved so much that protocolized care
has less impact. This was demonstrated recently across a group of
hospitals in North America in a study identifying that early
compliance with basic care elements meant illness did not progress
and meant patients were subsequently ineligible for EGDT as they did
not meet entry criteria [39]. A pragmatic approach, using basic
physiological principles, is to fluid resuscitate using a suitable end
point, such as warm peripheries, improved GCS score, and good urine
output; to support persistent hypotension using vasopressors; and to
assess for and address signs of inadequate cardiac output or oxygen
delivery.
Despite fluid resuscitation, haemodynamic goals were not being achieved

and noradrenaline was started to maintain the patient’s MAP at greater
than 70 mmHg. This goal was chosen because of the patient’s previous
poorly controlled hypertension. Once the blood pressure had been
stabilized, an abdominal computed tomography scan was undertaken,
which identified diverticulitis without evidence of perforation or abscess
formation. On review, the surgical team decided on conservative
Page 19 of 36

Sepsis
management. The microbiology consultant recommended a change in

antibiotic therapy to meropenem.
LEARNING POINT Microbiology
Appropriate antibiotic therapy is an essential component in the

management of the septic patient. To initiate appropriate antibiotics,
and to subsequently narrow the spectrum in response to culture
results, it is essential to investigate the patient thoroughly to identify
a source of sepsis, and to take several samples for microbiology
testing. Ideally, microbiology samples should be collected prior to
commencement of antibiotic therapy, so long as this does not delay
administration of the treatment.
Liaison with a microbiologist ensures appropriate antibiotic choice

taking into account likely pathogens and local antibiotic resistance
patterns. It also enables narrowing of the antibiotic therapy when
culture results become available. Good antibiotic stewardship
involves the use of appropriate antibiotics, for an appropriate
duration, to effectively treat the underlying infection while
minimizing development of antimicrobial resistance.
The patient did not improve overnight, and so a PiCCO arterial line was
inserted to enable dynamic cardiac output measurement. This guided his
vasopressor requirement, and further crystalloid boluses were guided by
PLRs.
The vital signs at this time were:
Heart rate 89 bpm
BP (MAP) 98/43 (61) mmHg despite 0.32 mcg/kg/min

noradrenaline
SpO2 98%
GCS score 14 (E4 V4 M6)
Urine 35 mL/h
output
Arterial blood gas on 80% oxygen
pH 7.37 (7.35–7.45)
Page 20 of 36

Sepsis
PaCO2 (kPa) 7.34 (4.7–6)
PaO2 (kPa) 10.7 (>10)
HCO3− (mmol/L) 28.9 (22–28)
BE (mmol/L) −5.8 (±2)
Na (mmol/L) 143 (135–145)
K (mmol/L) 3.8 (3.5–5)
Cl− (mmol/L) 111 (97–107)
A bedside focused cardiac ultrasound was undertaken, enabling specific

conditions to be excluded from contributing to his increasing inotropic
requirement. The focused echocardiogram showed good global cardiac
function without any regional wall movement abnormalities or major
valve dysfunction, no pericardial effusion, normal right-sided pressures,
and a subjectively adequate volume status.
LEARNING POINT Indicators of perfusion and

adequacy of treatment
Several variables have been studied as indicators of disease severity,

adequacy of perfusion, and as a measure of response to treatment.
Lactate
A raised lactate (>2 mmol/L) has long been identified as an indicator
of severity of illness, and is associated with organ dysfunction and
mortality in septic patients [43]. The raised lactate reflects increased
production and possibly decreased clearance. It is produced by
anaerobic metabolism resulting from mitochondrial hypoxia as a
result of the septic process, as well as increased sodium–potassium
pump activity and ATP use through catecholamine stimulation and
cytokine-mediated uptake of glucose associated with the stress
response [44]. Hepatic dysfunction and inhibition of the rate-limiting
enzyme pyruvate dehydrogenase reduces lactate clearance [45].
Page 21 of 36

Sepsis
A value of at least 4 mmol/L is used as the marker of severity in

defining shock in septic patients [46]. In a recent analysis from the
SSC database, a cut-off value of greater than 4 mmol/L, especially
with hypotension, identified a significant increase in mortality.
Comparing patients with a lactate greater than 4 mmol/L and
hypotension, with patients with a lactate less than 2 mmol/L and no
hypotension, mortality was 44.5% versus 29% [47].
Lactate clearance has been used as a measure of successful

resuscitation. This strategy assumes that the hyperlactataemia results
from global tissue hypoxia [48]. If tissue dysfunction and increased
lactate does result from a predominantly anaerobic metabolic stress
response, then its early decrease indicates a reversal of this stress
response. However, further use of lactate clearance as a goal beyond
this initial decrease would not be beneficial and possibly harmful if
used as an exclusive target [49].
Venous blood oxygen saturation

If the mixed venous blood oxygen saturation (SvO2) is reduced in the
context of normal oxygen content of arterial blood, it represents
either decreased oxygen delivery or increased consumption and,
theoretically, is a determinant of the severity of shock. With the
declining use of the pulmonary artery catheter, the ScvO2 has been
used in its place but its values do not correlate with those of the SvO2
in critically ill patients because of altered perfusion and metabolic
patterns. Normalization of both was included in Rivers’ EGDT
protocol as a goal indicating adequate tissue oxygenation, with
apparent success in previous studies [50]. However, recent studies
suggest these end points (and lactate clearance) do not affect survival
[51, 52, 53].
In most patients with sepsis, the ScvO2 is normal or even high—

indicating either a problem of oxygen consumption by tissues or an
anaerobic metabolic stress response [54, 55]. The SCC no longer
recommends the routine use of ScvO2.
Measures of the microcirculation

The disruption to the macrocirculation caused by sepsis, and
mediated by vasodilatation and increased capillary permeability, has
been the main focus of sepsis identification and management because
it provides systemic variables which can be measured easily even
outside critical care environments. However, sepsis also disrupts the
regulation of microcirculatory perfusion, which is responsible for the
maintenance of the blood–tissue interface. This disruption can persist
after the correction of the macrocirculation, leading to tissue hypoxia,
mitochondrial stress, and organ dysfunction [56]. This may manifest
as persistent hyperlactataemia, or worsening organ dysfunction or
Page 22 of 36

Sepsis
metabolic status, despite apparently acceptable macrocirculatory

indices and adequate fluid resuscitation and perfusion.
Despite technological developments enabling assessment of

microcirculatory function, they are not used clinically because they
are expensive and there is no consensus on how to interpret the
results [57].
Methods available include:
● Video microscopic techniques [58]:
◦ Nailfold videocapillaroscopy
◦ Sublingual videocapillaroscopy
● Laser Doppler
● Near-infrared spectroscopy.
Currently, sublingual videocapillaroscopy and near-infrared

spectroscopy appear to show the greatest promise.
EXPERT COMMENT
Lactate is an adaptive, endogenous compound used by organs

including the heart as a metabolic substrate in stress situations.
Hyperlactataemia is associated with an adverse outcome, but the
presence of lactate per se may not be harmful. Lactate clearance as a
therapeutic target is reasonable in the immediate period following
presentation, but a failure to achieve a reduction in lactate levels
after administration of 30 mL/kg of crystalloid (or equivalent) should
be considered as indicative of microcirculatory (rather than
macrocirculatory) failure and prompt urgent critical care admission
for invasive monitoring and organ support rather than more fluids.
Despite a lack of evidence of outcome benefit, vasopressin was added as a

second-line therapy once the noradrenaline infusion rate had increased to
0.60 mcg/kg/min, in an attempt to achieve a MAP of 70 mmHg [40, 41].
Hydrocortisone was added at a physiological dose of 50 mg
hydrocortisone four times a day, despite scant evidence in support [42].
This combination led to achievement of the target MAP and within 12
hours the noradrenaline infusion rate had been decreased to 0.45 mcg/kg/
min. The patient’s oxygen requirement continued to increase.
Page 23 of 36

Sepsis
LEARNING POINT Vasopressors and inotropes
In patients with sepsis-induced hypotension, vasopressors and/or

inotropes may be required to restore circulatory function. Ideally,
they are started once patients have been identified as fluid
unresponsive; however, they are often required to maintain an
adequate MAP and to improve tissue perfusion while fluid
resuscitation continues. If the perfusion pressure to organs decreases
below a certain threshold (60 mmHg in animal studies [59]), regional
autoregulatory mechanisms are lost and tissue perfusion decreases
linearly with further reductions in perfusion pressure. Regional
autoregulation is further disrupted by the pathophysiological changes
in sepsis and by microcirculatory dysfunction.
A target MAP of 65 mmHg has been recommended by the SSC, but

individualized target pressures are more rational, for example, a
higher pressure for those with chronic hypertension whose
autoregulatory window may have shifted.
Patients with sepsis may have a high, normal, or low cardiac output
depending on previous reserves and the severity of sepsis. Initially, a
reduced systemic vascular resistance may result in a high cardiac
output and at this stage vasopressor support may be required to
counteract hypotension. While this physiological response to sepsis in
otherwise healthy individuals is typically seen in compensation for
vasodilatory shock, sepsis can also lead to both systolic and diastolic
myocardial dysfunction. No benefit has been shown in increasing a
normal cardiac output to supranormal values; in fact, by increasing
cardiac oxygen consumption it may be harmful [60]. Normovolaemic
patients with a reduced cardiac output may require inotropic support.
Vasopressors
Noradrenaline, a mixed alpha and beta1 adrenergic agonist, is the
preferred vasopressor. It counteracts the vasodilation caused by
sepsis and causes venoconstriction, which increases venous return
and therefore cardiac output. Noradrenaline is also an inotrope,
increasing cardiac output via beta1 adrenoreceptors. High-dose
noradrenaline may cause intense vasoconstriction and, despite
increasing blood pressure, may reduce tissue perfusion.
Adrenaline is a potent alpha and beta adrenergic agonist and is a

second-line therapy that can be used in addition to noradrenaline, or
alone, to maintain the blood pressure if noradrenaline alone is
insufficient. Adrenaline provides both inotropic and vasopressor
effects. It can cause hyperglycaemia and a transient increase in
lactate, caused by glycolysis, lipolysis, and insulin resistance rather
than hypoperfusion of tissues.
Page 24 of 36

Sepsis
Vasopressin (also known as ADH, arginine vasopressin, and

argipressin) acts on vasopressin receptors in the circulation and
kidney to cause vasoconstriction and water retention. It may be added
and can enable reduction in the dose of noradrenaline. It appears safe
when used early, but it has not been shown to improve outcome from
septic shock [41, 61].
In comparison with noradrenaline, dopamine (required in high doses

for a vasopressor effect) is associated with increased side effects
(mainly arrhythmias) and its use in sepsis is not recommended.
Phenylephrine is a pure alpha agonist, which tends to reduce cardiac
output and is not recommended for the treatment of sepsis. An
analysis of a large US database has shown that the use of
phenylephrine instead of noradrenaline to treat septic shock was
associated with increased mortality [62].
Inotropes
Once intravascular volume and vascular tone have been adequately
addressed, any further impairment of perfusion is likely to reflect
reduced cardiac function—clinical suspicion should be confirmed
where possible with appropriate cardiac output monitoring or
echocardiography.
Sepsis-induced myocardial dysfunction is caused by inflammatory

mediators, nitric oxide, interstitial myocarditis, coronary ischaemia,
calcium channel dysfunction, endothelin receptor antagonism, and
apoptosis [63]. The myocardial dysfunction can be treated with
inotropes, which improve cardiac contractility and perfusion,
although this may be at the expense of tachycardia. An increase in
myocardial oxygen demand relative to the cardiac output may cause
or worsen ischaemia.
Targeting supranormal cardiac output is not desirable—the aim is to

restore a low cardiac output state to normal. Dobutamine is typically
used as the first-line inotrope: its beta1 agonist properties confer
inotropy while beta2 properties cause mild vasodilatation, though this
may be affected by pre-existing medication (e.g. beta blockers) or
morbidity (e.g. cardiac failure) that alter individual patients’
responsiveness. Dobutamine has a ceiling of action and further
inotropic activity may then require the addition of adrenaline, though
this is likely to increase myocardial oxygen demand and may also
cause excessive vasoconstriction.
EXPERT COMMENT
Page 25 of 36

Sepsis
In practice, most patients with septic shock are managed using

vasopressors alone—most commonly noradrenaline. It would be good
practice, but is not always feasible, to assess cardiac output
immediately following resuscitation in all patients with sepsis. If a
patient stabilizes rapidly following low-dose noradrenaline, for
example, 0.08 mcg/kg/min, and clinical indices of perfusion including
mentation, urine output, and lactate levels improve, then it would be
deemed reasonable to omit formal cardiac output monitoring. There
is no clear guidance as to what level of vasopressor support cardiac
output assessment should be undertaken. A pragmatic approach
would be to institute cardiac output monitoring within the first few
hours for all patients in whom indices of perfusion do not normalize
with vasopressor support alone, and in any patient requiring higher
dose vasopressors (e.g. >0.3 mcg/kg/min of noradrenaline). Once
blood pressure is restored, attention should never deviate from the
harmful effects of vasopressors and, as with IV fluids, a ‘just enough
is enough’ approach is adopted. Early reduction of vasopressor
support may help in reducing long-term complications and
tachyphylaxis. Drugs such as enoximone and milrinone
(phosphodiesterase-3 inhibitors, inodilators) and the calcium
sensitizer levosimendan are infrequently used in sepsis, but may have
a role in complex cases (see Case 2).
LEARNING POINT Other supportive therapies
Several other therapies are used to treat patients with sepsis—some

are considered standard care for all critically ill patients, including
the following:
● Glucose control. Although initial work showed promise in

maintaining tight glycaemic control in sepsis, it is now understood
that the harmful effects of severe hypoglycaemia which might
result outweigh any perceived benefit. The avoidance of significant
hyperglycaemia is now the goal, with an appropriate target of 4–10
mmol/L [64, 65].
● Stress ulcer prophylaxis. Feeding early and continuously and
treating with a proton pump inhibitor until receiving full feed is a
mainstay of avoidance of stress ulcers and gastrointestinal
bleeding
● Thromboprophylaxis. See Case 13.
● Nutritional support. See Case 13.
● Lung protective ventilation strategies. See Case 3.
● Diuretics and renal replacement therapy. Initial sepsis
management invariably produces a positive fluid balance; however,
once stabilized, aim for a negative balance to counteract
Page 26 of 36

Sepsis
administered drug solutions and feeds. Several diuretics (e.g.

furosemide combined with spironolactone and
bendroflumethiazide or metolazone) may be useful in combination
to improve diuresis and minimize the side effects of a single agent.
● Sedation and analgesia. See Case 10.
Steroid therapy and the use of blood products are also important
aspects of the treatment of sepsis.
Corticosteroids
An adequate hypothalamic–pituitary–adrenal axis response to the
stress of sepsis has been linked to survival, with relative insufficiency
of endogenous corticosteroids implicated in adverse outcomes and
delayed reversal of shock [66]. Supplemental hydrocortisone reduces
the time to shock reversal but the mechanisms involved are complex
and not fully understood [67]. Steroids increase vessel sensitivity to
alpha agonists, aiding restoration of MAP by catecholamine
vasopressors, and they can improve vasopressor-unresponsive septic
shock (hypotension despite fluid resuscitation and vasopressors for
more than 60 min). Some systematic reviews have demonstrated
reduced mortality, albeit only in those severely ill (expected 28-day
mortality >50%); however, the more recent Corticosteroid Therapy of
Septic Shock (CORTICUS) trial [42] failed to show a mortality benefit
in patients without sustained shock.
Tests of hypothalamic–pituitary–adrenal axis function are difficult to

interpret in the critically ill and for this reason testing for
adrenocortical suppression is not recommended. In practice,
hydrocortisone 50 mg 6 hourly is typically started once the dose of
noradrenaline exceeds approximately 0.25–0.3 mcg/kg/min and is
tapered off once vasopressors are no longer needed.
Blood products
Anaemia is common in critical illness and has multiple causes. Taking
blood for tests is an important contributor to anaemia in patients who
are on the ICU for prolonged periods and careful management of
testing and technique can limit the impact. Avoiding unnecessary use
of blood products is important. Accepting lower haemoglobin values
(70–90 g/L vs 100–120 g/L) has no effect on the mortality of critically
ill adults [68, 69]. The transfusion trigger should be a haemoglobin
concentration of 70 g/L and the haemoglobin target of 70–90 g/L,
except for patients with active coronary artery disease where the
trigger is 90 g/L.
Use of erythropoietin does not improve outcome in septic patients

and may cause harm because of increased rates of thrombosis.
Guidance on the use of platelets and fresh frozen plasma in sepsis is
the same as for any critically ill patient.
Page 27 of 36

Sepsis
EXPERT COMMENT
The 2000s saw the rise and fall in popularity of recombinant activated
protein C for sepsis. Early studies suggested significant benefit but
this was not seen in subsequent studies and the drug is no longer
available. This is a typical picture that has been observed with many
previous sepsis-specific modulatory therapies. Failure of these
therapeutic agents may not only be due to lack of efficacy of the
agents, but may also reflect the enormous heterogeneity of patients
included and their source of infection, pathogen and microbial load,
host response characteristics, and the clinical time course of the
septic episode before presentation to healthcare and subsequent
recognition of sepsis.
Despite the inotropic requirement starting to reduce, the patient’s oxygen

requirement rose further, and invasive ventilation was commenced, along
with propofol and alfentanil sedation. A chest X-ray showed bilateral
opacities consistent with pulmonary oedema, and a repeat bedside
focused echocardiogram showed good biventricular function, with no
atrial or ventricular dilation. In the face of reducing inotropic
requirement, and little response to bolus diuretics, a furosemide infusion
was commenced to achieve a significant negative fluid balance. This had
no adverse effect on the inotropic dosing, which continued to improve.
EXPERT COMMENT
All patients with sepsis and septic shock are at risk of acute
respiratory failure. The fluid volumes used in the initial resuscitation,
combined with endothelial leakage, predispose these patients to
pulmonary oedema, but sepsis is also a common trigger for acute
respiratory distress syndrome (see Case 3), which can make
differentiating between them difficult. A key principle in these
patients, particularly in the face of improving haemodynamic state, is
to ensure a negative fluid balance. This can be achieved by bolus
diuretic use, by diuretic infusion, or through haemofiltration.
After 48 hours of invasive ventilation, using a lung protective strategy,

combined with 2 days of negative fluid balance of 2000 mL each, the
patient had progressed to a spontaneous breathing mode, and the oxygen
requirement significantly improved. He was extubated onto nasal high-
flow oxygen (see Case 16), which was gradually weaned off over the
following 24 hours. By this time, the vasopressin was stopped and the
noradrenaline weaned off over a further 36 hours. He was able to give a
Page 28 of 36

Sepsis
history of having diarrhoea and vomiting for the week preceding

admission. He was discharged from ICU on day 9.
Discussion
Epidemiology and pathogenesis
The incidence of sepsis requiring ICU admission is 0.25–0.38 per 1000

population per year, equating to approximately 20,000 cases per year in
the UK and more than 20 million cases per year globally. Despite
improvements in medicine, the incidence of sepsis is increasing. Data
from the UK Intensive Care National Audit & Research Centre identified
that hypotensive sepsis accounts for 10% of all admissions with an ICU
mortality of 18.2% and hospital mortality of 28.3% [70].
The Sepsis Occurrence in Acutely ill Patients (SOAP) study described the
incidence of sepsis in ICUs in Europe in 2002 [71]. It found that 37.4% of
adult patients in ICU had sepsis, of whom 24.7% had sepsis on admission,
with a mortality rate of 18.5% on ICU and 24.1% in hospital. The
causative organism was identified in 60% of cases, being Gram positive in
40%, Gram negative in 38%, and fungal in 17%. The most common source
of infection was the lung (68%) followed by the abdomen (22%).
Pathophysiology of sepsis
The immune system involves the complex interaction of cellular and

humoral responses designed to eradicate pathogens and resultant
infections. The inflammatory mediator process consists of a balance
between a proinflammatory process, designed to eliminate the pathogens,
and an anti-inflammatory process, to contain the response to the infected
area.
SIRS is a disorderly activation of the inflammatory process leading to an

unbalanced systemic response with resultant harm. The development of
SIRS and sepsis involves dysfunction of both the innate and adaptive
immune systems. Endothelial cells play an important role in the immune
response by altering vascular tone, permeability, adhesion molecule
expression, and coagulation function to facilitate an effective immune
response. The coagulation and fibrinolytic systems are closely linked to
both the immune system and endothelial function, and are also affected
by sepsis. Altered bleeding times and decreased platelet counts are seen
clinically.
Arterial vasodilation reduces perfusion pressure and venous vasodilation

causes a relative hypovolaemia and reduced cardiac output. The resultant
hypotension is worsened by any cardiac dysfunction and causes tissue
hypoperfusion. It is this reduced perfusion which decreases global oxygen
delivery.
Page 29 of 36

Sepsis
The microvascular effects caused by systemic endothelial dysfunction

lead to capillary vasodilation, loss of the endothelial glycocalyx layer, and
increased endothelial permeability. Capillary beds lose their
autoregulation ability, which further compromises tissue perfusion
already affected by the poor perfusion pressure from the microvascular
dysfunction. This is also exacerbated by coagulation dysfunction causing
microthrombus formation in the capillaries where blood flow has become
disorganized and stagnant. A combination of tissue hypoperfusion and
shunt results. As well as the vascular effects, mitochondrial dysfunction
occurs during sepsis, ultimately resulting in apoptosis and cell death.
The combination of reduced oxygen delivery (from macrovascular

dysfunction) and the reduced capillary flow and blood/tissue gas
exchange (from microvascular dysfunction), together with impaired
utilization of oxygen at a cellular level (from mitochondrial dysfunction),
mean tissues are no longer able to function. Organ systems begin to shut
down in a protective mechanism to prevent widespread cell death and
multiple organ dysfunction syndrome ensues. If not reversed, this process
leads to vital organ system failure and death.
Difficulties in the treatment of sepsis
Challenges remain around antimicrobial treatment with source control,

and fluid therapy.
The use of IV fluids, while being the foundation of supportive

management, is an area which generates controversy. The balance
between restoring cardiovascular function and fluid overloading is
delicate. The physiology is more complex than it initially appears. IV fluid
therapy does not generate the volumes of distribution expected from
Starling’s original model of semipermeable capillaries, leading to a
revised equation which includes the effect of the endothelial glycocalyx
layer. This is further influenced by the capillary pressure at the time of
infusion, as well as the patient and their pathology (e.g. damage to the
glycocalyx layer caused by inflammation).
The most effective therapy for sepsis is adequate, early antimicrobial

therapy and source control. Management is then supportive to maintain
organ function and prevent death until sepsis subsides. Targeted broad-
spectrum antibiotics are commenced initially, but the choice of antibiotic
should be narrowed as soon as possible. Emerging antibiotic resistance is
an increasing clinical problem, and with limited new antibiotics coming to
market, effective antibiotic stewardship is an essential component of good
clinical care.
A FINAL WORD FROM THE EXPERT
Page 30 of 36

Sepsis
Strategies toward the recognition and management of sepsis are

continually evolving as our understanding of the condition develops.
In time, our knowledge of both individual pathogenic profiles and host
response, coupled with more rapid pathogen and biomarker profile
identification, is likely to advance such that therapies can be tailored
to the disease profile. For now, however, a broad brush and a culture
of awareness are our best weapons.
References
1. Levy M, Fink M, Marshall J, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS
International sepsis definitions conference. Intensive Care Med.
2003;29:530–8.
2. Surviving Sepsis Campaign. Surviving Sepsis Campaign [Internet].

Available from: http://www.survivingsepsis.org/ (accessed November
2016).
3. Singer M, Deutschman C, Seymour C, et al. The third international

consensus definitions for sepsis and septic shock (sepsis-3). JAMA.
2016;23:801–10.
4. Churpek M, Snyder A, Han X, et al. qSOFA, SIRS, and early warning

scores for detecting clinical deterioration in infected patients outside the
ICU. Am J Respir Crit Care Med. 2016;195:906–11.
5. National Institute for Health and Care Excellence (NICE). Sepsis:

Recognition, Diagnosis and Early Management. NICE Guideline [NG51].
London: NICE; 2016. Available from: https://www.nice.org.uk/guidance/
ng51.
6. Nutbeam T, Daniels R, Keep J. The UK Sepsis Trust. ED/AMU Sepsis

Screening & Action Tool [Internet]. sepsistrust.org. Available from: http://
sepsistrust.org/ (accessed November 2016).
7. Mikkelsen M, Miltiades A, Gaieski D, et al. Serum lactate is associated

with mortality in severe sepsis independent of organ failure and shock.
Crit Care Med. 2009;37:1670–7.
8. Levy M, Dellinger R, Townsend S, et al. The Surviving Sepsis

Campaign: results of an international guideline-based performance
improvement program targeting severe sepsis. Intensive Care Med.
2010;36:222–31.
9. Kumar A, Roberts D, Wood K, et al. Duration of hypotension before

initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med. 2006;34:1589–96.
Page 31 of 36

Sepsis
10. Daniels R, Nutbeam T, McNamara G, et al. The sepsis six and the
severe sepsis resuscitation bundle: a prospective observational cohort
study. Emerg Med. 2011;28:507–12.
11. Daniels R, Nutbeam T, Laver K. Survive Sepsis Manual, 1st edn. The
official training programme of the Surviving Sepsis Campaign.
Birmingham: Good Hope Hospital, Heart of England Foundation Trust;
2007.
12. Robson WP, Daniels R. The Sepsis Six: helping patients to survive
sepsis. Br J Nurs. 2008;17:16–21.
13. Martin DS, Grocott MP. Oxygen therapy in critical illness: precise
control of arterial oxygenation and permissive hypoxemia. Crit Care Med.
2013;41:423–32.
14. Asfar P, Schortgen F, Boisrame-Helms J, et al. Hyperoxia and

hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two
factorial, multicentre, randomised, clinical trial. Lancet. 2017;5:180–90.
15. Marik PE. Fluid responsiveness and the six guiding principles of fluid
resuscitation. Crit Care Med. 2016;44:1920–2.
16. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications,
mortality, and resource utilization after open abdominal surgery: 0.9%
saline compared to Plasma-Lyte. Ann Surg. 2012;255:821–9.
17. Bellomo R, Hegarty C, Story D, et al. Association between a chloride-

liberal vs chloride-restrictive intravenous fluid administration strategy
and kidney injury in critically ill adults. JAMA. 2012;308:1566–72.
18. Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid

solution vs saline on acute kidney injury among patients in the intensive
care unit: the SPLIT randomized clinical trial. JAMA. 2015;314:1701–10.
19. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline

for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–11.
20. Delaney AP, Dan A, McCaffrey J, et al. The role of albumin as a

resuscitation fluid for patients with sepsis: a systematic review and meta-
analysis. Crit Care Med. 2011;39:386–91.
21. Patel A, Laffan MA, Waheed U, et al. Randomised trials of human

albumin for adults with sepsis: systematic review and meta-analysis with
trial sequential analysis of all-cause mortality. BMJ. 2014;349:4561.
22. Murphy CV, Schramm GE, Doherty JA, et al. The importance of fluid
management in acute lung injury secondary to septic shock. Chest.
2009;136:102–9.
Page 32 of 36

Sepsis
23. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is

associated with a worse outcome in patients with acute renal failure. Crit
Care. 2008;12:R74.
24. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic
shock: a positive fluid balance and elevated central venous pressure are
associated with increased mortality. Crit Care Med. 2011;39:259–65.
25. Silva JM, de Oliveira AM, Nogueira FA, et al. The effect of excess fluid
balance on the mortality rate of surgical patients: a multicenter
prospective study. Crit. Care. 2013;17:R288.
26. Chung FT, Lin SM, Lin SY, et al. Impact of extravascular lung water
index on outcomes of severe sepsis patients in a medical intensive care
unit. Respir Med. 2008;102:956–61.
27. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid
responsiveness? An updated meta-analysis and a plea for some common
sense. Crit Care Med. 2013;41:1774–81.
28. Monnet X, Marik P, Teboul JL. Passive leg raising for predicting fluid
responsiveness: a systematic review and meta-analysis. Intensive Care
Med. 2016;42:1935–47.
29. Lee JH, Kim JT, Yoon SZ, et al. Evaluation of corrected flow time in
oesophageal Doppler as a predictor of fluid responsiveness. Br J Anaesth.
2007;99:343–8.
30. Hett DA, Jonas MM. Non-invasive cardiac output monitoring. Intensive
Crit Care Nurs. 2004;20:103–8.
31. Charron C, Caille V, Jardin F, et al. Echocardiographic measurement of

fluid responsiveness. Curr Opin Critical Care. 2006;12:249–54.
32. Marik PE. Surviving sepsis: going beyond the guidelines. Ann
Intensive Care. 2011;1:17.
33. Marik PE. Hemodynamic parameters to guide fluid therapy. Transfus

Altern Transfus Med. 2010;11:102–12.
34. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in

the treatment of severe sepsis and septic shock. N Engl J Med.
2001;345:1368–77.
35. ProCESS Investigators. A randomized trial of protocol-based care for

early septic shock. N Engl J Med. 2014;2014:1683–93.
36. Arise Investigators, ANZICS Clinical Trials Group. Goal-directed

resuscitation for patients with early septic shock. N Engl J Med.
2014;2014:1496–506.
37. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed
resuscitation for septic shock. N Engl J Med. 2015;372:1301–11.
Page 33 of 36

Sepsis
38. Surviving Sepsis Campaign. Updated Bundles in Response to New

Evidence [Internet]. Available from: http://www.survivingsepsis.org/
SiteCollectionDocuments/SSC_Bundle.pdf (accessed 24 April 2015).
39. Miller III RR, Dong L, Nelson NC, et al. Multicentre implementation of
a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care
Med. 2013;188:77–82.
40. Russell JA, Walley KR, Singer J, et al. Vasopressin versus

norepinephrine infusion in patients with septic shock. N Engl J Med.
2008;358:877–87.
41. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early

vasopressin vs norepinephrine on kidney failure in patients with septic
shock: the VANISH randomized clinical trial. JAMA. 2016;316:509–18.
42. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for

patients with septic shock. N Engl J Med. 2008;358:111–24.
43. Gattinoni L, Vasques F, Camporota L, et al. Understanding Lactatemia

in Human Sepsis. Potential Impact for Early Management. Am J Respir
Crit Care Med. 2019;200:582–9.
44. Bakker J, Nijsten MW, Jansen TC. Clinical use of lactate monitoring in
critically ill patients. Ann Intensive Care. 2013;3:12.
45. Vary TC. Sepsis-induced alterations in pyruvate dehydrogenase

complex activity in rat skeletal muscle: effects on plasma lactate. Shock.
1996;6:89–94.
46. Trzeciak S, Dellinger RP, Chansky ME, et al. Serum lactate as a

predictor of mortality in patients with infection. Intensive Care Med.
2007;33:970–7.
47. Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in

sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis
Campaign database. Crit Care Med. 2015;43:567–73.
48. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is
associated with improved outcome in severe sepsis and septic shock. Crit
Care Med. 2004;32:1637–42.
49. Marik PE, Bellomo R. Lactate clearance as a target of therapy in

sepsis: a flawed paradigm. OA Crit Care. 2013;1:3.
50. Castellanos-Ortega Á, Suberviola B, García-Astudillo LA, et al. Impact

of the Surviving Sepsis Campaign protocols on hospital length of stay and
mortality in septic shock patients: results of a three-year follow-up quasi-
experimental study. Crit Care Med. 2010;38:1036–43.
Page 34 of 36

Sepsis
51. Gao F, Melody T, Daniels DF, et al. The impact of compliance with 6-
hour and 24-hour sepsis bundles on hospital mortality in patients with
severe sepsis: a prospective observational study. Crit Care. 2005;9:R764.
52. Sebat F, Johnson D, Musthafa AA, et al. A multidisciplinary community

hospital program for early and rapid resuscitation of shock in nontrauma
patients. Chest 2005;127:1729–43.
53. Lin SM, Huang CD, Lin HC, et al. A modified goal-directed protocol
improves clinical outcomes in intensive care unit patients with septic
shock: a randomized controlled trial. Shock. 2006;26:551–7.
54. Ince C, Sinaasappel M. Microcirculatory oxygenation and shunting in

sepsis and shock. Crit Care Med. 1999;27:1369–77.
55. Pope JV, Jones AE, Gaieski DF, et al. Multicenter study of central
venous oxygen saturation (ScvO2) as a predictor of mortality in patients
with sepsis. Ann Emerg Med. 2010;55:40–6.
56. Ince C. The microcirculation is the motor of sepsis. Crit Care.

2005;9:S13.
57. De Backer D, Hollenberg S, Boerma C, et al. How to evaluate the

microcirculation: report of a round table conference. Crit Care.
2007;11:R101.
58. Romagnoli S, Tujjar O, De Gaudio AR. Microcirculation in clinical

practice. OA Anaesthetics. 2013;1:16.
59. Bersten AD, Holt AW. Vasoactive drugs and the importance of renal
perfusion pressure. New Horiz. 1995;3:650–61.
60. Sharma VK, Dellinger R. The International Sepsis Forum’s frontiers in

sepsis: high cardiac output should not be maintained in severe sepsis. Crit
Care. 2003;7:272–5.
61. Russell JA, Cooper DJ, Walley KR, et al. Vasopressin and septic shock
trial (VASST): baseline characteristics and organ dysfunction in
vasopressor dependent patients with septic shock. Am J Respir Crit Care
Med. 2003;167:A548.
62. Vail E, Gershengorn HB, Hua M, et al. Association between US

norepinephrine shortage and mortality among patients with septic shock.
JAMA. 2017;317:1433–42.
63. Fernandes Jr CJ, Akamine N, Knobel E. Myocardial depression in

sepsis. Shock. 2008;30:14–17.
64. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional

glucose control in critically ill patients. N Engl J Med. 2009;360:1283–97.
Page 35 of 36

Sepsis
65. Griesdale DE, de Souza RJ, van Dam, et al. Intensive insulin therapy
and mortality among critically ill patients: a meta-analysis including
NICE-SUGAR study data. CMAJ. 2009;180:821–7.
66. Schroeder S, Wichers M, Lehmann LE, et al. The hypothalamic-

pituitary-adrenal (HPA) axis of patients with severe sepsis: altered
response to corticotropin-releasing hormone. Crit Care Med.
2001;29:310–16.
67. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low

doses of hydrocortisone and fludrocortisone on mortality in patients with
septic shock. JAMA. 2002;288:862–71.
68. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized,

controlled clinical trial of transfusion requirements in critical care. N
Engl J Med. 1999;340:409–17.
69. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher

hemoglobin threshold for transfusion in septic shock. N Engl J Med.
2014;371:1381–91.
70. Intensive Care National Audit & Research Centre. Sepsis [Internet].
Icnarc.org. Available from: https://www.icnarc.org/Our-Audit/Audits/Cmp/
Our-National-Analyses/Sepsis (accessed 24 January 2015).
71. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care
units: results of the SOAP study. Crit Care Med. 2006;342:344–53.
Page 36 of 36

Acute heart failure

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Acute heart failure
Chapter: Acute heart failure
Author(s): Amy Krepska
DOI: 10.1093/med/9780198814924.003.0002
Expert commentary by Deirdre Murphy
Case history
A 38-year-old female, who was previously fully active with no

significant past medical history, presented with a 4-week history of a viral
prodromal illness including fevers and chills. In the last 2 weeks, she had
developed orthopnoea, shortness of breath on minimal exertion, lethargy,
and abdominal discomfort.
On examination, she was warm and well perfused, with a heart rate of
170 beats per minute (bpm), blood pressure of 90/50 mmHg, and a raised
jugular venous pressure. She had normal heart sounds with no murmurs.
She had a tachypnoea of 28 breaths/min and on examination of her chest
had crackles up to the mid zones. Oxygen saturation by pulse oximetry
(SpO2) was 94% breathing 6 L/min via a Hudson mask.
Page 1 of 18
Acute heart failure
Her electrocardiogram (ECG) showed a narrow complex supraventricular

tachycardia with widespread T-wave inversion. Initial blood tests are
shown in Table 2.1.
Table 2.1 Initial blood tests (normal range in brackets)
Hb (g/L) 135 (130–165)
MCV (fL) 92 (77–95)
Plt (×109/L) 345 (150–450)
WCC (×109/L) 12.2 (4.0–11.0)
Na (mmol/L) 135 (135–145)
K (mmol/L) 3.6 (3.5–5.0)
Urea (mmol/L) 7.2 (3.3–6.7)
Cr (μmol/L) 105 (45–120)
Glucose (mmol/L) 6.3 (3.5–8.5)
Bili (μmol/L) 12 (3–20)
ALT (IU/L) 135 (10–50)
ALP (IU/L) 140 (30–130)
Albumin (g/L) 38 (35–50)
Corrected Ca (mmol/L) 2.1 (2.15–2.6)
Troponin (ng/mL) 0.7 (0–0.4)
INR 1.4 (0.9–1.4)
TSH (mIU/L) 3.8 (0.5–5)
Arterial blood gas
pH 7.29 (7.35–7.45)
PO2 (kPa) 7.6 (>10)
Page 2 of 18

Acute heart failure
PCO2 (kPa) 3.5 (4.4–6.1)
HCO3− (mmol/L) 22.4 (22–26)
BE (mmol/L) −5.1 (±2)
Lactate (mmol/L) 3.6 (≤2)
ALP, alkaline phosphatase; ALT, alanine aminotransferase; BE, base

excess; Bili, bilirubin; Ca, calcium; Cr, creatinine; Hb, haemoglobin;
HCO3− , bicarbonate; INR, international normalized ratio; K,
potassium; MCV, mean cell volume; Na, sodium; PCO2, partial pressure
of carbon dioxide; PO2, partial pressure of oxygen; Plt, platelets; TSH,
thyroid-stimulating hormone; WCC, white cell count.
An urgent chest X-ray showed pulmonary oedema and a large heart and a
diagnosis of acute heart failure was made. She was treated with diuretics
(furosemide 80 mg) and opiates (diamorphine 5 mg). However, despite
this therapy, she continued to be hypoxaemic with a SpO2 of 87%
breathing 15 L/min supplementary oxygen via a non-rebreather mask.
She was therefore admitted to the intensive care unit (ICU) for non-
invasive ventilation (NIV).
LEARNING POINT Acute heart failure

pathophysiology
The European Society of Cardiology defines acute heart failure as the

rapid onset of symptoms and signs secondary to abnormal cardiac
function [1]. Although the most common presentation of acute heart
failure seen in the ICU is a patient with decompensated chronic heart
failure with underlying coronary artery disease, acute heart failure is
a very heterogeneous condition with a constellation of signs and
symptoms [2, 3, 4]. These have been classified by the European
Society of Cardiology (Table 2.2) and impact prognosis and
management.
Table 2.2 Classification of different types of acute heart failure by

the European Society of Cardiology
Type of Criterion Criterion Criterion 3

heart failure 1 2
Heart failure Symptoms LVEF

with reduced and signs <40%
ejection
Page 3 of 18

Acute heart failure
fraction
(HFrEF)
Heart failure Symptoms LVEF 40– Elevated

with mid- and signs 49% natriuretic peptide
range At least one
ejection additional
fraction criterion: relevant
(HFmrEF) structural heart
disease, e.g. LVH
± left atrial
enlargement.
Diastolic
enlargement
Heart failure Symptoms LVEF Elevated

with and signs ≥50% natriuretic peptide
preserved At least one
ejection additional
fraction criterion: relevant
(HFpEF) structural heart
disease, e.g. LVH
± left atrial
enlargement.
Diastolic
enlargement
LVEF, left ventricular ejection fraction; LVH, left ventricular

hypertrophy.
Source: data from 2016 ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure. The Task Force for
the diagnosis and treatment of acute and chronic heart failure of
the European Society of Cardiology (ESC). European Heart
Journal, 37(27), 2129–2200. Copyright © 2016 ESC and Oxford
University Press.
Pulmonary oedema and congestive heart failure are the most common
presentations [5]. Only a minority of patients present with
cardiogenic shock, with de novo presentations of acute heart failure
being particularly prevalent in this group. Some patients have
reversible causes for their heart failure and it is especially important
to identify these rarer aetiologies. It is also important to differentiate
the presentation—that is, whether there is predominantly forward
failure (low output and cardiogenic shock) or pulmonary congestion
and/or right heart failure, as the treatment for these conditions will
be significantly different.
Page 4 of 18

Acute heart failure
EXPERT COMMENT
The seemingly normal systolic function on echocardiography can be

misleading as there tends to be non-uniform systolic contraction,
longitudinal contraction being compensated for by radial contraction
[6]. Furthermore, diastolic dysfunction is significant with abnormal
ventricular compliance and impaired relaxation so that high filling
pressures are necessary to maintain stroke volume. The TOPCAT trial
showed some benefit in giving spironolactone [7]. However, the use of
beta blockade is controversial [8]. As renal dysfunction often
accompanies heart failure with reduced (HFrEF) or preserved
ejection fraction (HFpEF), it is a significant health problem with
potentially a poor prognosis [9].
LEARNING POINT Role of non-invasive ventilation
There is a consensus to use NIV and, where possible, to avoid

intubation and ventilation in the treatment of pulmonary oedema [10,
11]. The National Institute for Health and Care Excellence (NICE)
guidelines recommend NIV if there is severe dyspnoea and acidaemia
[12]. Continuous positive airway pressure (CPAP) can be used alone
or with inspiratory support but the latter is not proven to be superior
to CPAP alone [13]. CPAP reduces both preload and left ventricular
afterload and therefore reduces myocardial oxygen consumption and
inhibits sympathetic tone. Increasingly, high-flow nasal oxygen is also
used. This provides heated and humidified gas with a higher and
more constant oxygen concentration with improved comfort and
tolerance, although the evidence for its benefit in this setting is still
limited [14, 15].
In the ICU, an urgent transthoracic echocardiograph showed normal left

ventricular size but increased left ventricular wall thickness and severe
global systolic impairment with an ejection fraction of approximately
10%. The heart valves were normal. Spontaneous echocardiographic
contrast was seen within the left ventricular cavity with no definite
thrombus. There was normal right ventricular size and wall thickness
with severe systolic impairment and very high atrial filling pressures. The
features were highly suggestive of myocarditis. The patient was referred
for a subendocardial biopsy. Table 2.3 details blood testing in heart
failure.
Table 2.3 Description of key laboratory tests in acute heart failure
Page 5 of 18

Acute heart failure
Test Key result
Full blood Anaemia, raised white cell count, macrocytosis

count (alcohol, thyroid dysfunction), eosinophilia
Urinary tests Beta human chorionic gonadotropin

Drug screen, e.g. amphetamines, cocaine
Liver function Alcohol toxicity

tests Rapid rise in serum aminotransferases and
moderate bilirubin, suggestive of hepatic hepatitis
Moderate rise in alkaline phosphatase and raised
bilirubin, suggestive of hepatic congestion
secondary to right heart failure
Urea and Renal impairment due to poor perfusion

electrolytes
Thyroid Hyperthyroidism
function
Cardiac Beta-type natriuretic peptide (BNP)

biomarkers Troponin
LEARNING POINT The role of echocardiography in

acute heart failure
Echocardiography is recommended as part of the workup for acute

heart failure presentations by all of the major cardiology societies [2,
10, 16]. Echocardiography is used to determine left and right
ventricular systolic function for diagnosis of HFrEF or HFpEF.
Increasingly, intensivists are becoming skilled in bedside
echocardiography and its role is expanding in the ICU so that it is
now a quasi-monitor with repeated echocardiography being used to
evaluate and guide the response to therapy in critically ill patients.
The following are just some of the features that can be identified with
echocardiography and used to assess patients with heart failure:
● Left ventricular function: left ventricular size, evidence of

regional wall motion abnormalities, ejection fraction, and features
to suggest acute inflammation or chronicity (i.e. thinning of the
myocardium and structural heart disease, e.g. hypertrophic
cardiomyopathy).
Page 6 of 18

Acute heart failure
● Right ventricular function: right ventricular ejection fraction and

right ventricular size and systolic function; tricuspid annular plane
systolic excursion (TAPSE) is a simple and reliable measure of
right ventricular function.
● Valvular function: congenital or acquired (degenerative) valvular
pathologies and endocarditis.
● Pericardial disease: constrictive or restrictive cardiomyopathies.
● Non-invasive haemodynamics: severity of valvular lesions,
cardiac output estimation, non-invasive estimation of pulmonary
pressures, left atrial filling pressures, diastolic left and right
ventricular function, and shunt fractions.
LEARNING POINT History taking
Careful history taking is especially vital in acute decompensated

heart failure to try to identify and exclude rare but reversible causes
of de novo heart failure. In the critical care setting this is often
overlooked and a collaborative history from the family can be
especially useful. Vital points are length of prodromal illness,
comorbidities, especially chronic inflammatory syndromes, family
history, medications including chemotherapeutic drugs, alcohol, and
illicit drug use, and recent pregnancy, as well as extracardiac
symptoms and signs of rare infections such as Lyme and Chagas
diseases. Symptoms such as palpitations, chest pain, dyspnoea, and
orthopnoea indicate the extent of the failure; abdominal discomfort
and nausea may indicate right heart failure.
CLINICAL TIP Dilated cardiomyopathy
With chronic processes, patients have time to adapt to their

symptoms. Patients with a new diagnosis of dilated cardiomyopathy
commonly give a short symptom history, often citing a viral
precipitant. Careful exploration may reveal details they have
discounted because of habituation, such as they now need to sleep
semi-recumbent and wake up if they have fallen off the pillows or they
no longer play sport as they feel tired all the time. One memorable
young patient had to pause several times as she walked up the aisle
at her own wedding. Her family did not think this unusual. She had
thyrotoxicosis-induced heart failure with an ejection fraction at
presentation of less than 10%.
Page 7 of 18

Acute heart failure
LEARNING POINT Clinical examination
Essential elements of a clinical examination are to assess for end-

organ perfusion (e.g. mentation, peripheral perfusion, and urinary
output) and to look for evidence of left, right, or biventricular failure
(basal crackles, raised jugular venous pressure, and ankle oedema).
Evidence of sepsis, rash, chronic liver disease, and joint involvement
should also be sought.
LEARNING POINT Investigations to identify aetiology

and assess severity
Blood tests including renal function, eosinophil count, inflammatory

markers, and liver and thyroid function should be performed. A
urinary drug and pregnancy screen could also be included. Serial
ECG and echocardiography also form an important part of
management.
Beta-type natriuretic peptide (BNP) and troponin biomarkers can also

be helpful. BNP can be a useful tool in the diagnosis and risk
stratification of patients with heart failure. However, there is
considerable controversy about interpretations of values especially in
the setting of renal insufficiency and in the perioperative period [6].
LEARNING POINT Myocarditis
Myocarditis, although relatively uncommon, is a very important

diagnosis to make as it can present with fulminant heart failure in
previously healthy young patients. It has a very good prognosis when
identified and treated early [6, 17]. It is a heterogeneous disease with
a variable presentation, pathophysiology, and prognosis, and no
standardized diagnostic criteria. It is caused commonly by a virus
including Coxsackie B, cytomegalovirus, echovirus, Epstein–Barr
virus, and human immunodeficiency virus infection. Other causes
include other infectious agents such as Mycoplasma or
Corynebacterium diphtheriae, autoimmune disease (e.g. systemic
lupus erythematosus, giant cell myocarditis), or drugs such as
anthracyclines (e.g. doxorubicin, daunorubicin, etc.) [6].
Diagnosis is based on several factors. Clinical presentation with

evidence of myocardial dysfunction and laboratory abnormalities,
including leucocytosis, eosinophilia, and a high erythrocyte
sedimentation rate, is important. Troponin values tend to be elevated,
with a reasonable specificity and positive predictive value [6]. The
Page 8 of 18

Acute heart failure
presentation can mimic sepsis and other conditions, so a high degree

of clinical suspicion is needed. Investigations such as ECG,
echocardiography, endocardial biopsy, and gadolinium-enhanced
magnetic resonance imaging (MRI) can be more specific. ECG most
commonly shows T-wave inversion and ST-segment depression. A
biopsy can be particularly helpful as it can guide treatment, with
some subtypes such as giant cell myocarditis being amenable to
immunosuppression.
Intensive care patients may be too unstable to undergo an MRI and

biopsy results take time to be processed. Therefore echocardiography
is increasingly useful to diagnose and quantify the extent of the
pathology, assessing for regional or global left ventricular wall motion
abnormalities, left ventricular wall thickness, left ventricular and
right ventricular size and function, and valvular regurgitation.
Further blood tests were undertaken in the ICU including cardiac

biomarkers. She was administered a loading dose of intravenous
amiodarone (5 mg/kg over 1 hour) and her heart rate reduced to 96 bpm.
A repeat ECG showed sinus tachycardia with widespread ST-segment
depression and T-wave inversion. Amiodarone was continued for another
24 hours.
LEARNING POINT Rate control in acute heart failure
American and European guidelines recommend that beta blockade

should only be started at a low dose and in stable patients presenting
with acute decompensated heart failure [10, 16]. Be particularly
careful when using beta blockers in patients who required inotropes
during their hospital course [10, 18]. If possible, avoid acute
withdrawal of beta blockade.
EXPERT COMMENT
Myocarditis is a frequent cause of ventricular and atrial arrhythmias.

Inappropriate use of rate control and negative inotropic agents (beta
blockers) can precipitate the need for mechanical circulatory support.
Fulminant myocarditis such as this patient had (i.e. presentation with
acute heart failure and significant haemodynamic compromise)
paradoxically can have a more favourable prognosis for full recovery
as long as the patient can be supported during the acute phase of the
illness. With fulminant myocarditis, the ejection fraction is often
severely limited and the heart has not dilated as it is an acute
process. The only way in which patients can maintain their cardiac
Page 9 of 18

Acute heart failure
output is by maintaining a rapid heart rate as they cannot increase

the stroke volume. By comparison, patients with chronic dilated
cardiomyopathies can have a larger stroke volume simply due to the
degree of ventricular dilatation as the ventricle dilates over time in
response to the heart failure in an effort to preserve stroke volume
despite a low ejection fraction.
EXPERT COMMENT
Another important and increasingly recognized condition to consider

in young patients presenting with new heart failure, arrhythmia, or
out-of-hospital cardiac arrest is arrhythmogenic right ventricular
cardiomyopathy. This is a form of cardiomyopathy which is familial in
origin in a third of cases and has probably been underreported. It
causes fibrofatty replacement of right ventricular tissue with a
characteristic appearance of right ventricular impairment on
echocardiography and cardiac MRI. It is present in between 1 in 2000
and 1 in 5000 people [19]. Presentation varies from sudden cardiac
death to syncope and arrhythmias. Heart failure presentations
typically are with right heart failure but left ventricular involvement
is also possible.
Over the next few hours, the patient became more hypotensive (systolic
blood pressure of 90–100 mmHg) and developed oliguria. Inotropic
support was started with adrenaline at 0.1 mcg/kg/min and milrinone at
15 mcg/min and preparations were made to establish renal replacement
therapy.
LEARNING POINT Inotropic therapy
The best drug for the treatment of acute decompensated heart failure
is unclear. The key issue is to maintain sufficient perfusion pressure
and minimize myocardial oxygen demand. The choice of drug is
influenced by the systolic blood pressure, the presence of coronary
artery disease, and the underlying pathophysiology, such as
peripartum cardiomyopathy or post cardiotomy. Large trials that have
studied the use of inotropes in acute heart failure, such as OPTIME
CHF and SURVIVE [20, 21], focus on exacerbations of chronic heart
failure. Even in this group, no definitive benefit has been described
with the use of milrinone, levosimendan, and dobutamine. If
cardiogenic shock is not resolving, mechanical support should be
considered early.
Page 10 of 18

Acute heart failure
The patient became agitated and her arterial blood gas results showed a
pH of 7.15, a PaCO2 of 15 kPa, and a lactate concentration of 10 mmol/L.
An intra-aortic balloon pump (IABP) was considered but it was decided
that more support was needed and emergency percutaneous venoarterial
extracorporeal membrane oxygenation (VA ECMO) support via the
common femoral vein and artery was chosen. Minimal sedation was
provided during the procedure and particular care was taken with
placement of the venous wire to avoid provoking arrhythmia. VA ECMO
flow was established at 3.6 L/min. A back-perfusion cannula was also
inserted into the superficial femoral artery to provide adequate perfusion
of the limb (Figure 2.1). Subsequently she was intubated and her lungs
ventilated.
Figure 2.1
An example of a peripheral VA ECMO circuit.
Courtesy of Vin Pellegrino, The Alfred Hospital, Melbourne.
After starting VA ECMO, urine output, peripheral circulation, and

mentation improved. Inotropes were provided to maintain pulsatility of
her native circulation and avoid complications such as intracardiac clot.
LEARNING POINT The role of an intra-aortic balloon

pump
An IABP is placed in the thoracic aorta via the femoral artery, with
balloon inflation in diastole and deflation in early systole. The
diastolic inflation improves coronary blood flow proximally and
improves systemic perfusion distally. The systolic deflation decreases
Page 11 of 18

Acute heart failure
afterload thus unloading the left ventricle. It can be used in many

settings including cardiogenic shock not responding to fluids and
inotropic support, or for haemodynamic support while awaiting
myocardial recovery after intervention. Absolute contraindications
include aortic regurgitation and aortic dissection; relative
contraindications include severe peripheral vascular disease and an
abdominal aortic aneurysm [22].
There has been debate about its use in patients awaiting

revascularization because the Intraaortic Balloon Pump in
Cardiogenic Shock II (IABP-SHOCK II) trial showed no significant
improvement in mortality with its use in this setting [23].
EVIDENCE BASE The IABP-SHOCK II trial
In the IABP-SHOCK II trial, 600 patients with acute myocardial

infarction complicated by cardiogenic shock were assigned randomly
to IABP support or no IABP support. All these patients were expected
to have early revascularization, either percutaneous coronary
intervention or coronary artery bypass surgery. The primary end point
was 30-day all-cause mortality with secondary outcomes including
time to haemodynamic stabilization, ICU length of stay, and serum
lactate level. There was no significant difference in any of these
primary or secondary outcomes. Another important finding was that
there were no significant differences in complication rates between
the groups. The key conclusion was that the use of IABP did not
benefit mortality or other secondary outcomes in patients who are
intended for revascularization. Notably, it has been argued that this
trial may have been underpowered because the expected mortality
rate in both groups was lower than expected [24].
EXPERT COMMENT
Since the IABP-SHOCK II trial results, the use of IABP for acute heart
failure seems to have decreased. One of the main limitations of IABP
support in cardiogenic shock is the relatively small amount of
circulatory support that it can provide, equivalent to an increase in
cardiac output of approximately 0.3–0.5 L/min (i.e. 6–10% of normal
resting cardiac output). The use of IABP support prophylactically in
high-risk percutaneous procedures is now being superseded by VA
ECMO and other forms of mechanical circulatory support (e.g.
Impella, TandemHeart).
Page 12 of 18

Acute heart failure
LEARNING POINT Ultrafiltration in acute heart

failure
Volume overload is a significant problem in acute heart failure.

Diuretic resistance is common, possibly as a result of upregulation of
neuroendocrine pathways combined with decreased renal function.
Patients with chronic heart failure may be considered for
ultrafiltration to remove fluid and correct hyponatraemia [25].
Removal of fluid may improve the patient’s haemodynamic state by
shifting them to a more favourable part of their Starling curve. In
contrast to high-dose diuretic therapy, ultrafiltration may induce less
neurohormonal activation and vasoconstriction [26].
LEARNING POINT Early referral to an ECMO or

ventricular assist device centre
VA ECMO is indicated for cardiac failure that is potentially reversible

but is unresponsive to conventional therapy. Myocarditis is an
excellent example of this: patients tend to respond well in the limited
time frame that VA ECMO can offer support. VA ECMO can therefore
be used either as a bridge to recovery or to transplant. It is therefore
vital that any such patients are referred early. Patients with
myocarditis can have a very good prognosis and hence it is important
to have an aggressive therapeutic approach, including using
mechanical devices when appropriate [27]. Any patient with
suspected myocarditis should be referred urgently to a transplant/
ventricular assist device centre.
Patients are unlikely to be suitable if they are over 65 years of age or

have malignancy or other severe organ failure. Figure 2.2 shows the
inclusion and exclusion criteria used by The Alfred Hospital,
Melbourne, Australia.
Page 13 of 18

Acute heart failure
Figure 2.2
An example of criteria for VA ECMO support.
Courtesy of Vin Pellegrino, The Alfred Hospital, Melbourne.
Over the next week, repeat echocardiograms showed persistently poor

function and the patient was discussed at a multidisciplinary meeting for
consideration for a ventricular assist device as a bridge to
transplantation. The endocardial biopsy was consistent with giant cell
myocarditis. The patient was started on a combination of
immunosuppression including prednisolone.
LEARNING POINT Role of other mechanical devices

and transplantation
ECMO support is a time-limited therapy so all patients on ECMO

support should have multidisciplinary input early to enable bridges to
other therapies to be considered. Both European and NICE guidelines
[1, 28] recommend that mechanical assist devices be used only as a
bridge to transplantation or recovery. Workup for mechanical devices
and transplantation is complex. In addition to the patient’s
comorbidities, organ functions, and the pathophysiology of their heart
failure, psychosocial factors are also fundamental.
NICE recommends that there should be a discussion with a centre

that provides mechanical circulatory support for all patients with
potentially reversible, severe acute heart failure and those who are
potential candidates for transplantation [12].
Page 14 of 18

Acute heart failure
Over the subsequent week, there was gradual normalization of left

ventricular function on echocardiography with her ejection fraction
improving. She continued to have arrhythmias and an automated
implantable cardioverter defibrillator was inserted. An ECMO weaning
study was undertaken, whereby ECMO flows are reduced electively, and
haemodynamic and echocardiography variables were assessed to
determine if support could be withdrawn. As there was sufficient
myocardial recovery to successfully separate from ECMO, it was agreed
that a left ventricular assist device and transplantation were not required.
Her left ventricular function continued to improve and she was weaned
from ECMO, ventilation, renal replacement therapy, and inotropic
support. Once extubated and stable she was transferred from the ICU to
the coronary care unit.
In the subsequent week, a cardiac MRI showed an increased early

relative enhancement and delayed enhancement pattern typical of recent
myocarditis. She tolerated the introduction of beta blockade and
angiotensin-converting enzyme inhibitor. At outpatient follow-up, 8 weeks
after presentation, she was symptomatically almost back to her pre-illness
state and her left ventricular ejection fraction had improved to 40%.
Discussion
Heart failure represents a considerable economic and social

burden and affects up to 2% of the adult population in developed
countries [1]. It leads to more than 67,000 hospital admissions each year
in England and Wales, with 50% being readmitted within 12 months.
There is a wide variation in management with one-third of patients dying
within a year of their first hospital admission. There is therefore a need
for ongoing review of practice [2].
It is critical that efforts are made early in the patient’s admission to

define the type of cardiac failure and also to seek out and treat any
treatable causes. This requires a logical and structured approach. This is
likely to require collaboration between ICU, cardiology, radiology, and
possibly other medical teams. As end-organ failure may be a
contraindication to specialist support and advanced treatments, all efforts
should be made to preserve organ function and an early assessment
should be made as to whether the patient can be best treated in the
hospital they presented to or whether referral to a specialist centre is
required.
Many district general hospitals will not have the resources described
in this chapter (endocardial biopsy, IABP, rapid access to cardiac MRI)
and only in specialist centres will ECMO, ventricular assist devices,
and access to transplantation be available. Early discussion with a
Page 15 of 18

Acute heart failure
specialist centre is likely to be of benefit for the majority of patients

presenting with acute heart failure and will enable the specialist
centre, where necessary, to advise the clinicians in the district
general hospital and facilitate timely transfer for specialist services if
this becomes necessary.
References
1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure: the Task
Force for the diagnosis and treatment of acute and chronic heart failure
of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2129–
200.
2. Dworzynski K, Roberts E, Ludman A, et al. Diagnosing and managing

acute heart failure in adults: summary of NICE guidance. Br Med J.
2014;5695:g5695.
3. Mosterd A, Hoes A. Clinical epidemiology of heart failure. Heart.

2007;93:1137–46.
4. Nieminen M, Bohm M, Cowie M, et al. Guidelines on the diagnosis and

treatment of acute heart failure. Endorsed by the European Society of
Intensive Care Medicine (ESICM). Eur Heart J. 2005;26:384–416.
5. Rudiger A, Streit M, Businger F, Schmid E, Follath F, Maggiorini M.

Presentation and outcome of critically ill medical and cardiac-surgery
patients with acute heart failure. Swiss Med Wkly. 2009;139:110–16.
6. Mebazaa A, Gheorghiade M, Zannad F, Parrillo J (eds). Acute Heart

Failure. London: Springer; 2008.
7. Pitt B, Pfeffer M, Assmann S, et al. Spironolactone for heart failure with

preserved ejection fraction. N Engl J Med. 2014;370:1383–92.
8. Bergstrom A, Andersson B, Edner M, et al. Effect of carvedilol on

diastolic function in patients with diastolic heart failure and preserved
systolic function. Results of the Swedish Doppler-echocardiographic study
(SWEDIC). Eur J Heart Fail. 2004;6:453–61.
9. Bhatia R, Tu J, Lee D, et al. Outcome of heart failure with preserved

ejection fraction in a population-based study. N Engl J Med.
2006;355:260–9.
10. The Task Force for the Diagnosis and Treatment of Acute and Chronic
Heart Failure 2012 of the European Society of Cardiology. ESC Guidelines
for the diagnosis and treatment of acute and chronic heart failure 2012.
Eur Heart J. 2012;33:1787–847.
Page 16 of 18

Acute heart failure
11. Gray A, Goodacre S, Newby D, et al. Noninvasive ventilation in acute

cardiogenic pulmonary edema. N Engl J Med. 2008;359:142–51.
12. National Institute for Health and Care Excellence. Acute Heart
Failure: Diagnosing and Managing Acute Heart Failure in Adults. London:
National Institute for Health and Care Excellence; 2014.
13. Weng CL, Zhao YT, Liu QH, et al. Noninvasive ventilation in acute
cardiogenic pulmonary edema. Ann Intern Med. 2010;152:590–600.
14. Papazian L, Corley A, Hess D, et al. Use of high-flow nasal cannula

oxygenation in ICU adults: a narrative review. Intensive Care Med.
2016;42:1336–49.
15. Nishimura M. High-flow nasal cannula oxygen therapy in adults. J

Intensive Care. 2015;3:15.
16. Yancy C, Jessop M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the
management of heart failure: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Circulation. 2013;128:e240–32.
17. Schultz JC, Hillard A, Cooper L, et al. Diagnosis and treatment of viral
myocarditis. Mayo Clin Proc. 2009;84:1001–9.
18. Jessup M, Abraham W, Casey D, et al. 2009 focused update: ACCF/

AHA Guidelines for the Diagnosis and Management of Heart Failure in
Adults: a report of the American College of Cardiology Foundation/
American Heart Association Task Force on Practice Guidelines.
Circulation. 2009;119:1977–2016.
19. Marcus F, McKenna W, Sherrill D, et al. Diagnosis of arrhythmogenic

right ventricular cardiomyopathy/dysplasia. Circulation 2010;121:1533–
41.
20. Felker GM, Benza R, Chandler A, et al. Heart failure etiology and
response to milrinone in decompensated heart failure: results from the
OPTIME-CHF study. J Am Coll Cardiol. 2003;41:997–1003.
21. Mebazaa A, Nieminen M, Packer M, et al. Levosimendan vs

dobutamine for patients with acute decompensated heart failure: the
SURVIVE randomized trial. JAMA. 2007;297:1883–91.
22. Krishna M, Zacharowski K. Principles of intra-aortic balloon pump

counterpulsation. Contin Educ Anaesthesia Crit Care Pain. 2008;9:24–8.
23. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for
myocardial infarction with cardiogenic shock. N Engl J Med.
2012;367:1287–96.
Page 17 of 18

Acute heart failure
24. Perera D, Lumley M, Pijis N, et al. Intra-aortic balloon pump trials:

questions, answers, and unresolved issues. Circ Cardiovasc Interv.
2013;6:317–21.
25. National Institute for Health and Care Excellence. Acute Heart
Failure: Diagnosing and Managing Acute Heart Failure in Adults, Draft
Guidelines. London: National Institute for Health and Care Excellence;
2014.
26. Valchanov K, Parameshwar J. Inpatient management of advanced

heart failure. Contin Educ Anaesthesia Crit Care Pain. 2008;8:167–71.
27. Senderek T, Malecka B, Zabek A, et al. Fulminant heart failure due to

giant cell myocarditis affecting the left ventricle. Adv Interv Cardiol.
2015;11:351–3.
28. National Institute for Health and Care Excellence. Extracorporeal

Membrane Oxygenation (ECMO) for Acute Heart Failure in Adults.
London: National Institute for Health and Care Excellence; 2014.
Page 18 of 18

Acute respiratory failure

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Acute respiratory failure
Author(s): Catherine Bryant
DOI: 10.1093/med/9780198814924.003.0003
Expert commentary by Sanjoy Shah
Case history
A 32-year-old woman presented to the emergency department

with a 3-day history of a cough productive of yellow sputum, fever, and
worsening shortness of breath. She had a past medical history of asthma,
depression, and alcohol dependence and was previously an intravenous
(IV) drug user.
Her observations and examination were as follows:
A. Oxygen saturation by pulse oximetry (SpO2) 90% on 15 L/min via

a non-rebreathe face mask.
B. Respiratory rate 30 breaths/min. She was using accessory
muscles of respiration. Auscultation identified bronchial breathing
and coarse crepitations over the right mid zone.
Page 1 of 29
C. Heart rate was 120 beats per minute (bpm) with a thready pulse
and cool peripheries. Capillary refill time was 4 seconds. Blood
pressure was 90/50 mmHg.
D. Glasgow Coma Scale score 14 (E3, V5, M6).
E. Temperature 38.5°C.
LEARNING POINT Definition of pneumonia
Features of pneumonia include the symptoms of cough, purulent

sputum, increasing breathlessness, and haemoptysis, with signs of
fever, tachycardia and tachypnoea, increased vocal fremitus, and
bronchial breathing. It includes laboratory features of leucocytosis
with neutrophilia, raised inflammatory markers (e.g. CRP,
procalcitonin), radiology showing air bronchograms or consolidation,
and positive microbiology [3, 4].
Two 16-gauge peripheral venous cannulae were inserted and venous

blood samples sent for full blood count, urea and electrolytes, liver
function tests, lactate, C-reactive protein (CRP), clotting, and blood
cultures. A fluid challenge was undertaken with 500 mL of a balanced
crystalloid solution. A urinary catheter was inserted to monitor urine
output and urinalysis performed. The patient was commenced on IV co-
amoxiclav 1.2 g three times daily and clarithromycin 500 mg twice daily.
EXPERT COMMENT
The management of patients with sepsis in the emergency

department follows the care bundle proposed by the Surviving Sepsis
Campaign [1]. The Sepsis Six tool improves implementation of the
Surviving Sepsis Campaign care bundle [2]. The Sepsis Six are as
follows:
Take 3
1. Take blood cultures.
2. Measure serial serum lactates.
3. Measure accurate hourly urine output.
Give 3
4. Administer oxygen to maintain saturations at greater than
94% (88–92% in patients with chronic lung disease).
5. Give broad-spectrum antibiotics.
6. Give IV fluid challenges if the patient is hypotensive or their
lactate is elevated.
Page 2 of 29

For more detail, see Case 1.
Her blood results and arterial blood gas values are shown in Table 3.1.
Table 3.1 Blood results and arterial blood gas values
Full blood count
Hb (g/L) 150 (130–180)
Plat (×109/L) 300 (150–400)
WCC (×109/L) 18.5 (4–11)
CRP (mg/L) 258 (<10)
Na (mmol/L) 130 (135–145)
K (mmol/L) 4.8 (3.5–5)
Urea (mmol/L) 7.8 (2.5–6.7)
Cr (μmol/L) 90 (60–110)
Arterial blood gas on 15 L/min
pH 7.24 (7.35–7.45)
PaCO2 (kPa) 7.2 (4.7–6.0)
PaO2 (kPa) 8.0 (>10)
HCO3− (mmol/L) 21.0 (22–28)
Base excess (mmol/L) −2.3 (±2)
Lactate (mmol/L) 2.0 (0.5–2.0)
Cr, creatinine; CRP, C-reactive protein; Hb, haemoglobin; K,

potassium; Na, sodium; WCC, white cell count.
Her chest X-ray (CXR) (Figure 3.1) showed right upper lobe
consolidation.
Page 3 of 29

Figure 3.1
Chest X-ray on admission.
LEARNING POINT Differential diagnosis of

consolidation on chest X-ray
The causes of consolidation can be categorized by the type of matter

that is displacing air in the alveoli:
1. Pus—pneumonia (typical and atypical)

2. Fluid—pulmonary oedema (cariogenic and non-cardiogenic)
3. Food or gastric contents—aspiration pneumonia/pneumonitis
4. Blood—pulmonary haemorrhage
5. Specific cell types—bronchogenic carcinoma, eosinophilic
pneumonia
The patient was moved into a resuscitation bay for continued

management, and an urgent intensive care referral was sought for her
acute respiratory failure. Her cardiovascular status improved following
the initial fluid bolus, with heart rate decreasing to 110 bpm and blood
pressure improving to 95/55 mmHg, and a second fluid challenge was
performed with 500 mL crystalloid which resulted in a further
improvement of her cardiovascular parameters.
LEARNING POINT Acute respiratory failure
Acute respiratory failure is defined as impaired pulmonary gas

exchange leading to hypoxaemia and/or hypercapnia. It comprises
two main subtypes:
Page 4 of 29

Type I—hypoxaemic, often parenchymal in origin:
● Alveolar pathology
● Interstitial or diffusion pathology
● Impairment in oxygen-carrying capacity:
◦ Impaired circulation:
■ Low cardiac output

■ Low circulation volume
◦ Impaired oxygen carriage:
■ Haemoglobinopathy or low haemoglobin concentration or

high-affinity haemoglobinopathy
Type II—hypercapnic, often mechanical in origin:
● Reduction in respiratory rate

● Reduction in ventilation
Common causes
Acute respiratory failure has a variety of causes, including primary
pulmonary pathology or an extrapulmonary cause, although it is often
multifactorial. Causes are categorized as shown in Table 3.2.
Table 3.2 Causes of respiratory failure
Location Examples
Lung Pneumonia, acute interstitial pneumonitis

parenchymaa
Pleurala Pneumothorax, pleural effusion,

haemothorax
Pulmonary Pulmonary embolism, pulmonary

vasculara haemorrhage
Chest wallb Flail chest
Upper airways Upper airway obstruction, asthma,

anaphylaxis
Page 5 of 29

Cardiovasculara Acute pulmonary oedema associated with

acute coronary syndrome, valvular heard
disease, myocardial infarction
Central Cerebrovascular accident, raised

Brainstem/spinal Infarction, vertebral artery dissection,

cord trauma
Neuromuscular Myasthenia gravis, Guillain–Barré syndrome,

poliomyelitis
Miscellaneous Poisoning (intentionalb, accidental)
a Common cause of type I respiratory failure.
b Common cause of mixed type I and II respiratory failure.
LEARNING POINT Approach to investigating

pneumonia
Appropriate investigations for pneumonia [3, 5, 6] include the

following:
Haematology:
● Full blood count

● Coagulation profile
Biochemistry:
● Liver and renal function

● Urine analysis/dipstick
● Acute phase reactants: CRP, procalcitonin
● Cardiac enzymes if associated/underlying cardiac disease
Microbiology:
● Blood culture
● Sputum culture
● Nasopharyngeal swabs for virology
Page 6 of 29

● Urinary antigen for Streptococcus pneumoniae and Legionella

pneumoniae
● Atypical serology for Mycoplasma pneumoniae
Radiology:
● CXR
● Computed tomography (CT) scan of the chest with consideration
for a pulmonary angiogram
● Ultrasonography of chest
● Two-dimensional echocardiography
The patient was reviewed by the intensive care physician in the

emergency department. The patient was increasingly agitated and non-
compliant with medical intervention, pulling at her face mask. She was
transferred to the intensive care unit (ICU) to enable provision of
ventilation and multiorgan support. She was preoxygenated using a tight-
fitting facemask delivering as close to 100% oxygen as possible, and
manually applied positive end-expiratory pressure (PEEP). Nasal high-
flow oxygen was applied at 50 L/min of 100% oxygen to provide apnoeic
oxygenation during laryngoscopy. Her trachea was intubated with a 7.5
mm tracheal tube following a rapid sequence induction with ketamine 2
mg/kg and rocuronium 1 mg/kg and sedation was maintained with
infusions of propofol and alfentanil.
EXPERT COMMENT
Preoxygenation can be difficult to optimize in the critical care setting,

especially when the patient is agitated. This, combined with a higher
incidence of difficult intubation, makes a profound hypoxaemia more
likely after induction of anaesthesia. This risk is reduced by optimal
patient positioning and the use of rapid sequence induction
checklists. The use of nasal cannulae, or ideally high-flow nasal
oxygen, can eliminate or minimize hypoxaemia by providing apnoeic
oxygenation during laryngoscopy. Nasal cannulae may need to be
removed if intubation fails because they prevent a good seal between
the mask and the face.
Ketamine is a first-line induction drug in those with cardiovascular

instability. Induction with propofol can cause profound hypotension,
particularly if the patient is hypovolaemic, because it reduces
systemic vascular resistance.
Page 7 of 29

The patient’s lungs were ventilated with a respiratory rate of 26 breaths/

min and a tidal volume of 6 mL/kg of ideal body weight and oxygenated
with a fraction of inspired oxygen (FiO2) of 0.6 and PEEP of 12 cmH2O.
Monitoring was instituted with central venous and arterial access with a
pulse contour cardiac output (PiCCO) system. A passive leg raise test was
performed to access fluid responsiveness (see Case 1) [7, 8]. This
confirmed the need for further fluid resuscitation, which was continued
with crystalloid boluses. A noradrenaline infusion was commenced
targeting a mean arterial pressure of 65 mmHg, urine output of greater
than 0.5 mL/kg/min, and haemoglobin value higher than 70 g/L [9, 10,
11].
EXPERT COMMENT
In the initial stages of sepsis, it is vital to achieve cardiovascular

stability; this is usually achieved with a combination of fluid
resuscitation and vasopressor and inotropic support. If substantial
quantities of crystalloid are required, the Surviving Sepsis Campaign
guidelines collaborators suggest also using albumin [1, 12, 13].
Excessive fluid resuscitation may impair respiratory function and gas
exchange and once cardiovascular stability has been achieved, close
attention is paid to fluid balance. Consider aiming for a negative fluid
balance as early as after the first 48 hours and consider the early use
of renal replacement therapy to achieve this [14, 15, 16, 17, 18]. For
more detail, see Case 1.
LEARNING POINT Principles of management
The principles of management of acute respiratory failure are those of

resuscitation, with diagnosis and treatment of the specific underlying
cause, while also providing supportive care to maintain oxygenation
and prevent further harm:
1. Resuscitate, diagnose, and treat as clinically relevant:

a. Resuscitate. Administer oxygen to treat hypoxaemia.
Implement sepsis bundle [19].
b. Diagnosis. Targeted history and examination and specific
investigations including arterial blood gas analysis, blood
tests, microbiological assessment, and imaging (CXR/CT) to
identify the cause.
c. Treat. Treat the underlying cause where appropriate, for
example:
i. Antibiotics for pneumonia
ii. Analgesia/fixation of a flail chest
Page 8 of 29

iii. Intercostal drain insertion for pneumothorax or

pleural effusion
2. Good supportive care:

a. Early nutrition: enteral whenever possible
b. Attention to fluid and electrolyte balance
c. Glycaemic control
d. Minimize use of sedation
e. Regular assessment and management of pain, agitation,
and delirium (PAD guidelines) [20]
f. Skin and pressure area care
3. Minimize harm:
a. Lung protective ventilation
b. Sedation break and spontaneous breathing trial [21, 22]
c. Early mobilization
d. Deep vein thrombosis and stress ulcer prophylaxis
e. Prevent ventilator-associated pneumonia and catheter-
related bloodstream infections
CLINICAL TIP How to establish a patient with acute

respiratory failure on a ventilator
Principles include the following [23, 24]:
1. Maintain adequate oxygenation:

a. Partial pressure of oxygen (PaO2) = 8–9 kPa or arterial
blood oxygen saturation of 88–95%.
b. Titrate PEEP according to the PEEP and FiO2 algorithm
that was used by the National Institutes of Health Acute
Respiratory Distress Syndrome (ARDS) Network tidal
volume trial (Table 3.3) [25, 26].
2. Accept permissive hypercapnia but maintain pH at 7.20 or

higher (excluding patients with raised intracranial pressure).
3. Avoid ventilator-induced lung injury by adopting lung
protective ventilation strategies.
Page 9 of 29

Table 3.3 Lower and higher PEEP/FiO2 combination tables
Lower PEEP/FiO2 combination
FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18–24
Higher PEEP/FiO2 combination
FiO2 0.3 0.3 0.4 0.4 0.5 0.5 0.5 0.6 0.7 0.8 0.8 0.9 1.0
PEEP 12 14 14 16 16 18 20 20 20 20 22 22 22–24
PEEP, positive end-expiratory pressure in cmH2O.
Source: data from Sahetya SK., et al. Fifty Years of Research in ARDS. Setting Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome.
American Journal of Respiratory Critical Care Medicine. 195:1429–1438. Copyright © 2017 American Thoracic Society.
Page 10 of 29
and Legal Notice).
LEARNING POINT Lung trauma
In acute respiratory failure, use a lung protective ventilation strategy

as demonstrated in the ARDS Network tidal volume trial [27]. This
ventilation strategy is based on the principle that traditional
mechanical ventilation injures the diseased lung by one or more of
five mechanisms [24, 28]:
1. Volutrauma—alveolar damage caused by excessive tidal

volumes.
2. Barotrauma—alveolar damage caused by excessive inflation
pressures.
3. Atelectrauma—alveolar damage caused by cyclical opening
and closing, causing a sheering effect and subsequent damage.
4. Oxygen toxicity—damage caused by high FiO2 concentration
and resulting free oxygen radicals.
5. Biotrauma—worsening lung injury and distant organ
dysfunction caused by inflammatory mediators and the
translocation of pathogens from ventilator-induced lung injury.
EXPERT COMMENT Determinants of oxygenation
Oxygenation is a product of the FiO2 and the functional residual

capacity (FRC) of the lung. The FRC is the volume of lung open at the
end of expiration; this is determined partly by PEEP and reflected in
the mean airway pressure. Mean airway pressure and FiO2 determine
oxygenation and minute ventilation determines carbon dioxide (CO2)
clearance. Use of inverse ratio ventilation will increase mean airway
pressure and therefore oxygenation. Volutrauma is minimized by
setting a low tidal volume (6 mL/kg predicted body weight) and
offsetting it with a relatively high respiratory rate (up to 35 breaths/
min) while accepting a high partial pressure of CO2 and relatively low
pH so long as it does not cause cardiovascular instability.
LEARNING POINT Key studies
A lung protective ventilation strategy using a low tidal volume (4–8

mL/kg predicted body weight) and plateau airway pressure less than
30 cmH2O is consistent with the clinical practice guidelines of the
Page 11 of 29

American Thoracic Society/European Society of Intensive Care

Medicine/Society of Critical Care Medicine [23].
Ventilation with lower tidal volumes as compared with

traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome (ARDS Network
study)
● Multicentre randomized controlled trial (RCT) [27], n = 861.

● Acute lung injury entry criteria.
● Tidal volume of 6 mL/kg (peak inspiratory pressure (PIP) <30
cmH2O) versus 12 mL/kg (PIP <50 cmH2O).
● PEEP algorithm same for both groups (shown in the upper
section of Table 3.3).
● The lower tidal volume group had:
◦ a lower rate of death before discharge home (31.0% vs 39.8%;

P = 0.007)
◦ higher rates of breathing without assistance by day 28 (65.7%
vs 55.0%; P <0.001)
◦ more ventilator-free days (over days 1–28) (12 ± 11 vs 10 ±
11; P = 0.007)
◦ more days without failure of non-pulmonary organs or
systems (during days 1–28) (15 ± 11 vs 12 ± 11; P = 0.006).
● In patients with acute lung injury and ARDS, mechanical

ventilation with lower tidal volumes results in decreased mortality
and an increased number of ventilator-free days.
Higher versus lower positive end-expiratory pressures

in patients with the acute respiratory distress
syndrome (ALVEOLI study)
● Multicentre RCT [25], n = 549.

● Acute lung injury and ARDS entry criteria.
● Assigned to receive mechanical ventilation at a tidal volume of 6
mL/kg and PIP less than 30 cmH2O with lower or higher PEEP
values, set according to different tables of combinations of PEEP
and FiO2.
● PEEP values (days 1–4): 8.3 ± 3.2 cmH2O (lower PEEP) versus
13.2 ± 3.5 cmH2O (higher PEEP) (P <0.001).
● No difference in rate of death before hospital discharge (24.9%
(lower PEEP) vs 27.5% (higher PEEP); P = 0.48) or number of days
of unassisted breathing (14.5 ± 10.4 days (lower PEEP) vs 13.8 ±
10.6 days (higher PEEP); P = 0.50).
Page 12 of 29

● In this study of patients with acute lung injury and ARDS who
received lung protective mechanical ventilation, clinical outcomes
are similar whether lower or higher PEEP values were used.
Two other studies, the Lung Open Ventilation (LOV) study and
Expiratory Pressure (Express) study, which compared different PEEP
strategies also failed to demonstrate any difference in mortality
among patients with ARDS [29, 30]. These three studies may have
failed to show any difference in mortality because they recruited
heterogeneous cohorts with ARDS ranging from mild to severe based
on the recent Berlin criteria (see later discussion) [31]. A subsequent
individual patient meta-analysis found that higher PEEP values
improved survival among those with moderate or severe ARDS (PaO2/
FiO2 (P/F) ≤200 mmHg) but might increase mortality among those
with mild ARDS [26, 32].
EXPERT COMMENT
There have been many criticisms made of the ARDS Network study,
but most importantly that the control arm included a target tidal
volume that was higher than the standard of care at the time. Thus, a
safe tidal volume (6 mL/kg) was compared with an unsafe tidal
volume (10–12mL/kg); instead, the study should have compared tidal
volumes of 6 mL/kg with 8 mL/kg.
Nevertheless, the study demonstrated a low mortality rate when

patients with ARDS are ventilated with a lower tidal volume and
patients ventilated with lower tidal volume had less non-pulmonary
organ failure.
Over the next 12 hours, there was a further deterioration in respiratory

function and the FiO2 was increased to 0.8 aiming for arterial blood
oxygen saturation of at least 92% (Table 3.4).
Table 3.4 Arterial blood gas results
FiO2 0.8
pH 7.39 (7.35–7.45)
PaCO2 (kPa) 6.5 (4.7–6)
PaO2 (kPa) 8.0 (>10)
Page 13 of 29

P/F ratio (kPa) 10 (<13.3 is severe ARDS)
In light of the deteriorating gas exchange, a CT chest was undertaken to

evaluate the pulmonary infiltrates, and to exclude pleural pathology such
as a large effusion, pneumothorax, or pulmonary embolism. The CT scan
showed bilateral extensive ground-glass infiltrates with bibasal
consolidation and bilateral small pleural effusions (Figure 3.2). There was
no evidence of pneumothorax.
Figure 3.2
CT chest, showing bilateral extensive infiltrates (ground glass) with
bibasal consolidation and bilateral small pleural effusions.
The patient was turned prone at this stage, and prone ventilation was
continued for 16-hour periods (16:00–08:00) for 5 days.
LEARNING POINT Acute respiratory distress

syndrome
ARDS is an acute, diffuse, inflammatory lung condition causing injury

to the lung parenchyma, increased pulmonary vascular permeability,
and subsequent acute severe hypoxaemia [33]. Despite advances in
understanding of the pathophysiology and management of ARDS,
there are few specific treatment options and it remains associated
with a high mortality rate [33].
Diagnosis
The most recently updated definition of ARDS was generated by a
panel of experts in 2011 and is termed the Berlin definition. It
describes four key features required to diagnose ARDS [31]:
1. Acute onset, over 1 week or less.

2. Presence of bilateral opacities consistent with pulmonary
oedema on CXR or CT.
Page 14 of 29

3. P/F ratio less than 300 mmHg (<40 kPa) with a minimum of 5
cmH2O PEEP.
4. Must not be fully explained by cardiac failure or fluid
overload.
A 1994 consensus conference previously defined acute lung injury as

a P/F ratio of 26.6–40 kPa, ARDS as a P/F ratio less than 26.6 kPa,
and severe ARDS as a P/F ratio less than 13.3 kPa [34]. The Berlin
definition replaces these terms with mild, moderate, or severe ARDS
(Table 3.5).
Table 3.5 The Berlin definition
P/F ratio P/F ratio Mortality

(mmHg) with (kPa) with (%)
PEEP ≥ 5 PEEP ≥ 5
cmH2O cmH2O
Mild 200–300 26.6–40 27
Moderate 100–200 13.3–26.6 32
Severe <100 <13.3 45
P/F, PaO2/FiO2.
Aetiology
The causes of ARDS are considered in two broad categories—direct/
pulmonary causes (direct injury to the lung) and indirect/
extrapulmonary causes (secondary to systemic injuries). Examples
include:
Direct/pulmonary causes Pneumonia
Aspiration of gastric contents
Pulmonary contusion
Inhalational injury
Fat embolism
Indirect/extrapulmonary Sepsis
causes
Severe trauma
Page 15 of 29

Acute pancreatitis
Burns
Acute drug reactions
Transfusion reactions/
transfusion related acute lung
injury (TRALI)
Pathophysiology
Generally, ARDS follows four phases, irrespective of the cause [33]:
1 The acute or exudative phase—starts early and lasts for up to 7

days. It involves disruption of the alveolar capillary membrane,
infiltration by inflammatory cells, haemorrhage, and leakage of
protein-rich fluid into the alveoli. This causes hypoxaemia and
pulmonary infiltrates on the CXR.
2 The subacute or proliferative phase—occurring from day 5.
Proliferation of inflammatory cells and type 2 alveolar cells leads
to interstitial fibrosis, ongoing hypoxaemia, and reduced lung
compliance.
3 The chronic or fibrotic phase—infiltration with fibroblasts and
subsequent fibrosis, causes loss of the normal lung structure and
worsening lung compliance.
4 The resolution phase—may take up to several weeks to start
but results in slow repair and restoration of the normal lung
architecture.
These pathophysiological changes do not occur homogeneously in the

lungs, with different alveoli in different phases of injury at the same
time. There may also be inflammation in other areas of the body,
causing shock and injury or dysfunction of other organs, resulting in
multiorgan failure. Mortality associated with severe ARDS is up to
45% in some studies and is invariably due to multiorgan failure.
The patient continued to receive infusions of propofol and alfentanil and

was commenced on an infusion of atracurium (a neuromuscular blocking
drug (NMBD)) for the first 48 hours. Once the infusion of atracurium was
discontinued, she received a sedation hold in the morning when she was
turned supine. Sedation was recommenced to facilitate safe turning from
the prone position.
The patient’s inflammatory markers (temperature, white blood count, and

CRP) increased over the next 3 days. On day 2 of her ICU stay, her
urinary antigen was positive for pneumococcal pneumonia. She was
Page 16 of 29

maintained on dual antibiotic therapy with IV co-amoxiclav and

clarithromycin for the first 72 hours. This spectrum of this therapy was
later narrowed to IV benzyl penicillin 2.4 g 6-hourly. She received
antibiotics for a total of 7 days.
LEARNING POINT Usual organisms
Common microbiology aetiology of community-acquired pneumonia in

the UK [3, 4, 35] includes:
Bacteria Viruses
Streptococcus pneumoniae Influenza viruses
Haemophilus influenza Rhinovirus
Staphylococcus aureus Parainfluenza viruses
Klebsiella pneumoniae Adenovirus
Pseudomonas aeruginosa Human metapneumovirus
Mycoplasma pneumoniae
Moraxella catarrhalis
Legionella pneumoniae
Gram-negative organisms
Mycobacterial tuberculosis
LEARNING POINT Community-acquired pneumonia:

specific pathogens and epidemiological conditions and
risk factors
1. Chronic obstructive pulmonary disease/smoking: Haemophilus

influenza, Pseudomonas aeruginosa, Streptococcus pneumoniae,
and Moraxella catarrhalis.
2. Alcoholism: Streptococcus pneumoniae, Klebsiella
pneumoniae, oral anaerobes, and Mycobacterium tuberculosis.
Page 17 of 29

3. HIV early stages: Haemophilus influenza, Streptococcus

pneumoniae, and Mycobacterium tuberculosis.
4. HIV late stages: early-stage pathogens plus Pneumocystis
jirovecii (PCP), Cryptococcus, atypical mycobacterial disease,
Haemophilus influenza, and Pseudomonas aeruginosa.
5. IV drug abuse: Staphylococcus aureus, Mycobacterium
tuberculosis, and Streptococcus pneumoniae.
6. Influenza activity in the community: influenza, Staphylococcus
aureus, Streptococcus pneumoniae, and Haemophilus influenza.
Her vasopressor requirement peaked at 36 hours after intubation

(noradrenaline requirement = 0.4 mcg/kg/min). Her cardiovascular
function stabilized over the subsequent 24 hours, enabling weaning of the
noradrenaline. By day 4, a daily negative fluid balance of 500–1000 mL
could be achieved. Fluid input was minimized by rationalizing drug
dilutions and avoiding ‘maintenance fluids’. Her PaO2 improved by day 3
of prone ventilation, with a simultaneous reduction in the FiO2 to 0.5. The
lung protective ventilation strategy was maintained, including prone
ventilation for a total of 5 days.
LEARNING POINT Conservative approach to fluid

management
IV fluid management in the patient with ARDS can be a significant

challenge. While fluid infusion may increase cardiac output and
improve end-organ perfusion, it may also worsen pulmonary gas
exchange. Patients with ARDS have, by definition, non-cardiogenic
pulmonary oedema with an altered capillary permeability. Excessive
IV fluid will increase the capillary hydrostatic pressure and decrease
the oncotic pressure, thereby worsening lung oedema. The benefit of
adopting a conservative approach to fluid therapy was demonstrated
by the Fluids and Catheters Treatment Trial (FACTT) [15], which
compared a conservative fluid strategy (−136 mL cumulative balance
over the first 7 days) with a liberal fluid strategy (+6992 mL
cumulative balance over the first 7 days). This was achieved within
the conservative group with a combination of avoidance of
maintenance fluids and the administration of diuretics. Although
there was no significant difference in mortality, patients in the
conservative fluid group spent less time on a ventilator and had a
shorter ICU stay. This was achieved without an increase in clinically
significant adverse events such as non-pulmonary organ failure. It is
now accepted that when treating ARDS patients, once the fluid
resuscitation phase (rescue and optimization) has been completed, a
Page 18 of 29

conservative approach to fluid therapy can be adopted in the

stabilization and de-escalation phases [17, 18].
LEARNING POINT Rescue therapies in acute

respiratory distress syndrome
Prone positioning
Positioning the patient prone improves alveolar ventilation/perfusion
(V/Q) matching and therefore oxygenation [36, 37]. In ARDS, there is
atelectasis within the posterior and basal (dependent) regions of the
lungs, as demonstrated in the patient’s CT scan (Figure 3.2). These
regions are therefore poorly compliant and difficult to recruit during
ventilation in the supine position. Pulmonary blood flow is maximal in
these dependent regions. Placing the patient prone improves lung
mechanics and oxygenation as well as aiding the clearance of
respiratory secretions. Blood flow remains higher in the dorsal region
of the lungs and as these regions are better ventilated when prone, V/
Q matching is improved. The prone position improves the P/F ratio,
reduces the rate of ventilator-associated pneumonia, and is not
associated with major adverse airway complications. Turning the
patient with moderate to severe ARDS (P/F ratio <20 kPa) prone early
on (within 24 hours of diagnosis) and for prolonged durations (at least
16 hours daily) can improve survival [36, 37].
Prone positioning in severe acute respiratory distress

syndrome (PROSEVA study)

● Severe ARDS (P/F ratio <20 kPa, FiO2 ≥0.6, PEEP ≥5 cmH2O,
and tidal volume 6 mL/kg) for less than 24 hours.
● After checking eligibility, a 12–24-hour stabilization period was
observed and inclusion was confirmed only at the end of this
period.
● Assigned to receive prone-positioning sessions of at least 16
hours or left in supine position.
● The proned group had:
◦ a lower 28-day mortality (16.0% vs 32.8%; P <0.001)

◦ a lower 90-day mortality (23.6% vs 41.0%; P <0.001)
◦ no increase in complications compared to the supine group—
in fact the incidence of cardiac arrests was higher in the supine
group.
Page 19 of 29

● In patients with severe ARDS, early prone ventilation for

prolonged durations significantly decreases the 28-day and 90-day
mortality.
Neuromuscular blockade
Studies have shown that the addition of an infusion of a NMBD
improves survival in patients with severe ARDS without increasing
muscle weakness [38, 39]. The mechanism for this benefit is unclear;
however, there are several possible advantages. Use of a NMBD may
improve patient:ventilator synchrony, which may reduce ventilator-
associated lung injury. It also helps reduce the excessive tidal
volumes caused by an increased respiratory drive secondary to
alveolar hypoxia, permissive hypercapnia, anxiety, and lung reflexes,
which can also cause barotrauma and volutrauma. In a proof-of-
concept study, partial neuromuscular blockade during partial
ventilator support facilitated lung protective ventilation [40].
Spontaneous ventilation with excessive tidal volumes is now
considered harmful in patients with severe ARDS [41]. NMBDs are
also thought to have a direct anti-inflammatory effect, decreasing
lung or systemic inflammation and subsequent organ dysfunction and
failure—a common complication of ARDS. While NMBDs are
associated with muscle weakness [42], use for short durations does
not increase muscle weakness significantly and their benefits in terms
of improved survival, improved lung recruitment, decreased
ventilator-associated lung injury, and enabling both prone positioning,
permissive hypercapnia, and non-physiological ventilation modes (e.g.
inverse ratio) outweigh any risks in patients with severe ARDS.
Neuromuscular blockers in early acute respiratory

distress syndrome (ACURASYS study)

● Severe ARDS (P/F ratio <150 mmHg, PEEP ≥5 cmH2O, and tidal
volume 6–8 mL/kg) for less than 48 hours.
● Infusion of cisatracurium versus placebo for 48 hours.
● The cisatracurium group had:
◦ a lower 28-day mortality (23.7% vs 33.3%; P = 0.05)

◦ a lower 90-day mortality (31.6% vs 40.7%; P = 0.05).
● No significant difference in the rate of ICU-acquired paresis

between the two groups.
● Early administration of a NMBD improved 90-day mortality in
patients with severe ARDS without increasing muscle weakness.
Page 20 of 29

EXPERT COMMENT
Many ICUs have adopted standard operating procedures for prone

ventilation. It typically requires one person to control the head,
ensure the airway is secure, and ensure that central lines are not
pulled out during the turn. It is common practice to secure the patient
with lower and upper sheets (this has several regional terms, e.g. the
Cornish pasty technique) and to use a sliding sheet—it normally
requires two people either side of the patient in addition to the
person controlling the head. Complications of prone ventilation
include displacement of the airway, intravascular catheters, and other
devices during the turn, and pressure sores. If NMBDs are used to
facilitate ventilation in the prone position, use of a bispectral index
(BIS) monitor will help to ensure that sedation is adequate (indicated
by BIS values in the range 50–70).
On day 6, the patient’s FiO2 had decreased to 0.3 with PaO2 consistently
greater than 9 kPa over the preceding 18 hours. She was also weaned
from a synchronized intermittent mandatory ventilation mode to pressure
support ventilation. Her heart rate was less than 90 bpm, her blood
pressure was stable without vasopressors, and fluid balance was negative
for more than 48 hours. The patient underwent a sedation break and
became agitated; Confusion Assessment Method (CAM)-ICU scoring
confirmed delirium. Her sedation was recommenced at half the original
rate and despite reassurance and reorientation by the nursing staff, she
required nasogastric quetiapine 25 mg twice a day and IV clonidine 1.0
mcg/kg/hour. Over the course of the day, her sedation with propofol and
alfentanil was weaned further and by later that evening she required
minimal sedation. She was mobilized to the edge of her bed by the
physiotherapist. On the evening review, she was commenced on IV
dexamethasone to facilitate a trial of extubation the following morning.
Dexamethasone was started to reduce cord oedema and help reduce the
risk of post-extubation respiratory failure [43].
EXPERT COMMENT
The incidence of post-extubation stridor is about 5%. Patients with a

reduced cuff leak are at the highest risk of post-extubation stridor
and respiratory failure. Pretreatment with IV steroids, commenced 12
hours before a planned extubation, reduces the incidence of post-
extubation laryngeal oedema and reintubation in this subgroup of
patients [43].
Page 21 of 29

On day 7 of her stay, she remained afebrile, her inflammatory markers

had decreased, she was haemodynamically stable, and breathing an FiO2
of 0.25. On a further sedation hold she was found to be obeying
commands and moving all four limbs appropriately but CAM-ICU scoring
still confirmed delirium. The clonidine and quetiapine were continued.
She was then weaned from pressure support with a trial of spontaneous
breathing with continuous positive airways pressure at 5 cmH2O. She
tolerated this for 30 min without any signs of respiratory distress and was
extubated to high-flow nasal oxygen and remained on this over the next
24 hours, before being weaned to supplemental oxygen via a nasal
cannula aiming for a peripheral arterial oxygen saturation of 94–98%.
LEARNING POINT Weaning the patient from

mechanical ventilation—spontaneous breathing trials
The ability to successfully wean the patient from mechanical

ventilation is dependent on several factors [21, 22, 44]; these include:
● resolution of the underlying cause of respiratory failure

● adequate conscious level, without problematic delirium after
discontinuation of deep sedation and NMBDs, to enable protection
of the airway after extubation
● adequate arterial oxygenation breathing a low FiO2 (<0.5) and
PEEP less than or equal to 5 cmH2O
● adequate respiratory muscle function and cough/clearance of
secretions
● haemodynamic stability with minimal inotropic and/or
vasopressor agent.
Once identified, patients should undergo a spontaneous breathing

trial to simulate those respiratory conditions that would occur
following extubation, and to observe their ability to cope. Successful
completion of spontaneous breathing trial(s) increases the likelihood
of the patient successfully separating from mechanical ventilation,
and studies have shown that approximately 75% of patients who
complete a spontaneous breathing trial can be extubated without the
need for reintubation. The rate of successful weaning is higher with
spontaneous breathing trials than with more modern ventilator
weaning techniques. In a comparison of four methods of weaning
patients, daily trials of spontaneous breathing resulted in extubation
three times more quickly than with synchronized intermittent
mandatory ventilation and twice as quickly than with pressure-
support ventilation [22]. Both a once-daily trial or the performance of
multiple daily trials appear to be equally successful, and the trial can
be completed with the patient breathing spontaneously on the
ventilator (continuous positive airways pressure) with or without a
Page 22 of 29

low level of pressure support or removed from the ventilator and

breathing on a T-piece. The spontaneous breathing trial duration can
vary from 30 to 120 min, and should be discontinued if there is any
evidence of respiratory distress, such as:
● respiratory rate greater than 40 breaths/min or less than 6

breaths/min for 5 min or longer
● arterial blood oxygen saturation less than 92%
● heart rate greater than 140 bpm or less than 60 bpm or greater
than 25% above baseline
● systolic blood pressure greater than 40 mmHg above baseline
● agitation, anxiety, or discomfort.
The patient was reviewed by the physiotherapist and was mobilized from
bed to chair. She received a total of three doses of IV dexamethasone and
completed a total of 7 days of antibiotics for her pneumonia. Her arterial
and central venous cannulae were removed and a new peripheral venous
cannula was inserted. She was weaned from IV clonidine. Her swallow
was assessed and confirmed safe; she was then encouraged to have sips
of fluids. A carefully planned dietary programme was instituted by the
ICU dietician before stopping nasogastric feeding.
Over the next 48 hours, quetiapine was stopped once she was no longer
delirious and she continued to mobilize on the ICU with the help of the
nurses and physiotherapist.
LEARNING POINT Non-resolving pneumonia
Normal resolution of pneumonia is difficult to define. Hospitalized

patients with community-acquired pneumonia typically show signs of
improvement within 3–5 days of treatment. Normal resolution of
pneumonia depends on multiple factors including host factors,
comorbidities, aetiological factors, and development of complications.
About 15% of patients hospitalized with pneumonia develop non-
resolving pneumonia and about 20% are due to non-infectious causes.
Patients should have an improvement in tachycardia, oxygenation,

and hypotension in 2–3 days, symptoms in 3–5 days, and cough and
fatigue in 10–14 days.
Causes of non-resolving pneumonia
● Age: older than 50 years, about 30% have resolution of X-rays at

1 month
Page 23 of 29

● Comorbidities: alcoholism, immunocompromised state (e.g. long-

term steroids, diabetes mellitus, AIDS)
● Misdiagnosis: tuberculosis, fungal infections, Nocardia, and
Actinomyces
● Bacterial resistance
● Complications:
◦ Pulmonary complications: lung abscess and empyema

◦ Non-pulmonary complications: infective endocarditis, septic
arthritis, osteomyelitis, and discitis
● Non-infectious causes: bronchogenic carcinoma, inflammatory

disease (vasculitis), pulmonary embolism, and drug-induced lung
disease
Diagnostic approach
This includes:
● a thorough history including recent travel, lifestyle, and

assessment of non-infectious causes
● assessment of risk factors: age, comorbidities, severity, and
specific pathogens
● review of specific complications associated with pneumonia
● radiological assessment: CT chest with consideration of
pulmonary angiogram
● repeat laboratory tests including sputum and blood cultures and
urinary antigen evaluation
● bronchoalveolar lavage with or without transbronchial biopsy or
CT-guided biopsy
● lung biopsy: open versus video-assisted.
Discussion
Community-acquired pneumonia can be defined as an acute

infection of the lung parenchyma where the infection is acquired in the
community. The overall incidence in adults is 5.1–6.1 cases per 1000
persons per year and this increases with increasing age. The rates are
higher in men than for women and there are seasonal variations.
Streptococcus pneumoniae is the most frequently identified cause for
community-acquired pneumonia.
Page 24 of 29

Streptococcal pneumonia is a classic cause of lobar consolidation. The

classic presentation is that of fever, chills, cough with rusty sputum, and
pleuritic chest pain with clinical signs of consolidation (increased vocal
fremitus and bronchial breathing). The diagnosis is often confirmed by
blood cultures or a positive urinary antigen. The optimum antibiotic
regimen depends upon the presence of comorbidities, need for
hospitalization, and presence of antibiotic resistance. In the UK, most
empiric antibiotic regimens contain beta lactams and are often effective
against streptococcal pneumonia (consult your microbiologist for local
susceptibility patterns). A typical duration of antibiotics is 5–7 days in
mild–moderate cases and up to 10–14 days in severe cases. Pulmonary
complications of streptococcal pneumonia include empyema, necrotizing
pneumonia, lung abscess, and ARDS.
Acute respiratory distress syndrome manifests as acute-onset (<7 days),

hypoxic respiratory failure with bilateral lung infiltrates often due to a
clear precipitating factor. The alveolar injury and inflammation can be of
alveolar origin (e.g. pneumonia) or endothelial/systemic in origin (e.g.
acute pancreatitis). Over the past three decades there have been
numerous attempts to define ARDS. The 2012 Berlin definition was
validated based on hypoxaemia and bilateral pulmonary infiltrates in over
4000 patients. The Berlin definition stipulates an onset of less than 7
days, that the patient is ventilated with PEEP at least at 5 cmH2O, and
that it can be diagnosed in the presence of cardiac failure. It also
includes, for the first time, chest CT as an alternative form of imaging for
lung infiltrates.
The principles of management of acute respiratory failure include

resuscitation, diagnosis, and treatment of the underlying disease. Lung
protective mechanical ventilation and the avoidance of fluid overload are
fundamental to the successful management of ARDS. Patients with severe
hypoxaemia can be managed with early short-term use of neuromuscular
blockade, prone position ventilation, or extracorporeal membrane
oxygenation. The use of inhaled nitric oxide is rarely indicated and both
beta2 agonists and late corticosteroids should be avoided. A detailed
discussion of extracorporeal membrane oxygenation and other rescue
therapies is covered in a recent review [33]. Despite the recent advances,
mortality from ARDS remains greater than 30%.
It is vital to have a sound working knowledge of the common causes

of community-acquired pneumonia, and the local and national
recommendations for its treatment. It is important to have a strategy
for the management of acute respiratory failure which includes initial
resuscitation, a structured approach to investigations and treatment
Page 25 of 29

of the underlying disease, and measures to provide organ support and

to minimize healthcare associated complications.
References
1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign:
international guidelines for management of sepsis and septic shock: 2016.
Intensive Care Med. 2017;43:304–77.
2. Daniels R, Nutbeam T, McNamara G, Galvin C. The sepsis six and the

severe sepsis resuscitation bundle: a prospective observational cohort
study. Emerg Med J. 2011;28:507–12.
3. Prina E, Ranzani OT, Torres A. Community-acquired pneumonia.

Lancet. 2015;386:1097–108.
4. Musher DM, Thorner AR. Community-acquired pneumonia. N Engl J

Med. 2014;371:1619–28.
5. Baron EJ, Miller JM, Weinstein MP, et al. A guide to utilization of the
microbiology laboratory for diagnosis of infectious diseases: 2013
recommendations by the Infectious Diseases Society of America (IDSA)
and the American Society for Microbiology (ASM). Clin Infect Dis.
2013;57:e22–121.
6. Metlay JP, Fine MJ. Testing strategies in the initial management of

patients with community-acquired pneumonia. Ann Intern Med.
2003;138:109–18.
7. Monnet X, Teboul JL. Passive leg raising. Intensive Care Med.

2008;34:659–63.
8. Monnet X, Marik P, Teboul JL. Passive leg raising for predicting fluid
responsiveness: a systematic review and meta-analysis. Intensive Care
Med. 2016;42:1935–47.
9. Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based
care for early septic shock. N Engl J Med. 2014;370:1683–93.
10. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed
resuscitation for septic shock. N Engl J Med. 2015;372:1301–11.
11. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al.
Goal-directed resuscitation for patients with early septic shock. N Engl J
Med. 2014;371:1496–506.
12. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients

with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–21.
Page 26 of 29

13. Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a

resuscitation fluid for patients with sepsis: a systematic review and meta-
analysis. Crit Care Med. 2011;39:386–91.
14. Martin GS, Mangialardi RJ, Wheeler AP, Dupont WD, Morris JA,
Bernard GR. Albumin and furosemide therapy in hypoproteinemic
patients with acute lung injury. Crit Care Med. 2002;30:2175–82.
15. National Heart, Lung, and Blood Institute Acute Respiratory Distress
Syndrome Clinical Trials Network. Comparison of two fluid-management
strategies in acute lung injury. N Engl J Med. 2006;354:2564–75.
16. Semler MW, Wheeler AP, Thompson BT, et al. Impact of initial central
venous pressure on outcomes of conservative versus liberal fluid
management in acute respiratory distress syndrome. Crit Care Med.
2016;44:782–9.
17. Silversides JA, Major E, Ferguson AJ, et al. Conservative fluid

management or deresuscitation for patients with sepsis or acute
respiratory distress syndrome following the resuscitation phase of critical
illness: a systematic review and meta-analysis. Intensive Care Med.
2017;43:155–70.
18. Hoste EA, Maitland K, Brudney CS, et al. Four phases of intravenous
fluid therapy: a conceptual model. Br J Anaesth. 2014;113:740–7.
19. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and
mortality during mandated emergency care for sepsis. N Engl J Med.
2017;376:2235–44.
20. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the
management of pain, agitation, and delirium in adult patients in the
intensive care unit. Crit Care Med. 2013;41:263–306.
21. Girard TD, Alhazzani W, Kress JP, et al. An official American Thoracic
Society/American College of Chest Physicians clinical practice guideline:
liberation from mechanical ventilation in critically ill adults.
Rehabilitation protocols, ventilator liberation protocols, and cuff leak
tests. Am J Respir Crit Care Med. 2017;195:120–33.
22. Esteban A, Frutos F, Tobin MJ, et al. A comparison of four methods of

weaning patients from mechanical ventilation. Spanish Lung Failure
Collaborative Group. N Engl J Med. 1995;332:345–50.
23. Fan E, Del Sorbo L, Goligher EC, et al. An official American Thoracic
Society/European Society of Intensive Care Medicine/Society of Critical
Care Medicine clinical practice guideline: mechanical ventilation in adult
patients with acute respiratory distress syndrome. Am J Respir Crit Care
Med. 2017;195:1253–63.
24. Goligher EC, Ferguson ND, Brochard LJ. Clinical challenges in

mechanical ventilation. Lancet. 2016;387:1856–66.
Page 27 of 29

25. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower
positive end-expiratory pressures in patients with the acute respiratory
distress syndrome. N Engl J Med. 2004;351:327–36.
26. Sahetya SK, Goligher EC, Brower RG. Fifty years of research in ARDS.
Setting positive end-expiratory pressure in acute respiratory distress
syndrome. Am J Respir Crit Care Med. 2017;195:1429–38.
27. The Acute Respiratory Distress Syndrome Network. Ventilation with

lower tidal volumes as compared with traditional tidal volumes for acute
lung injury and the acute respiratory distress syndrome. N Engl J Med.
2000;342:1301–8.
28. Pinhu L, Whitehead T, Evans T, Griffiths M. Ventilator-associated lung

injury. Lancet. 2003;361:332–40.
29. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low
tidal volumes, recruitment maneuvers, and high positive end-expiratory
pressure for acute lung injury and acute respiratory distress syndrome: a
randomized controlled trial. JAMA. 2008;299:637–45.
30. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure

setting in adults with acute lung injury and acute respiratory distress
syndrome: a randomized controlled trial. JAMA. 2008;299:646–55.
31. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory
distress syndrome: the Berlin Definition. JAMA. 2012;307:2526–33.
32. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-

expiratory pressure in patients with acute lung injury and acute
respiratory distress syndrome: systematic review and meta-analysis.
JAMA. 2010;303:865–73.
33. Sweeney RM, McAuley DF. Acute respiratory distress syndrome.

Lancet. 2016;388:2416–30.
34. Bernard GR, Artigas A, Brigham KL, et al. The American-European

Consensus Conference on ARDS. Definitions, mechanisms, relevant
outcomes, and clinical trial coordination. Am J Respir Crit Care Med.
1994;149:818–24.
35. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the
management of community acquired pneumonia in adults: update 2009.
Thorax. 2009;64 Suppl. 3:iii1–55.
36. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe

acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–68.
37. Beitler JR, Shaefi S, Montesi SB, et al. Prone positioning reduces
mortality from acute respiratory distress syndrome in the low tidal
volume era: a meta-analysis. Intensive Care Med. 2014;40:332–41.
Page 28 of 29

38. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in

early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–
16.
39. Alhazzani W, Alshahrani M, Jaeschke R, et al. Neuromuscular blocking

agents in acute respiratory distress syndrome: a systematic review and
meta-analysis of randomized controlled trials. Crit Care. 2013;17:R43.
40. Doorduin J, Nollet JL, Roesthuis LH, et al. Partial neuromuscular

blockade during partial ventilatory support in sedated patients with high
tidal volumes. Am J Respir Crit Care Med. 2017;195:1033–42.
41. Yoshida T, Fujino Y, Amato MB, Kavanagh BP. Fifty years of research
in ARDS. Spontaneous breathing during mechanical ventilation. Risks,
mechanisms, and management. Am J Respir Crit Care Med.
2017;195:985–92.
42. Kress JP, Hall JB. ICU-acquired weakness and recovery from critical
illness. N Engl J Med. 2014;370:1626–35.
43. Francois B, Bellissant E, Gissot V, et al. 12-h pretreatment with

methylprednisolone versus placebo for prevention of postextubation
laryngeal oedema: a randomised double-blind trial. Lancet.
2007;369:1083–9.
44. McConville JF, Kress JP. Weaning patients from the ventilator. N Engl J
Med. 2012;367:2233–9.
Page 29 of 29

Early management of multi-trauma

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Early management of multi-trauma
Author(s): Marius Rehn
DOI: 10.1093/med/9780198814924.003.0004
Expert commentary by David J. Lockey
Case history
A 22-year-old male cyclist was hit from the right side by a lorry
while crossing a busy road junction. The cyclist was trapped underneath
the lorry and could not be reached by bystanders. Paramedic-staffed
ground emergency medical services (EMS) and a doctor-staffed
helicopter EMS were immediately dispatched to the scene. On arrival, the
patient was found to be clammy and agitated with a Glasgow Coma Scale
(GCS) score of 12 (E3, V4, M5).
EXPERT COMMENT
Cyclists are very vulnerable at junctions and several road safety

campaigns have attempted to introduce initiatives to improve safety.
These include awareness campaigns, alteration of road junction
Page 1 of 23
layouts, and modifications to large vehicles. Despite this, accidents

still occur and cyclists are vulnerable particularly to large vehicles
which can transfer huge energy and devastating injury at low speeds.
LEARNING POINT Epidemiology of multi-trauma
Globally, over 15,000 people die daily as a consequence of injuries,

and many more become permanently or temporarily disabled [1, 2, 3].
The global trauma burden represents 10% of the world’s deaths and
is an increasing health problem that causes incalculable suffering for
individuals, families, and societies [4]. Almost twice as many men as
women die from injuries, which are the leading cause of death among
those aged 5–44 years. Approximately one-quarter of these deaths
result from road traffic collisions and almost one-quarter from suicide
and homicide. Other main causes of fatal injury include falls,
drowning, and war, with considerable geographical variation. Road
traffic injuries are the most common cause of death between the ages
of 15 and 29, whereas falls are a leading cause of fatal injury in the
elderly. More than 90% of injury deaths occur in low- and middle-
income countries, where the healthcare systems are often less
resourced to cope with the challenges [5]. Although the death toll is
largest among the poor, injuries also constitute a major public health
problem in high-income European countries with an annual injury
mortality rate approaching 50 per 100,000.
The patient was extricated by fire service personnel using hydraulic jacks
18 min after helicopter EMS arrival. The patient had partial airway
obstruction and noisy breathing and two nasopharyngeal airways were
placed together with nasal oxygen cannulae with integrated capnography
and a reservoir oxygen mask delivering 15 L/min of oxygen. A 16-gauge
intravenous (IV) cannula was placed in the patient’s right antecubital
fossa. The patient became more alert and complained of difficulty in
breathing and of severe pain in the abdomen, pelvis, and both legs. Two
20 mg IV boluses of ketamine were administered. In-line immobilization
of the neck was maintained during extrication.
EXPERT COMMENT
Cervical spine immobilization has long been a key component of early

trauma management. Guidelines still emphasize immobilization but
other factors may influence outcome (e.g. airway obstruction or rapid
extrication) and take priority over immobilization [6, 7]. Patients who
have been intubated can be safely transported in the supine position.
Where intubation cannot be carried out before transfer to hospital
Page 2 of 23

and patients have a decreased level of consciousness, there is a

potential conflict between cervical spine immobilization in the supine
position and airway patency. Removal of the front component of a
collar prior to intubation (with manual in-line stabilization) is
standard practice. In the unconscious or sedated patient on the
intensive care unit (ICU), cervical spine immobilization can be safely
removed once computed tomography (CT) scanning has excluded
unstable injury and this should be done to reduce the risk of collar-
related venous compression and pressure injuries.
LEARNING POINT Analgesia and sedation
Trauma patients should have their analgesic needs promptly assessed

and addressed at all stages of the trauma pathway. Potential masking
of clinical signs is not a reason to withhold pain relief. Effective use of
analgesia enables clinicians to meet essential clinical end points, such
as reducing blood loss by facilitating fracture manipulation. Judicious
use of analgesics will also facilitate extrication and thereby reduce
time to critical interventions and definitive care. When feasible,
analgesia should be delivered intravenously and titrated to effect. In
circumstances where IV access is difficult, intramuscular injection is
an alternative for some drugs. Continuous waveform capnography,
pulse oximetry, and clinical assessment should be used to detect
airway obstruction, hypoventilation, or bradypnoea in both
spontaneously breathing and ventilated patients. Analgesic and
anxiolytic drugs used in the early phases of multi-trauma care should
ideally have relative haemodynamic stability and acceptable risk
profiles for adverse effects. Drugs with a relatively wide therapeutic
margin are beneficial since patient weight is usually estimated.
Commonly used drugs

Ketamine
An NMDA receptor antagonist classified as a dissociative agent and
known to produce a state resembling general anaesthesia without
cardiorespiratory depression. Ketamine is effective for analgesia,
sedation, and as an induction drug for rapid sequence induction. It
can be used for painful interventions on-scene, in the emergency
department (ED), or on the ICU. Recovery agitation occurs in 10–20%
of patients, but may be minimized with co-administration of
benzodiazepines [8].
Midazolam
A rapid-onset, short-acting benzodiazepine with potent anxiolytic and
hypnotic properties that also reduces skeletal muscle spasticity. It is
reversible and is often used with ketamine to reduce dysphoric
Page 3 of 23

reactions [8]. Side effects include paradoxical reactions and

cardiorespiratory depression.
Morphine
An opioid analgesic with rapid onset, long-lasting analgesic effect,
well-known pharmacokinetics, and reversibility. Side effects include
cardiorespiratory depression and nausea and vomiting. It should be
given with an antiemetic. Incremental IV morphine is the analgesic of
choice in recent UK National Institute for Health and Care Excellence
(NICE) trauma guidelines [9].
Fentanyl
A potent, synthetic opioid analgesic with rapid onset, short duration
of action, and reversibility. Although fentanyl is associated with
cardiorespiratory depression, studies support its safety for analgesia
in normotensive trauma patients [10, 11]. It is equally as effective and
safe as morphine in treating acute pain and is increasingly used as a
first-line drug in trauma analgesia.
The patient’s clothing was completely removed and he was placed

directly on to an orthopaedic scoop stretcher. A pelvic binder was applied
at the level of the greater trochanters as the mechanism of injury and
initial examination raised the possibility of a significant pelvic fracture.
CLINICAL TIP Extrication
Removing the patient’s clothes early on and placing the patient on an

orthopaedic scoop stretcher minimizes movement and clot disruption
prior to imaging and surgery. Spinal boards are extrication devices
and should not be used for transfer. The patient should be removed
from the scoop stretcher in a controlled fashion on arrival at the ED.
LEARNING POINT Pelvic injuries
In patients with major blunt trauma, the incidence of pelvic fractures

is around 10%, with a 7–37% mortality rate that is influenced by type
of fracture and the associated injuries [12, 13, 14]. High-energy
trauma from road traffic collisions and falls are the most common
mechanisms for pelvic fracture [13, 15]. The vascular anatomy of the
pelvis predisposes to a risk of exsanguinating haemorrhage after
fractures. Therapeutic options include endovascular control (usually
by interventional radiologists although temporary control techniques
have been reported in the ED and prehospital care carried out by
Page 4 of 23

non-radiologists [16, 17]) and extraperitoneal packing. Endovascular

haemorrhage control is effective in arterial bleeding (approximately
75% of significant pelvic bleeds are of venous origin) and
angiography is recommended unless immediate open surgery is
required to manage bleeding from other organs. The mechanism of
injury together with clinical and radiological examination are used to
assess the pelvis for instability. Non-invasive pelvic circumferential
compression devices (pelvic binders) should be applied if active
bleeding is suspected [9]. Pelvic binders have been widely integrated
into early resuscitation guidelines and aim to decrease the volume of
the disrupted pelvis and promote haemostasis by splinting fractures.
The presence of a binder also prompts providers to avoid unnecessary
movement of the patient as this may dislodge blood clots and promote
bleeding. The splint is applied directly to skin over the greater
trochanter and is tightened until the alignment appears normal.
Pelvic binders enable laparotomy, but restrict complete assessment of
the perineum. To avoid skin necrosis at bony prominences the splint is
removed, but only after radiological examination excludes instability
or other means of stabilization are initiated. The effect of pelvic
binders on outcome is debated and their role in pelvic vertical shear
fractures remains undefined [18, 19, 20].
LEARNING POINT Packaging and spinal precautions
Patient handling (also known as packaging) is an important part of

the therapeutic process and is relevant in both the pre- and in-
hospital resuscitation phases of care. Gentle patient handling
minimizes spinal movement and reduces the risk of clot disturbance
and further bleeding. It may also reduce heat loss and minimize
cytokine release. Cervical spinal injuries occur in approximately 2%
of all patients with blunt trauma and are more common in the
presence of head injury [21]. Although a thorough log roll is a well-
established part of trauma care, multi-trauma patients undergo
extensive imaging, and an early clinical examination of the back must
be weighed against the risks of clot disturbance in the very unstable
patient. Inserting the two halves of an orthopaedic scoop stretcher on
scene and careful removal through counter-traction after arrival in
the ED enables transportation and transfer with minimal movement
[22, 23]. For head-injured patients with head blocks and tape in place,
the cervical collar can be loosened but left in situ to prevent increases
in intracranial pressure caused by venous obstruction [24]. If the
patient is to be moved, the collar is resecured. If possible, these
patients are positioned with a slight head-up tilt (20°) to assist venous
drainage.
Page 5 of 23

The stretcher was then put into a thermal bag to avoid hypothermia.
EXPERT COMMENT
In cold climates, hypothermia will occur quickly in trauma patients

who have been undressed. General anaesthesia will accelerate the
hypothermia process. Thermal bags may reduce the rate of cooling
but active rewarming will be required to restore the temperature in
patients with established hypothermia.
The vital signs monitor revealed a non-invasive blood pressure of 95/56

mmHg, irregular heart rate of 135 beats/min (bpm), oxygen saturation by
pulse oximetry (SpO2) of 91%, respiratory rate of 16 breaths/min, and
end-tidal carbon dioxide (ETCO2) value of 4.5 kPa. The primary survey
identified crepitus over the left iliac crest and pelvic asymmetry that
suggested a pelvic fracture. The abdomen was rigid, with a left flank
abrasion. The chest had left-sided crepitus with a flail segment, surgical
emphysema, and possible reduced air entry (auscultation was difficult
due to background noise) suggesting a left-sided pneumothorax. The
irregular sinus tachycardia and bruising on the anterior chest wall raised
suspicion of a possible cardiac contusion. There were no external signs of
head injury. During initial assessment, a closed left femoral fracture, a
closed right tibia/fibula fracture, and partial degloving of the right arm
were also noted. A further 10 mg of ketamine and 2 mg of midazolam
were administered IV. The femoral fracture was reduced using a traction
device.
EXPERT COMMENT
Ketamine is the drug of choice for procedural sedation and analgesia

for fracture reduction in the prehospital and ED phases of trauma
care. It was historically considered to be contraindicated in patients
with head injury because of concerns about elevation of intracranial
pressure. A growing body of evidence demonstrates no increase in
intracranial pressure when ketamine is used with controlled
ventilation and in combination with other sedatives [25]. It is now
frequently used as an induction drug when these patients require
emergency anaesthesia. Careful prevention of hypercapnia and
hypocapnia is important in sedated and anaesthetized patients with
actual or potential head injury.
Page 6 of 23

EXPERT COMMENT Tourniquets
The use of tourniquets has been routine in recent military conflicts

and has been associated with decreased mortality in patients with
severe limb injuries [28]. Use has been enthusiastically replicated in
civilian prehospital care, but it is unclear whether delayed application
of a tourniquet (by ambulance providers) is likely to be as effective as
immediate application by a military victim or ‘buddy’ immediately
after injury.
LEARNING POINT Haemorrhage control
Optimal haemorrhage control involves minimizing blood loss and clot

disruption while maximizing clot formation. Minimizing patient
handling and use of splinting enhances natural tamponade and are
fundamental parts of haemorrhage control. Compression bandages
are used to control obvious external bleeding. Application of
tourniquets will stop extremity bleeding and outcomes are improved
when tourniquets are applied before shock occurs [26]. Nevertheless,
tourniquets are a temporary measure of haemorrhage control and
ischaemic time must be minimized to avoid complications [27].
Where there are injuries to the vessels of the neck, axilla, perineum,
and groin, compressive dressings are often ineffective and proximal
control tourniquets are impossible to apply [23]. Topical agents such
as factor concentrates, mucoadhesive agents, and procoagulant
agents are commonly used in the battlefield and may be packed into
wound cavities to control haemorrhage [29]. To reduce the soft tissue
into which bleeding can occur, limb fractures are drawn out to length
and splinted. A pelvic binder is applied when a pelvic fracture is
suspected and may reduce the volume of open-book pelvic fractures
and reduce bleeding. Cumulative blood loss from small wounds
should also be attended to, for instance, by suturing bleeding scalp
wounds [23, 30]. Haemorrhage that is not suitable for external
compression (e.g. in the neck) can also be compressed by insertion
and inflation of the balloon of a Foley catheter [31].
Standard venous access for fluid replacement is a 14- or 16-gauge

cannula in the antecubital fossa. Where possible, an arm that is not
injured and contralateral to any chest injuries is chosen. Subclavian
venous access might be appropriate particularly when the chest has
been decompressed and there is a low risk of causing undetected
pneumothorax. Intraosseous access is usually considered inferior to
venous access, but offers a safe and simple alternative [32].
Page 7 of 23

The limb fractures were reduced and splinted; a compression bandage

was applied to the degloved right arm. After the fractures were reduced,
the GCS score decreased to 8 (E2, V2, M4); his vital signs were blood
pressure 72/45 mmHg, heart rate 141 bpm, SpO2 94%, respiratory rate
18 breaths/min, and ETCO2 3.8 kPa. A needle decompression of the left
side of the chest was performed as a bridge to formal chest
decompression, but without any apparent clinical benefit. The patient was
transfused with 1 unit of prewarmed red blood cells while he was
anaesthetized using a rapid sequence induction, and intubated.
EXPERT COMMENT
A major change in trauma practice in the last 10 years has been the
recognition that the optimal replacement fluid for significant blood
loss is blood. If possible, major trauma patients with suspected
ongoing haemorrhage should be treated with blood and blood
products as soon as possible, rather than crystalloids. This has
resulted in mandatory major trauma transfusion protocols in
receiving trauma hospitals. Although controversial, current guidelines
promote administration of a one-to-one ratio of blood and fresh frozen
plasma, and early administration of tranexamic acid. Other aspects of
the protocols (e.g. the threshold for platelet transfusion) are more
variable and often subject to local practice [9, 33].
LEARNING POINT Transfusion and coagulopathy
Extensive tissue trauma and haemorrhagic shock drives an

endogenous physiological response that causes a haemostatic
disequilibrium termed acute traumatic coagulopathy [34, 35].
Acute traumatic coagulopathy, metabolic acidosis, and hypothermia

constitute the ‘triad of death’ and this is exacerbated by aggressive
fluid resuscitation with crystalloids and colloids. Acute traumatic
coagulopathy develops quickly and deranged coagulation has been
found in up to 25% of major trauma patients on arrival in hospital.
Acute traumatic coagulopathy is associated with increased
transfusion requirement, multiorgan failure, and death [36]. Although
prognostic models are available, early identification of acute
traumatic coagulopathy to guide therapy and improve outcome
remains a challenge [37, 38]. While rotation thromboelastometry
(ROTEM) and thromboelastography enable evaluation of the dynamic
haemostatic equilibrium, no definitive diagnostic test for acute
traumatic coagulopathy has been established [39, 40]. In the absence
of a validated point-of-care diagnostic test for coagulopathy, clinicians
should anticipate acute traumatic coagulopathy when trauma patients
Page 8 of 23

present with hypotension and extensive tissue trauma. Current

‘damage control resuscitation’ strategies for targeting acute
traumatic coagulopathy include permissive hypotension, avoidance of
acidosis, avoidance of hypothermia, and more aggressive use of blood
products [41]. Administration of tranexamic acid has shown clinically
relevant survival benefit during trauma haemorrhage and is part of
almost all major haemorrhage protocols [9, 35, 42]. An initial dose of
1 g is injected and a further 1 g infused over the following 8 hours.
The use of prehospital transfusion is associated with improved short-
term outcomes; however, the effect on overall survival remains
controversial [43, 44, 45, 46].
EXPERT COMMENT Acute traumatic coagulopathy
Acute traumatic coagulopathy was described in 2003 and although

the mechanisms of the process are still not entirely clear, the previous
concept of coagulopathy after trauma caused by consumption of
clotting factors does not account for the early coagulopathy seen in
this patient group.
Immediately after initiation of positive pressure ventilation, a left-sided

thoracostomy was performed which relieved air and drained
approximately 200 mL of blood.
EXPERT COMMENT Needle decompression and

thoracostomy
Needle decompression is an easy procedure to perform but is often

ineffective. Thoracostomy—the first stage of chest drain insertion—is
the creation of a communication between the pleural space and the
outside and can be achieved quickly. It is increasingly used as an
emergency procedure to decompress suspected tension
pneumothorax in mechanically ventilated patients. It is always
followed by formal chest drain insertion.
LEARNING POINT Chest trauma
Major objectives in chest injury management are to maximize oxygen

delivery as early as possible and to avoid any ventilatory contribution
to hypoxia, while aiming for normocapnia (particularly in the
presence of head injury). Tension pneumothoraces may cause
Page 9 of 23

respiratory distress and, at a late stage, lateral shift of the

mediastinum and hypotension, so should be decompressed as soon as
possible after injury. Pneumothoraces may be difficult to identify and
may become apparent only after a period of positive pressure
ventilation. Common signs and symptoms of pneumothorax include
dyspnoea, external signs of trauma with significant mechanism of
injury, surgical emphysema, bony crepitus, flail chest, decreased air
entry, and wheeze. The traditional supine anteroposterior trauma
chest X-ray has low sensitivity, but high specificity for detecting
pneumothorax. A computed tomography (CT) scan remains the
standard imaging modality for haemodynamically stable adult
patients with chest injuries. However, chest ultrasonography as a part
of the primary survey provides an additional point-of-care test with
acceptable accuracy in detecting pneumothoraces [9, 47]. Pleural
decompression is required in approximately 25% of patients
presenting with major trauma and management strategies include
needle thoracocentesis, thoracostomy, and tube thoracocentesis [48].
Open pneumothoraces are covered with a simple occlusive dressing
and observed for development of tension pneumothorax [9].
Needle thoracocentesis often fails to reach and decompress the

pleural space. The cannula may also kink or puncture major vessels
or even the heart [49, 50]. However, it is a quick procedure that may
be indicated in peri-arrest situations or in trapped victims before
progressing to thoracostomy or tube thoracocentesis.
Thoracostomy involves blunt dissection and digital decompression

through the pleura and is only suitable in patients undergoing
positive pressure ventilation: the open parietal pleura then prevents
development of a tension pneumothorax. The technique simplifies
treatment in the prehospital phase as drainage and insertion of a
chest tube is a secondary priority [51]. Thoracostomy is not suitable
for self-ventilating patients as it will create an open pneumothorax.
Tube thoracocentesis is used for definitive chest decompression and

can also be indicated to decompress a clinically significant
pneumothorax in a self-ventilating patient [9]. Complications include
tube misplacements causing injury to thoracic and abdominal
structures [52]. Once sutured in place, the drain and its collecting
system become a closed system and have the potential to allow re-
tension to occur.
EXPERT COMMENT Tension pneumothorax
Recent NICE guidelines recommend that in patients with suspected

tension pneumothorax, chest decompression should be performed
before imaging only if there is haemodynamic instability or severe
Page 10 of 23

respiratory compromise. This is a departure from previous trauma

practice where a large pneumothorax present on imaging was viewed
by some as bad practice. Where immediate decompression is
required, open thoracostomy followed by a chest drain is indicated.
Drains should be sufficiently large to enable drainage of blood where
present and should be inserted by operators trained and familiar with
the chosen technique.
The patient’s blood pressure increased to 92/65 mmHg. Other vital signs
were heart rate 122 bpm, SpO2 96%, and ETCO2 4.0 kPa. He was given
tranexamic acid 1 g IV and two more units of blood during transfer to the
nearest major trauma centre (MTC) bypassing the local hospital
(transportation time 25 min). A pre-warning call was made and a full
trauma team attended the patient.
LEARNING POINT Trauma team activation
Early identification of major trauma enables EMS providers to classify

patients according to injury severity and efficiently couple available
resources with patients’ needs. Triage remains a core component of a
trauma system as inaccurate assessment of injury severity wastes
resources and compromises quality of care [53]. To optimize patient
outcome, EMS providers may bypass local hospitals and transport
directly to a dedicated MTC where immediate resuscitation is
provided by trained, experienced multidisciplinary trauma teams [54].
Accordingly, triage encompasses processes such as hospital
destination decisions and trauma team activation. A well-performing
triage system will have no under-triage (i.e. all patients with major
trauma will be triaged as major trauma and taken to an MTC). To
achieve this, there will always be an element of over-triage (i.e.
patients triaged to an MTC with suspected major trauma who turn out
not to be severely injured).
EXPERT COMMENT
MTCs are a well-defined and established part of trauma care in the

US. The concept that low mortality and morbidity can be best
achieved in centres with key specialities on site with high throughput
of significantly injured patients is generally accepted and this has led
to the formation of trauma networks in the UK (in 2012) and other
countries. A significant reduction in trauma mortality was reported by
NHS England only 2 years after the introduction of trauma networks
in England (Figure 4.1). Transfer of patients identified as having
Page 11 of 23

major trauma directly to the MTC is facilitated by trauma triage tools

used by ambulance services and trauma units.
Figure 4.1
Improvement in mortality after the introduction of major trauma
centres in England.
Reproduced with permission from NHS England. NHS saves lives of

hundreds more trauma victims just two years after changes to care—
Independent audit. 1 July 2014. Copyright © 2014 NHS England.
Contains public sector information licensed under the Open
Government Licence v3.0. Available at https://www.england.nhs.uk/
2014/07/trauma-independent-audit/.
The trauma team completed pleural drainage by inserting a chest drain

into the pleural cavity. The patient remained haemodynamically unstable
and was taken directly to the operating room for damage control
laparotomy. A splenic laceration was identified and a splenectomy was
performed. A whole-body CT confirmed an ‘open-book’ pelvic fracture, an
L1 vertebral extension fracture without cord involvement, and bilateral
lung contusions. The CT showed no head injury, suggesting that the most
likely causes of the initial drop in GCS score were hypotension,
administered analgesics, and/or hypoxia.
EXPERT COMMENT
Most adult major trauma patients with this presentation would have a
whole-body CT. Recent NICE recommendations are a vertex-to-toes
scanogram (i.e. scout scan before full imaging) with CT from vertex to
mid thigh and further limb imaging guided by the scanogram and
clinical assessment [9]. Patients with severe haemodynamic instability
and suspected intra-abdominal injury may still rarely be moved
Page 12 of 23

directly to theatre for haemorrhage control. A whole-body CT scan

would then be performed as soon as possible after surgery.
EXPERT COMMENT
The spleen is a commonly injured solid abdominal organ. Historically,

splenectomy was frequently performed when splenic injury was
identified, but a more conservative approach is now common.
Avoidance of unnecessary laparotomy and the long-term potential for
infection in post-splenectomy patients are important advantages of a
conservative approach. If a trauma patient is haemodynamically
stable, splenic injury is assessed with contrast CT. Based on injury
grade and an assessment of active bleeding, splenectomy can often be
avoided with alternative approaches being interventional radiology
and selective vascular embolization or a conservative non-operative
approach.
The pelvis was initially managed conservatively and had definitive

surgical fixation on day 6. The femur and tibia/fibula fractures were
managed with external fixation, and the spinal fracture was stabilized
with internal fixation plates. The patient received a total of 12 units of red
blood cells, 8 units of platelets, and 11 units of plasma. Consecutive
ROTEM tests indicated an initial coagulopathy that subsequently
normalized. Low-molecular-weight heparin was started on day 2 but had
to be interrupted several times for planned returned to theatre.
LEARNING POINT Thromboprophylaxis
Although early mortality from trauma is often associated with

haemorrhage and coagulopathy, trauma patients are also at high risk
of subsequent venous thromboembolism and thromboprophylaxis is
recommended as soon as it is practical. Mechanical prophylaxis can
be commenced early when lower limbs are uninjured. Low-molecular-
weight heparins are often commenced at 48 hours post injury
although this can be controversial in the presence of intracranial
bleeding which is not considered sufficiently settled [55, 56, 57].
EXPERT COMMENT
The timing of surgery is an important aspect of intensive care

management of trauma patients with multiple injuries [61].
Page 13 of 23

Historically, unstable patients spent many hours having all their

injuries definitively managed. This early total management is now
considered inappropriate for very unstable patients. Damage control
surgery—early surgery to achieve haemostasis and control of
contamination—may be more appropriate to enable correction of
coagulopathy, temperature, and volume status and prevent severe
systemic inflammatory response syndrome. Definitive surgery is
delayed for these interventions. Fracture haemostasis can often be
achieved with the use of effective splinting and external fixation
techniques. In civilian practice, the need for damage control surgery
is uncommon, but it is vital in the small proportion of severely
injured, shocked patients received by MTCs. Most stable patients can
be treated with early fracture fixation. Multidisciplinary discussion
and coordination of trauma intensive care is vital to effective timing
of surgery.
Enteral nutrition via a nasogastric tube was commenced on the day of

admission to ICU. The patient remained in ICU sedated and his lungs
ventilated with a lung protective ventilation strategy, particularly because
of the presence of lung contusions [58, 59].
LEARNING POINT Lung injury and lung protective

ventilation
Trauma patients are at risk of acute lung injury and acute respiratory
distress syndrome for many reasons—for example, aspiration,
hypoperfusion, direct lung injury, transfusion, fat embolus, systemic
inflammatory response syndrome, and infection.
Lung protective ventilation with low tidal volumes (6 mL/kg predicted

body weight), relatively high positive end-expiratory pressure (PEEP),
and plateau pressures less than 30 cmH2O is adopted early—ideally
as soon as intubation has occurred to minimize risk. This can be
challenging with severe chest injury (where lung contusion may
necessitate use of relatively high PEEP values) or with a combination
of chest injuries and head injury where lung protective ventilation
strategies can conflict with ideal oxygenation and carbon dioxide
management for head injury. There has been considerable recent
interest in the potential benefits of non-invasive ventilation and newer
modes of ventilation such as airway pressure release ventilation in
trauma patients [59, 60].
EXPERT COMMENT
Page 14 of 23

The management of severe lung injury can be difficult particularly in

the presence of other pathologies with conflicting management
requirements (particularly severe head injury). Non-invasive
ventilation or high-flow nasal cannula oxygen are acceptable modes of
support in non-intubated patients with respiratory compromise.
Intubated patients with pulmonary contusion and/or flail chest should
not be excessively fluid restricted, but fluid therapy should be titrated
to achieve adequate organ perfusion. Thoracic epidurals provide
analgesia and aid weaning in patients with only a few fractured ribs
and no significant coagulopathy. In patients with major flail segments
and compromise, evaluation by a thoracic surgeon for rib fixation
should be considered. Although controversial, this procedure is
increasingly performed and is associated with positive outcomes [63,
64].
After returning from initial surgery, a thorough tertiary survey was

performed.
EXPERT COMMENT
Trauma patients are particularly susceptible to gut hypoperfusion,

sepsis, and multiorgan impairment. Early enteral nutrition has been
associated with improved gut perfusion, lower rates of sepsis, lower
rates of bacterial translocation, and improved mortality. Other
therapies, including glutamine feed supplementation, lipid-rich
enteral feeds, and protease inhibitors, have been suggested to
improve outcomes, but are unproven [62].
The tertiary survey in this patient revealed soft tissue injuries which were
cleaned and dressed, and debrided during a subsequent trip to the
operating theatre. Although the arrhythmias from the cardiac contusion
quickly settled, the patient underwent echocardiography and cardiology
evaluation including troponin testing.
EXPERT COMMENT
Patients with cardiac rupture usually die at the scene and even if they
arrive in the ED alive have a low survival rate. In patients with
isolated chest injury, cardiac contusion can be excluded with a normal
electrocardiogram and normal cardiac troponin values. When present,
cardiac contusions are usually in the anterior heart (often the right
ventricle). Most contusions resolve over days or weeks and do not
usually cause long-term problems. Intensive care management of
Page 15 of 23

cardiac contusion is supportive with good fluid management,

arrhythmia management, and inotropic support. Echocardiographic
evaluation can detect the site and effect of contusions on cardiac
function.
LEARNING POINT Tertiary survey and missed injuries
Standardized trauma documentation is an important component of

care after admission. It enables documentation of the fact that
tertiary survey and appropriate imaging has occurred. This increases
the likelihood that all injuries are detected and, where necessary,
treated. Missed injuries are a particular problem in unconscious
patients with multiple injuries.
Regular multidisciplinary meetings between trauma, orthopaedic, and

plastic surgeons, cardiologists, and intensivists were held. The patient’s
young age and the lack of pre-injury comorbidity were considered pivotal
for his rapid recovery. Frequent complications such as haematomas,
infections, and ventilatory problems did not occur. The patient was
successfully extubated on day 5. At day 14 he was discharged for
rehabilitation.
EXPERT COMMENT
Effective rehabilitation is essential to return trauma patients to

maximum functional status. This aspect of care has frequently been
neglected. When the need for specialist rehabilitation is identified
very early, referral is good practice—this includes spinal cord injury,
brain injury, and prosthetics. In MTCs with well-functioning
rehabilitation services, assessment of need and identification of likely
complex rehabilitation needs are ideally assessed in the first few days
after admission. This early assessment and commencement of
rehabilitation has been termed acute or hyperacute rehabilitation.
This may well occur on the ICU.
Discussion
This chapter describes the patient pathway from the accident

scene through to rehabilitation. This is intentional because critical care
principles and interventions can be applied to improve outcomes at all
points of the trauma patient pathway—not just within the confines of the
ICU—this is in effect a restatement of the concept of ‘critical care without
Page 16 of 23

walls’ which stimulated the development of intensive therapy unit

outreach services [65].
Optimal early management of multi-trauma is based on rapid and

accurate identification of time-critical pathology. Multi-trauma is best
managed with a multidisciplinary approach and careful coordination of
surgical operations. Major trauma coordinators who monitor, track, and
coordinate care of major trauma patients from admission to discharge are
a key part of an effective trauma service.
Although in this case several aspects of intensive care have been

highlighted that are specific to major trauma patients, most of the care
delivered to trauma patients has much in common with the organ support
and meticulous care that is required for all critically ill patients. One key
difference between trauma and medical intensive care patients was often
stated to be the relative youth of trauma patients. Although major trauma
is still common in young adults, it is an increasingly common reason for
elderly patients to be admitted to ICUs.
Most major trauma patients will spend some time in a critical care or
high dependency area. However, this is only one part of the patient
pathway and it is important to understand that the documented
improvements in outcome for this group of patients have occurred
only after implementation of inclusive trauma networks which include
mandatory standards of care from incident to discharge. The
monitoring and implementation of high-quality care is only possible
when data are submitted to a national audit or registry. Regular
dashboards and reports can then be generated to highlight areas for
improvement or good practice. UK major trauma practice (in common
with UK intensive care practice) has an effective system in place to
achieve this in the form of the Trauma Audit and Research Network
(TARN) (https://www.tarn.ac.uk).
Mortality is compared among centres and unexpected survivors and

unexpected deaths are highlighted to direct quality improvement
initiatives. Every hospital receiving trauma patients receives
quarterly reports that document compliance with nationally defined
quality indicators.
References
1. World Health Organization. The Global Burden of Disease: 2004
update. Geneva: World Health Organization; 2008.
Page 17 of 23

2. World Health Organization. Injuries and Violence: The Facts. Geneva:

World Health Organization; 2010.
3. Global Burden of Disease Study Collaborators. Global, regional, and

national incidence, prevalence, and years lived with disability for 301
acute and chronic diseases and injuries in 188 countries, 1990–2013: a
systematic analysis for the Global Burden of Disease Study 2013. Lancet.
2015;386:743–800.
4. Sasser S, Varghese M, Kellermann A, Lormand J. Prehospital Trauma

Care Systems. Geneva: World Health Organization; 2005.
5. Gosselin RA, Spiegel DA, Coughlin R, Zirkle LG. Injuries: the neglected
burden in developing countries. Bull World Health Organ. 2009;87:246.
6. Oteir AO, Smith K, Stoelwinder JU, Middleton J, Jennings PA. Should

suspected cervical spinal cord injury be immobilised?: a systematic
review. Injury. 2015;46:528–35.
7. Kreinest M, Gliwitzky B, Schuler S, Grutzner PA, Munzberg M.

Development of a new Emergency Medicine Spinal Immobilization
Protocol for trauma patients and a test of applicability by German
emergency care providers. Scand J Trauma Resusc Emerg Med.
2016;24:71.
8. Strayer RJ, Nelson LS. Adverse events associated with ketamine for
procedural sedation in adults. Am J Emerg Med. 2008;26:985–1028.
9. National Institute for Health and Care Excellence. Major Trauma:

Assessment and Initial Management. London: National Institute for
Health and Care Excellence; 2016.
10. Galinski M, Dolveck F, Borron SW, et al. A randomized, double-blind

study comparing morphine with fentanyl in prehospital analgesia. Am J
Emerg Med. 2005;23:114–19.
11. Soriya GC, McVaney KE, Liao MM, et al. Safety of prehospital
intravenous fentanyl for adult trauma patients. J Trauma Acute Care
Surg. 2012;72:755–9.
12. Arroyo W, Nelson KJ, Belmont PJ Jr, Bader JO, Schoenfeld AJ. Pelvic
trauma: what are the predictors of mortality and cardiac, venous
thrombo-embolic and infectious complications following injury? Injury.
2013;44:1745–9.
13. Croce MA, Magnotti LJ, Savage SA, Wood GW 2nd, Fabian TC.
Emergent pelvic fixation in patients with exsanguinating pelvic fractures.
J Am Coll Surg. 2007;204:935–9.
14. Demetriades D, Karaiskakis M, Toutouzas K, Alo K, Velmahos G, Chan

L. Pelvic fractures: epidemiology and predictors of associated abdominal
injuries and outcomes. J Am Coll Surg. 2002;195:1–10.
Page 18 of 23

15. Gustavo Parreira J, Coimbra R, Rasslan S, Oliveira A, Fregoneze M,

Mercadante M. The role of associated injuries on outcome of blunt
trauma patients sustaining pelvic fractures. Injury. 2000;31:677–82.
16. Morrison JJ, Galgon RE, Jansen JO, Cannon JW, Rasmussen TE, Eliason
JL. A systematic review of the use of resuscitative endovascular balloon
occlusion of the aorta in the management of hemorrhagic shock. J Trauma
Acute Care Surg. 2016;80:324–34.
17. Sadek S, Lockey DJ, Lendrum RA, Perkins Z, Price J, Davies GE.
Resuscitative endovascular balloon occlusion of the aorta (REBOA) in the
pre-hospital setting: an additional resuscitation option for uncontrolled
catastrophic haemorrhage. Resuscitation. 2016;107:135–8.
18. Ghaemmaghami V, Sperry J, Gunst M, et al. Effects of early use of

external pelvic compression on transfusion requirements and mortality in
pelvic fractures. Am J Surg. 2007;194:720–3.
19. Pizanis A, Pohlemann T, Burkhardt M, Aghayev E, Holstein JH.

Emergency stabilization of the pelvic ring: clinical comparison between
three different techniques. Injury. 2013;44:1760–4.
20. Spanjersberg WR, Knops SP, Schep NW, van Lieshout EM, Patka P,
Schipper IB. Effectiveness and complications of pelvic circumferential
compression devices in patients with unstable pelvic fractures: a
systematic review of literature. Injury. 2009;40:1031–5.
21. Crosby ET. Airway management in adults after cervical spine trauma.
Anesthesiology. 2006;104:1293–318.
22. Krell JM, McCoy MS, Sparto PJ, Fisher GL, Stoy WA, Hostler DP.
Comparison of the Ferno Scoop Stretcher with the long backboard for
spinal immobilization. Prehosp Emerg Care. 2006;10:46–51.
23. Lockey DJ, Weaver AE, Davies GE. Practical translation of hemorrhage
control techniques to the civilian trauma scene. Transfusion. 2013;53
Suppl. 1:17S–22S.
24. Hunt K, Hallworth S, Smith M. The effects of rigid collar placement on

intracranial and cerebral perfusion pressures. Anaesthesia. 2001;56:511–
13.
25. Chang LC, Raty SR, Ortiz J, Bailard NS, Mathew SJ. The emerging use
of ketamine for anesthesia and sedation in traumatic brain injuries. CNS
Neurosci Ther. 2013;19:390–5.
26. Kragh JF Jr, Walters TJ, Baer DG, et al. Survival with emergency
tourniquet use to stop bleeding in major limb trauma. Ann Surg.
2009;249:1–7.
Page 19 of 23

27. Lakstein D, Blumenfeld A, Sokolov T, et al. Tourniquets for

hemorrhage control on the battlefield: a 4-year accumulated experience. J
Trauma Acute Care Surg. 2003;54:S221–5.
28. Kragh JF Jr, Dubick MA, Aden JK, et al. U.S. Military use of
tourniquets from 2001 to 2010. Prehosp Emerg Care. 2015;19:184–90.
29. Granville-Chapman J, Jacobs N, Midwinter MJ. Pre-hospital

haemostatic dressings: a systematic review. Injury. 2011;42:447–59.
30. Geeraedts LM Jr, Kaasjager HA, van Vugt AB, Frolke JP.
Exsanguination in trauma: a review of diagnostics and treatment options.
Injury. 2009;40:11–20.
31. Ball CG, Wyrzykowski AD, Nicholas JM, Rozycki GS, Feliciano DV. A
decade’s experience with balloon catheter tamponade for the emergency
control of hemorrhage. J Trauma Acute Care Surg. 2011;70:330–3.
32. Olaussen A, Williams B. Intraosseous access in the prehospital setting:

literature review. Prehosp Disaster Med. 2012;27:468–72.
33. Etchill E, Sperry J, Zuckerbraun B, et al. The confusion continues:

results from an American Association for the Surgery of Trauma survey
on massive transfusion practices among United States trauma centers.
Transfusion. 2016;56:2478–86.
34. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J

Trauma Acute Care Surg. 2003;54:1127–30.
35. Frith D, Davenport R, Brohi K. Acute traumatic coagulopathy. Curr

Opin Anaesth. 2012;25:229–34.
36. Davenport R, Manson J, De’Ath H, et al. Functional definition and

characterization of acute traumatic coagulopathy. Crit Care Med.
2011;39:2652–8.
37. Mitra B, Cameron PA, Mori A, et al. Early prediction of acute

traumatic coagulopathy. Resuscitation. 2011;82:1208–13.
38. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for
massive transfusion in combat casualty patients. J Trauma Acute Care
Surg. 2008;64:S57–63.
39. Rugeri L, Levrat A, David JS, et al. Diagnosis of early coagulation

abnormalities in trauma patients by rotation thrombelastography. J
Thromb Haemo. 2007;5:289–95.
40. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid
thrombelastography can replace conventional coagulation tests in the
emergency department: experience with 1974 consecutive trauma
patients. Ann Surg. 2012;256:476–86.
Page 20 of 23

41. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation:

directly addressing the early coagulopathy of trauma. J Trauma Acute
Care Surg. 2007;62:307–10.
42. CRASH-2 Trial Collaborators, Shakur H, Roberts I, et al. Effects of

tranexamic acid on death, vascular occlusive events, and blood
transfusion in trauma patients with significant haemorrhage (CRASH-2):
a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.
43. Miller BT, Du L, Krzyzaniak MJ, Gunter OL, Nunez TC. Blood
transfusion: in the air tonight? J Trauma Acute Care Surg. 2016;81:15–20.
44. Brown JB, Sperry JL, Fombona A, Billiar TR, Peitzman AB, Guyette FX.
Pre-trauma center red blood cell transfusion is associated with improved
early outcomes in air medical trauma patients. J Am Coll Surg.
2015;220:797–808.
45. Holcomb JB, Donathan DP, Cotton BA, et al. Prehospital transfusion of
plasma and red blood cells in trauma patients. Prehosp Emerg Care.
2015;19:1–9.
46. O’Reilly DJ, Morrison JJ, Jansen JO, Apodaca AN, Rasmussen TE,
Midwinter MJ. Prehospital blood transfusion in the en route management
of severe combat trauma: a matched cohort study. J Trauma Acute Care
Surg. 2014;77:S114–20.
47. Wilkerson RG, Stone MB. Sensitivity of bedside ultrasound and supine
anteroposterior chest radiographs for the identification of pneumothorax
after blunt trauma. Acad Emerg Med. 2010;17:11–17.
48. Heng K, Bystrzycki A, Fitzgerald M, et al. Complications of intercostal

catheter insertion using EMST techniques for chest trauma. ANZ J Surg.
2004;74:420–3.
49. Stevens RL, Rochester AA, Busko J, et al. Needle thoracostomy for
tension pneumothorax: failure predicted by chest computed tomography.
Prehosp Emerg Care. 2009;13:14–17.
50. Rawlins R, Brown KM, Carr CS, Cameron CR. Life threatening
haemorrhage after anterior needle aspiration of pneumothoraces. A role
for lateral needle aspiration in emergency decompression of spontaneous
pneumothorax. Emerg Med J. 2003;20:383–4.
51. Lockey D, O’Brien B, Wise D, Davies G. Prehospital thoracostomy. Eur

J Emerg Med. 2008;15:283.
52. Maybauer MO, Geisser W, Wolff H, Maybauer DM. Incidence and

outcome of tube thoracostomy positioning in trauma patients. Prehosp
Emerg Care. 2012;16:237–41.
Page 21 of 23

53. Sasser SM, Hunt RC, Faul M, et al. Guidelines for field triage of
injured patients: recommendations of the National Expert Panel on Field
Triage, 2011. MMWR Recomm Rep. 2012;61:1–20.
54. National Institute for Health and Care Excellence. Major Trauma:
Service Delivery. London: National Institute for Health and Care
Excellence; 2016.
55. Van PY, Schreiber MA. Contemporary thromboprophylaxis of trauma

patients. Curr Opin Crit Care. 2016;22:607–12.
56. Guyatt GH, Akl EA, Crowther M, et al. Executive summary:

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest. 2012;141:7S–47S.
57. Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH.
Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev.
2013;3:CD008303.
58. Simon B, Ebert J, Bokhari F, et al. Management of pulmonary

contusion and flail chest: an Eastern Association for the Surgery of
Trauma practice management guideline. J Trauma Acute Care Surg.
2012;73:S351–61.
59. Parry NG, Moffat B, Vogt K. Blunt thoracic trauma: recent advances
and outstanding questions. Curr Opin Crit Care. 2015;21:544–8.
60. Andrews PL, Shiber JR, Jaruga-Killeen E, et al. Early application of

airway pressure release ventilation may reduce mortality in high-risk
trauma patients: a systematic review of observational trauma ARDS
literature. J Trauma Acute Care Surg. 2013;75:635–41.
61. Gandhi RR, Overton TL, Haut ER, et al. Optimal timing of femur
fracture stabilization in polytrauma patients: a practice management
guideline from the Eastern Association for the Surgery of Trauma. J
Trauma Acute Care Surg. 2014;77:787–95.
62. Patel JJ, Rosenthal MD, Miller KR, Martindale RG. The gut in trauma.
Curr Opin Crit Care. 2016;22:339–46.
63. Cataneo AJ, Cataneo DC, de Oliveira FH, Arruda KA, El Dib R, de
Oliveira Carvalho PE. Surgical versus nonsurgical interventions for flail
chest. Cochrane Database Syst Rev. 2015;7:CD009919.
64. Slobogean GP, MacPherson CA, Sun T, Pelletier ME, Hameed SM.
Surgical fixation vs nonoperative management of flail chest: a meta-
analysis. J Am Coll Surg. 2013;216:302–11.
65. Hillman K. Critical care without walls. Curr Opin Crit Care.
2002;8:594–9.
Page 22 of 23

Page 23 of 23

Severe traumatic brain injury

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Severe traumatic brain injury
Author(s): Virginia Newcombe
DOI: 10.1093/med/9780198814924.003.0005
Expert commentary by Jamie Cooper
Case history
An 18-year-old male, restrained front seat passenger was involved

in a high-speed motor vehicle collision. The driver of the vehicle died at
the scene. On arrival at the scene the paramedics noted that he had
obstructed-sounding breathing and initial arterial blood oxygen
saturation by pulse oximetry (SpO2) of 84%. This improved with simple
airway manoeuvres and administration of oxygen. His initial blood
pressure was 94/63 mmHg. His initial Glasgow Coma Scale (GCS) score
was 8 (E2, V1, M5), his pupils were equal and reactive at 3 mm, and he
was agitated. A rapid sequence induction was performed at the scene and
he was intubated without incident. He was transferred to the nearest
major trauma centre by road ambulance.
On arrival, the patient was received by a trauma team. A primary survey

was performed which was unremarkable except for a scalp laceration.
Page 1 of 34
Given the mechanism of injury, he was taken for a trauma series

computed tomography (CT) scan that included head, neck, chest,
abdomen, and pelvis. His initial CT head showed multiple skull fractures,
bifrontal contusions, traumatic subarachnoid haemorrhage, a right-sided
subdural haemorrhage, multiple intracerebral petechial haemorrhages,
and signs of tentorial herniation (Figure 5.1). No other injuries were
found on the rest of his imaging.
Figure 5.1
Progression of lesions after traumatic brain injury. The initial CT showed
extensive bifrontal contusions, right parieto-occiptal contusion, right-
sided subdural haemorrhage with midline shift, traumatic subarachnoid
haemorrhage, and petechial haemorrhages. There are also signs of raised
intracranial pressure with effacement of the ventricles, loss of the basal
cisterns, and loss of grey/white differentiation. The CT performed on day
2 exhibits the right-sided hemicraniectomy and the progression of the
contusions especially bifrontal. The MRI performed at day 10
demonstrates slices from the fluid-attenuated inversion recovery (FLAIR)
sequence with the resolving haematomas still surrounded by vasogenic
oedema.
LEARNING POINT Imaging after traumatic brain

injury
The short imaging time and ease of acquisition means that CT

scanning enables early assessment of the extent of injury after
traumatic brain injury (TBI) and remains the standard imaging
modality used [1, 2] (Table 5.1).
Page 2 of 34

Table 5.1 The National Institute for Health and Care Excellence
(NICE) and Scottish Intercollegiate Guidelines Network (SIGN)
guideline recommendations of indications for a head CT following
TBI in adults. NICE currently advises that a provisional radiology
report should be available within 1 hour of the scan
Timing of scan NICE guidelines SIGN guidelines
Immediate CT GCS score <13 on Eye opening only to

(within 1 hour) initial assessment in pain or not
of risk factor the emergency conversing (GCS
being identified department score ≤12)
GCS score <15 at 2 Confusion or

hours after the injury drowsiness (GCS
on assessment in the score 13–14)
emergency followed by failure
department to improve within 1
Suspected open or hour of clinical
depressed skull observation or
fracture within 2 hours of
injury (whether or
not intoxication
from drugs or
alcohol is a possible
contributory factor)
Any sign of basal Base of skull or

skull fracture: panda depressed skull
eyes, fracture and/or
haemotympanum, suspected
cerebrospinal fluid penetrating injuries
leakage from the ear A deteriorating
or nose, Battle’s sign level of
Post-traumatic consciousness or
seizure new focal
Focal neurological neurological signs
deficit Full consciousness
More than one (GCS score 15) with
episode of vomiting no fracture but
other features, e.g.
severe and
persistent
headache, two
distinct episodes of
vomiting
Page 3 of 34

A history of
coagulopathy (e.g.
warfarin use) and
loss of
consciousness,
amnesia, or any
neurological feature
CT within 8 For adults with any Age >65 (with loss

hours of injury of the following risk of consciousness or
factors who have amnesia)
experienced some Clinical evidence of
loss of consciousness a skull fracture (e.g.
or amnesia since the boggy scalp
injury: haematoma) but no
Age ≥65 years clinical features
Any history of indicative of an
bleeding or clotting immediate CT scan
disorders Any seizure activity
Dangerous Significant
mechanism of injury retrograde amnesia
(a pedestrian or (>30 min)
cyclist struck by a Dangerous
motor vehicle, an mechanism of injury
occupant ejected (pedestrian struck
from a motor vehicle, by motor vehicle,
or a fall from a occupant ejected
height of >1 metre from motor vehicle,
or five stairs) significant fall from
More than 30 min height) or
retrograde amnesia significant assault
of events (e.g. blunt trauma
immediately before with a weapon)
the head injury
Anticoagulation For patients (adults A history of

treatment and children) who coagulopathy (e.g.
have sustained a warfarin use)
head injury with no irrespective of
other indications for clinical features
a CT head scan and (high-quality
who are on warfarin, observation is an
perform a CT head appropriate
scan within 8 hours alternative to
of the injury scanning in this
group of patients)
Page 4 of 34

NICE, National Institute for Health and Care Excellence; SIGN,

Scottish Intercollegiate Guidelines Network.
Source: data from National Institute for Health and Care

Excellence (NICE). Head Injury: assessment and early
management (CG176). Copyright © 2017 NICE. Available at
https://www.nice.org.uk/guidance/cg176/; and Scottish
Intercollegiate Guidelines Network (SIGN). Early management of
patients with a head injury, Guideline 110. Copyright © 2017
SIGN. Available at http://www.sign.ac.uk/pdf/sign110.pdf.
Magnetic resonance imaging (MRI) can provide more detail; however,

the logistics of transporting a ventilated patient with potentially high
intracranial pressure (ICP) to the MRI suite means that it can be
difficult to perform early and so is performed only in select centres.
Later MRIs in patients, particularly those who do not wake, may be
useful.
CLINICAL TIP Spinal clearance in the unconscious

patient
Cervical spine injuries occur in up to 7% of blunt trauma patients

with the incidence increasing in those with coexisting TBI. Altered
levels of consciousness increase the risk of missing such injuries.
However, potential complications of prolonged spinal immobilization
include risks of decubitus ulceration (especially cervical spine
related), increased ICP, increased need for sedation and subsequent
delay in extubation, delays in percutaneous tracheotomy, central
venous access difficulties, deep venous thrombosis, enteral feeding
intolerance due to supine positioning, increased respiratory
compromise, and increased risk of cross-infection due to extra staff
required for patient position changes [3]. It is therefore important to
carefully exclude the possibility of a spinal injury in the TBI patient
requiring intensive care unit (ICU) management as soon as is
practical.
Even in those not intubated, agitation and distracting injuries may

render it impossible to perform an accurate clinical assessment and
to safely exclude spinal injuries. Patients who require a CT head
should also undergo a CT of their cervical spine to help with cervical
spine clearance (Table 5.2). Spinal X-rays should be reserved for those
who have no clear indication for a CT or imaging of other body areas.
Table 5.2 NICE and SIGN guideline recommendations of

indications for cervical spine scanning following TBI in adults
Page 5 of 34

NICE guidelines SIGN

guidelines
Three-view Only if does not meet

cervical X-rays criteria for CT cervical
spine
If it is not considered
safe to assess the range
of movement in the neck
Safe assessment of range
of neck movement shows
that the patient cannot
actively rotate their neck
to 45° to the left and
right
CT cervical GCS score <13 on initial In adult patients

spine scan assessment with GCS score
(within 1 hour The patient has been <15 with
of intubated indications for a
identification Plain X-rays are CT head scan,
of risk factor) technically inadequate the scan should
(e.g. the desired view is include the
unavailable) cervical spine
Plain X-rays are Cervical spine
suspicious or definitely CT scan should
abnormal include the base
A definitive diagnosis of of skull to T4
cervical spine injury is Patients who
needed urgently (e.g. meet criteria for
before surgery) a CT scan should
The patient is having not have plain
other body areas scanned radiographs of
for head injury or multi- the cervical
region trauma spine taken as
The patient is alert and routine
stable, there is clinical
suspicion of cervical
spine injury, and any of
the following apply:
● Age 65 years or
older
● Dangerous
mechanism of injury
(fall from a height of
>1 metre or five
stairs)
Page 6 of 34

● Axial load to the

head, e.g. diving
● High-speed motor
vehicle collision
● Rollover motor
accident
● Ejection from a
motor vehicle
● Accident involving
motorized recreational
vehicles
● Bicycle collision
● Focal peripheral
neurological deficit
● Paraesthesia in the
upper or lower limbs
NICE, National Institute for Health and Care Excellence; SIGN,

Scottish Intercollegiate Guidelines Network.

Excellence (NICE). Head Injury: assessment and early
management (CG176). Copyright © 2017 NICE. Available at
https://www.nice.org.uk/guidance/cg176/; and Scottish
Intercollegiate Guidelines Network (SIGN). Early management of
patients with a head injury, Guideline 110. Copyright © 2017
SIGN. Available at http://www.sign.ac.uk/pdf/sign110.pdf.
The presence of vertebral malalignment, a fracture involving the

transverse foramina or lateral processes, or a posterior circulation
syndrome might indicate a vascular injury and in these cases CT or
MRI angiography of the neck should be performed.
After trauma many patients undergo whole-body CT to assess for

thoracoabdominal injuries. This data can be reformatted to enable
review of the entire spine and enable identification of fractures, their
stability, and spinal alignment.
Fractures of the spine are demonstrated more clearly with CT than

with MRI. In the unconscious TBI patient, dynamic flexion–extension
fluoroscopy studies of the cervical spine provide no more information
than fine-cut CT and are not recommended [4, 5]. Consider cervical
spine MRI if a patient has signs and symptoms of spinal cord injury, or
if the CT scan in an unconscious patient is indicative or suggestive of
discoligamentous injury, or they are elderly with evidence of spine
degeneration.
Page 7 of 34

On return to the resuscitation bay after his CT scan, the patient’s left
pupil was noted to be 8 mm and unreactive and his right pupil was 3 mm
and reactive. He was given a bolus of 350 mL 20% mannitol (70 g,
estimated 1 mg/kg), sedation was increased, he was reparalysed, and his
ventilation was increased to reduce the end-tidal carbon dioxide (CO2) to
4.0–4.5 kPa. He was taken urgently to the operating room where an
emergency right-sided decompressive hemicraniectomy was performed
and an intraparenchymal pressure monitor inserted. An external
ventricular drain (EVD) could not be inserted because of the small
ventricular size. His initial ICP was 50 mmHg, decreasing to 23 mmHg
after decompression. On arrival in the ICU, his pupils were both 2 mm
and reactive.
LEARNING POINT Hypocapnia/hyperventilation
Hypocapnia causes cerebral vasoconstriction, reducing cerebral

blood volume, which can decrease ICP rapidly and increase cerebral
perfusion pressure (CPP). However, this is usually accompanied by a
global decrease in cerebral blood flow that may lead to cerebral
ischaemia [6]. Hyperventilation should therefore be used only as a
temporizing measure while instituting other therapies to reduce
intracranial hypertension. If it is used, brain tissue oxygen values or
jugular venous oximetry should be used to monitor adequacy of
oxygen delivery [7]. However, metabolic imaging with positron
emission tomography scanning has shown that even moderate
reductions in PaCO2 may cause ischaemia in focal areas not detected
with jugular venous oximetry, thus even with this monitoring,
hyperventilation may be harmful [6].
LEARNING POINT Osmotherapy
There are multiple mechanisms by which hyperosmolar therapy, most

commonly mannitol or hypertonic saline (HS), is purported to reduce
raised ICP. Traditionally such therapy is thought to raise plasma
osmolality and so cause an osmotic withdrawal of cerebral water
though an intact blood–brain barrier. However, they may also reduce
erythrocyte and endothelial cell size, improve erythrocyte
deformability, and affect leucocyte adhesion. These effects are
believed to contribute to improved microvascular flow. Typically they
are given as boluses to reduce acute rises in ICP, and their role in
long-term ICP reduction is unclear.
Mannitol (0.25–2.0 g/kg, usually given as a 20% solution) is the

traditionally used hyperosmolar agent. If used after the first few
hours of injury, it may cause a secondary increase in ICP if the blood–
Page 8 of 34

brain barrier is disrupted. Hypernatraemia, intravascular depletion,

and arterial hypotension may occur secondary to the osmotic diuresis.
Recurrent use may cause renal impairment and so it should be
discontinued if it no longer produces a significant ICP reduction, and
plasma osmolality greater than 320 mOsm/L.
HS solutions are available in variable concentrations (3% up to

28.4%). Usual doses are approximately 2 mL/kg of 5% saline or 10 mL
of 28.4% HS. This may be repeated if serum sodium remains at less
than 155 mmol/L and plasma osmolality is less than 320 mOsm/L.
Targeting a specific serum sodium is unwise as total body sodium and
water will progressively rise and may contribute to delayed
intracranial hypertension. Treatment with HS is generally considered
safe in TBI but it can cause central pontine myelinolysis if given to
patients with pre-existing chronic hyponatraemia.
EXPERT COMMENT
Equimolar doses of mannitol and HS reduce ICP equally, but HS does

not cause the diuresis associated with mannitol [8] and therefore does
not risk decreasing intravascular volume and cerebral blood flow. It is
thought that HS may improve CPP to a greater extent than mannitol
and may improve brain tissue oxygen values [9]. In a small study of
38 patients, HS provided better ICP control than mannitol with a
concomitant reduction in inotropic requirements, but this
physiological advantage did not translate into improved outcomes
[10]
HS seems to be gaining favour in most places, but a meta-analysis of

randomized controlled trials (RCTs) comparing the two directly has
found trials to have been underpowered and did not find statistically
significant differences in outcome or mortality [11]. In practice, it is
common to give mannitol or the lower-concentration HS solutions
(7.5% and below) on presentation of a patient before central venous
access has been established.
LEARNING POINT Cerebral perfusion pressure
Current Brain Trauma Foundation guidelines focus on targeted

management of ICP and CPP where:
Page 9 of 34

The Neuroanaesthesia Society of Great Britain and Ireland and the

Society of British Neurological Surgeons currently recommend that
the arterial transducer is set at the level of the tragus (approximating
the middle cranial fossa), regardless of the patient position, rather
than the phlebostatic axis (heart level) to enable more accurate
calculation of CPP. Individual differences in cerebral arterial and
venous circulations mean that it is not possible to determine a
coefficient (C) that accurately takes this into account if the
transducer is left at the phlebostatic axis:
A CPP target of 60–70 mmHg is commonly used as cerebral

oxygenation decreases at lower pressures even with an intact
cerebral autoregulation. CPP is used as a surrogate for cerebral blood
flow, but cerebral vascular resistance is variable, so even with an
adequate CPP there may still be areas of reduced perfusion. CPP may
be increased by augmenting MAP or reducing ICP, but these
interventions (including vasopressors, inotropes, or fluid
resuscitation) may be harmful.
Cerebrovascular pressure reactivity is the ability of cerebral vessels

to respond to changes in transmural pressure. The relationship
between ICP and arterial blood pressure can be used to determine
the cerebrovascular pressure reactivity index (PRx) for each patient.
PRx can be interpreted as an index of cerebral autoregulation
(positive implies impaired reactivity, negative intact cerebral
reactivity).
To target the best blood pressure, individualized CPP thresholds or an

‘optimal CPP’, can be determined. This is the lowest point on a CPP
versus PRx graph, that is, where cerebral autroregulation is working
at its best. Use of the optimal CPP has been associated with an
improved outcome and may present an avenue for more personalized
care.
LEARNING POINT Intracranial pressure monitoring

devices
Raised ICP is associated with worse neurological outcomes. ICP

monitoring is considered to be the standard of care for severe TBI
worldwide [12].
Brain Trauma Foundation guidelines list the following indications for

ICP monitoring:
● Patients with moderate–severe TBI who cannot be serially

neurologically assessed.
Page 10 of 34

● Severe head injury (GCS <8) with an abnormal CT scan.

● Severe head injury (GCS <8) with a normal CT if any two of the
following are present: age over 40 years, systolic blood pressure
less than 90 mmHg, or abnormal posturing [12].
The most commonly used devices to monitor ICP are intraventricular

catheters (EVD or a ventriculostomy drain) and intraparenchymal
fibreoptic monitors.
EVDs are the gold standard, and are placed in the lateral ventricle at
the level of the foramen of Monro. Zero level is the external auditory
meatus. These drains have the advantage of enabling monitoring as
well as treatment of an elevated ICP via cerebrospinal fluid drainage.
Risks of an EVD include parenchymal haematoma, infection (usually
ventriculitis), damage to brain parenchyma, and overventing of
cerebrospinal fluid.
Intraparenchymal monitors have lower complication rates including

less risk of bleeding, and infection. Their smaller diameter also leads
to less neuronal injury compared to an EVD. However, they are only
able to be calibrated prior to insertion and are prone to drift off the
zero point over time after insertion. They also do not indicate
infratentorial pressure.
Extradural monitors use a catheter inserted via a burr hole but that
does not penetrate the dura. They often have signal damping and so
underestimate high ICP.
In general, an ICP greater than 15 mmHg is considered to be

abnormally high. Most guidelines aim for either an ICP less than 20
mmHg or less than 25 mmHg, but there is little evidence for an exact
cut off. Some protocols allow for a target of 20 mmHg to be relaxed to
25 mmHg if an adequate CPP is maintained.
EVIDENCE BASE Benchmark Evidence from South

American Trials: Treatment of Intracranial Pressure
(BEST:TRIP) [13]
● 324 patients (ICP monitoring group, n = 157; imaging-clinical

examination group, n = 167)
● Intervention: ICP monitoring with treatment targeted at
maintaining ICP at less than 20 mmHg versus treatment based on
clinical finding and CT scan results.
● Primary outcome: composite of 21 components including
measures of survival, functional status, and neurocognitive status.
Page 11 of 34

● No significant difference between the groups for the primary

outcome measure.
EXPERT COMMENT
Rather than a test of ICP as a target per se this trial tested two
different TBI management strategies in a resource-limited setting. It
indicates that we need to refine how ICP is used in TBI management,
better integrating signals from all available information and monitors.
The patient was admitted to the ICU. He was sedated with propofol and
alfentanil infusions. A nasogastric tube was inserted, after a base of skull
fracture was been excluded on CT, and enteral feed started. Tier one
neuroprotective measures were instituted to keep his ICP at less than 20
mmHg and CPP greater than 60 mmHg (see Learning point on ‘Tiered
approach to management of raised ICP’).
LEARNING POINT Tiered approach to management of

raised intracranial pressure
Protocolized management of severe TBI has been shown to improve

outcomes [14]. Such protocols tend to be organized into tiers that
reflect increasing intensity of therapy and increasing risk of side
effects secondary to this therapy. The simplest approach is two tiers;
however, some protocols break down the tiers further to encourage a
step-wise progression in ICP management ensuring the simplest and
safest interventions are done first. There is no clear consensus on
how therapies should be split across two-, three-, or four-tier
protocols and this should be considered when interpreting the results
of RCTs or reading different protocols. An example of a split into tier
one and tier two therapies is given in Table 5.3.
Table 5.3 Tiered treatments for management of raised ICP
Tier one
1 Sit the patient up at 30–45°. Improve venous drainage. If

this is not possible because of pelvic and other injuries, sit
the patient up as much as allowed to reduce ICP without
reduction in CPP, or tilt the entire bed
Page 12 of 34

2 Avoid jugular compression by positioning the head facing

forward
3 Remove the cervical spine collar. This may reduce ICP by

approximately 4–5 mmHg. In a patient with an uncleared
cervical spine, make it obvious to staff that spinal
precautions are still in place, e.g. by placing sandbags on
either side of the neck
4 Improve cerebral venous outflow by ensuring tracheal tube

ties are not tight
5 Avoid internal jugular lines where possible, due to the

increased risk of thrombus
6 Decrease PEEP if feasible while ensuring adequate

oxygenation. A PEEP of 5 cmH2O has no effect on ICP but
in patients with raised ICP, PEEP of 10–15 cmH2O may
increase ICP by 1–2 mmHg
7 If there is an EVD, vent cerebrospinal fluid
8 Aim for normocarbia (PaCO2 4.5–5.0 kPa)
9 Sedation and analgesia
10 Paralysis
11 Osmotherapies (mannitol, hypertonic saline)
Tier two
1 Barbiturate coma
2 Therapeutic hypothermia (moderate, 32–34°C)
3 Decompressive craniectomy
PEEP, positive end-expiratory pressure.
LEARNING POINT Sedation
Page 13 of 34

Benzodiazepines and propofol reduce cerebral metabolic rate

(CMRO2), cerebral blood flow, and ICP without impairing cerebral
autoregulation and CO2 reactivity. However, as the level of metabolic
suppression achieved with midazolam is much less than with
propofol, and it is associated with increased incidence of delirium and
withdrawal symptoms, propofol is the sedative of choice.
Higher-dose, prolonged propofol infusions greater than 4 mg/kg/hour

are associated with propofol infusion syndrome and the risk of
propofol infusion syndrome is exacerbated by factors which may
impair propofol metabolism (e.g. therapeutic hypothermia). This
poorly understood syndrome is associated with progressive cardiac
failure, rhabdomyolysis, metabolic acidosis, and renal failure. High
propofol requirements therefore may require the addition of a
benzodiazepine. Another indication includes patients with
benzodiazepine dependency to avoid unrecognized withdrawal.
Opioids are not directly neuroprotective but are hypnotic sparing,

provide analgesia, and have antitussive properties. This may be
particularly useful to minimize ICP rises secondary to coughing, while
enabling neurological assessment in suitable patients.
Barbiturates, typically thiopentone, are very effective at reducing ICP

via profound cerebral metabolic suppression. They modulate the
GABA chloride-ion channel, inhibiting the action potential by
producing neuronal hyperpolarization. They also inhibit excitatory
L-glutamate AMPA receptors, stopping calcium transport through
voltage-gated calcium channels. Following a bolus of thiopentone,

termination of its effects occurs mainly by redistribution of the
relatively lipophilic drug into tissues, particularly fat. Prolonged
infusions lead to significant accumulation in fat and continuing
sedation long after infusions have been stopped. This long ‘context-
sensitive half-life’ (thiopentone 6–46 hours) causes the kinetics to
change from first order to zero order when burst suppression is
achieved. Myocardial depression, central vasomotor depression, and
haemodynamic instability may occur. These side effects mean that
barbiturates tend to be restricted to patients with intracranial
hypertension refractory to safer treatments.
LEARNING POINT Venous thromboembolism

prophylaxis
The hypercoagulability induced in TBI increases the risk of deep vein

thrombosis, which affects approximately one in six patients [15].
However, the precise time for safe and effective chemical prophylaxis
without contributing to progression of intracranial haemorrhage is
uncertain. There is little evidence on which to base guidelines, which
Page 14 of 34

has led to considerable practice variation and clinical uncertainty. A

common approach is to wait for stabilization of bleeding seen on
serial CT scans, with chemical prophylaxis being started 24–48 hours
after lack of progression is demonstrated [16]. In patients who are
not on chemoprophylaxis, thromboembolic disease stocking and/or
intermittent pneumatic compression devices should be used where
possible. Other options include the use of inferior vena cava filters,
these may be particularly of use in patients with a concurrent pelvic
injury (see also Case 13).
LEARNING POINT Nutritional support
After a severe TBI patients tend to be hypermetabolic, hypercatabolic,

and hyperglycaemic. Early enteral feeding is recommended, as it
helps to stimulate gut function, preserve intestinal mucosal integrity,
preserve the immunological gastrointestinal tract barrier function,
and reduce infection rates. A Cochrane review (284 patients) found
no difference in the mortality rate of patients who were fed early
compared with those fed later [17]. (See also Case 13.)
LEARNING POINT Fluids
Isotonic crystalloids should be used for fluid management and 0.9%

sodium chloride is the recommended solution. However, large
volumes of 0.9% sodium chloride cause hyperchloraemic metabolic
acidosis. Hypotonic solutions (e.g. 5% dextrose) may reduce serum
osmolality and should be avoided in the acute phase of injury. In the
Saline versus Albumin Fluid Evaluation (SAFE) trial, 4% albumin was
associated with increased mortality in patients with TBI and therefore
should be avoided [18].
Over the first few hours in ICU, his urine output increased to more than
250 mL/hour and his plasma sodium increased from an admission value of
140 mmol/L to 159 mmol/L (Figure 5.2). Matched plasma (320 mOsm/L)
and urinary osmolality (<300 mOsmol/L) were consistent with diabetes
insipidus and he was administered 1-deamino-8-D-arginine vasopressin
(DDAVP); this led to a rapid reduction in urine output to normal volumes.
Page 15 of 34

Figure 5.2
Course of sodium for the first week after intensive care admission. The
initial sharp rise corresponds to the development of diabetes insipidus.
LEARNING POINT Sodium in traumatic brain injury
Disorders of sodium homeostasis are common after TBI. Repeated

hyperosmolar therapy is a common cause of hypernatraemia. Mild
increases in sodium may be tolerated. Approximately 1% of patients
may develop central diabetes insipidus voiding large volumes of dilute
urine, and are at risk of dehydration. The more severe
hypernatraemia of diabetes insipidus will require DDAVP. Intravenous
water replacement may reduce the osmolality too rapidly and enteral
water is preferred. Hypernatraemia is associated with an increased
risk of death even in patients without diabetes insipidus [19].
Hyponatraemia is common and may worsen cerebral oedema,

decrease consciousness, and reduce the seizure threshold. It is
usually considered to be secondary to either the syndrome of
inappropriate antidiuretic hormone secretion or cerebral salt-wasting
syndrome but the distinction is often difficult (Table 5.4). The speed at
which hyponatraemia should be normalized depends on its chronicity,
as rapid correction in chronic hyponatraemia may cause central
pontine myelinolysis. Whether this is due to rapid sodium correction
per se, or whether it is due to other factors in predisposed patients
(e.g. chronic alcoholism) is unclear.
Page 16 of 34

Table 5.4 Disordered sodium homeostasis after TBI
Serum sodium Volume status Plasma osmolality Urine osmolality Management
Dehydration Increased Hypovolaemic Increased Increased Volume replacement
Central diabetes Increased Hypovolaemic Increased Decreased DDAVP

insipidus May need 5%
dextrose or 0.45%
normal saline
Syndrome of Decreased Euvolaemic or Decreased Increased Fluid restriction

inappropriate hypervolaemic If not effective,
antidiuretic hormone consider hypertonic
secretion (SIADH) saline
Cerebral salt wasting Decreased Hypovolaemic Decreased Increased Volume replacement

with normal saline.
If not effective,
consider hypertonic
saline and
fludrocortisone
Page 17 of 34
and Legal Notice).
The patient’s ICP continued to remain a problem despite the tier one
interventions. While his serum sodium level remained less than 155
mmol/L and plasma osmolarity level less than 320 mOsm/L he was given
HS boluses. After this, boluses of thiopentone were administered which
temporarily reduced the ICP. On the second day, a CT brain scan was
repeated to exclude a surgically amenable cause for the ICP rises. This
scan demonstrated that the cerebral contusions had markedly increased
in size.
LEARNING POINT Surgical management after

Prompt evacuation of subdural and extradural haemorrhage causing

mass effect is well established as appropriate therapy. However,
evidence is lacking about how best to manage intraparenchymal
haemorrhages and contusions, as well as raised ICP refractory to
medical management. These knowledge gaps have stimulated several
surgical trials over the past decade.
EVIDENCE BASE
Surgical Trial in Traumatic Intracerebral

Haemorrhage (STITCH(Trauma)) [20, 21]
● Halted early by the UK funding authority for failure to recruit.

Results need to be interpreted in this context.
● Included 170 randomized patients (initial target 840).
● Inclusion criteria: to recruit within 48 hours of TBI. Up to two
intraparenchymal haemorrhages of greater than 10 mL without an
extradural or subdural haematoma that required surgery.
● Exclusion criteria: significant surface haematoma (extradural or
subdural haemorrhage) needing surgery, three or more separate
haematomas, cerebellar haemorrhage, or contusion.
● Intervention: early evacuation of the haematoma by a method of
the surgeon’s choice (within 12 hours of randomization), combined
with appropriate best medical treatment versus initial conservative
treatment. This was best medical treatment combined with
delayed (>12 hours after randomization) evacuation if indicated by
GCS score, neurology, and ICP/CPP in invasively monitored
patients.
● Outcome measure: dichotomized Glasgow Outcome Scale.
Page 18 of 34

● Result: no significant difference between the two groups.

● Conclusions: surgery in this group cannot currently be
recommended. Study was likely under-powered.
Decompressive Craniectomy (DECRA) trial [22]
● Included 155 patients (3478 patients screened)

● Inclusion criteria: ages 15–59 years, severe non-penetrating
injury (GCS score <8) or moderate diffuse injury on CT (Marshall
grade III)
● Exclusion criteria: unsurvivable injury, dilated unreactive pupils,
mass lesions requiring surgery, spinal cord injury, or cardiac
arrest.
● Intervention: early (within 72 hours) decompressive craniectomy
(n = 73) versus standard care (n = 82) of whom 15 required
craniectomy.
● Trigger for intervention: spontaneous (non-stimulated) increase
in ICP for longer than 15 min within 1-hour period, despite
optimized first-tier interventions.
● Outcome measure: unfavourable (composite of death, vegetative
state, or severe disability) on extended Glasgow Outcome Scale
(eGOS) at 6 months.
● Results: patients in the craniectomy group had:
◦ less time with ICP above treatment threshold (P <0.001)

◦ fewer interventions for increased ICP (P <0.02)
◦ fewer days in ICU (P <0.001)
◦ (primary outcome) worse scores on eGOS than those who had
standard care and greater risk of unfavourable outcome.
● Rates of death at 6 months were similar in the craniectomy

group (19%) and the standard-care group (18%).
Randomised Evaluation of Surgery with Craniectomy

for Uncontrollable Elevation of Intracranial Pressure
(RESCUE-ICP) [23]
● Included 408 patients.

● Inclusion criteria: 10–65 years, abnormal CT, ICP monitoring in
situ, raised ICP (>25 mmHg) for 1–12 hours despite tier one and
tier two measures described previously. Patients could be included
if they had already had surgery as long as the operation was not a
craniectomy (so bone flap was replaced at the end of procedure).
● Exclusion criteria: bilateral fixed dilated pupils, bleeding
diathesis, or injury deemed to be unsurvivable.
Page 19 of 34

● Primary outcome: eGOS at 6 months using a proportional odds

model.
● Primary results: lower mortality and higher rates of vegetative
state, lower severe disability and upper severe disability than
medical care in intervention group. Rates of moderate disability
and good recovery were similar.
● Secondary outcomes: at 12 months more patients with
craniectomy had favourable outcomes (upper severe disability or
better) than those in the medical group (45.4% vs 32.4%; P =
0.01).
EXPERT COMMENT
While RESCUE-ICP showed a clear survival benefit for late

decompression, more survivors in the surgical group had severe
disability at 6 months. This trial supports the need for more
investigation into how best to select patients for decompressive
craniectomy after TBI.
On day 4, the patient became febrile to 39°C with increased respiratory

secretions and a rise in his oxygen requirements. After a full septic
screen, he was started on antibiotics for a ventilator-associated
pneumonia. Concurrent with the rise in temperature, it became more
difficult to keep his ICP and CPP within target ranges. He was cooled to
normothermia with subsequent improvement in ICP and CPP control.
LEARNING POINT Temperature management
Peak temperatures below 37°C and above 39°C in the first 24 hours
after ICU admission have been associated with an increased risk of
death compared with normothermia [24]. There is some evidence that
patients who arrive hypothermic have worse outcomes. It is likely that
hypothermia is a marker of injury severity and active rewarming of
such patients is generally not recommended. However, in practice
many patients with TBI have multiple injuries and are often
aggressively rewarmed to reduce bleeding.
In contrast, especially during the early phase of TBI, aggressive

management of hyperthermia is considered beneficial because it
decreases ICP and mitigates the increase in metabolic rate normally
associated with fever. Fever will increase glutamate release and
inflammatory activity, further compromising an already injured brain.
Page 20 of 34

It is important not to assume that hyperthermia has a neurogenic

cause until other causes including sepsis and drugs and have been
excluded.
Hypothermia reduces intracranial hypertension, may provide

neuroprotection, and may prevent secondary brain injury via a variety
of mechanisms including the reduction of CMRO2, inflammation, and
oedema. However, hypothermia also has many side effects and
complications including immunosuppression, bradycardia, reduced
cardiac contractility, electrolyte abnormalities (which may be
secondary to cold diuresis), coagulopathy, and shivering. Whether and
when therapeutic hypothermia should be used is controversial;
consequently, its use is commonly limited to when elevated ICP is
refractory to other therapies. Rewarming must be controlled and
performed slowly (0.3–0.5°C/hour) to avoid systemic side effects
including haemodynamic compromise from vasodilation, arrhythmias,
and elevated ICP. Rapid rewarming has been associated with poorer
neurological outcomes in small studies [25].
EXPERT COMMENT
Eurotherm3235 provides evidence that using hypothermia as an early

measure to control ICP is harmful [26]. However, it provides no
guidance on the use of hypothermia for either refractory intracranial
hypertension after the failure of tier two or other tier three
interventions, or very early before intracranial hypertension and
injury are established. The Prophylactic Hypothermia Trial to Lessen
Traumatic Brain Injury (POLAR) is an RCT attempting to answer the
second question, by using cooling within 4 hours of injury, and is
currently recruiting [27].
EVIDENCE BASE European Study of Therapeutic

Hypothermia (32–35°C) for Intracranial Pressure
Reduction after Traumatic Brain Injury (Eurotherm3235)
[26]
● Included 387 patients (209 intervention group, 170 control

group).
● ICP greater than 20 mmHg despite tier one therapy.
● Intervention: hypothermia (32–25°C) with tier two therapy only
if cooling failed versus standard care with tier two therapies. Tier
three therapies (barbiturates and decompressive craniectomy)
were only used if tier two therapies failed to control ICP.
Page 21 of 34

● Primary outcome: eGOS at 6 months.

● Results: favourable outcome (eGOS 5–8, moderate disability or
good recovery) in 26% in the hypothermia group versus 37% in the
control group (P = 0.03).
By the second week, ICP was stable at less than 20 mmHg with no
intervention required. With sedation holds the patient became
hypertensive and tachycardic and he was intolerant of the tracheal tube;
his neurology remained poor at E2, M4. An electroencephalogram
showed no evidence of seizure activity.
LEARNING POINT Post-traumatic seizures
Post traumatic seizures occur ‘early’ (within 7 days) and/or ‘late’ (>7
days) with an incidence ranging between 4–25% and 9–42%
respectively. The exact incidence is difficult to quantify accurately
because of difficulties in clinically diagnosing seizures, as well as
potentially masking signs with the use of sedatives. Risk factors for
early post-traumatic seizures are a GCS score less than 10,
intracranial haematoma, contusions, penetrating injuries, and
depressed skull fractures.
Seizures in the acute phase may increase ICP, as well as place an

increased metabolic demand on damaged brain tissue and so
aggravate secondary brain injury. While a recent Cochrane review
found only low-quality evidence that early treatment with an
antiepileptic drug compared with placebo or standard care reduced
the risk of early post-traumatic seizures, the adverse sequelae of such
seizures mean it is not uncommon for clinicians to prescribe 7 days of
antiepileptic drugs. Phenytoin or levetiracetam are commonly used,
and while there is no clear evidence favouring either, there is some
literature suggesting that phenytoin may be associated with worse
neurological and functional outcomes [28]. Subclinical seizures may
be found using continuous electroencephalographic monitoring but
the significance of these is as yet unknown. There is no evidence that
using antiepileptic drugs reduces the risk of late seizures or improves
neurological outcome or mortality.
EXPERT COMMENT
This is a contentious area with a paucity of good evidence on which to

base recommendations. There is no consensus on the need for
prophylactic antiepileptic drugs, which drug to give, and the duration
Page 22 of 34

of treatment. Given the need to balance side effects of antiepileptic

drugs with avoiding the detrimental effect of seizures, those at
highest risk may represent a subgroup in whom to target therapy.
Those wanting more detail about the pros and cons of seizure
prophylaxis are directed to a pro/con debate in the literature [29].
An MRI was performed on day 10 which revealed expected progression of

the contusions, and importantly that there were no brainstem lesions. A
decision was made to insert a percutaneous tracheostomy. The patient
continued to make slow neurological improvement and was discharged to
a rehabilitation centre.
He returned 6 months later for follow-up at the neurotrauma clinic where

it was found that he had made steady progress, and while he still
required assistance with activities of daily living he was expected to be
discharged home in the next month.
LEARNING POINT Prognosis after traumatic brain

injury
Outcomes after TBI range from complete recovery through to severe

disability, including vegetative states, and death. Being able to
accurately predict outcome would help to support early clinical
decision-making, improve individual management, and enable more
effective clinical trials to be developed. As yet, there is no tool that is
sufficiently accurate for the prediction of outcome to use on an
individual basis in clinical practice. The IMPACT model (International
Mission for Prognosis and Analysis of Clinical Trials; http://www.tbi-
impact.org) is the most extensively validated scoring system,
developed on a cohort of more than 9000 patients. There is a clear
association with poor outcome with advancing age, a low GCS score
(especially the motor component), bilateral fixed pupil(s), single
episodes of hypotension or hypoxaemia, and certain CT abnormalities
including the presence of traumatic subarachnoid haemorrhage.
Important scoring systems

The GCS was designed for use in the acute phase of TBI [30]. It is a
useful tool for the early assessment of injury severity in addition to
providing some crude prognostic information (Table 5.5). Immediately
after an injury, the GCS may be depressed by other factors including
hypoxaemia, hypotension, and seizures. Post-resuscitation, pre-
intubation GCS score is the most common score used in prognostic
models but the optimal timing to assess the GCS score is unclear.
Page 23 of 34

Table 5.5 Important scoring systems
Glasgow Coma Scale Glasgow Outcome Scale
Eye opening 1 Dead
Spontaneous 4 2 Vegetative Exhibits no cortical

function
To sound 3 3 Severe disability Dependent for daily

support
To pain 2
No response 1
Best verbal response 4 Moderate disability Disabled but independent,

no assistance with
Orientated 5 activities of daily living
Confused 4
Inappropriate words 3 5 Good recovery Resumption of normal life,

may have minor deficits
Incomprehensible sounds 2
None 1
Page 24 of 34
and Legal Notice).
Best motor response
Obeys commands 6 Extended Glasgow Outcome Scale
Localizes pain 5 1 Dead
Flexion (withdrawal) 4 2 Vegetative state
Flexion (abnormal) 3 3 Lower severe disability
Extension 2 4 Upper severe disability
5 Lower moderate disability
6 Upper moderate disability
None 1 7 Lower good recovery
8 Upper good recovery
Page 25 of 34
and Legal Notice).
The Glasgow Outcome Scale and its extended version (eGOS) are the
most common outcome scores used in clinical trials of TBI [31]. Many
studies dichotomize these scores for ease of analysis. For example,
the Glasgow Outcome Scale may be categorized into good outcome
(score of 4–5) and poor outcome (score of 1–3). For the eGOS, a good
outcome is generally judged as a score of 4–8 and poor as 1–3. The
scores are relatively quick and easy to apply to large numbers of
patients in the context of a clinical trial, but they do not give a true
reflection of the neurocognitive status, functional status, or
psychiatric issues that patients may experience after TBI.
Discussion
TBI is a major cause of death and disability, particularly in those

less than 40 years of age and the elderly. In the UK alone, TBI affects 0.5–
1 million people annually, resulting in nearly 150,000 hospital admissions
per year (http://www.hesonline.nhs.uk). The great complexity and
variability of TBI represents a significant barrier to the identification and
implementation of effective treatment strategies.
Conceptually, TBI has been divided into primary and secondary injury.
After the initial insult there is a complex cascade of events that occur as a
result of the primary insult, as well as secondary injury that occurs
because of complications of the injury including ischaemia, hypoxaemia,
hypotension, and cerebral oedema. The mainstay of ICU management is
supportive care aimed at minimizing secondary injury, particularly that
caused by cerebral ischaemia. The pathophysiological complexity
requires a coordinated approach, and there is a consensus that rigorous
and continuous monitoring and management of TBI is associated with an
improved outcome. Using ICP and CPP target-directed management
based on the Brain Trauma Foundation guidelines remains a standard of
care following TBI [7].
It is common to take a staged or tiered approach to ICP and CPP

management. In general, the tiers reflect increasing intensity of therapy
and increasing risk of side effects. To minimize side effects, simple
measures are instituted first. In addition to neuroprotective measures,
general ICU management is optimized, including optimization of cardiac
and respiratory function, glycaemic control, pyrexia management, and
early enteral nutrition.
The clinical neurological examination in a sedated and ventilated patient

with TBI is often an insensitive tool to monitor disease progression and/or
response to therapies. However, the BEST:TRIP study showed that
clinical examination may still play an important role, with patients
managed using clinically and CT-guided therapy having similar outcomes
to ICP-guided therapy in resource-poor settings [13].
Page 26 of 34

To aid clinical examination, the combination of many monitoring

techniques (commonly termed ‘multimodality monitoring’ (MMM)) may
help to guide management by providing important information about
brain physiology and metabolism, to assist titration of medical and
surgical therapies. The European Society of Intensive Care Medicine in
collaboration with the Neurocritical Care Society has released a
consensus summary statement on the use of MMM [32].
ICP measurement is the most commonly used neurointensive care-

specific monitor but it simply reflects the severity of disease. In patients
at particular risk of cerebral ischaemia, hypoxaemia, energy failure, and
glucose deprivation, it may be useful to use more specialized techniques
such as cerebral microdialysis and brain parenchymal oxygen tension in
addition to ICP monitoring. Some specialist monitors (e.g. brain tissue
oxygen) are becoming increasingly used outside of the academic
environment, and the concepts of MMM are more commonly being
applied across all neurointensive care units. The invasive and labour
intensive nature of these more specialized monitors, along with
difficulties in integrating and interpreting large amounts of temporal
data, is challenging. Tools are being developed which enable such
integration to be done in a clinically meaningful way (Figures 5.3 and
5.4).
Figure 5.3
Example of the ICM+ software which enables continuous measurement
and visualization of variables. In this example, about midway along the
graph, the CPP suddenly drops despite a constant arterial blood pressure.
This corresponds to a rise in ICP above 30 mmHg and may represent a
plateau wave. Lagging slightly behind, the brain tissue oxygen tension
(PbtO2) decreases, indicating ischaemic stress. The rise in PbtO2 is
secondary to a rise in the fraction of inspired oxygen (FiO2) as part of the
therapeutic intervention.
Page 27 of 34

Figure 5.4
Example of MMM in a patient with bifrontal contusions. (a) The lactate/
pyruvate (L/P) ratio was high in this patient (up to 78) despite an ICP less
than 20 mmHg and adequate brain tissue oxygenation. The L/P ratio was
reflected by a low cerebral glucose (not shown) and resolved with a
higher blood glucose level. Panel (b) shows the location of the monitors
on CT which were in normal-appearing white matter. Panel (c) gives an
example of a triple bolt through which an intraparenchymal pressure
transducer (red arrow), brain tissue oxygen monitor (green arrow), and a
cerebral microdialysis catheter (blue arrow) have been inserted.
There are many benefits to using MMM in TBI and these include the
following:
● Monitoring the temporal changes in a patient’s pathophysiology and

their response to treatment.
● Better and earlier detection of secondary events that may be
amenable to intervention.
● Potential to enable more targeted and individualized therapy.
● Enables cross-validation between the different monitors to enable
artefact rejection and improved confidence in treatment decisions.
LEARNING POINT Intracranial pressure waveforms
There are three distinct peaks to an ICP waveform, synchronous with

the arterial pulse (Figure 5.5). Each peak is only 10–30% of mean ICP
(so usually <4 mmHg in amplitude):
Page 28 of 34

Figure 5.5
ICP waveforms.
● Percussion wave (P1): correlates with the arterial pulse being

transmitted.
● Tidal wave (P2): represents cerebral compliance.
● Dicrotic wave (P3): correlates with the closure of the aortic
valve.
LEARNING POINT Examples of specialized

monitoring
Oxygenation
Global: jugular bulb oxygen saturation (SjvO2)
A venous catheter is sited in the jugular bulb to detect ischaemia
(oxygen saturation <55%) and hyperaemia (oxygen saturation >75%).
However, it is a global measurement and even normal values cannot
rule out clinically important ischaemia; for this reason it is not
commonly used.
Focal: brain parenchymal oxygen tension (PbtO2)

Typically sited in the right frontal white matter or on the side of a
focal lesion, it enables a continuous focal measurement of cerebral
oxygenation. Normal values are 23–35 mmHg and values below 20
mmHg represent compromised brain oxygen and intervention should
be considered. It is not yet clear if targeting parenchymal oxygen
tension improves outcome.
Focal metabolism
Page 29 of 34

Cerebral microdialysis
A fine coaxial catheter is inserted into frontal white matter. It has a
dialysis membrane on its outer surface and low flow rates of dialysis
fluid are passed through the catheter using a pump mechanism. Vials
of fluid are removed every 10–60 min which enables the measurement
of concentrations of substances in the cerebral extracellular fluid
which commonly include lactate, pyruvate, and glucose, but
neurotransmitters and cytokines may also be measured. Being a focal
monitor, the values obtained must be interpreted in the context of
catheter location, for example, is it located in normal-appearing brain
or is it peri-contusional? Persistently low glucose or an elevated
lactate/pyruvate ratio, or both, is a strong predictor of mortality and
poor outcome. These abnormalities in the microdialysis
measurements are also associated with long-term atrophy.
LEARNING POINT Systemic complications of

The presence of extracranial injuries has a significant impact on

outcome after TBI, both in the acute phase and through rehabilitation
and beyond. However, even in the absence of direct extracranial
organ injury, more than 80% of patients exhibit dysfunction of at least
one non-neurological organ system after severe TBI. Multiorgan
dysfunction occurs in 60% and is independently associated with
poorer outcomes. Iatrogenic injuries may also occur, for example,
cardiorespiratory complications may be associated with interventions
to optimize CPP.
LEARNING POINT Neuroprotective agents
As yet, while many agents have shown promise as neuroprotective

agents in animal models, there have been no phase III trials that
support the use of any agent. The lack of translation from animals to
humans is thought to be, at least in part, because animal models do
not reflect accurately the complex pathophysiological processes that
occur in humans after TBI, as well as the great heterogeneity of
disease patterns. Examples of therapies studied include the following:
● Steroids: the Medical Research Council (MRC) Corticosteroid

Randomization After Significant Head injury (CRASH) trial
investigated 10,000 patients of all severities of TBI [33].
Intervention was 48 hours of intravenous steroids versus placebo.
The trial was stopped early as mortality was increased within 14
Page 30 of 34

days and at 6 months, and there was an increased risk of severe

disability in the intervention group. As a result, steroids are not
recommended in the management of TBI. A low dose of steroids to
replace endogenous deficiency was not studied in CRASH and in
selected patients such therapy may be appropriate.
● Erythropoietin: experimentally it has neuroprotective, anti-
inflammatory properties but two recent studies showed no
improvement in neurological status in patients who received the
drug.
● Progesterone: in animal models, progesterone had multifactorial
effects including inhibition of inflammatory cytokines, reduction of
apoptosis, and reduction of vasogenic oedema. However, two
phase III trials found no treatment effect.
LEARNING POINT Tranexamic acid
CRASH-2 showed that tranexamic acid reduced mortality in trauma

patients with significant extracranial bleeding when given within 8
hours of injury. The CRASH-3 trial is being conducted to assess the
effect of tranexamic acid on risk of death or disability in patients with
TBI.
The intensive care management of TBI is centred on a

comprehensive, multimodal, and often protocolized approach that is
aimed at the prevention of secondary cerebral insults, maintenance of
adequate CPP, and prevention of cerebral ischaemia. Improved
understanding of the pathophysiology after TBI, as well as the effects
of different management strategies, may provide an opportunity for
more personalized care in the future.
References
1. National Institute for Health and Care Excellence. Head Injury:
Assessment and Early Management. Clinical guideline [CG176]. London:
National Institute for Health and Care Excellence; 2014. Available from:
https://www.nice.org.uk/guidance/cg176/.
2. Scottish Intercollegiate Guidelines Network. Early Management of

Patients with a Head Injury. Guideline 110. Edinburgh: Scottish
Page 31 of 34

Intercollegiate Guidelines Network; 2009. Available from: http://

www.sign.ac.uk/assets/sign110.pdf.
3. Ackland H, Cooper D, Malham G, Kossmann T. Factors predicting

cervical collar-related decubitus ulceration in major trauma patients.
Spine. 2007;32:423–8.
4. Padayachee L, Cooper D, Irons S, et al. Cervical spine clearance in

unconscious traumatic brain injury patients: dynamic flexion-extension
fluoroscopy versus computed tomography with three-dimensional
reconstruction. J Trauma. 2006;60:341–5.
5. Oh J, Asha S, Curtis K. Diagnostic accuracy of flexion-extension

radiography for the detection of ligamentous cervical spine injury
following a normal cervical spine computed tomography. Emerg Med
Australas. 2016;28:450–5.
6. Coles J, Minhas P, Fryer T, et al. Effect of hyperventilation on cerebral

blood flow in traumatic head injury: clinical relevance and monitoring
correlates. Crit Care Med. 2002;30:1950–9.
7. Brain Trauma Foundation, American Association of Neurological

Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the
management of severe traumatic brain injury. VIII. Intracranial pressure
thresholds. J Neurotrauma. 2007;24:S55–8.
8. Francony G, Fauvage B, Falcon D, et al. Equimolar doses of mannitol

and hypertonic saline in the treatment of increased intracranial pressure.
Crit Care Med. 2008;36:795–800.
9. Oddo M, Levine J, Frangos S, et al. Effect of mannitol and hypertonic

saline on cerebral oxygenation in patients with severe traumatic brain
injury and refractory intracranial hypertension. J Neurol Neurosurg
Psychiatry. 2009;80:916–20.
10. Jagannatha A, Sriganesh K, Devi B, Rao G. An equiosmolar study on

early intracranial physiology and long term outcome in severe traumatic
brain injury comparing mannitol and hypertonic saline. J Clin Neurosci.
2016;27:68–73.
11. Burgess S, Abu-Laban R, Slavik R, Vu EN, Zed P. A systematic review

of randomized controlled trials comparing hypertonic sodium solutions
and mannitol for traumatic brain injury: implications for emergency
department management. Ann Pharmacother. 2016;50:291–300.
12. Carney N, Totten A, O’Reilly BS, et al. Guidelines for the management
of severe traumatic brain injury, 4th edition. Neurosurgery. 2017;80:6–15.
13. Chesnut R, Temkin N, Carney N, et al. A trial of intracranial-pressure

monitoring in traumatic brain injury. N Engl J Med. 2012;367:2471–81.
Page 32 of 34

14. Patel H, Menon D, Tebbs S, Hawker R, Hutchinson P, Kirkpatrick P.

Specialist neurocritical care and outcome from head injury. Intensive
Care Med. 2002;28:547–53.
15. Nichol A, French C, Little L, et al. Erythropoietin in traumatic brain

injury (EPO-TBI): a double-blind randomised controlled trial. Lancet.
2015;386:2499–506.
16. Paydar S, Sabetian G, Khalili H, et al. Management of deep vein

thrombosis (DVT) prophylaxis in trauma patients. Bull Emerg Trauma.
2016;4:1–7.
17. Perel P, Yanagawa T, Bunn F, Roberts I, Wentz R, Pierro A. Nutritional

support for head-injured patients. Cochrane Database Syst Rev.
2006;4:CD001530.
18. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and

saline for fluid resuscitation in the intensive care unit. N Engl J Med.
2004;350:2247–56.
19. Maggiore U, Picetti E, Antonucci E, et al. The relation between the

incidence of hypernatremia and mortality in patients with severe
traumatic brain injury. Critical care 2009;13:R110.
20. Gregson B, Rowan EN, Francis R, et al. Surgical Trial In Traumatic

intraCerebral Haemorrhage (STITCH): a randomised controlled trial of
early surgery compared with initial conservative treatment. Health
Technol Assess. 2015;19:1–138.
21. Mendelow A, Gregson B, Rowan E, et al. Early Surgery versus Initial

Conservative Treatment in Patients with Traumatic Intracerebral
Hemorrhage (STITCH[Trauma]): the first randomized trial. J
Neurotrauma. 2015;32:1312–23.
22. Cooper D, Rosenfeld J, Murray L, et al. Decompressive craniectomy in

diffuse traumatic brain injury. N Engl J Med. 2011;364:1493–502.
23. Hutchinson P, Kolias A, Timofeev I, et al. Trial of decompressive

craniectomy for traumatic intracranial hypertension. N Engl J Med.
2016;375:1119–30.
24. Saxena M, Young P, Pilcher D, et al. Early temperature and mortality

in critically ill patients with acute neurological diseases: trauma and
stroke differ from infection. Intensive Care Med. 2015;41:823–32.
25. Thompson H, Kirkness C, Mitchell P. Hypothermia and rapid

rewarming is associated with worse outcome following traumatic brain
injury. J Trauma Nurs. 2010;17:173–7.
26. Andrews PJ, Sinclair HL, Rodriguez A, et al. Hypothermia for

intracranial hypertension after traumatic brain injury. N Engl J Med.
2015;373:2403–12.
Page 33 of 34

27. Nichol A, Gantner D, Presneill J, et al. Protocol for a multicentre

randomised controlled trial of early and sustained prophylactic
hypothermia in the management of traumatic brain injury. Crit Care
Resusc. 2015;17:92–100.
28. Szaflarski J. Is there equipoise between phenytoin and levetiracetam

for seizure prevention in traumatic brain injury? Epilepsy Curr.
2015;15:94–7.
29. Verduzco-Gutierrez M, Reddy C, O’Dell MW. Is there a need for early

seizure prophylaxis after traumatic brain injury? PM R. 2016;8:169–75.
30. Teasdale G, Jennett B. Assessment of coma and impaired

consciousness. A practical scale. Lancet. 1974;2:81–4.
31. Jennett B, Snoek J, Bond MR, Brooks N. Disability after severe head
injury: observations on the use of the Glasgow Outcome Scale. J Neurol
Neurosurg Psychiatry. 1981;44:285–93.
32. Le Roux P, Menon D, Citerio G, et al. Consensus summary statement

of the International Multidisciplinary Consensus Conference on
Multimodality Monitoring in Neurocritical Care: a statement for
healthcare professionals from the Neurocritical Care Society and the
European Society of Intensive Care Medicine. Intensive Care Med.
2014;40:1189–209.
33. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous

corticosteroids on death within 14 days in 10008 adults with clinically
significant head injury (MRC CRASH trial): randomised placebo-
controlled trial. Lancet. 2004;364:1321–8.
Page 34 of 34

Post-cardiac arrest care and prognostication

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Post-cardiac arrest care and prognostication
Author(s): Justine Barnett
DOI: 10.1093/med/9780198814924.003.0006
Expert commentary by Jerry Nolan
Case history
A 73-year-old man sustained a witnessed out-of-hospital cardiac

arrest (OHCA) at home. Cardiopulmonary resuscitation was started by a
family member immediately and the emergency services were called.
Paramedics arrived 7 min later. The electrocardiogram (ECG) showed the
initial heart rhythm was ventricular fibrillation (VF). A standard
resuscitation protocol was followed and after four shocks and a single
dose of adrenaline return of spontaneous circulation (ROSC) was
achieved. The time from collapse to ROSC was approximately 15 min.
During resuscitation, the patient’s airway was managed with an i-gel
supraglottic airway device and after ROSC he remained unconscious. He
was transferred to hospital with his lungs ventilated via the i-gel.
Page 1 of 21
EXPERT COMMENT
Paramedics are increasingly using supraglottic airways instead of

tracheal intubation when treating patients with OHCA. This is
because it has been difficult to get sufficient training in tracheal
intubation and to maintain these skills. A supraglottic airway is easier
to insert, is associated with shorter interruptions in chest
compressions, and, unlike tracheal intubation, is not associated with a
risk of unrecognized oesophageal intubation. A recent cluster
randomized trial (AIRWAYS-2) reported no overall difference in
neurological outcome, improved outcome in the i-gel group as this
enabled advanced airway management in a larger number of patients.
On hospital arrival, he remained in sinus rhythm with a heart rate of 88

beats/min (bpm) and arterial blood pressure of 115/55 mmHg. The
patient’s Glasgow Coma Scale (GCS) score was 5 (E1, V1, M3). Invasive
arterial monitoring was established and intravenous anaesthesia
commenced, the i-gel was then exchanged for a tracheal tube and
mechanical ventilation continued. During laryngoscopy, there was no
evidence of aspiration and his chest X-ray confirmed clear lung fields.
LEARNING POINT Post-cardiac arrest syndrome
Of the 60,000 people who have an OHCA in England each year, the
emergency medical services attempt resuscitation in approximately
29,000 (roughly 50%) and about 25% of these survive to be admitted
to an intensive care unit (ICU). Of those admitted, 30–40%
(approximately 7–9% of the original 29,000) survive to hospital
discharge, the majority with good neurological function [1].
Resuscitation care does not stop at the return of circulation and the
immediate and longer-term care, usually undertaken in an ICU, is
vital to ensure the best possible outcomes for these patients.
Post-cardiac arrest syndrome is the term given to the

pathophysiological changes that occur after a period of whole-body
ischaemia. These changes are exacerbated by the primary cause of
the arrest and any pre-existing comorbidities of the patient [2].
It includes:
● post-cardiac arrest brain injury

● post-cardiac arrest myocardial dysfunction
● systemic ischaemia/reperfusion
● precipitating pathology.
Page 2 of 21

In the emergency department, oxygen was titrated to maintain arterial

blood oxygen saturation at 94–96%. His lungs were ventilated with a tidal
volume of 6 mL/kg ideal body weight and positive end-expiratory pressure
of 5 cmH2O. The ventilation rate was adjusted to achieve a partial
pressure of carbon dioxide of 5.3–6.0 kPa (40–45 mmHg).
The patient did not have a history of hypertension so an initial mean

arterial pressure (MAP) of at least 65 mmHg was targeted. His
temperature was 35.9°C. With sedation established, he was administered
boluses of a neuromuscular blocking drug to prevent shivering.
LEARNING POINT Best practice guidelines
The optimal management of those in cardiac arrest and after ROSC is

reviewed regularly by the International Liaison Committee on
Resuscitation (ILCOR). Guidance is updated every 5 years after
evidence reviewers use the most recent literature to answer specific
resuscitation questions. The ‘Consensus on Cardiopulmonary
Resuscitation Science and Treatment Recommendations’ are graded
on the quality of the evidence and are then used as the basis for
national resuscitation guidelines. The latest ILCOR guidelines were
published in 2015 [3].
Best practice guidelines do not cite a specific GCS score at which a

post-cardiac arrest patient should be intubated and sedated; instead,
tracheal intubation is considered for any such patient who is
obtunded.
Hyper- and hypoxaemia is harmful to vulnerable neurons; for this

reason, when it can be measured reliably, arterial blood oxygen
saturation should be maintained in the range of 94–98%. A
randomized clinical trial (RCT) of air versus supplemental oxygen in
ST-elevation myocardial infarction documented increased myocardial
injury, recurrent myocardial infarction, major cardiac arrhythmia, and
larger infarct size at 6 months in the group given supplemental
oxygen therapy [4].Normocapnia is targeted because hypocapnia
causes cerebral ischaemia in the post-cardiac arrest population [5].
Although two observational studies have documented an association
between mild hypercapnia and better neurological outcome among
post-cardiac arrest patients, a recent systematic review documented
better outcomes among those with normocapnia in comparison with
those with hypercapnia [6]. A recent phase II RCT documented an
attenuated increase in neuron-specific enolase (NSE) values in post-
arrest patients treated with targeted mild hypercapnia compared with
targeted normocapnia [7]. A larger RCT comparing mild hypercapnia
Page 3 of 21

with normocapnia is planned and will include long-term survival as

the primary outcome.
The optimal MAP in the post-cardiac arrest patient is unknown but

likely needs to be individualized. Although some guidelines advocate
a target MAP of 65–70 mmHg, there is increasing evidence that
higher blood pressures are preferable (e.g. MAP of 85–105 mmHg),
particularly in the first few hours after ROSC, when cerebrovascular
resistance tends to be high [8]. The degree of myocardial dysfunction
after cardiac arrest varies and can be evaluated by serial
echocardiography. Fluid, dobutamine, and noradrenaline are the most
commonly used agents to support the circulation. Try to achieve a
systolic pressure sufficient to achieve a urine output of 1 mL/kg/hour
and a normal or decreasing lactate [9].
A 12-lead ECG showed marked ST depression in the inferior leads and an

acute coronary event was thought the likely cause of his cardiac arrest;
300 mg aspirin per rectum was administered.
After a discussion with the interventional cardiologist on call, the patient

was transferred directly to the coronary catheterization laboratory where
he underwent coronary angiography. This demonstrated a culprit lesion in
the right coronary artery; he was treated with primary percutaneous
coronary intervention (PCI) involving placement of a single stent which
re-established good distal flow.
The current recommendations on the management of patients undergoing

PCI were followed. These included giving aspirin and ticagrelor as
antiplatelet drugs, starting a statin, and introducing a beta blocker and
angiotensin-converting enzyme (ACE) inhibitor when his cardiac and
renal function allowed.
An echocardiogram after PCI demonstrated moderate left ventricular

systolic dysfunction and hypokinetic segments in the basal and mid-
inferior region consistent with a recent right coronary artery occlusion.
The right ventricle had good function and there were no valve
abnormalities identified.
LEARNING POINT Timing of coronary angiography
If the ECG shows ST elevation, immediate coronary angiography and

PCI is indicated because over 80% of patients will have an acute
coronary lesion [10]. Consider immediate angiography in patients
with ROSC in whom acute coronary syndrome (ACS) is suspected, for
example, left bundle branch block or minor ST or T-wave changes,
particularly in those resuscitated from a shockable rhythm [11].
There is currently no consensus on the timing of angiography among
Page 4 of 21

post-arrest patients without ST elevation on their 12-lead ECG but

they should be discussed with the nearest centre that provides
emergency PCI.
The use of troponins at 0 and 2 hours as a stand-alone measure for

excluding the diagnosis of ACS is strongly discouraged [12]. Follow
standard guidelines for the use of antiplatelet and anticoagulant
therapy in the management of ACS [13]. The management of ACS is a
subject under frequent review as stent technology and drug therapy
progresses. In general, it will include antiplatelet drugs, statins, beta
blockade, and ACE inhibitors. The timing of starting these drugs in
post-cardiac arrest patients will be determined by the amount of
organ dysfunction they develop after ROSC.
Identifying patients who have a non-cardiac cause for their arrest is

important, especially those with intracranial haemorrhage for whom
anticoagulation would be harmful. However, delaying PCI by
computed tomography (CT) scanning all arrest patients is also
unhelpful. If there is evidence of a prodrome of neurological or
respiratory symptoms (e.g. headache, seizure, focal deficits,
shortness of breath, or hypoxia) before the cardiac arrest, then a CT
head and chest is obtained before coronary angiography [14].
EXPERT COMMENT
Immediately after resuscitation from cardiac arrest, the 12-lead ECG

is unreliable for detecting acute coronary occlusion [15]. Although
there is general agreement that post-cardiac arrest patients with ST
elevation on the 12-lead ECG should undergo urgent coronary
angiography with PCI as required, there is no consensus on the
management of post-cardiac arrest patients with other ECG changes.
Many experts now advocate urgent coronary angiography for all post-
cardiac arrest patients without a clear non-cardiac cause of their
cardiac arrest [11]; others restrict this intervention to those patients
with an initial rhythm of VF/pulseless ventricular tachycardia.
Following a pilot trial [16], a randomized trial of expedited transfer to
a cardiac arrest centre for non-ST elevation VF OHCA is about to
start in London, UK.
There is no consensus on whether a CT brain scan should be

undertaken routinely before coronary angiography is performed in
the comatose survivor of OHCA. A group from Paris with considerable
experience in the treatment of such patients recommends direct
transfer to the cardiac catheterization laboratory without an initial
brain CT scan in those patients that have no prodrome before their
sudden cardiac arrest—these are highly likely to be primary cardiac
arrests [14]. Patients with neurological or respiratory prodromes
Page 5 of 21

undergo immediate CT brain and, if this is normal, chest CT with

pulmonary angiography to rule out pulmonary embolism and other
potential respiratory causes of cardiac arrest.
After tracheal intubation, the patient was sedated with infusions of

propofol and alfentanil. With his MAP consistently above 65 mmHg his
urine output was greater than 1 mL/kg/hour. His temperature was
monitored closely and, with sedation and exposure during the PCI, it
remained between 35°C and 36°C without intervention.
After PCI, the patient had a CT of his brain to exclude intracranial

pathology. He was then admitted to the ICU for ongoing care including
targeted temperature management (TTM).
In ICU, mechanical ventilation with a routine lung protective strategy was

continued. An intravascular temperature control catheter was inserted
into the femoral vein and a temperature-sensing urinary catheter sited.
With this, his temperature was maintained at 36°C. Neuromuscular
blocking drugs were used intermittently to prevent shivering and during
their use sedation was titrated to a Richmond Agitation–Sedation Scale
(RASS) of −4 (deep sedation) to avoid potential awareness.
LEARNING POINT Sedation
Sedatives are given to reduce cerebral and cardiac oxygen

consumption by reducing the metabolic rate and hence oxygen
demand. Short-acting drugs such as propofol, alfentanil, and
remifentanil are advocated so that residual sedation does not
interfere with clinical examination findings when assessing
neurological function. Metabolism of even short-acting drugs is
reduced by 30% in mild hypothermia. The optimal duration of
sedation is not clear but is generally continued for at least 24 hours
and while TTM is occurring.
LEARNING POINT Therapeutic hypothermia and

targeted temperature management
Cooling injured brains has long been hypothesized as a form of

neuroprotection. The cerebral metabolic rate for oxygen drops by 6%
for every 1°C reduction in core temperature although this is probably
not the main mechanism for potential benefit in cardiac arrest
patients. It is also thought to modify or abort apoptosis.
Page 6 of 21

Two RCTs showing improved neurological outcome following

therapeutic hypothermia for those with VF/pulseless ventricular
tachycardia OHCA were published in 2002 [17, 18]. Observational
studies suggested benefit for comatose survivors (usually defined as
unresponsive to voice or GCS score ≤8) for all arrest rhythms and 12–
24 hours of therapeutic hypothermia was recommended in
international guidelines from 2003. The TTM randomized trial,
published in 2013, compared outcomes of 950 all-rhythm OHCA
patients treated with a target temperature of either 33°C or 36°C.
There was no difference in survival or neurological outcome between
the two groups: good neurological outcome occurred in 46% in the
33°C group compared with 48% in the 36°C group (risk ratio 1.01;
95% confidence interval 0.89–1.14) [19]. The current European
Resuscitation Council and European Society of Intensive Care
Medicine (ERC/ESICM) guidelines recommend maintaining a
constant, target temperature between 32°C and 36°C for at least 24
hours [9]. More high-quality trials are needed to determine the
optimal temperature and duration of temperature control.
EXPERT COMMENT
All patients enrolled in the TTM trial had their temperature

controlled. That the outcomes were the same in the 36°C and 33°C
groups is not a reason to abandon active temperature control,
because hyperthermia is associated with worse neurological outcome.
Animal data indicate improved outcomes with mild hypothermia after
a global hypoxic–ischaemic cerebral injury but the results of the TTM
trial makes it difficult to make a firm recommendation about a
specific target temperature. There will be fewer physiological
changes (e.g. bradycardia, electrolyte shifts, and shivering) at 36°C
compared with 33°C but some post-cardiac arrest patients (e.g. those
with more severe neurological injury) might get better
neuroprotection from the lower temperature. The forthcoming TTM2
study will compare comatose all-rhythm post-cardiac arrest patients
treated with either TTM at 33°C or temperature control only when
the temperature exceeds 37.5°C.
CLINICAL TIP Inducing and maintaining hypothermia
Options to induce hypothermia or TTM include the following:
● Ice packs, these work rapidly and are easily available but do not
stop temperature fluctuations or enable controlled rewarming.
● Air cooling blankets or water-filled pads.
Page 7 of 21

● Intravascular cooling catheters, which circulate cold fluid in a

counter-current manner. Usually placed in the femoral or internal
jugular vein and maintain the intended temperature by using
feedback from a centrally placed thermometer (usually bladder or
oesophagus).
● Transnasal evaporative cooling.
● Extracorporeal circulation. Available in only a few centres in the
UK but in many other developed countries is used increasingly
commonly to treat refractory cardiogenic shock after cardiac
arrest [20]. Accurate temperature control is a benefit as a heater is
included in the extra corporal circuit.
It would seem logical to start TTM as soon as possible after ROSC.

However, trials comparing pre-hospital cooling with cooling delayed
until hospital arrival have not shown benefit. This may have been
because of the cooling method used [21]. The target temperature is
maintained for at least 24 hours.
Monitor core temperature continuously during cooling. Options

include oesophageal, bladder, or intravascular probes. Other sites
may not reflect core temperature during cooling; consider a second
site when using a closed feedback cooling system [22].
Shivering can occur at both 36°C and 33°C and should be avoided
because it increases oxygen consumption and core body temperature.
Muscle relaxation, with adequate sedation, is the most effective
treatment. Magnesium sulphate may also decrease the shivering
threshold [23].
After hypothermia, rewarming is undertaken slowly at no more than

0.25–0.5°C/hour. Avoid hyperthermia at 37.5°C or higher which is
harmful to vulnerable neurons. Rebound hyperthermia is associated
with poorer neurological outcomes.
EXPERT COMMENT
Until recently, the use of 2 L of 4°C 0.9% saline or Hartmann’s

solution was considered to be a safe and effect method for initiating
cooling—it reduces core temperature by 1.0–1.5°C. An RCT of
prehospital cooling with up to 2 L of 4°C 0.9% saline versus no
prehospital cooling following ROSC after all-rhythm OHCA showed no
difference in survival to hospital discharge or neurological recovery
[21]. Among those treated with prehospital cooling, there were
significantly more rearrests during transport to hospital and a higher
incidence of pulmonary oedema seen on the first chest X-ray. In a
further study, infusion of up to 2 L of cold fluid during prehospital
cardiac arrest was associated with a decrease in the rate of ROSC in
Page 8 of 21

patients with shockable rhythm [24]. Based on these results, cold

intravenous fluid should not be used prehospital or pre-ROSC, but its
use to initiate cooling after ROSC in a closely monitored environment,
such as the emergency department, may still be reasonable.
LEARNING POINT Side effects of hypothermia
Side effects of hypothermia include:
● shivering
● an increase in systemic vascular resistance
● arrhythmias—most commonly bradycardia which may have a
beneficial effect in reducing diastolic dysfunction and frequently
does not need treating
● diuresis
● hypokalaemia via intracellular redistribution
● hypomagnesaemia and hypophosphataemia
● hyperglycaemia from decreased insulin secretion and sensitivity
● elevated serum amylase
● decreased clearance of drugs including sedatives and
neuromuscular blockade
● mild coagulopathy
● mild immunosuppression—the incidence of pneumonia in this
population is high and should be actively sought and treated.
Frequent assessments of volume status and end-organ perfusion were

made. The MAP did drop below target intermittently. This was clinically
thought to be due to the sedatives reducing the systemic vascular
resistance rather than worsening left or ventricular or right ventricular
function. This was consistent with readings from a pulse index contour
cardiac output catheter that had been inserted into a femoral artery.
Small boluses of fluid were given to restore intravascular volume and
then noradrenaline was started to maintain blood pressure. He developed
a bradycardia of 45 bpm; a 12-lead ECG confirmed it was a sinus
bradycardia and it was not treated. Serum potassium values were
maintained above 4.0 mmol/L and serum magnesium values above 0.8
mmol/L.
A nasogastric tube was inserted and enteral feed started. Blood glucose
values were controlled between 4 and 10 mmol/L with an intravenous
insulin infusion. A statin was started on the evening of admission.
Prophylactic low-molecular-weight heparin was used along with
Page 9 of 21

compression stockings and an intermittent pneumatic compression device

to reduce the risk of venous thromboembolism.
After 24 hours at 36°C the patient was allowed to rewarm slowly. The
intravascular cooling catheter remained in place until 72 hours post
ROSC for further cooling in case his temperature went above 37°C and to
ensure it did not exceed 37.5°C. Sedation was stopped but would have
been restarted if he was shivering or displayed ventilator dyssynchrony.
Without sedation the noradrenaline was weaned off. He was commenced

on a small dose of cardioselective beta blocker (bisoprolol) and an ACE
inhibitor; both were titrated up over the next 2 weeks.
At 72 hours after ROSC his best GCS score was 5T (E2, VT, M3). It was
noted he had some abnormal movements of his facial muscles that could
have been a focal seizure. These were intermittent, not associated with
stimulation, and resolved spontaneously in less than 1 min. An
electroencephalogram (EEG) did not show epileptiform activity.
LEARNING POINT Treatment of seizures
Seizures are common in patients with ROSC: myoclonus occurs in up

to 25% and post-anoxic status epilepticus in up to 31% depending on
the diagnostic criteria used [25]. Not all clinical seizures will be
epileptic in origin. Seizures are treated because they increase the
cerebral metabolic rate and will mask clinical examination findings.
Sodium valproate, levetiracetam, phenytoin, benzodiazepines,
propofol, or barbiturates have all been used for this indication. There
is no strong evidence for the first choice of drug in this population;
however, experts now recommend the use of sodium valproate and/or
levetiracetam for myoclonic status epilepticus [26]. Seizure control
may be challenging and may require several drugs used at maximal
doses. EEGs to confirm seizure control and exclude non-convulsive
status epilepticus may be indicated and assistance from a neurologist
may be helpful in these cases. There is no role for prophylactic
anticonvulsants.
Myoclonic status epilepticus is defined as spontaneous, repetitive,

unrelenting, generalized multifocal myoclonus in a comatose patient
and is usually, but not always, associated with severe cortical damage
and poor outcome. Other forms of myoclonus (e.g. intention
myoclonus) may not represent irreversible brain injury and the
sedative effects of treatment instigated for myoclonus should be
considered when assessing neurological recovery [25, 27].
Page 10 of 21

Over the next 48 hours, the patient’s motor score continued to improve.
When he was localizing consistently, breathing spontaneously with
minimal pressure support, and a strong cough, his trachea was
extubated. He was delirious but not agitated, for the next 2 days, which
resolved without needing pharmacological intervention. He was
discharged to the neurology ward for rehabilitation 8 days after his
cardiac arrest.
After a further 2 weeks of inpatient care the patient was discharged home
with support from his wife and rehabilitation within the community. He
reported mild problems with memory and severe fatigue but otherwise
made an uneventful recovery.
LEARNING POINT Predicting outcome
Time to ROSC or initial rhythm is not a reliable predictor of outcome.

Similarly, no examination finding or clinical test has demonstrated
100% sensitivity at predicting poor neurological outcome after
hypoxic brain injury while avoiding false positives. Prognostication
studies can be separated into to those before and after TTM became a
standard of care. The quality of evidence in most studies is limited by
the lack of blinding and the fact that the outcome predictor under
investigation is subsequently used in treatment decisions including
the withdrawal of life-sustaining therapies; thus, becoming a self-
fulfilling prophecy of poor prognosis. First, it is important to define
what is meant by good outcome.
Classifying outcomes
The American Heart Association published a consensus statement on
the best outcome measures for clinical trials in resuscitation medicine
[28]. Neurological outcome is frequently graded into several
categories and then dichotomized into ‘good’ or ‘poor’ outcomes.
The time point at which these assessments are made is relevant, as

neurological function may improve for several months after a cardiac
arrest. The dependence described in a ‘good’ outcome in research
terms may not correspond to the hopes or expectations of individual
patients and relatives.
Cerebral performance category (CPC) is used in many studies to

describe good (CPC 1 and 2) and poor (CPC 4 and 5) neurological
outcomes. Authors of earlier studies often included CPC 3 as a good
outcome but in the vast majority of studies in recent years, CPC 3 is
defined as a poor outcome.
Page 11 of 21

CPCs are defined as follows:
1. Conscious and alert with normal function or only slight

disability
2. Conscious and alert with only moderate disability. Sufficient
cerebral function for independent activities of daily living and
able to work in a sheltered environment. May have hemiplegia,
seizures, ataxia, dysarthria, dysphasia, or permanent memory or
mental changes.
3. Conscious with severe disability. Dependent on others for
daily support because of limited brain function. Ranges from
ambulatory state to severe dementia or paralysis.
4. Comatose or persistent vegetative state.
5. Brain dead or death from other causes.
CPC at hospital discharge is often used as a surrogate measure of

long-term survival because these data are easy to collect; however,
several recent studies have shown marked improvement in CPC
scores between hospital discharge and 6–12 months later. A study of
980 patients documented a 5-year survival in each CPC domain as
follows: CPC 1, 74%; CPC 2, 55%; CPC 3, 44%; and CPC 4, 22% [29].
The modified Rankin score (mRS) and the extended Glasgow Outcome
Scale are alternative neurological outcome descriptors used in
cardiac arrest research [30, 31].
EXPERT COMMENT
Many experts consider a non-reactive EEG background to be a

reliable prognosticator of a poor outcome when this is assessed after
return to normothermia [36]; however, residual sedation may
influence this and false positives have been reported. EEG reactivity
is assessed by evaluating the EEG response to a stimulus such as
sound, eye opening, or deep tracheal suction.
LEARNING POINT Prognostication
Clinical assessment
Most deaths in ICU patients who are admitted after ROSC are from
withdrawal of life-sustaining treatment, based on the expectation of
poor neurological outcome [32].
As no prognostication tool fully predicts outcome, neurological

examination remains the most important tool for assessing progress
after cardiac arrest. It may be confounded by hypotension, seizures,
Page 12 of 21

sedatives, or neuromuscular blocking drugs. Clearance of sedatives is

reduced during even mild hypothermia, which necessitates waiting
longer after stopping sedation before reliable neurological
assessment can be undertaken.
A markedly reduced motor component of the GCS is a poor prognostic

sign but even an absent or extensor motor response (GCS M1 or M2)
72 hours after ROSC does not reliably predict a poor prognosis—
there is a false-positive rate of 5% (95% confidence interval 2–9%).
Bilateral absence of pupillary light and corneal reflexes at 72 hours
after ROSC has a very low false-positive rate but also low sensitivity
in identifying patients with a poor prognosis [33, 34, 35].
Electroencephalogram
The EEG is non-invasive, mobile, and more readily available than
other outcome predictors. It can detect non-convulsive status
epilepticus that occurs in up to 25% of comatose post-cardiac arrest
patients. Specific EEG abnormalities that persist beyond rewarming
can be associated with a poor outcome. They include:
● absence of reactivity
● burst suppression pattern
● status epilepticus.
However, interpretation can be hindered by a lack of universal

classification systems, observer variability, and drug and metabolic
effects. No single EEG abnormality has a 0% false-positive rate when
predicting poor outcome. Normal and abnormal EEGs are shown in
Figures 6.1–6.3.
Figure 6.1
Normal reactive posterior alpha-frequency rhythm with the eyes
closed.
Reproduced courtesy of Dr A. Michell, Department of Clinical

Neurophysiology Addenbrooke’s Hospital.
Page 13 of 21

Figure 6.2
Mild to moderate generalized slowing in post-anoxic coma.

Figure 6.3
Burst suppression in a patient after out-of-hospital cardiac arrest.

LEARNING POINT Prognostication
Evoked potentials
Somatosensory evoked potentials (SSEPs) test the integrity of
neuronal pathways between the peripheral and central nervous
system [37]. They are less affected than other tests by drugs and
metabolic abnormalities. Bilateral absence of the N20 cortical
response to median nerve SSEPs during hypothermia or after
rewarming does predict a poor outcome with a false-positive rate less
than 1% [38]. However, presence of the N20 response does not
Page 14 of 21

reliably predict a good outcome and the test is not yet widely
available.
Neuroimaging
Multiple modalities of neuroimaging have been studied for
prognostication after a cardiac arrest but most have a small sample
size and have inherent selection bias. The level of evidence is not high
and therefore no single imaging test can be recommended for
prognostication at present.
CT changes that reflect brain swelling after anoxic coma include loss
of grey–white matter differentiation and sulcal effacement. These are
visible within 24 hours of ROSC.
Magnetic resonance imaging (MRI) has been used to demonstrate

abnormalities in the cortical or deep grey matter in several sequences
around 3–5 days after ROSC. Diffusion-weighted imaging is the most
extensively studied and the apparent diffusion coefficient is a
quantitative measure of these ischaemic changes [39].
Biomarkers
Serum NSE is the most studied biomarker of neuronal damage after
cardiac arrest. It is a cytoplasmic glycolytic enzyme found in neurons
and neuroendocrine tumours. NSE values are consistently raised in
neuronal injury and with more severe injury tend to increase in the
first 72 hours but, despite early promise, like other tests, this
biomarker is not completely reliable in predicting a poor outcome.
NSE values may also be elevated in haemolysis and in the presence of
neuroendocrine tumours. S100 beta is a calcium binding protein from
astroglial and Schwann cells and is another potential biomarker.
Variability in the assay used, cut-off values, and clinical availability

currently limit biomarker use in predicting outcome. Increasing
values of NSE between 48 and 72 hours after ROSC is associated with
a poor outcome [40, 41].
Discussion
A multimodal prognostication strategy is advocated rather than

relying on a single test to predict outcome. Clinical examination is the
first step once confounding factors including sedation, metabolic
derangement, and hypothermia are excluded. Figure 6.4 summarizes the
2015 ERC/ESICM algorithm for those patients that remain GCS M1 or M2
at 72 hours after ROSC [35].
Page 15 of 21

Figure 6.4
Algorithm for multimodal prognostication in patients who remain GCS
motor score M1 or M2 72 hours after ROSC.
Reproduced from Sandroni, C., et al. Prognostication in comatose

survivors of cardiac arrest: An advisory statement from the European
Resuscitation Council and the European Society of Intensive Care
Medicine. Resuscitation. 2014;85:1779–1789. Copyright © Elsevier Inc.
All rights reserved. Open Access.
Bilaterally absent pupillary and corneal reflexes at 72 hours or later or

bilaterally absent N20 SSEP at 24 hours or later are the most robust
predictors of poor outcome (i.e. with very low false-positive rates). If
these reflexes are present, observe for a further 24 hours and consider
other tests including EEG, CT, or MRI or serial biomarkers to aid
treatment decisions. A combination of a least two of these predictors is
suggested. All these test neurological function only and do not take into
account the outcome from coexisting organ failure, premorbid conditions,
and frailty. Most survivors will recover consciousness within 10 days [42].
In a series of 194 comatose post-cardiac arrest patients who awoke, 30%
did not awake until more than 48 hours after sedation was stopped [43].
Age over 59 years (odds ratio (OR) 2.1), post-arrest shock (OR 2.6), and
renal failure on admission (OR 3.1) were all associated with delayed
awakening.
There has been a considerable increase in the volume of data relating to

the prediction of outcome in the comatose post-cardiac arrest patient.
Inevitably, these are all observational studies. Recent international
guidelines recommend a multimodal approach to prognostication (clinical
examination plus at least one other modality, typically an
electrophysiological investigation such as EEG or SSEP, or imaging) [19,
33]. Generally, prognostication should not be attempted until at least 72
hours after ROSC. There is evidence that withdrawal of life-sustaining
treatment decisions are being increasingly delayed but many are still
made prematurely [1]. The increasing tendency to regionalize post-
Page 16 of 21

resuscitation care, which is generally predicated on the need for 24/7

access to a cardiac catheterization laboratory, may enable more of these
patients to access the full range of prognostic investigations [44].
Patients with ROSC after cardiac arrest now account for more than
12% of mechanically ventilated ICU admissions [1]. Optimal
treatment of post-cardiac arrest syndrome may be prolonged and
accurate early prognostic factors have not been identified. Avoiding
premature prognostication of futility without creating unreasonable
hopes of recovery or survivors with severe neurological impairment is
the goal of post-cardiac arrest care. Allowing sufficient time for the
patient to recover is important. Combining clinical assessment,
ancillary tests, multidisciplinary opinion, premorbid status, and the
likely wishes of the patient is currently the best way of approaching
this difficult scenario.
References
1. Hawkes C, Booth S, Ji C, et al. Epidemiology and outcome from out-of-
hospital cardiac arrests in England. Resuscitation. 2017;110:133–40.
2. Nolan J, Neumar R, Adrie C, et al. Post-cardiac arrest syndrome:

epidemiology, pathophysiology, treatment, and prognostication. A
Scientific Statement from the International Liaison Committee on
Resuscitation; the American Heart Association Emergency Cardiovascular
Care Committee; the Council on Cardiovascular Surgery and Anesthesia;
the Council on Cardiopulmonary, Peri-operative, and Critical Care; the
Council on Clinical Cardiology; the Council on Stroke. Resuscitation.
2008;79:350–79.
3. Nolan J, Hazinski M, Aickin R. 2015 International Consensus on

Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Science with Treatment Recommendations. Resuscitation. 2015;92:e1–31.
4. Stub D, Smith K, Bernard S, et al. Air versus oxygen in ST-segment

elevation myocardial infarction. Circulation. 2015;131:2143–50.
5. Bouzat P, Suys T, Sala N, Oddo M. Effect of moderate hyperventilation

and induced hypertension on cerebral tissue oxygenation after cardiac
arrest and therapeutic hypothermia. Resuscitation. 2013;84:1540–5.
6. McKenzie N, Williams T, Tohira H, Ho K, Finn J. A systematic review

and meta-analysis of the association between arterial carbon dioxide
Page 17 of 21

tension and outcomes after cardiac arrest. Resuscitation. 2017;111:116–

26.
7. Eastwood G, Schneider A, Suzuki S, et al. Targeted therapeutic mild

hypercapnia after cardiac arrest: a phase II multi-centre randomised
controlled trial (the CCC trial). Resuscitation. 2016;104:83–90.
8. Van den Brule J, Vinke E, van Loon L, van der Hoeven J, Hodemaekers
C. Middle cerebral artery flow, the critical closing pressure, and the
optimal mean arterial pressure in comatose cardiac arrest survivors—an
observational study. Resuscitation. 2017;110:85–9.
9. Nolan J, Soar J, Cariou A. European Resuscitation Council and

European Society of Intensive Care Medicine Guidelines for Post-
resuscitation Care 2015 Section 5 of the European Resuscitation Council
Guidelines for Resuscitation 2015. Resuscitation. 2015:95;202–22.
10. Garcia-Tejada J, Jurado-Roman A, Rodriguez J, et al. Post-resuscitation

electro-cardiograms, acute coronary findings and in-hospital prognosis of
survivors of out-of-hospital cardiac arrest. Resuscitation. 2014;85:1245–
50.
11. Dumas F, Bougouin W, Geri G, et al. Emergency percutaneous

coronary intervention in post-cardiac arrest patients without ST-segment
elevation pattern: insights from the PROCAT II Registry. JACC Cardiovasc
Interv. 2016;9:1011–18.
12. Soar J, Callaway C, Aibiki B, et al. Part 4: Advanced Life Support 2015
International Consensus on Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care Science with Treatment
Recommendations. Resuscitation. 2015;95:e71–120.
13. Roffi M, Patrono C, Collet J, et al. 2015 ESC Guidelines for the
management of acute coronary syndromes in patients presenting without
persistent ST-segment elevation: Task Force for the Management of Acute
Coronary Syndromes in Patients Presenting without Persistent ST-
Segment Elevation of the European Society of Cardiology (ESC). Eur
Heart J. 2016;37:267–315.
14. Chilly J, Mongardon N, Dumas F, et al. Benefit of an early and

systematic imaging procedure after cardiac arrest: insights from the
PROCAT (Parisian Region Out of Hospital Cardiac Arrest) registry.
Resuscitation. 2012;83:1444–50.
15. Sideris G, Voicu S, Dillinger JG, et al. Value of post-resuscitation

electrocardiogram in the diagnosis of acute myocardial infarction in out-
of-hospital cardiac arrest patients. Resuscitation. 2011;82:1148–53.
16. Patterson T, Perkins G, Joseph J, et al. A randomised trial of expedited

transfer to a cardiac arrest centre for non-ST elevation ventricular
Page 18 of 21

fibrillation out-of-hospital cardiac arrest: the ARREST pilot randomised

trial. Resuscitation. 2017;115:185–91.
17. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic

hypothermia to improve the neurologic outcome after cardiac arrest. N
Engl J Med. 2002;346:549–56.
18. Bernard S, Gray T, Buist M, et al. Treatment of comatose survivors of

out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med.
2002;346:557–63.
19. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature

management at 33 degrees C versus 36 degrees C after cardiac arrest. N
Engl J Med. 2013;369:2197–206.
20. Pineton de Chambrun M, Bréchot N, Lebreton G, et al. Venoarterial

extracorporeal membrane oxygenation for refractory cardiogenic shock
post-cardiac arrest. Intensive Care Med. 2016;42:1999–2007.
21. Kim F, Nichol G, Maynard C, et al. Effect of pre-hospital induction of

mild hypothermia on survival and neurological status among adults with
cardiac arrest: a randomized clinical trial. JAMA. 2014;311:45–52.
22. Knapik P, Rychlik W, Duda D, Golyszny R, Borowik D, Ciesla D.

Relationship between blood, nasopharyngeal and urinary bladder
temperature during intravascular cooling for therapeutic hypothermia
after cardiac arrest. Resuscitation. 2012;83:208–12.
23. Wadhwa A, Sengupta P, Durrani J, et al. Magnesium sulphate only

slightly reduces the shivering threshold in humans. Br J Anaesth.
2005;94:756–62.
24. Bernard S, Smith K, Finn J, et al. Induction of therapeutic

hypothermia during out-of-hospital cardiac arrest using a rapid infusion
of cold saline: the RINSE Trial (Rapid Infusion of Cold Normal Saline).
Circulation. 2016;134:797–805.
25. Seder D, Sunde K, Rubertsson S, et al. Neurologic outcomes and

postresuscitation care of patients with myoclonus following cardiac
arrest. Crit Care Med. 2015;43:965–72.
26. Reynolds AS, Claassen J. Treatment of seizures and postanoxic status

epilepticus. Semin Neurol. 2017;37:33–9.
27. English W, Giffin N, Nolan J. Myoclonus after cardiac arrest: pitfalls in

diagnosis and prognosis. Anaesthesia. 2009;64:908–11.
28. Becker L, Aufderheide T, Geocadin G, et al. Primary outcomes for

resuscitation science studies. A Consensus Statement from the American
Heart Association. Circulation. 2011;124:2158–77.
Page 19 of 21

29. Phelps R, Dumas F, Maynard C, Silver J, Rea T. Cerebral performance

category and long-term prognosis following out-of-hospital cardiac arrest.
Crit Care Med. 2013;41:1252–7.
30. Bonita R, Beaglehole R. Modification of Rankin Scale: recovery of

motor function after stroke. Stroke. 1988;19:1497–500.
31. Wilson J, Pettigrew L, Teasdale G. Structured interviews for the

Glasgow Outcome Scale and the Extended Glasgow Outcome Scale:
Guidelines for Their Use. J Neurotrauma. 1997;15:573–85.
32. Cronberg T, Kuiper M. Withdrawal of life-sustaining therapy after

cardiac arrest. Semin Neurol. 2017;37:81–7.
33. Dragancea I, Horn J, Kuiper M, et al. Neurological prognostication

after cardiac arrest and targeted temperature management 33°C versus
36°C: results from a randomised controlled clinical trial. Resuscitation.
2015;93:164–70.
34. Sandroni C, Cavallaro F, Callaway CW, et al. Predictors of poor

neurological out-come in adult comatose survivors of cardiac arrest: a
systematic review and meta-analysis. Part 2: patients treated with
therapeutic hypothermia. Resuscitation. 2013;84:1324–38.
35. Sandroni C, Cariou A, Cavallaro F, et al. Prognostication in comatose

survivors of cardiac arrest: an advisory statement from the European
Resuscitation Council and the European Society of Intensive Care
Medicine. Resuscitation. 2014;85:1779–89.
36. Rossetti A, Rabinstein A, Oddo M. Neurological prognostication of

outcome in patients in coma after cardiac arrest. Lancet Neurol.
2016;15:597–609.
37. Horn J, Tjepkema-Cloostermans MC. Somatoensory evoked potentials

in patients with hypoxic-ischaemic brain injury. Semin Neurol.
2017;37:60–5.
38. Young G, Doig G, Ragazzoni A. Anoxic–ischemic encephalopathy:

clinical and electrophysiological associations with outcome. Neurocrit
Care. 2005;2:159–64.
39. Hahn D, Geocadin R, Green D. Quality of evidence in studies

evaluating neuroimaging for neurologic prognostication in adult patients
resuscitated from cardiac arrest. Resuscitation. 2014;85:165–72.
40. Stammet P, Collignon O, Hassager C, et al. Neuron-specific enolase as

a predictor of death or poor neurological outcome after out-of-hospital
cardiac arrest and targeted temperature management at 33°C and 36°C. J
Am Coll Cardiol. 2015;65:2104–14.
41. Stammet P. Blood biomarkers of hypoxic-ischemic brain injury after

cardiac arrest. Semin Neurol. 2017;37:75–80.
Page 20 of 21

42. Gold B, Puertas L, Davis S, et al. Awakening after cardiac arrest and
post resuscitation hypothermia: are we pulling the plug too early?
Resuscitation. 2014;85:211–14.
43. Paul M, Bougouin W, Geri G, et al. Delayed awakening after cardiac

arrest: prevalence and risk factors in the Parisian registry. Intensive Care
Med. 2016;42:1128–36.
44. Elmer J, Rittenberger J, Coppler P, et al. Long-term survival benefit

from treatment at a specialty center after cardiac arrest. Resuscitation.
2016;108:48–53.
Page 21 of 21

Subarachnoid haemorrhage

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Subarachnoid haemorrhage
Author(s): Matthew A. Kirkman
DOI: 10.1093/med/9780198814924.003.0007
Expert commentary by Martin Smith
Case history
A 66-year-old female presented to her local emergency

department via ambulance having developed a sudden-onset, severe
headache while at work. She described it as the ‘worst headache’ of her
life, reaching maximal intensity within minutes of onset. Associated
symptoms included nausea, vomiting, neck stiffness, and photophobia.
Except for treated hypertension she had no past medical history of note,
although she was a smoker with a 40 pack-year history and drank 20
units of alcohol per week.
On examination, the patient was eye opening to speech, disorientated but

obeying commands; her Glasgow Coma Scale (GCS) score was 13 out of
15 (E3, V4, M6). Her pupils were 3 mm and reactive to light bilaterally,
and she had no other cranial nerve or limb focal neurological deficits. She
had nuchal rigidity and a positive Kernig’s sign. Based on the history and
Page 1 of 26
examination, a subarachnoid haemorrhage (SAH) was suspected, and this

was confirmed by an urgent non-enhanced computed tomography (CT)
scan of the head. The clinical grade of the SAH, according to the World
Federation of Neurosurgical Societies (WFNS) classification, was 2.
EXPERT COMMENT
Headache alone is non-discriminatory for SAH; only around 1% of

patients presenting to emergency departments with headache have a
confirmed SAH. Associated clinical features such as neck stiffness,
vomiting, altered consciousness, and seizures make the diagnosis of
SAH more likely and should prompt further investigation. Standard
non-contrast CT is diagnostic in around 95% of cases, although a
normal scan, particularly early after symptom onset, does not exclude
SAH. In the presence of a good history for SAH and normal CT scan, a
lumbar puncture should be performed. Demonstration of red blood
cells or their metabolites in the cerebrospinal fluid (CSF) identifies an
additional 3% of patients who subsequently have positive cerebral
angiography. The diagnostic sensitivity of lumbar puncture is
increased when performed at least 6 to 12 hours after SAH onset,
although waiting leads to a delay in diagnosis and definitive
treatment.
LEARNING POINT Clinical grading of subarachnoid

haemorrhage
There are several grading systems used in SAH, based on clinical

and/or radiological criteria, which can be used to communicate
disease severity and for prognostication. The most frequently used
clinical grading scale is the WFNS scale, which incorporates the GCS
and the presence or absence of a focal neurological deficit (Table 7.1)
[1]. The higher the WFNS score, the worse the patient’s likely
outcome.
Table 7.1 World Federation of Neurosurgical Societies

subarachnoid haemorrhage grading system
Grade Glasgow Coma Scale Focal neurological

score deficit
1 15 Absent
2 13–14 Absent
Page 2 of 26

3 13–14 Present
4 7–12 Present or absent
5 <7 Present or absent
Note: if a patient has hydrocephalus which is likely to affect the

conscious level, WFNS grading should be applied after treatment
of the hydrocephalus to ensure optimal prognostic value. A patient
who is alert and orientated (GCS score of 15) but has a
neurological deficit, such as a hemiparesis, is classified as grade 3.
Source: data from Drake, CG., et al. Report of World Federation of

Neurological Surgeons Committee on a Universal Subarachnoid
Hemorrhage Grading Scale. Journal of Neurosurgery. 1988; 68:
985–6. Copyright © 1988 American Association of Neurological
Surgeons.
The CT scan demonstrated blood within the basal cisterns, particularly

around the region of the right internal carotid artery but also in the
posterior horns of both lateral ventricles and over the right cerebral
convexity, and early signs of hydrocephalus (Figure 7.1a, b). A computed
tomography angiogram (CTA) was subsequently performed and
demonstrated a 6×4 mm bilobed aneurysm of the right terminal internal
carotid artery (Figure 7.1c).
Page 3 of 26

Figure 7.1
Neuroimaging after subarachnoid haemorrhage. (a, b) Non-enhanced CT
scan of the head demonstrating a large amount of subarachnoid blood,
largely on the right side in the region of the terminal internal carotid
artery and middle cerebral artery (arrow in (a)). The blood has tracked
into the ventricular system (arrows in (b)) and is associated with
hydrocephalus. The ventricles are dilated asymmetrically, the left side
being more dilated than the right. (c) CT angiogram and (d) subsequent
digital subtraction angiography demonstrate a terminal right internal
carotid artery aneurysm (circled).
EXPERT COMMENT
Approximately 85% of cases of SAH are caused by spontaneous

rupture of an intracranial aneurysm. Non-aneurysmal peri-
mesencephalic bleeds, with haemorrhage centred anterior to the
midbrain or pons, account for 10% of cases. The remaining 5% are
divided between multiple rarer pathologies, including traumatic SAH.
The patient was transferred urgently to the local neuroscience centre

where she was placed on bed rest and commenced on nimodipine,
laxatives, analgesia, and intravenous fluid therapy. An admission
electrocardiogram (ECG) was normal.
EXPERT COMMENT
Page 4 of 26

Patients should be transferred to a neuroscience centre as soon as the

diagnosis of SAH has been confirmed and the patient stabilized.
Definitive treatment of the ruptured aneurysm should be undertaken
within 24–48 hours of SAH onset. Treatment in high-volume centres
with timely access to multidisciplinary teams is associated with
improved outcomes after SAH.
Shortly after admission to the neurosciences centre, the patient’s GCS

deteriorated to 8/15 (E2, V2, M4) and a repeat cranial CT scan showed
worsening hydrocephalus. An external ventricular drain was inserted to
treat the hydrocephalus. After discussion between the neurosurgical and
interventional neuroradiology teams, the patient underwent endovascular
coiling of the right internal carotid artery aneurysm (Figure 7.1d), during
the same anaesthetic.
EXPERT COMMENT
Early (within 24 hours) neurological deterioration after SAH is most

likely to be related to rebleeding or the development of
hydrocephalus.
Rebleeding was previously the primary cause of death following poor-

grade SAH but rates have dramatically reduced since the shift
towards early securing of the ruptured aneurysm. Antifibrinolytic
therapy may reduce the risk of rebleeding by up to 40% but does not
improve outcome, possibly because of treatment-related
microthrombosis and cerebral ischaemia. The short-term use of
antifibrinolytics can be considered in selected cases at high risk of
rebleeding in whom definitive treatment of the aneurysm is delayed.
Hydrocephalus develops in around 50% of patients after SAH, and

deterioration due to worsening of hydrocephalus requires immediate
insertion of an external ventricular drain. Up to 30% of patients with
poor-grade SAH improve neurologically with CSF drainage even in
the absence of overt hydrocephalus.
LEARNING POINT Treatment of aneurysms: coiling or

clipping?
Prior to the introduction of coil embolization technology in the early

1990s, aneurysms were treated through craniotomy and placement of
a clip around the aneurysm neck. Since then, the role of endovascular
treatment of intracranial aneurysms has expanded, allowing
minimally invasive and effective treatment even in the sickest
Page 5 of 26

patients. This is important because early aneurysm control reduces

the risk of rebleeding and allows higher arterial blood pressure to
prevent or treat cerebral hypoperfusion.
The most important trial to date investigating the treatment of

ruptured intracranial aneurysms is the International Subarachnoid
Aneurysm Trial (ISAT) [2]. Between 1994 and 2002, this study
randomized 2143 patients from 42 centres (largely within the UK and
Europe) with ruptured intracranial aneurysms to receive either
neurosurgical clipping or endovascular coiling. The primary outcome
measure was death or dependency (defined as a modified Rankin
scale of 3–6) at 1 year, and secondary outcomes included rebleeding
and seizure rate. ISAT found a significantly reduced risk of death or
dependency at 1 year in the endovascular coiling group compared to
the neurosurgical clipping group. The risk of rebleeding was low
overall, but late rebleeding was more common following coiling. The
risk of seizures following coiling was substantially lower than
following neurosurgical clipping. Many concerns were raised
following the publication of ISAT, particularly with regards to the
durability of coil technology and the risk of rebleeding. Subsequent
follow-up of the ISAT cohort has shown that, although rebleeding was
more likely in the endovascular coiling group at 10 years following
treatment, the overall risk of rebleeding remains small [3]. Of the
1003 patients followed up at 10 years, rebleeding from the treated
aneurysm occurred in only 13 of 531 in the endovascular coiling
group and in 4 of 472 in the neurosurgical clipping group. Although
rates of dependency alone were similar in the two groups at 10-year
follow-up, the probability of death or dependency was significantly
greater in the neurosurgical clipping group. Thus endovascular
coiling appears to be effective and durable.
ISAT has been criticized for many reasons [4]. Sixty-nine per cent of
the 9559 patients eligible for recruitment into the study were
excluded because of lack of equipoise and, since almost all
intracranial aneurysms can be treated by surgery, it follows that a
large proportion of patients were excluded because of a local
assessment that their aneurysm was not suitable for coiling. There
was also underrepresentation of middle cerebral artery and posterior
circulation aneurysms in the study and, because these are
preferentially treated by clipping and coiling respectively, this also
raises the possibility of sample bias. Larger aneurysms were also
underrepresented in the study. There have been significant
developments in endovascular technology in recent years, including
the development of stents and flow diverters, and this may
significantly influence the outcomes following endovascular coiling.
Such developments may also enable aneurysms that were unsuitable
for coiling at the time of ISAT (such as larger aneurysms) to be
treated by this method today. The authors of ISAT have therefore
established another randomized controlled trial (RCT) (ISAT 2) that
Page 6 of 26

aims to include a wider range of aneurysm types, including many of

those that were excluded from the original study [5]. This study will
need to take account of any effects on rebleeding rates and outcome
of dual antiplatelet therapy which is often required following the
deployment of stents and flow diverters.
Decisions about the optimal treatment for an intracranial aneurysm

require multidisciplinary consensus between neurosurgeons and
neuroradiologists. This must account for the healthcare resources
available (including surgical and endovascular expertise), the age and
clinical status of the patient, and the anatomy and location of the
aneurysm. At present, factors favouring surgical clipping include the
presence of intraparenchymal haematomas requiring surgical
evacuation, wide-necked aneurysms, and those causing acute
brainstem compression. In contrast, endovascular coiling is often
preferred in elderly and comorbid patients, posterior circulation
aneurysms, and in poor-grade patients.
Following the procedure, which was uneventful, the patient was

transferred sedated and ventilated to the intensive care unit (ICU) for
neurological and cardiovascular monitoring, and systemic physiological
optimization. Treatment targets included euvolaemia, systolic blood
pressure at 20% above baseline level, normoglycaemia, and
normothermia.
CLINICAL TIP Principles of ICU management
Optimization of systemic physiological variables, particularly arterial

blood gases, arterial blood pressure, blood glucose, and temperature,
is the cornerstone of the ICU management of SAH. Abnormalities of
fluid balance are common, with hypovolaemia occurring in 17–30% of
patients. Isotonic crystalloids are the replacement fluid of choice.
Mineralocorticoids, such as fludrocortisone or hydrocortisone, have
been shown to limit natriuresis and associated water loss, and the
amount of fluid required to maintain euvolaemia. However, they are
not used routinely since no outcome benefits have been
demonstrated. Hyperglycaemia occurs in around 30% of patients
after SAH and is associated with poor outcome. A blood glucose
target of 6–10 mmol/L is recommended; very tight glycaemic control
is avoided to minimize the risk of hypoglycaemia which is harmful to
the injured brain. Fever occurs in up to 70% of patients, is more
common in poor-grade SAH, and is associated with worse outcome.
An infective cause should be excluded or treated, but fever is often
related to the hypothalamic or inflammatory effects of subarachnoid
blood. Temperature should be monitored frequently and standard
measures used to maintain normothermia, particularly during the
Page 7 of 26

period of risk of delayed cerebral ischaemia (DCI). Anaemia is also

very common after SAH and is associated with a poor outcome,
although blood transfusion is similarly associated with an adverse
outcome. Current guidance recommends transfusion to maintain the
haemoglobin concentration between 80–100 g/L [6], although higher
thresholds might be appropriate in patients at high risk of DCI. SAH
patients are at risk of venous thromboembolism, and intermittent
compression devices should be applied in all patients on admission to
the ICU. Pharmacological thromboprophylaxis can be started 24
hours after aneurysm treatment.
The sedation was stopped and the patient awoke and was extubated later
that day. Her GCS at this stage was 12/15 (E3, V4, M5). Daily testing of
full blood count and serum electrolytes was performed, with particularly
close monitoring of serum sodium levels. Daily serial transcranial Doppler
(TCD) examinations and ECG were obtained.
LEARNING POINT Aneurysmal subarachnoid

haemorrhage management protocol
The general principles of managing SAH are shown in Figure 7.2.

Close and frequent neurological and cardiorespiratory monitoring is
important in SAH. Although SAH patients are often managed in high
dependency unit or ICU settings that facilitate such monitoring,
some, including many that are WFNS grade 1, can be safely managed
in a neurosurgical ward. However, irrespective of care location, close
clinical observation with regular neurological assessment is crucial
with a low threshold for escalation of care. Strict bed rest minimizes
fluctuations in blood pressure that may adversely affect outcome, and
the use of laxatives minimizes straining and hence intracranial
hypertension. All patients should be commenced on nimodipine
immediately after symptom onset where clinical suspicion is high, and
those in whom SAH is subsequently confirmed should complete a 21-
day course as a standard of care. Nimodipine is typically administered
at a dose of 60 mg orally or via nasogastric tube every 4 hours.
Intravenous nimodipine, at a dose of 1 mg/hour (or 500 mcg/hour if
body weight <70 kg or blood pressure unstable) increased to 2 mg/
hour after 2 hours if blood pressure remains stable, can be used in
the presence of poor enteral absorption. Maintenance of adequate
hydration is important since many patients with SAH have
intravascular fluid depletion. Maintenance of euvolaemia minimizes
the risk of cerebral ischaemia. ECG and chest X-ray are essential for
the assessment of cardiopulmonary complications.
Page 8 of 26

Figure 7.2
Principles of management of aneurysmal subarachnoid haemorrhage.
CBF, cerebral blood flow; CPP, cerebral perfusion pressure; CSF,
cerebrospinal fluid; CTA, computed tomography angiography; CTP,
computed tomography perfusion; DCI, delayed cerebral ischaemia;
ECG, electrocardiography; FBC, full blood count; HDU, high
dependency unit; ICP, intracranial pressure; ICU, intensive care unit;
TCD, transcranial Doppler ultrasonography.
Urgent identification of an aneurysm as the cause of the SAH is

imperative. Early treatment of an unsecured aneurysm, ideally as
soon as possible but within 48 hours of symptom onset, is
recommended to prevent rebleeding. Early transfer to a neuroscience
centre with appropriate facilities and continuous availability of all
members of the multidisciplinary team are crucial to facilitate early
intervention. Early treatment may not always be possible or
appropriate, for example in a poor-grade, elderly patient with
multiple comorbidities or patients with highly complex aneurysm
anatomy.
Hypertension is a normal response to SAH, although high blood

pressure increases the risk of rebleeding. On the other hand,
excessive reductions in blood pressure risk the development of
cerebral ischaemia. Extreme hypertension should be treated
cautiously with a short-acting agent. Current guidelines recommend
that before the aneurysm is treated, systolic and mean blood pressure
should be no higher than 160 mmHg and 110 mmHg, respectively [6].
Hypotension is meticulously avoided, and chronic antihypertensive
medications are withheld initially. Once the aneurysm is secured,
systolic blood pressure is often managed at 20% above baseline. In
the presence of hydrocephalus, CSF diversion is required. External
ventricular drainage through a transfrontal catheter is the most
common method. Use of antibiotic- or silver-impregnated catheters
can reduce the infection risk associated with this intervention [7].
Insertion of an external ventricular drain, in addition to permitting
therapeutic drainage of CSF, also enables measurement of
intracranial pressure. Lumbar puncture or insertion of a lumbar drain
Page 9 of 26

can also be used for therapeutic CSF drainage, although it is

relatively contraindicated in the presence of obstructive
hydrocephalus that may result from the presence of intraventricular
blood. Lumbar drainage of CSF can also be used to clear blood from
the CSF and prevent stasis of clots, but there is currently no
conclusive evidence of benefit. Overall, what evidence there is does
not support a concern about the safety of lumbar drains [8].
Anticonvulsants are generally not recommended unless there are

documented seizures, as their use has been associated with
unfavourable outcomes [6]. However, these data are based primarily
on the use of phenytoin and it is unclear whether the same holds true
for newer anticonvulsants. Levetiracetam is being increasingly used
in this context, because of its superior pharmacodynamic and kinetic
profiles compared to phenytoin: levetiracetam has minimal protein
binding and no hepatic metabolism, resulting in a lower risk of drug
interactions and better tolerability. At present, there are no outcome
data demonstrating benefits of levetiracetam over phenytoin after
SAH.
The monitoring and management of DCI is covered later in this

chapter.
On the first postoperative day, the ECG showed T-wave inversion in the
lateral leads and a prolonged QTc interval. There was a modest rise in
serum troponin, but an echocardiogram was normal. A ‘watch and review’
approach was taken.
EXPERT COMMENT
Cardiac complications are common after SAH and related to

sympathetic hyperactivity and catecholamine-induced myocyte
dysfunction. They may result in minimal clinical effects but, in severe
cases, can lead to cardiogenic shock and pulmonary oedema.
Cardiovascular dysfunction often resolves spontaneously after a
variable period, emphasizing the importance of general supportive
critical care during periods of instability. There is no specific curative
therapy. Although modification of the sympathetic response might
limit cardiac dysfunction after SAH, there is no strong evidence to
recommend this line of therapy which may risk hypotension and the
development of cerebral ischaemia. Vasopressors and inotropes may
be used for haemodynamic augmentation, but there is no definitive
evidence to recommend one agent over another.
Page 10 of 26

LEARNING POINT Management of cardiac

abnormalities after subarachnoid haemorrhage
Cardiac complications are common after SAH and associated with

DCI and poor outcome [9]. These manifest as ECG abnormalities,
elevated cardiac troponin I (cTnI), and a spectrum of ventricular
dysfunction collectively referred to as the neurogenic stunned
myocardium (NSM) syndrome. ECG abnormalities are extremely
common after SAH. ST-segment changes have been reported in up to
50% of patients, inverted or isoelectric T waves in up to 90%, QTc
prolongation in almost two-thirds, and cardiac arrhythmias in more
than one-third [10]. Elevation of cTnI occurs in approximately one-
third of patients, and left ventricular dysfunction in around 18% [11].
The underlying mechanism of NSM is believed to relate to
sympathetic nervous system activation and excessive noradrenaline
release from myocardial sympathetic nerve terminals [12]. This
causes a physiological denervation in the presence of normal
coronary perfusion and a characteristic pattern of left ventricular
regional wall motion abnormalities involving the basal and middle
portions of the anteroseptal and anterior ventricular walls with
relative apical sparing, reflecting the distribution of sympathetic
nerves rather than specific vascular territories [13].
Left ventricular dysfunction is usually temporary, although some

patients require cardiovascular support [14]. Risk factors for the
development of NSM include worse SAH clinical grade at
presentation, smoking, and increasing age [15]. A known history of
hypertension before SAH has been associated with a lower risk of
NSM [15]. Nuclear imaging in a cohort of 30 patients with
aneurysmal SAH has shown that the majority had altered cardiac
glucose metabolism (83%) and sympathetic innervation (90%) but
preserved cardiac perfusion (100%) [16], suggesting that many SAH
patients may have subclinical alterations in cardiac metabolism.
Although cardiopulmonary and haemodynamic status should be

optimized, no class I data (i.e. from RCTs) exists to guide the
management of cardiac abnormalities after SAH. Characterizing
cardiac performance using echocardiography and continuous cardiac
output monitoring may be useful in guiding therapy in patients with
symptomatic NSM. Dobutamine has been used to increase cardiac
output, but the influence on outcomes is unclear [17]. Potassium and
magnesium values should be checked and corrected if necessary.
Crucially important is the avoidance of delays in securing the
aneurysm in patients with ECG and other cardiac abnormalities in the
presence of clinical stability.
Page 11 of 26

On the third day after admission the patient developed acute

hyponatraemia. Her serum sodium decreased to 121 mmol/L from 135
mmol/L on the previous day. She was treated with infusion of hypertonic
saline (1.8%), and this corrected her sodium values slowly over 48 hours.
EXPERT COMMENT
Aneurysmal SAH is commonly associated with abnormalities of fluid

balance and electrolyte derangements, which can negatively affect
outcome. Hyponatraemia (serum sodium <135 mmol/L) may be
related to iatrogenic haemodilution, the cerebral salt-wasting
syndrome, or the syndrome of inappropriate antidiuretic hormone
secretion. The major risk of acute hyponatraemia is the development
of cerebral oedema secondary to fluid shifts as plasma tonicity
reduces. Fluid restriction to treat hyponatraemia from whatever
cause is no longer recommended after SAH because of the risk of
cerebral infarction caused by hypovolaemic hypoperfusion.
Hypertonic (1.8%) saline can be used to maintain euvolaemia in
hyponatraemic patients, particularly those at high risk of DCI.
Prophylactic use of mineralocorticoids may limit natriuresis and
hyponatraemia, but careful electrolyte monitoring is essential as
hypokalaemia and hyperglycaemia may ensue. The correction of
hyponatraemia can itself lead to neurological sequelae, particularly
osmotic demyelination syndrome. This risk is minimized by gradual
correction of sodium deficits. Hypertonic saline infusion should be
discontinued when serum sodium reaches 125–130 mmol/L.
LEARNING POINT Management of hyponatraemia in

subarachnoid haemorrhage
Hyponatraemia is the most common electrolyte abnormality in

hospital inpatients [18]. It is particularly common in patients with
SAH [19], with some studies suggesting an incidence greater than
50% [20]. Correct and timely management of hyponatraemia is
important as it is associated with an increased risk of cerebral
oedema, vasospasm, and cerebral infarction following SAH.
The underlying pathophysiology of hyponatraemia following SAH is

unclear, but it is associated with elevated values of atrial [21, 22] and
brain natriuretic peptides [23, 24]. Cerebral salt wasting (CSW) is
thought to be the predominant mechanism of hyponatraemia in
patients with SAH, although the syndrome of inappropriate
antidiuretic hormone (SIADH) is also common. SIADH occurs because
of excess antidiuretic hormone secretion causing water retention and
volume overload, and leads to a dilutional hyponatraemia. CSW on the
Page 12 of 26

other hand is associated with raised atrial and brain natriuretic

peptide and excessive renal sodium and water loss, leading to
circulating volume contraction. The administration of large volumes
of isotonic saline can increase extracellular fluid volume, activate
atrial natriuretic peptides (ANPs), and suppress aldosterone.
Significant fluid administration can also result in a ‘normal’
physiological pressure natriuresis [25].
A detailed management protocol for hyponatraemia in patients with

SAH is beyond the scope of this chapter, and for this the reader is
referred elsewhere [25]. Accurately establishing the underlying cause
of hyponatraemia in SAH is vital for appropriate management.
Several therapies used in the management of SAH can complicate the
assessment of the underlying cause of hyponatraemia. For example,
the calcium channel antagonist nimodipine can lead to hyponatraemia
through activation of atrial natriuretic peptides [26] and inhibition of
aldosterone activity [27]. Noradrenaline, often used to augment blood
pressure, may lead to a pressure diuresis and hypovolaemic
hyponatraemia [28]. Whether a clinically significant difference
between CSW and SIADH exists is unclear [29]—most laboratory
criteria cannot distinguish between the two. However, the consensus
is that the clinical and laboratory assessment of extracellular fluid
status is important for differentiation (Table 7.2).
Table 7.2 Features of the syndrome of inappropriate antidiuretic

hormone secretion and cerebral salt wasting
SIADH CSW
Serum sodium (mmol/L) <135 <135
Serum osmolality (mOsm/kg) <285 <285
Urine osmolality (mOsm/kg) >200 >200
Urinary sodium (mmol/L) >25 >25
Extracellular fluid volume Increased or no Reduced

change
Central venous pressure (cmH2O) ≥6 <6
Fluid balance Positive Negative
CSW, cerebral salt-wasting syndrome; SIADH, syndrome of

inappropriate antidiuretic hormone secretion.
Page 13 of 26

The management of hyponatraemia depends on the underlying cause,

and whether it is acute and symptomatic (e.g. seizures, coma, dilated
pupils, and neurogenic pulmonary oedema) or chronic. The volume of
hypertonic saline administered should be individualized, guided by
frequent serum sodium level monitoring to minimize the risk of
overcorrecting, or correcting hyponatraemia too rapidly. Acute
symptomatic hyponatraemia can be corrected with hypertonic saline
(1.8%) to raise plasma sodium by 1–2 mmol/hour to a total of 4–6
mmol [30], after which guidelines for correction of chronic
hyponatraemia are followed by correcting sodium values by no more
than 0.5 mmol/hour, to a maximum of 8–10 mmol/24 hours, to avoid
the risk of osmotic demyelination syndrome. For SIADH, lithium and
demeclocycline can also be used. Fludrocortisone [31] and
hydrocortisone [32] may also have a role in reducing natriuresis, but
further evidence is required before these can be considered routine
options. Vasopressin-2 receptor antagonists are currently licensed in
the UK for the treatment of SIADH (and in the US for treatment of
chronic hyponatraemia), but there is little evidence for their use
specifically in patients with SAH and extreme caution is advised
because of the risk of hypovolaemia.
Five days after admission, the patient developed a left-sided hemiparesis

that correlated with TCD-derived indices of vasospasm (middle cerebral
artery velocity 180 cm/s; Lindegaard ratio 5.2—see later). Induced
hypertension to a target systolic blood pressure of 160–180 mmHg using
a noradrenaline infusion improved her neurological deficit.
EXPERT COMMENT
Euvolaemia is the target for both prophylaxis and treatment of DCI,

and induced hypertension can be effective in reversing established
DCI. Systemic blood pressure is increased slowly while monitoring for
evidence of neurological or perfusion improvement, and after 2–3
days can be gradually weaned while continuing monitoring for
deterioration. There is preliminary evidence that early goal-directed
haemodynamic therapy might reduce the risk of DCI and improve
outcome after SAH, but large, randomized controlled outcome studies
are required before its widespread adoption into clinical practice.
LEARNING POINT Diagnosis and management of

vasospasm and delayed cerebral ischaemia
Page 14 of 26

There are many causes of delayed (>24 hours) neurological

deterioration after SAH, which can be related to systemic and
intracranial causes (Figure 7.3). DCI is a term applied to any
neurological deterioration, including focal neurological deficits and
altered consciousness, which persists for more than 1 hour and is not
attributable to other causes including a complication of aneurysm
occlusion, hyponatraemia, or fever. Although death caused by DCI is
infrequent in patients with SAH [33], the associated morbidity is high
and it doubles the risk of a poor outcome.
Figure 7.3
Causes of delayed neurological deterioration after subarachnoid
haemorrhage. CPP, cerebral perfusion pressure; DCI, delayed
cerebral ischaemia; ICP, intracranial pressure; SIRS, systemic
inflammatory response syndrome.
Factors associated with delayed cerebral ischaemia include:
● severe early brain injury (from the acute effects of subarachnoid

blood and the transient global ischaemia that may accompany
aneurysm rupture)
● volume, density, and persistence of the subarachnoid blood
● extent and severity of angiographic vasospasm
● increased cerebral metabolic demand/factors reducing the
supply of oxygen and glucose
● low cardiac output
● raised intracranial pressure
● hypotension
● existing collateral and anastomotic blood flow (protective)
● genetics (e.g. apolipoprotein E ε4 allele)
● choice of treatment used for the aneurysm (rates of DCI are
higher following neurosurgical clipping compared to endovascular
coiling) [56]
● smoking
Page 15 of 26

● pre-existing hypertension
● diabetes and hyperglycaemia
● systemic inflammatory response syndrome
● hydrocephalus.
Pathophysiology
The pathophysiology of DCI is complex and incompletely understood.
Angiographic vasospasm is associated with DCI, but vasospasm and
DCI are not synonymous. While approximately two-thirds of patients
with SAH develop angiographic vasospasm approximately 3–14 days
after the initial injury [34], symptoms develop in only 20–30% [35].
Ischaemia often involves more than one vascular territory, suggesting
that mechanisms other than simple vessel constriction contribute to
the development of DCI. These mechanisms include cortical
spreading ischaemia, microthrombosis, and microcirculation
constriction and have been comprehensively reviewed elsewhere
(Figure 7.3) [36].
Diagnosis
The diagnosis of DCI can be made on clinical and radiological
grounds (Figure 7.2), after exclusion of other neurological and
systemic causes for the neurological deterioration. Clinically, patients
may present with a spectrum of impaired consciousness, focal
neurological deficits, or pupillary abnormalities. The clinical diagnosis
is often difficult or impossible in poor-grade and sedated and
ventilated patients, in whom it is necessary to rely on other diagnostic
criteria. Of the potential contributors to DCI, angiographic vasospasm
is the most readily detectable and cerebrovascular imaging therefore
plays a key role in the investigation of DCI. Although catheter
angiography is the gold standard test for diagnosing vasospasm, CTA
is increasingly being used. The main limitations of CTA include the
possibility of overestimating the degree of vessel narrowing, and the
presence of artefacts from the treated aneurysm (clips and coils),
although this can be overcome with adjustment of the image
reconstruction plane and appropriate windowing and levelling of the
CT. CT perfusion permits calculation of the mean transit time taken
for blood to perfuse a tissue region of interest, and is also used as a
marker of cerebral vasospasm. A meta-analysis has confirmed a high
diagnostic accuracy for both CTA and CT perfusion in the diagnosis of
cerebral vasospasm in SAH [37].
TCD is widely used as a bedside tool for diagnosing and monitoring

vasospasm, and can also be used to detect impaired cerebral
autoregulation [38]. Increased middle cerebral artery flow velocity to
greater than 120 cm/s is consistent with vasospasm, but increases in
flow velocity can also be related to hyperaemia. The Lindegaard ratio,
which compares the mean flow velocity in the middle cerebral artery
Page 16 of 26

and that in the ipsilateral extracranial internal carotid artery,

overcomes this issue and is often preferred. A ratio greater than 3 is
considered diagnostic of vasospasm [39]. Although a sensitivity of
97% for the TCD detection of severe vasospasm has been reported
[40], TCD is a user-dependent tool that requires skilled personnel for
interpretation and only assesses a small number of large arteries.
Treatment decisions should not be based on TCD values alone [41].
Prevention and treatment

The only drug with class I evidence of improving outcomes following
SAH is the L-type calcium channel antagonist nimodipine, which
reduces the risk of both DCI and poor outcome [42]. Interestingly, in
most clinical trials, nimodipine does not reduce the incidence of
angiographic vasospasm, suggesting that its action is at least in part
through the inhibition of cortical spreading ischaemia and
antifibrinolytic activity that reduces microthrombus formation [43,
44]. The prevention of DCI focuses on the avoidance of factors that
adversely affect the delivery of oxygen and glucose to the brain.
These include optimization of fluid status and blood pressure.
Traditionally, hypervolaemia, hypertension, and haemodilution (triple-
H therapy) were central to the prevention and management of DCI,
without evidence of outcome benefits from RCTs. In recent years,
evidence has accumulated to suggest that not all aspects of triple-H
therapy are beneficial, and that some are detrimental. A
multimodality neuromonitoring study found that induced
hypertension improved cerebral blood flow and brain tissue
oxygenation (measured using brain tissue oxygen tension (PbtO2)
monitoring) after SAH, whereas hypervolaemia had an adverse effect
on PbtO2 [45]. Hypervolaemic haemodilution is also associated with
increased systemic complications, including acute lung injury, and
reduction of haemoglobin to dangerously low values [46]. In the latest
guidelines on the management of SAH from the Neurocritical Care
Society, euvolaemia and induced hypertension are recommended,
with firm advice to avoid haemodilution [6].
Significant efforts have been directed into RCTs of drug treatment for
SAH. While many have been shown to minimize the development of
vasospasm and/or DCI, most have not resulted in improved clinical
outcomes [47]. In particular, high-profile trials of magnesium [48] and
statins [49] have been disappointing. Endothelin-A antagonists have
been studied extensively after SAH because of the key role that
endothelin plays in maintaining vascular tone. The endothelin-A
antagonist clazosentan reduces angiographic vasospasm but has no
significant effect on outcome [50]. There are also no robust data to
support approaches targeting pathophysiological aspects of DCI other
than vasospasm, including microthromboembolism and platelet
aggregation. A meta-analysis of RCTs of antiplatelet therapies to
target microthromboembolism reported a reduction in poor outcomes
Page 17 of 26

and increased risk of intracranial complications, neither of which was

statistically significant [51].
Data on other drugs for SAH are promising, but methodological

limitations of the studies necessitate caution in their interpretation.
The rho-kinase inhibitor fasudil has been shown in several studies to
reduce the incidence of angiographic vasospasm and cerebral
infarction, and improve the odds ratio for good recovery compared to
placebo or nimodipine and other drugs (odds ratio 1.58; 95%
confidence interval 1.12–2.23) [52]. However, these studies had
several limitations and the drug is not used in Europe or North
America. The delivery of localized intrathecal thrombolytic agents to
remove the clot have been found in RCTs to significantly reduce the
incidence of vasospasm, delayed neurological deficits, hydrocephalus,
and poor outcomes [53], although these studies also had several
limitations. A small RCT of erythropoietin showed fewer cerebral
infarcts, less protracted cerebral autoregulatory dysfunction, and
improved clinical outcomes [54], although further data are required
to confirm these preliminary findings.
Several study limitations might have accounted for the multiple

‘negative’ results, including inappropriate or insensitive outcome
measures, lack of selection of high-risk patients, and higher reliance
on rescue therapy in the placebo arm of trials which may have offset
any benefit of the intervention arm. Although future studies should
aim to address these and other methodological limitations, it also
seems clear that targeting a single pathway in a disease with a
complex pathophysiology is unlikely to lead to dramatic
improvements in outcome.
‘Rescue’ therapies are often used when a patient with SAH develops
DCI. This can include haemodynamic therapy or endovascular
angioplasty. Attention should be paid to the fluid status and blood
pressure. Euvolaemia and induced hypertension is recommended.
Systemic blood pressure should be increased in a stepwise fashion
guided by assessment of neurological function, neuromonitoring, or
radiological evidence of improved perfusion. The higher blood
pressure is maintained for 2–3 days and gradually weaned while
monitoring for deterioration in clinical and neuromonitoring
variables. Although balloon angioplasty and intra-arterial injections of
vasodilating drugs are commonly used in clinical practice,
particularly if a patient does not respond to induced hypertension or
is intolerant of it, these interventions have not yet been subjected to
the rigours of a clinical trial [55]. Examples of vasodilating drugs
used in this setting include papaverine, nicardipine, nimodipine,
verapamil, and milrinone. All are short acting, can cause hypotension
in high doses, and should be considered only when medical treatment
has failed or is considered too risky because of cardiac or other
comorbidities.
Page 18 of 26

The patient made a good recovery, and the noradrenaline infusion was
slowly weaned after 2 days. Ten days following the endovascular
procedure, the patient was transferred to a neurosurgical ward for
ongoing care and rehabilitation.
Discussion
SAH comprises less than 5% of all strokes, but its societal impact
is profound because the mean age of affected patients is lower than that
of other stroke subtypes [57]. There has been a marked (up to 50%)
reduction in SAH-related mortality in recent decades [58, 59], but
morbidity remains high in the approximately 60% of patients who survive.
Survivors often have profound cognitive, neurological, or functional
deficits that impair their quality of life and ability to work [60].
Several factors are associated with poor outcome after SAH (see the
following list) [61]. The recent improvements in outcome are likely to be
multifactorial and related to earlier and improved diagnosis, greater
understanding of both the early and late pathophysiology of SAH and
their effects on outcome, and more aggressive management approaches
including early aneurysm repair, treatment of DCI, and improved medical
management of complications [62].
Factors associated with poor outcome following SAH include [61]:
● increased age
● worse neurological grade
● large blood load on admission CT scan
● symptomatic vasospasm
● cerebral infarction
● presence of intracerebral or intraventricular haemorrhage
● larger aneurysm size
● ruptured posterior circulation aneurysm
● elevated systolic blood pressure on admission
● previous diagnosis of hypertension, myocardial infarction, liver
disease, or SAH
● temperature greater than 38°C 8 days after SAH
● anticonvulsant use.
Early brain injury
Delayed neurological deterioration due to DCI and other causes (Figure

7.3) was described in detail earlier in this chapter. Early brain injury is
also an important pathophysiological process in patients with SAH.
Aneurysm rupture is associated with extravasation of blood into the
subarachnoid space and often into the ventricles and brain tissue. This is
associated with an acute increase in ICP that may result in impaired
Page 19 of 26

cerebral perfusion, transient global ischaemia, and temporary loss of

consciousness. Early brain injury after SAH results from this chain of
events in combination with the direct effects of the blood itself [36]. The
underlying pathophysiological changes associated with early brain injury
include impaired cerebral blood flow and autoregulation, disruption of the
blood–brain barrier, activation of cell death pathways, cerebral oedema,
impaired calcium homeostasis, oxidative stress, and inflammation. These
pathophysiological pathways have recently been comprehensively
reviewed [63]. It is anticipated that, in the future, pharmacological
treatments will be able to target this early damage associated with SAH
and improve outcomes.
Pending the development of treatments that target the early and delayed
brain injury associated with SAH, clinical management should focus on
early securing of the ruptured aneurysm and optimization of systemic
physiology and modifiable risk factors for DCI that are known to influence
outcome.
Aneurysmal SAH is a devastating disease associated with high

mortality and poor outcome in many survivors. Aggressive treatment
by a comprehensive multidisciplinary team in a high-volume centre is
associated with improved outcome. The critical care management of
SAH presents significant challenges and should focus on the following
key points:
1. Rapid intervention to secure the ruptured aneurysm to

minimize the risk of rebleeding, followed by implementation of
measures to minimize secondary brain injury.
2. Identification and treatment of acute intracranial
complications such as hydrocephalus.
3. Optimization of fluid balance to target euvolaemia, and careful
control of blood pressure.
4. Avoidance of hyperglycaemia, hyperthermia, and liberal blood
transfusions which are all associated with longer ICU and
hospital length of stay, higher mortality, and worse neurological
outcome in survivors.
5. Identification and management of non-neurological
complications including SAH-related cardiac dysfunction and
hyponatraemia.
6. Prevention and treatment of DCI through meticulous fluid
management, and induced hypertension in established DCI.
7. Early, aggressive treatment should be offered to all but the
most hopeless cases since substantial numbers of even poor-
grade patients may do well.
Page 20 of 26

References
1. Drake CG, Hunt WE, Kassell N, et al. Report of World Federation of
Neurological Surgeons Committee on a Universal Subarachnoid
Hemorrhage Grading Scale. J Neurosurg. 1988;68:985–6.
2. Molyneux AJ, Kerr RSC, Yu L-M, et al. International subarachnoid

aneurysm trial (ISAT) of neurosurgical clipping versus endovascular
coiling in 2143 patients with ruptured intracranial aneurysms: a
randomised comparison of effects on survival, dependency, seizures,
rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005;366:809–
17.
3. Molyneux AJ, Birks J, Clarke A, et al. The durability of endovascular

coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18
year follow-up of the UK cohort of the International Subarachnoid
Aneurysm Trial (ISAT). Lancet. 2015;385:691–7.
4. Britz GW. ISAT trial: coiling or clipping for intracranial aneurysms?

Lancet. 2005;366:783–5.
5. Darsaut TE, Jack AS, Kerr RS, Raymond J. International Subarachnoid

Aneurysm Trial—ISAT part II: study protocol for a randomized controlled
trial. Trials. 2013;14:156.
6. Diringer MN, Bleck TP, Hemphill C, et al. Critical care management of

patients following aneurysmal subarachnoid hemorrhage:
recommendations from the Neurocritical Care Society’s Multidisciplinary
Consensus Conference. Neurocrit Care. 2011;15:211–40.
7. Keong NC, Bulters DO, Richards HK, et al. The SILVER (Silver
Impregnated Line Versus EVD Randomized trial): a double-blind,
prospective, randomized, controlled trial of an intervention to reduce the
rate of external ventricular drain infection. Neurosurgery. 2012;71:394–
403.
8. Wolf S. Rationale for lumbar drains in aneurysmal subarachnoid

hemorrhage. Curr Opin Crit Care. 2015;21:120–6.
9. van der Bilt IAC, Hasan D, Vandertop WP, et al. Impact of cardiac
complications on outcome after aneurysmal subarachnoid hemorrhage: a
meta-analysis. Neurology. 2009;72:635–42.
10. Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of medical

complications on outcome after subarachnoid hemorrhage. Crit Care
Med. 2006;34:617–23.
11. Bruder N, Rabinstein A, Participants in the International Multi-

Disciplinary Consensus Conference on the Critical Care Management of
Subarachnoid Hemorrhage. Cardiovascular and pulmonary complications
Page 21 of 26

of aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011;15:257–

69.
12. Hinson HE, Sheth KN. Manifestations of the hyperadrenergic state

after acute brain injury. Curr Opin Crit Care. 2012;18:139–45.
13. Nguyen H, Zaroff JG. Neurogenic stunned myocardium. Curr Neurol

Neurosci Rep. 2009;9:486–91.
14. Mazzeo AT, Micalizzi A, Mascia L, et al. Brain-heart crosstalk: the

many faces of stress-related cardiomyopathy syndromes in anaesthesia
and intensive care. Brit J Anaesth. 2014;112:803–15.
15. Malik AN, Gross BA, Rosalind Lai PM, et al. Neurogenic stress
cardiomyopathy after aneurysmal subarachnoid hemorrhage. World
Neurosurg. 2015;83:880–5.
16. Prunet B, Basely M, D’Aranda E, et al. Impairment of cardiac

metabolism and sympathetic innervation after aneurysmal subarachnoid
hemorrhage: a nuclear medicine imaging study. Crit Care. 2014;18:R131.
17. Joseph M, Ziadi S, Nates J, et al. Increases in cardiac output can

reverse flow deficits from vasospasm independent of blood pressure: a
study using xenon computed tomographic measurement of cerebral blood
flow. Neurosurgery. 2003;53:1044–51.
18. Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in

the United States. Cost Eff Resour Alloc. 2006;4:10.
19. Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance of
hypernatremia and hyponatremia among patients with aneurysmal
subarachnoid hemorrhage. Neurosurgery. 2002;50:749–55.
20. Sherlock M, O’Sullivan E, Agha A, et al. The incidence and

pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clin
Endocrinol (Oxf). 2006;64:250–4.
21. Nakagawa I, Kurokawa S, Nakase H. Hyponatremia is predictable in

patients with aneurysmal subarachnoid haemorrhage – clinical
significance of serum atrial natriuretic peptide. Acta Neurochir (Wien).
2010;152:2147–52.
22. Espiner EA, Leikis R, Ferch RD, et al. The neuro-cardio-endocrine

response to acute subarachnoid haemorrhage. Clin Endocrinol (Oxf).
2002;56:629–35.
23. Berendes E, Walter M, Cullen P, et al. Secretion of brain natriuretic

peptide in patients with aneurysmal subarachnoid haemorrhage. Lancet.
1997;349:245–9.
Page 22 of 26

24. Sviri GE, Feinsod M, Soustiel JF. Brain natriuretic peptide and
cerebral vasospasm in subarachnoid hemorrhage. Clinical and TCD
correlations. Stroke. 2000;31:118–22.
25. Kirkman MA, Albert AF, Ibrahim A, Doberenz D. Hyponatremia and

brain injury: historical and contemporary perspectives. Neurocrit Care.
2013;18:406–16.
26. Shamiss A, Peleg E, Rosenthal T, Ezra D. The role of atrial natriuretic

peptide in the diuretic effect of Ca2+ entry blockers. Eur J Pharmacol.
1993;233:113–17.
27. Kosaka H, Hirayama K, Yoda N, et al. The L-, N-, and T-type triple
calcium channel blocker benidipine acts as an antagonist of
mineralocorticoid receptor, a member of nuclear receptor family. Eur J
Pharmacol. 2010;635:49.
28. Singh S, Bohn D, Carlotti AP, et al. Cerebral salt wasting: truths,
fallacies, theories, and challenges. Crit Care Med. 2002;30:2575–9.
29. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what
difference? J Am Soc Nephrol. 2008;19:194–6.
30. Mount DB. Fluid and electrolyte disturbances. In: Longo DL, Kasper
DL, Jameson JL, et al. (eds) Harrison’s Principles of Internal Medicine,
18th edn. Boston, MA: McGraw-Hill Medical; 2001, pp. 341–59.
31. Mori T, Katayama Y, Kawamata T, Hirayama T. Improved efficiency of

hypervolemic therapy with inhibition of natriuresis by fludrocortisone in
patients with aneurysmal subarachnoid hemorrhage. J Neurosurg.
1999;91:947–52.
32. Katayama Y, Haraoka J, Hirabayashi H, et al. A randomized controlled

trial of hydrocortisone against hyponatremia in patients with aneurysmal
subarachnoid hemorrhage. Stroke. 2007;38:2373–5.
33. Macdonald RL, Rosengart A, Huo D, Karrison T. Factors associated

with the development of vasospasm after planned surgical treatment of
aneurysmal subarachnoid hemorrhage. J Neurosurg. 2003;99:644–52.
34. Dorsch N. A clinical review of cerebral vasospasm and delayed

ischaemia following aneurysm rupture. Acta Neurochir Suppl.
2011;110:5–6.
35. Dehdashti AR, Mermillod B, Rufenacht DA, et al. Does treatment

modality of intracranial ruptured aneurysms influence the incidence of
cerebral vasospasm and clinical outcome? Cerebrovasc Dis. 2004;17:53–
60.
36. Macdonald RL. Delayed neurological deterioration after subarachnoid

haemorrhage. Nat Rev Neurol. 2014;10:44–58.
Page 23 of 26

37. Greenberg ED, Gold R, Reichman M, et al. Diagnostic accuracy of CT

angiography and CT perfusion for cerebral vasospasm: a meta-analysis.
AJNR Am J Neuroradiol. 2010;31:1853–60.
38. Aries MJH, Elting JW, De Keyser J, et al. Cerebral autoregulation in

stroke: a review of transcranial Doppler studies. Stroke. 2010;41:2697–
704.
39. Lindegaard KF, Nornes H, Bakke SJ, et al. Cerebral vasospasm

diagnosis by means of angiography and blood velocity measurements.
Acta Neurochir (Wien). 1989;100:12–24.
40. Fontanella M, Valfrè W, Benech F, et al. Vasospasm after SAH due to

aneurysm rupture of the anterior circle of Willis: value of TCD
monitoring. Neurol Res. 2008;30:256–61.
41. Carrera E, Schmidt JM, Oddo M, et al. Transcranial Doppler for

predicting delayed cerebral ischemia after subarachnoid hemorrhage.
Neurosurgery. 2009;65:316–23.
42. Dorhout Mees SM, Rinkel GJE, Feigin VL, et al. Calcium antagonists
for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev.
2007;3:CD000277.
43. Vergouwen MDI, Vermeulen M, Coert BA, et al. Microthrombosis after

aneurysmal subarachnoid hemorrhage: an additional explanation for
delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008;28:1761–70.
44. Dreier JP. The role of spreading depression, spreading depolarization

and spreading ischemia in neurological disease. Nat Med. 2011;17:439–
47.
45. Muench E, Horn P, Bauhuf C, et al. Effects of hypervolemia and

hypertension on regional cerebral blood flow, intracranial pressure, and
brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med.
2007;35:1844–51.
46. Treggiari MM, Deem S. Which H is the most important in triple-H

therapy for cerebral vasospasm? Curr Opin Crit Care. 2009;15:83–6.
47. Etminan N, Vergouwen MDI, Ilodigwe D, Macdonald RL. Effect of

pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and
clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a
systematic review and meta-analysis. J Cereb Blood Flow Metab.
2011;31:1443–51.
48. Dorhout Mees SM, Algra A, Vandertop WP, et al. Magnesium for
aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-
controlled trial. Lancet. 2012;380:44–9.
Page 24 of 26

49. Kirkpatrick PJ, Turner CL, Smith C, et al. Simvastatin in aneurysmal

subarachnoid haemorrhage (STASH): a multicentre randomised phase 3
trial. Lancet Neurol. 2014;13:666–75.
50. Vergouwen MDI, Algra A, Rinkel GJE. Endothelin receptor antagonists

for aneurysmal subarachnoid hemorrhage: a systematic review and meta-
analysis update. Stroke. 2012;43:2671–6.
51. Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJE.
Antiplatelet therapy for aneurysmal subarachnoid haemorrhage.
Cochrane Database Syst Rev. 2007;4:CD006184.
52. Liu GJ, Wang ZJ, Wang YF, et al. Systematic assessment and meta-
analysis of the efficacy and safety of fasudil in the treatment of cerebral
vasospasm in patients with subarachnoid hemorrhage. Eur J Clin
Pharmacol. 2012;68:131–9.
53. Kramer AH, Fletcher JJ. Locally-administered intrathecal

thrombolytics following aneurysmal subarachnoid hemorrhage: a
systematic review and meta-analysis. Neurocrit Care. 2011;14:489–99.
54. Tseng M-Y, Hutchinson PJ, Richards HK, et al. Acute systemic
erythropoietin therapy to reduce delayed ischemic deficits following
aneurysmal subarachnoid hemorrhage: a phase II randomized, double-
blind, placebo-controlled trial. J Neurosurg. 2009;111:171–80.
55. Kimball MM, Velat GJ, Hoh BL, Participants in the International Multi-
Disciplinary Consensus Conference on the Critical Care Management of
Subarachnoid Hemorrhage. Critical care guidelines on the endovascular
management of cerebral vasospasm. Neurocrit Care. 2011;15;336–41.
56. Dorhout Mees SM, Kerr RS, Rinkel GJE, et al. Occurrence and impact
of delayed cerebral ischemia after coiling and after clipping in the
International Subarachnoid Aneurysm Trial (ISAT). J Neurol.
2012;259:679–83.
57. Macdonald RL, Schweizer TA. Spontaneous subarachnoid

haemorrhage. Lancet. 2016;389:655–66.
58. Lovelock CE, Rinkel GJE, Rothwell PM. Time trends in outcome of
subarachnoid hemorrhage: population-based study and systematic review.
Neurology. 2010;74:1494–501.
59. Nieuwkamp DJ, Setz LE, Algra A, et al. Changes in case fatality of
aneurysmal subarachnoid haemorrhage over time, according to age, sex,
and region: a meta-analysis. Lancet Neurol. 2009;8:635–42.
60. Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional

outcome after aneurysmal subarachnoid hemorrhage. Stroke.
2010;41:e519–36.
Page 25 of 26

61. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic

factors for outcome in patients with aneurysmal subarachnoid
hemorrhage. Stroke. 2007;38:2315–21.
62. Smith M, Citerio G. What’s new in subarachnoid hemorrhage.

63. Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain
injury after subarachnoid hemorrhage. Prog Neurobiol. 2012;97:14–37.
Page 26 of 26

Acute-on-chronic respiratory failure

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Acute-on-chronic respiratory failure
Author(s): Richard Hunt
DOI: 10.1093/med/9780198814924.003.0008
Expert commentary by Peter MacNaughton
Case history
A 61-year-old male with acute respiratory distress was referred for

consideration for admission to the intensive care unit (ICU). He had
presented to the emergency department the day before with a 4-day
history of worsening dyspnoea. He had a 40 pack-year smoking history
with a past medical history of chronic obstructive pulmonary disease
(COPD). He had been seen by his general practitioner 3 days earlier who
had prescribed 40 mg prednisolone once daily. His regular medications
were an inhaled, combined long-acting beta2 agonist with a steroid and
an inhaled short-acting beta2 agonist. He was fully independent with
activities of daily living and could manage a flight of stairs, but would
struggle to walk around a supermarket without stopping to catch his
breath. He had never been admitted to hospital before and was not on
oxygen therapy at home.
Page 1 of 26
In the emergency department, examination showed a lean man in

significant respiratory distress using his accessory muscles. He was fully
conscious and orientated with a respiratory rate of 24 breaths/min,
hyperinflated chest with poor expansion, quiet breath sounds with
occasional wheeze and no focal signs. Circulation was unremarkable with
warm peripheries, no peripheral oedema, and jugular venous pressure did
not appear to be raised. His initial arterial blood gas (ABG) analysis,
taken breathing air, showed a moderate respiratory acidosis: pH 7.28,
partial pressure of oxygen (PaO2) 7.92 kPa, partial pressure of carbon
dioxide (PaCO2) 7.37 kPa, bicarbonate 27.2 mmol/L (alveolar–arterial
oxygen gradient 2.8 kPa and PaO2/fraction of inspired oxygen (FiO2) 37.7
kPa). He was treated with oxygen at 2 L/min via a Hudson mask,
salbutamol nebulizers 6-hourly, ipratropium nebulizers 8-hourly, and oral
prednisolone was continued. Admission bloods were unremarkable with a
white blood count of 7.4 × 109/L and C-reactive protein of 11 mg/L. An
initial chest X-ray (CXR) showed chronic changes associated with COPD
but no focal changes (Figure 8.1). His respiratory distress improved and
he was transferred to the medical admissions unit with a diagnosis of an
acute exacerbation of COPD (AECOPD).
Figure 8.1
Admission chest X-ray shows chronic changes classically seen in COPD
(increased lung markings, hyperexpansion, small cardiac shadow, bullae,
and old rib fractures secondary to steroid-induced osteoporosis) with no
focal signs.
Following admission to the medical admissions unit, he developed

worsening respiratory distress and arterial blood oxygen saturation by
pulse oximetry (SpO2) decreased to 80%. The oxygen mask was changed
to a Venturi mask with an FiO2 of 0.4 and urgent medical review
Page 2 of 26

requested. A repeat ABG showed pH 7.26, PaO2 17.8 kPa, PaCO2 8.37
kPa, and bicarbonate 27.1 mmol/L. He was reviewed by the medical
registrar who decreased his FiO2 to 0.28, started an intravenous
aminophylline infusion, and transferred him to the respiratory high
dependency unit for non-invasive ventilation (NIV).
Bi-level NIV was commenced using a full facemask and inspiratory and
expiratory airway pressures (IPAP/EPAP) of 15 cmH2O and 5 cmH2O
respectively with an FiO2 of 0.30. His respiratory distress improved and a
repeat ABG showed pH 7.30, PaO2 8.5 kPa, PaCO2 7.21 kPa, and
bicarbonate 27.2 mmol/L.
LEARNING POINT Controlled oxygen therapy
Significant worsening of hypercapnia in response to supplemental

oxygen exposure occurs in approximately 25% of patients with an
exacerbation of COPD. The cause of this clinically important
phenomenon is often incorrectly stated by clinicians.
Loss of hypoxic drive

This mechanism was first proposed in 1949 [1]. Despite several
subsequent clinical studies that could not confirm this theory, this
mechanism of oxygen-induced hypercapnia continues to be
perpetuated in clinical texts. This has resulted in an inappropriate
reluctance to administer oxygen to patients with COPD and severe
hypoxaemia. Clinical studies have revealed that minute ventilation is
not significantly reduced and that respiratory drive remains high in
patients with COPD who develop hypercapnia following oxygen
exposure [2]. Hypercapnia occurs because of an inability to increase
minute ventilation to compensate for an increased pulmonary arterial
carbon dioxide (CO2) load from two main mechanisms:
● Hyperoxia-induced ventilation/perfusion (V/Q) mismatch:

hypoxic pulmonary vasoconstriction ensures that blood flow to
poorly ventilated alveolar capillary units is minimized, maintaining
optimal V/Q matching. If a high inspired oxygen concentration is
administered, hypoxic vasoconstriction will be supressed in poorly
ventilated lung units. This results in V/Q mismatch and impaired
CO2 clearance. If the patient has ventilatory failure and is unable
to increase minute ventilation significantly in order to increase
CO2 clearance from other lung units, then arterial CO2 tension will
inevitably rise.
● The Haldane effect: this describes the process by which CO2 is
bound more readily to deoxygenated haemoglobin than oxygenated
haemoglobin. Administration of high inspired oxygen
concentrations will result in less CO2 bound to haemoglobin
thereby increasing PaCO2.
Page 3 of 26

Oxygen-induced hypercapnia is not restricted to patients with severe

COPD but may occur in any patient with chronic respiratory failure
who is unable to increase minute ventilation to compensate for the
mechanisms described. This includes COPD, morbid obesity
hypoventilation syndrome, and neuromuscular disorders. The British
Thoracic Society oxygen administration guidelines highlight the
priority in all patients of preventing severe hypoxaemia and that
therapy should be titrated to a target arterial blood oxygen saturation
of 88–92% in patients with chronic respiratory disease at risk of
hypercapnia [3].
LEARNING POINT Chronic obstructive pulmonary

disease
COPD is characterized by long-standing airflow obstruction with

limited reversibility. Smoking is the major cause, although
occupational exposures and genetic factors may contribute. Smoking
induces chronic inflammation resulting in both airway and
parenchymal damage. In England, it is the fifth most common cause
of mortality with more than 30,000 deaths per year and is a major
cost burden on the National Health Service [4].
LEARNING POINT Management of AECOPD
The British Thoracic Society and National Institute for Health and
Care Excellence (NICE) recommend the following on admission for
any patient with AECOPD [5]:
Baseline investigations
● ABG with documented FiO2.

● Full blood count, urea and electrolytes, blood cultures if
pyrexial.
● CXR.
● Electrocardiogram (ECG).
● Theophylline concentration.
● Sputum microscopy and culture (if purulent).
Medical therapy
● Oxygen to maintain SpO2 88–92%.

● Inhaled bronchodilators; the driving gas should be prescribed
for nebulizers.
Page 4 of 26

● Prednisolone 30 mg (7 to no longer than 14 days).

● Antibiotics (see next section).
● Methylxanthines: only if there is an inadequate response to
nebulized bronchodilators. Check levels after 24 hours.
● Doxapram: is rarely used and should be considered only in
obtunded patients with hypercapnia when NIV is unavailable or
inappropriate.
Antibiotics
● Prescribe in patients with a history of more purulent sputum

and/or evidence of consolidation on CXR or clinical signs of
pneumonia.
● Adhere to local microbiology guidelines.
● Change from broad-spectrum cover to targeted antibiotics when
sensitivities are available.
The following morning, when reviewed by the ICU team, the patient had
developed worsening respiratory distress, despite full medical therapy.
The patient was receiving NIV via a full face mask at pressures of 20/5
cmH2O. He was agitated, was not tolerating the NIV, and was struggling
to speak single words because of respiratory distress. His vital signs were
respiratory rate 34 breaths/min, blood pressure 134/78 mmHg, and pulse
114 beats/min. His SpO2 was 85% with FiO2 0.30, and ABG showed
worsening hypoxaemia with hypercapnia: pH 7.28, PaO2 6.70 kPa, PaCO2
7.68 kPa, and bicarbonate 26.3 mmol/L.
LEARNING POINT Causes of AECOPD
Although the cause for acute deterioration is unknown in around 30%

of cases [5], it is important to consider and, where appropriate, to
investigate/exclude the likely cause to ensure optimal treatment. The
most common causes are as follows:
Infective exacerbation
● Viral in up to 60%. Most commonly rhinovirus [6].

● Bacterial. Most commonly Haemophilus influenza, Streptococcus
pneumoniae, and Moraxella catarrhalis [7].
Page 5 of 26

Environmental pollution
● Epidemiological studies suggest this can be a significant factor

in urban areas. Exposure to nitrogen dioxide and sulphur dioxide
are implicated.
Pulmonary embolus
● This is present in 16% of patients with AECOPD who have no

evidence of infection [8].
● Consider when there is no evidence of infection and the CXR is
clear.
● Hypercapnia may be caused by increased alveolar dead space.
● The ECG and echocardiogram may show right heart strain/right
ventricular dilation as a result of chronic respiratory failure, which
reduces sensitivity in this patient group.
● A CT pulmonary angiogram is required for diagnosis.
Heart failure
● Acute left heart failure is present in up to 30% of patients with

AECOPD [9].
● Right heart failure may be precipitated by hypoxia-induced
pulmonary hypertension, pneumonia, or pulmonary embolus.
● Useful investigations include B-type natriuretic peptide, CXR,
and echocardiography.
● Pulmonary oedema in emphysematous lungs is associated with
predominately basal airspace shadowing on CXR and can be
misinterpreted as ‘bilateral pneumonia’.
Pneumothorax
● Exclude using CXR or thoracic ultrasonography.

● Do not confuse emphysematous bullae with pneumothorax
EXPERT COMMENT
The classic ABG pattern associated with a pulmonary embolus of

hypoxaemia and hypocapnia may be surprising when you consider the
underlying pathophysiology of reduced perfusion to lung units
(increased alveolar dead space). However, diversion of lung perfusion
to other less well ventilated lung units results in hypoxaemia (V/Q
mismatch) and the severe tachypnoea associated with pulmonary
Page 6 of 26

embolus results in a marked increase in minute ventilation

overcompensating for the increase in alveolar dead space producing a
low PaCO2. Patients with chronic lung disease such as COPD are
unable to increase minute ventilation significantly to compensate for
the increase in alveolar dead space with the result that a pulmonary
embolus will be associated with an increase in PaCO2.
In view of the failure of NIV, a decision was made to transfer the patient
to ICU for intubation and ventilatory support.
LEARNING POINT Non-invasive ventilation
NIV refers to the provision of ventilatory support without the use of

an artificial airway (tracheal tube or tracheostomy). It is typically
applied via a mask or hood to deliver either continuous positive
airway pressure (CPAP) or bi-level positive airway pressure. In bi-
level support, the airway pressure delivered during inspiration is
termed IPAP and the expiratory pressure, EPAP. The difference
represents the pressure support level. Bi-level NIV is considered a
standard of care for patients with severe exacerbations of COPD who
do not improve with standard medical care.
A Cochrane review assessed NIV in the management of AECOPD and

reported the following benefits [10]:
● Decreased need for intubation and ventilation (relative risk 0.42

(0.31–0.59)).
● Fewer treatment complications (relative risk 0.32 (0.18–0.56)).
● Shorter length of stay (mean 3.24 days).
● Decreased mortality (relative risk 0.41 (0.26–0.64)).
British Thoracic Society guidelines for the initiation of NIV [11]

advise the following:
● Begin NIV if the patient has decompensated hypercapnic

respiratory failure (pH <7.35) despite optimal medical therapy.
● NIV should be administered by appropriately trained staff in a
setting optimized for the management of such patients (e.g.
respiratory wards, medical high dependency unit (HDU), or ICU).
● Patients with pH less than 7.26 should be considered for
admission to an HDU or ICU if appropriate.
● Start at EPAP 5 cmH2O and IPAP 15 cmH2O and titrate IPAP
upwards at increments of 2–5 cm at a rate of approximately 5
cmH2O every 10 min until a therapeutic response is achieved or
the patient is unable to tolerate higher pressures.
Page 7 of 26

● Take ABGs at 1 hour and every hour after settings are changed.
Otherwise after 4 hours.
● Success in NIV is considered to be correction of acidaemia to pH
greater than 7.35.
● Plan what to do in the event of deterioration and agree ceilings
of therapy.
LEARNING POINT Indications of non-invasive

ventilation in other conditions
Other causes of acute-on-chronic respiratory failure, which are likely

to benefit from NIV, are outlined as follows:
Heart failure
Evidence suggests that bi-level and CPAP have a similar efficacy in
the treatment of patients with cardiogenic pulmonary oedema. A
Cochrane review [12] concluded that bi-level or CPAP were both
effective in reducing need for intubation, ICU length of stay, and
mortality.
NICE guidance for the management of patients with acute

cardiogenic pulmonary oedema recommends that NIV is not used
routinely but is started without delay in those with severe dyspnoea
and acidaemia at acute presentation and also in patients who do not
improve with initial medical management [13].
Obesity hypoventilation syndrome

Acute-on-chronic respiratory failure caused by obesity-associated
diseases is becoming more prevalent. The cost of treating these
diseases is projected to reach £2 billion/year in the UK by 2030 [14].
Obesity hypoventilation syndrome is defined as [15]:
● obesity (body mass index (BMI) >30 kg/m2)

● daytime hypoventilation (PaCO2 >6 kPa or bicarbonate >27
mmol/L)
● sleep-disordered breathing (e.g. obstructive sleep apnoea)
● absence of an alternative explanation (it is a diagnosis of
exclusion).
NIV is indicated in patients with obesity hypoventilation syndrome

with acute respiratory failure; indeed, outcomes appear to be as good
as, if not better, than for COPD patients [16].
Page 8 of 26

Postoperative surgical patients

Postoperative NIV may improve outcome in patients at high risk of
respiratory complications although strong evidence is lacking [17]. A
Cochrane review found weak evidence to support the use of CPAP in
patients after major abdominal surgery [18].
Post extubation in high-risk patients

See Case 16.
Contraindications to NIV
An inability to maintain an airway is an absolute contraindication to
NIV.
Other contraindications include:
● very poor gas exchange (e.g. need for high levels of positive end-
expiratory pressure (PEEP))
● emergency indication for intubation (e.g. cardiorespiratory
arrest)
● excessive secretion load
● mucous plugging
● agitation/intolerance
● severely impaired consciousness unless due to hypercapnia
● vomiting
● upper gastrointestinal haemorrhage
● recent surgery to the upper gastrointestinal tract
● recent surgery or trauma to the face or upper respiratory tract
● base of skull fracture
● cardiovascular instability.
CLINICAL TIP Do patients on non-invasive ventilation

need a nasogastric tube?
Placement of a nasogastric tube during NIV to prevent gastric

distension is unnecessary in the majority of patients. Nasogastric
tubes can impair patient ventilator synchrony because they can cause
significant mask leak and may paradoxically increase gastric
distension by splinting open the gastro-oesophageal junction. Most
patients will not require enteral feeding and will tolerate oral feeding
as their condition improves. Enteral feeding is undertaken cautiously
and not early in the treatment of patients during NIV because of the
Page 9 of 26

risk of aspiration if the patient vomits. Where a nasogastric tube is

required, use of a fine-bore tube will limit mask leak.
EXPERT COMMENT
The keys to successful initiation of NIV are:
● patient selection
● effective communication with the patient
● selecting an appropriate interface
● taking time to ensure an optimal fit to minimize any leaks
● adjusting ventilator settings to optimize synchrony
● gradual increase of pressures to ensure patient tolerance.
Once NIV has been established, ensure there is an escalation plan in

case NIV fails. This details whether admission to ICU for intubation
and ventilation is appropriate and whether the patient is for
resuscitation. Alternatively, document a plan for palliation [19].
CLINICAL TIP Interfaces for non-invasive ventilation
There is a range of devices that can be used to apply NIV. Nasal

masks are commonly used for patients receiving home ventilation but
are generally unsuitable in the acute setting when patients are
breathing through their mouth, hence a facemask will be required.
Facemasks need to be correctly sized to the patient to ensure any
leak is minimized. If correctly positioned, the mask should provide an
effective seal without the need for excessive tension in the mask
straps. Total face masks which seal around the perimeter of the face
above the eyes appear to be better tolerated and avoid the
complication of pressure damage to the nasal bridge. The helmet also
appears to be well tolerated. It was initially used to apply only CPAP
because the dead space is large; however, subsequent reports have
described successful use in hypercapnic respiratory failure.
LEARNING POINT High-flow nasal oxygenation
High-flow nasal oxygenation (HFNO) is increasingly used as an

alternative to NIV in patients with acute hypoxaemic respiratory
Page 10 of 26

failure. HFNO provides humidified oxygen at flow rates of up to 60 L/

min and has a number of beneficial effects including:
● effective delivery of high FiO2

● augments CO2 clearance by flushing out upper airway dead
space
● small PEEP-like effect
● improved secretion clearance.
HFNO is well tolerated and easy to implement. In the Clinical Effect

of the Association of Noninvasive Ventilation and High Flow Nasal
Oxygen Therapy in Resuscitation of Patients with Acute Lung Injury
(FLORALI) study, which involved predominately patients with
pneumonia, and excluded patients with COPD and heart failure [20],
mortality was lower in patients who received HFNO compared to NIV
or conventional oxygen therapy. HFNO also appears to be effective in
the management of respiratory failure following cardiac surgery [21]
and when used prophylactically following planned extubation it
reduces the need for reintubation [22].
LEARNING POINT Indications for invasive mechanical

ventilation
Intubation and mechanical ventilation is indicated in appropriate

patients who are not improving despite optimal NIV support, if they
are unable to tolerate NIV, or if there are contraindications to NIV.
Early recognition of the need for intubation is vital as delayed
intubation and ventilation results in much poorer outcomes. In
patients with severe acidaemia (e.g. pH <7.26), receiving NIV
outcome is improved if they are managed in an ICU setting so that
intubation can be undertaken without delay if needed [23].
There is some evidence that clinicians have been overly pessimistic

about the outcome of patients with AECOPD resulting in a failure to
refer or admit to ICU for invasive ventilation. A large, international,
multicentre study reported that the outcome of patients ventilated in
ICU with a diagnosis of AECOPD is significantly better than other
ventilated patients (mortality 22% in COPD, 52% in ARDS) [24, 25].
The largest study undertaken to date assessing the outcome of

patients with AECOPD admitted to an ICU in England and Wales is
the COPD and Asthma Outcome (CAOS) study. This prospective
cohort study assessed 180-day survival and quality of life in 832
patients admitted to 92 ICUs. Overall survival was 62% at 180 days
and of the 80% who responded to a questionnaire assessing quality of
life, 96% would choose to have a similar treatment again [26]. This
Page 11 of 26

study assessed outcome only in those patients admitted to ICU, thus

representing those who had been assessed as having a realistic
chance of survival.
The challenge for the clinician is to assess which patients are likely to
benefit from ICU admission and invasive ventilation. Factors which
have been associated with a high hospital mortality rate include
increasing age, poor nutritional status, acute comorbidity, and
previous admissions for acute exacerbations [27]. Additional factors,
associated with a high mortality after hospital discharge, include poor
functional status, cor pulmonale, and inability to perform activities of
daily living [28]. All these factors need to be considered when
assessing suitability for ICU admission.
LEARNING POINT Scoring systems in chronic

respiratory failure
DECAF score for AECOPD

The DECAF score uses five variables to classify patients with an
AECOPD into low-, intermediate-, or high-risk groups [29]. Its use was
recommended by the 2014 UK national COPD audit. The five
variables are:
● Dyspnoea (eMRCD) 5a 1
5b 2
● Eosinopenia (<0.05 × 109/L) 1
● Consolidation (On CXR) 1
● Acidaemia (pH <7.3) 1
● Fibrillation (Atrial fibrillation, including 1

paroxysmal atrial fibrillation)
eMRCD = extended MRC dyspnoea scale: patients should only score

5a (independent in washing or dressing) or 5b (dependant for both
washing and dressing) if they cannot leave the house without
assistance. Patients with a DECAF score greater than 3 are
considered high risk and may be suitable for escalation planning or
early palliation.
Page 12 of 26

BODE Index
The BODE index is a composite score which can be used to predict
long-term prognosis in COPD. It is based on BMI, severity of airflow
obstruction (forced expiratory volume in 1 second), dyspnoea
(Modified Medical Research Council Dyspnoea Scale), and exercise
capacity as assessed by the 6 min walk distance. NICE recommends
that it is calculated when the component values are available.
Body mass index

Low BMI is an indicator of poor prognosis in chronic respiratory
failure [30] and it becomes a more important prognosticator as
disease severity progresses. Reasons for a low BMI predicting a poor
outcome include:
● increased work of breathing

● decreased nutritional intake because of shortness of breath
● mitochondrial dysfunction because of chronic hypoxaemia [31]
● apoptosis and skeletal muscle wasting [32].
Shortly after arriving on the ICU the patient was intubated and invasive
ventilation initiated using synchronized intermittent mandatory
ventilation using a target tidal volume of 7 mL/kg based on predicted
body weight.
LEARNING POINT Mechanical ventilation in chronic

obstructive pulmonary disease
Increased airway resistance in patients with COPD may significantly

impair expiration during mechanical ventilation. The characteristic
slow and incomplete exhalation may mean that expiration is not
complete before the ventilator cycles to inspiration. This leads to gas
trapping or ‘dynamic hyperinflation’ also termed ‘breath stacking’.
Intrinsic PEEP is a measure of the degree of dynamic hyperinflation.
Suggested initial ventilator settings include:
● volume controlled mode

● tidal volume of 6–8 mL/kg predicted body weight
● low respiratory rate (10–12 breaths/min)
● shorter inspiratory time to ensure adequate expiration.
Monitor hyperinflation from the end inspiratory pressure (i.e. plateau

pressure) and measurement of the intrinsic PEEP level following an
end-expiratory pause. Pressure control modes are not recommended
Page 13 of 26

as the plateau pressure will not be apparent and as the pressure

delivered in the ventilator will not reflect the pressure within the
lungs at end inspiration it is difficult to set an acceptable and
effective inspiratory pressure. With volume control, the peak and
plateau pressures are readily appreciated with the goal of ensuring a
plateau pressure of less than 30 cmH2O and not being concerned
about a high peak airway pressure. These patients are at increased
risk of barotrauma and this is associated with increased plateau
pressures, not peak pressures.
Adjust the minute volume to target pH rather than PaCO2 to ensure

that patients with chronic CO2 retention are not made alkalaemic. If
attempts to control pH cause significant dynamic hyperinflation,
reduce the respiratory rate and allow the PaCO2 to rise (permissive
hypercapnia).
Minimizing equipment dead space by using an active humidifier

rather than a heat and moisture exchanger is a simple and safe
method to help reduce PaCO2.
EXPERT COMMENT
The use of external PEEP to offset intrinsic PEEP during mechanical

ventilation in patients with severe obstructive airways disease is
controversial. Intrinsic PEEP results in a significant load to the
inspiratory muscles during spontaneous breathing that needs to be
offset before inspiration is initiated. This may lead to either failure to
trigger if inspiratory efforts are weak or a high work of breathing if
the patient is able to generate strong inspiratory efforts.
Applying external PEEP towards but not exceeding the value of the
intrinsic PEEP does not add to the total PEEP but will offset the
inspiratory load reducing failure to trigger and work of breathing.
External PEEP may also prevent dynamic collapse of the airways
during expiration in patients with severe emphysema.
It is recommended that external PEEP is applied during spontaneous

modes of ventilatory support if high levels of intrinsic PEEP were
recorded during controlled ventilation
Controlled modes of ventilation are appropriate when initiating

invasive ventilatory support in patients with an acute exacerbation of
COPD. They ensure full respiratory muscle rest in order to correct
fatigue, reduce CO2 production as metabolic rate is lowered, and
enable respiratory rate to be adjusted to ensure that intrinsic PEEP is
minimized.
Page 14 of 26

The patient was established on volume-controlled ventilation and kept

sedated for 48 hours. Intrinsic PEEP was measured at 10 cmH2O. An
echocardiogram revealed good left ventricular function with a moderately
dilated right ventricle with reasonable function and a dilated inferior vena
cava. In view of the lack of evidence for acute infection precipitating the
acute deterioration, and the echocardiogram findings, a CT pulmonary
angiogram was performed which excluded pulmonary embolus but
revealed severe pan-lobar emphysema throughout both upper lobes and
moderate emphysematous changes to the middle and lower lobes (Figure
8.2).
Figure 8.2
CT scan showing multiple bullae leading to loss of alveoli and
hyperexpansion.
On day 3 of ICU admission, sedation was discontinued and the patient

commenced on pressure support ventilation set at 15 cmH2O with a PEEP
level of 10 cm in order to offset the measured intrinsic PEEP.
An attempt to extubate from this level of pressure support ventilation

directly to NIV failed because of worsening respiratory acidosis and
fatigue. A further attempt at extubation 3 days later also failed. At this
point the patient had limited capacity, so following discussion with his
family and in view of the failure to wean, a percutaneous tracheostomy
was performed 10 days after ICU admission. Initial attempts to wean
using pressure support ventilation failed.
Subsequently, respiratory support was slowly weaned by gradually

increasing twice-daily short periods of unsupported spontaneous
breathing on a tracheostomy mask with respiratory rest and pressure
support ventilation in between. After 21 days of weaning, the patient was
Page 15 of 26

fully liberated from mechanical ventilation. Two days later, the

tracheostomy was removed and he was discharged to the respiratory
ward the following day having been in ICU for 30 days. He was
discharged to his home 38 days after admission.
Discussion
LEARNING POINT Weaning from ventilator support
Patients with chronic respiratory diseases are challenging to liberate

from mechanical ventilator support. Weaning is usually undertaken by
first establishing the patient on a spontaneous mode of ventilatory
support such as pressure support. Patient ventilator dyssynchrony is
common in patients with COPD and may be a significant factor
contributing to respiratory distress during spontaneous ventilator
modes and preventing successful weaning.
Weaning can be undertaken by daily unsupported spontaneous

breathing periods using a tracheostomy mask or by a gradual
reduction in pressure support. The use of a protocol or guideline to
support weaning is associated with a reduction in the time taken,
independent of the mode used, though there is little evidence to
support one mode of weaning over another [33, 34].
Weaning and nutrition

A low BMI is common in severe COPD and associated with a poor
prognosis. Critical illness and ICU admission leads to further weight
loss. Delayed initiation of nutritional support will increase loss of
muscle mass and impair ability to wean from ventilatory support.
Provision of adequate nutritional support is therefore an important
aspect of the management of patients with chronic respiratory failure.
Enteral nutrition should be commenced as soon as possible, aiming
for a calorie intake of 25–30 kcal/kg/day. Excessive feeding should be
avoided as it will increase CO2 production and impair weaning. The
use of pulmonary feeds with a high fat content (reduced respiratory
quotient to reduce CO2 production) are not recommended as they
have only been shown to be effective with overfeeding and may have
a proinflammatory effect [35].
CLINICAL TIP Ventilator dyssynchrony during

pressure support ventilation
Patient ventilator dyssynchrony is a common but often unrecognized

problem during spontaneous modes of ventilatory support in patients
with COPD. Failure to trigger (missed breaths) due to the effect of
Page 16 of 26

intrinsic PEEP (see earlier discussion) and delayed inspiratory to

expiratory cycling are common manifestations. These can be
significant factors contributing to an apparent failure to wean.
In pressure support ventilation, the inspiratory phase is typically

terminated when inspiratory flow falls to 25% of the measured peak
value. In many patients with COPD, the peak inspiratory flow is low
because of the increased airway resistance and therefore does not fall
to 25% before the patient starts to breathe out. The result is that the
patient has to actively exhale against the pressure support level
before the ventilator cycles to expiration. This can be noted by
observing an increase in end inspiratory pressure immediately before
the onset of the expiratory phase. Forcing the patient to actively
initiate expiration causes discomfort and respiratory distress. Many
ICU ventilators now enable the inspiratory to expiratory cycling
threshold to be adjusted between 10% and 90% of peak flow rate to
enable optimal setting for the individual patient. A value greater than
50% of peak flow is likely to be indicated in patients with COPD.
LEARNING POINT Role of non-invasive ventilation to

support weaning
Initial attempts to wean using a phased reduction in pressure support

ventilation often fail in patients with COPD. One approach is to
extubate the patient onto NIV as soon as spontaneous breathing is
established and not to attempt traditional weaning of pressure
support or unsupported periods on tracheostomy mask.
A Cochrane review in 2013 highlighted the benefits of NIV as a

weaning technique in patients with COPD where it is associated with
a significantly improved mortality (relative risk 0.36; 95% confidence
interval 0.24–0.56) and rates of ventilator-acquired pneumonia
(relative risk 0.25; 95% confidence interval 0.15–0.43) [36].
Role of tracheostomy
Some may consider performing an early tracheostomy in patients
with COPD in order to assist weaning. However prospective trials do
not support this approach. The TracMan trial, a multicentre
randomized clinical trial which assessed early versus late
tracheostomy in a heterogeneous ICU population with 70% having
pulmonary pathology, found no benefit from undertaking
tracheostomy before 10 days. The evidence implies that tracheostomy
should be considered in patients with COPD only after failed attempts
to wean using NIV [37].
Page 17 of 26

Managing heart failure

Left ventricular failure is a common factor impairing weaning in
COPD and may be precipitated by the significant increase in cardiac
afterload that occurs during the transition from positive pressure
ventilation to spontaneous breathing. Judicious use of diuretics to
achieve a negative fluid balance combined with angiotensin-
converting enzyme inhibitors to reduce afterload can be very
effective. A fluid management strategy guided by B-type natriuretic
peptide measurements has been associated with a reduced time to
extubation [38].
EXPERT COMMENT
‘Delayed weaning’ has been defined as unsuccessful weaning after 2

weeks of attempts, with ‘weaning failure’ occurring after 3 weeks. A
trial undertaken in a long-term ventilation unit reported that classic
weaning with once-daily periods of spontaneous breathing with
complete ventilatory rest in between was associated with improved
weaning outcomes compared to gradual reduction in pressure
support [39].
Outcomes from specialist weaning centres suggest that up to 50% of

patients referred with weaning failure will be successfully liberated
from assisted ventilation with 35% requiring some form of long-term
ventilatory support and 15% not surviving [40]. However, long-term
survival was less good with less than 50% surviving 12 months and
few patients surviving 5 years (see also Case 16).
LEARNING POINT Treatment limitations and end of

life care
In many patients with severe and advanced chronic respiratory

disease, initiating or continuing to provide mechanical ventilatory
support may be considered inappropriate when the clinician
considers that there is no realistic chance that it will result in long-
term survival. There is usually a degree of uncertainty with such
decisions and the balance of risks and benefits needs to be
considered. Consultation with colleagues may provide useful second
opinions.
Clinicians may therefore be presented with several ethical challenges

such as making treatment limitation decisions, often in patients who
lack mental capacity, managing withdrawal of ventilatory support,
and instituting end of life care. The Mental Capacity Act 2005
Page 18 of 26

provides a clear framework for the legal and ethical management of

these issues in England and Wales. In Scotland, decision-making in
this area is covered by the Adults with Incapacity (Scotland) Act
2000. In Northern Ireland, decision-making is governed by the
common law though the Northern Ireland assembly is working
towards statutory regulation. The General Medical Council has
produced guidance for the care of patients without capacity in the
UK. Legal frameworks will differ in other countries, as may ethical
perspectives. These include different legislation and arrangements
around decision-making in those who lack mental capacity and
around end of life care. These arrangements also vary over time. The
following section relates to the UK at the time of writing.
Ideally, all patients with chronic respiratory failure who have limited
life expectancy should have discussions about the appropriateness
and effectiveness of interventions such as mechanical ventilation
before they become acutely ill and potentially lose the mental
capacity to be involved in their decision-making. Patient’s wishes may
have been recorded by means of an advance directive and clinicians
may be presented with such a document in the acute situation.
Advance decisions to refuse treatment are legally binding and should
be followed as long as they relate to the specific circumstances.
LEARNING POINT Advance decisions
Advance decisions may be legally binding in the UK and are described

in the Mental Capacity Act 2005.
An advance decision to refuse medical treatment is a legally binding

document that is very specific with regards to the treatments refused.
It may not encompass the complex array of physiological support that
may be provided in an ICU. It is legally binding as long as:
● the patient had capacity when they made it

● they have made the advance decision of their own accord
● they specify clearly which treatments they wish to refuse
● they explain the circumstances in which they wish to refuse
them
● the decision applies to the current situation
● it is signed by the patient and by a witness
● they have not said or done anything that would contradict the
advance decision since they made it (e.g. changing their mind).
An advance statement is not legally binding, but should be taken into

account when determining the patient’s view. An advance statement
is intended to communicate the patient’s wishes, feelings, and
Page 19 of 26

preferences to anyone involved in their care if they lose capacity. It

does not need to be signed nor does it need to be witnessed.
LEARNING POINT Assessing capacity using the

Mental Capacity Act 2005
In the acute setting, patients may have lost mental capacity and are
unable to be involved in decision-making. The Mental Capacity Act
2005 was developed to provide guidance in such settings. A key
component of the Act is that a person may have capacity to make
some decisions but not others, known as ‘decision-specific capacity’.
It recommends that the more serious the decision, for example, not to
undergo tracheal intubation and ventilation, the more formal the
capacity assessment.
A patient should always be assumed to have capacity unless they

cannot do one or more of the following:
● Understand information given to them about the decision.

● Retain the information for long enough to make the decision.
● Weigh up the information as part of the decision-making
process.
● Communicate their decision by any means.
The Mental Capacity Act 2005 allows people with capacity over 18
years of age to give lasting power of attorney (LPA) for health and
welfare to one or more people to make health and personal welfare
decisions when capacity is lost. This is not covered by a LPA for
financial affairs. Registration takes up to 10 weeks but once complete
it will give the attorney(s) the power to make decisions about the
patient’s medical care, including life-sustaining treatment. It can be
used only when the patient loses capacity.
It is still relatively unusual for patients to have given LPA for health
and welfare to someone close to them. Clinicians must then make
decisions that are judged to be in the patient’s best interests and
must consult others to find out what the patient’s views would be.
Anyone who has an interest in the welfare of the patient should be
consulted including close family, carers, and friends. If there is no one
who can be consulted then the advice of an Independent Mental
Capacity Advocate (IMCA) should be sought.
Page 20 of 26

LEARNING POINT Independent Mental Capacity

Advocate (IMCA)
IMCAs have a role created by the Mental Capacity Act 2005 to

represent people who lack capacity to make decisions and have no
family, friends, or other advocate who it is appropriate to consult.
Most IMCAs are based in the community to act on behalf of a person
with limited capacity, for example, an adult with learning difficulties
needing to make decisions about long-term accommodation. Intensive
care physicians are more likely to encounter non-instructed IMCAs
(i.e. employees of a local authority who of necessity are appointed to
act for a patient who they have not previously met) who act on behalf
of a person who is unable to give a clear indication of their views or
wishes in a specific situation.
IMCAs have the power to gather information, including reading the

patient’s notes, to gain an idea of what they might choose to do
should they have capacity. They also have the power to request a
second medical opinion if they believe it to be necessary. IMCAs act
as an advocate for the patient’s wishes in the same way as family or
friends would if they were present. The IMCA assists the medical
team in making decisions for the patient but it is not their position to
make decisions for the medical team. The IMCA service is not
available outside of office hours, at weekends, or during public
holidays.
LEARNING POINT Determining a patient’s best

interests.
A checklist devised by the Mental Capacity Act 2005 states:
● Does the patient lack the capacity to make this decision?

● Does the patient have an LPA or court-appointed deputy who has
the power to make this decision?
● Should an IMCA be involved?
● Is there an advance decision to refuse treatment?
● Can the decision wait until the patient regains capacity?
● Has the person been involved in the decision-making process as
effectively as possible?
Page 21 of 26

Management of conflict
Clinicians should aim to obtain a consensus from all those with an
interest in the patient’s welfare as to what treatment and care are in
the patient’s best interests if they lack capacity. Occasionally,
disagreements may arise within the clinical team or within those
close to the patient. These can usually be resolved with a number of
approaches including giving time to reflect, open and honest
discussion, organizing a case conference, or offering a second opinion
from an appropriately experienced and independent clinician. This
could be a clinician from a different specialty or from a neighbouring
ICU. If there remains serious disagreement despite these measures
then legal advice will need to be taken in order to apply to the
appropriate court for an independent ruling.
LEARNING POINT Withdrawal of assisted ventilation
If a decision is made to withdraw assisted ventilation in a ventilator-

dependent patient, it must be well managed in order to prevent
distress and discomfort to the patient and those close to the patient.
The Association for Palliative Medicine’s guidelines for the
withdrawal of assisted ventilation in patients with motor neuron
disease are relevant to withdrawal of ventilation in other patient
groups. Anticipate symptoms of breathlessness and distress and treat
with opioids and benzodiazepines. Sedate patients who are highly
ventilator dependent before ventilation is discontinued otherwise they
will quickly become distressed.
Consider whether the patient would wish to be an organ donor.

Discuss with the family and a specialist nurse in organ donation (see
Case 18).
Patients with an acute exacerbation of chronic respiratory failure may

present many clinical and ethical challenges. Unless there is clear
evidence that the patient has terminal respiratory failure or there is a
relevant advance directive, admission to ICU is usually appropriate.
Treatment should involve controlled oxygen therapy, optimizing
underlying and associated medical conditions, and NIV. Careful
consideration needs to be given before embarking on invasive
ventilation and although weaning may be protracted, the outcome is
often better than many would predict.
Page 22 of 26

References
1. Donald K, Simpson T, Mcmichael J, Lennox B. Neurological effects of
oxygen. Lancet. 1949;254:1056–7.
2. Abdo WF, Heunks LM. Oxygen-induced hypercapnia in COPD: myths

and facts. Crit Care. 2012;16:323.
3. O’Driscoll BR, Howard LS, Davison AG, British Thoracic Society. BTS
guideline for emergency oxygen use in adult patients. Thorax. 2008;63
Suppl 6:vi1–68.
4. Department of Health and Social Care. An Outcomes Strategy for

COPD and Asthma: NHS Companion Document. London: Department of
Health and Social Care; 2012.
5. National Institute for Health and Care Excellence. Chronic Obstructive

Pulmonary Disease. Clinical guideline [CG101]. London: National
Institute for Health and Care Excellence; 2010. Available from: https://
www.nice.org.uk/guidance/cg101.
6. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses,

symptoms, and inflammatory markers in acute exacerbations and stable
chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
2001;164:1618–23.
7. Garcha DS, Thurston SJ, Patel ARC, et al. Changes in prevalence and
load of airway bacteria using quantitative PCR in stable and exacerbated
COPD. Thorax. 2012;67:1075–80.
8. Aleva FE, Voets LWLM, Simons SO, de Mast Q, van der Ven AJAM,
Heijdra YF. Prevalence and localization of pulmonary embolism in
unexplained acute exacerbations of COPD. A systematic review and meta-
analysis. Chest. 2017;151:544–54.
9. Abroug F, Ouanes-Besbes L, Nciri N, et al. Association of left-heart

dysfunction with severe exacerbation of chronic obstructive pulmonary
disease. Am J Respir Crit Care Med. 2012;174:990–6.
10. Ram FS, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive

pressure ventilation for treatment of respiratory failure due to
exacerbations of chronic obstructive pulmonary disease. Cochrane
Database Syst Rev. 2004;1:CD004104.
11. Roberts CM, Brown JL, Reinhardt AK, et al. Non-invasive ventilation
in chronic obstructive pulmonary disease: management of acute type 2
respiratory failure. Clin Med. 2008;8:517–21.
12. Vital FMR, Ladeira MT, Atallah AN. Non-invasive positive pressure
ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema.
Page 23 of 26

13. National Clinical Guideline Centre (UK). Acute Heart Failure:

Diagnosing and Managing Acute Heart Failure in Adults. London:
National Institute for Health and Care Excellence; 2014.
14. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health

and economic burden of the projected obesity trends in the USA and the
UK. Lancet. 2011;378:815–25.
15. Mokhlesi B. Obesity hypoventilation syndrome: a state-of-the-art

review. Respir Care. 2010;55:1347–5.
16. Carrillo A, Ferrer M, Gonzalez Diaz G, et al. Noninvasive ventilation in

acute hypercapnic respiratory failure caused by obesity hypoventilation
syndrome and chronic obstructive pulmonary disease. Am J Respir Crit
Care Med. 2012;186:1279–85.
17. Glossop AJ, Shephard N, Shepherd N, Bryden DC, Mills GH. Non-
invasive ventilation for weaning, avoiding reintubation after extubation
and in the postoperative period: a meta-analysis. Br J Anaesth.
2012;109:305–14.
18. Ireland CJ, Chapman TM, Mathew SF, Herbison GP, Zacharias M.
Continuous positive airway pressure (CPAP) during the postoperative
period for prevention of postoperative morbidity and mortality following
major abdominal surgery. Cochrane Database Syst Rev.
2014;8:CD008930.
19. Kaul S, Pearson M, Coutts I, Lowe D, Roberts M. Non-invasive

ventilation (NIV) in the clinical management of acute COPD in 233 UK
hospitals: results from the RCP/BTS 2003 National COPD Audit. COPD.
2009;6:171–6.
20. Frat J-P, Thille AW, Mercat A, et al. High-flow oxygen through nasal
cannula in acute hypoxemic respiratory failure. N Engl J Med.
2015;372:2185–96.
21. Kilger E, Möhnle P, Nassau K, et al. Noninvasive mechanical

ventilation in patients with acute respiratory failure after cardiac surgery.
Heart Surg Forum. 2010;13:E91–5.
22. Hernández G, Vaquero C, González P, et al. Effect of postextubation

high-flow nasal cannula vs conventional oxygen therapy on reintubation
in low-risk patients: a randomized clinical trial. JAMA. 2016;315:1354–61.
23. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation
for acute exacerbations of chronic obstructive pulmonary disease on
general respiratory wards: a multicentre randomised controlled trial.
Lancet. 2000;355:1931–5.
24. Funk GC, Bauer P, Burghuber OC, et al. Prevalence and prognosis of
COPD in critically ill patients between 1998 and 2008. Eur Respir J.
2013;41:792–9.
Page 24 of 26

25. Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in

adult patients receiving mechanical ventilation: a 28-day international
study. JAMA. 2002;287:345–55.
26. Wildman MJ, Sanderson C, Groves J, et al. Implications of prognostic

pessimism in patients with chronic obstructive pulmonary disease (COPD)
or asthma admitted to intensive care in the UK within the COPD and
asthma outcome study (CAOS): multicentre observational cohort study.
BMJ. 2007;335:1132.
27. Burney PGJ, Patel J, Newson R, Minelli C, Naghavi M. Global and

regional trends in COPD mortality, 1990–2010. Eur Respir J.
2015;45:1239–47.
28. Steer J, Gibson GJ, Bourke SC. Predicting outcomes following

hospitalization for acute exacerbations of COPD. QJM. 2010;103:817–29.
29. Steer J, Gibson J, Bourke SC. The DECAF Score: predicting hospital
mortality in exacerbations of chronic obstructive pulmonary disease.
Thorax. 2012;67:970–6.
30. Chailleux E, Fauroux B, Binet F, Dautzenberg B, Polu JM. Predictors of

survival in patients receiving domiciliary oxygen therapy or mechanical
ventilation. A 10-year analysis of ANTADIR Observatory. Chest.
1996;109:741–9.
31. Rabinovich RA, Bastos R, Ardite E, et al. Mitochondrial dysfunction in

COPD patients with low body mass index. Eur Respir J. 2007;29:643–50.
32. Plataki M, Tzortzaki E, Rytila P, Demosthenes M, Koutsopoulos A,

Siafakas NM. Apoptotic mechanisms in the pathogenesis of COPD. Int J
Chron Obstruct Pulmon Dis. 2006;1:161–71.
33. Blackwood B, Alderdice F, Burns KE, Cardwell CR, Lavery G,

O’Halloran P. Protocolized versus non-protocolized weaning for reducing
the duration of mechanical ventilation in critically ill adult patients.
34. Butler R, Keenan SP, Inman KJ, Sibbald WJ, Block G. Is there a
preferred technique for weaning the difficult-to-wean patient? A
systematic review of the literature. Crit Care Med. 1999;27:2331–6.
35. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the
provision and assessment of nutrition support therapy in the adult
critically ill patient: Society of Critical Care Medicine (SCCM) and
American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J
Parenter Enteral Nutr. 2016;40:159–211.
36. Burns KEA, Meade MO, Premji A, Adhikari NKJ. Noninvasive positive-
pressure ventilation as a weaning strategy for intubated adults with
respiratory failure. Cochrane Database Syst Rev. 2013;12:CD004127.
Page 25 of 26

37. Young D, Harrison DA, Cuthbertson BH, Rowan K. Effect of early vs

late tracheostomy placement on survival in patients receiving mechanical
ventilation: the TracMan randomized trial. JAMA. 2013;309:2121–9.
38. Dessap AM, Roche-Campo F, Kouatchet A, et al. Natriuretic peptide-

driven fluid management during ventilator weaning. Am J Respir Crit
Care Med. 2012;186:1256–63.
39. Jubran A, Grant BJB, Duffner LA, et al. Effect of pressure support vs
unassisted breathing through a tracheostomy collar on weaning duration
in patients requiring prolonged mechanical ventilation: a randomized
trial. JAMA. 2013;309:671–7.
40. Rose L, Fraser IM. Patient characteristics and outcomes of a

provincial prolonged-ventilation weaning centre: a retrospective cohort
study. Can Respir J. 2012;19:216–20.
Page 26 of 26

Multiple organ support in an ageing population

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Multiple organ support in an ageing population
Author(s): Matt Oliver
DOI: 10.1093/med/9780198814924.003.0009
Expert commentary by Dave Murray
Case history
An 82-year-old man was brought to the emergency department by

ambulance with severe abdominal pain. He had been housebound for 3
days, and had been eating and drinking very little over the preceding
week due to increasing pain. His neighbours were concerned and had
contacted the emergency services.
The patient lived alone but was frail, requiring assistance in self-care,
cleaning, and shopping. He had to stop at least once on the short flight of
stairs up to his bedroom to catch his breath. He had ischaemic heart
disease (coronary stent inserted 5 years previously), controlled
hypertension, and chronic obstructive pulmonary disease. He took
ramipril 10 mg once daily, atorvastatin 40 mg once daily, clopidogrel 75
mg once daily, and Symbicort (400/12) one actuation twice daily. His
previous hospital records indicated he did not tolerate beta blockers.
Page 1 of 20
LEARNING POINT Interpretation of observations and

blood results
His clinical presentation includes hypotension and evidence of organ

dysfunction. He has all three of the criteria on a quick Sequential
(Sepsis-Related) Organ Failure Assessment for high risk of sepsis
(systolic blood pressure <100 mmHg, respiratory rate >22 breaths/
min, and altered mental state) (see Case 1). His initial investigations
show evidence of a normocytic anaemia, acute kidney injury, and
raised markers of inflammation.
Examination by the emergency medicine registrar identified abdominal

rigidity, guarding, and rebound tenderness; he was profoundly
dehydrated. Observations on presentation are shown in Table 9.1 and
initial blood results in Table 9.2. An electrocardiogram showed a sinus
tachycardia without any other abnormalities.
Table 9.1 Observations on presentation to the emergency department
Variable Observation
Heart rate (beats/min) 120
Blood pressure (mmHg) 90/65
Arterial blood oxygen saturation (on air) (%) 94
Respiratory rate (breaths/min) 22
Glasgow Coma Scale score 14
Temperature (°C) 38.2
Table 9.2 Initial blood results
Variable Value (reference range)
Haematology
Haemoglobin (g/L) 105 (130–180)
MCV (fL) 85 (85–97)
Page 2 of 20

Platelets (×109/L) 350 (150–400)
WCC (×109/L) 18.2 (4–11)
Neutrophils (×109/L) 15.8 (2–7)
HCT (%) 38 (40–52)
INR 1.2 (0.9–1.4)
APTT 28 (30–40)
Biochemistry
Na (mmol/L) 144 (135–145)
K (mmol/L) 5.4 (3.5–5.5)
Urea (mmol/L) 18.3 (2.5–6.7)
Cr (μmol/L) 220 (60–110)
Bilirubin (μmol/L) 18 (<22)
ALT (IU/L) 35 (5–40)
AST (IU/L) 29 (5–45)
Alkaline phosphatase (IU/L) 144 (40–129)
Albumin (g/L) 38 (34–48)
Glucose (mmol/L) 7.5 (3.5–8.5)
C-reactive protein (mg/L) 320 (<10)
Lactate (mmol/L) 4.2 (0.0–1.8)
ALT, alanine aminotransferase; APTT, activated partial thromboplastin

time; AST, aspartate transaminase; Cr, creatinine; HCT, haematocrit;
INR, international normalized ratio; K, potassium; MCV, mean cell
volume; Na, sodium; WCC, white cell count.
Page 3 of 20

EXPERT COMMENT
The delayed presentation and clinical findings are not atypical in an

elderly patient presenting with an acute abdominal problem and
subsequently needing an emergency laparotomy. The observations
reveal the effects of both dehydration and sepsis.
The patient was referred to the surgical team for immediate senior
review. In the meantime, referring to the hospital’s emergency
laparotomy pathway, the following actions were undertaken:
● Facemask oxygen (5 L/min) was administered.

● A 16-gauge intravenous (IV) cannula was sited.
● Blood samples (including peripheral blood cultures and venous
blood gas) were taken.
● A urethral catheter was inserted with institution of hourly urine
output measurements.
● A litre of crystalloid fluid was administered.
● Tazocin (4.5 g) IV was administered IV as per the local microbiology
guidelines.
● An urgent abdominal computed tomography (CT) scan was
requested.
CLINICAL TIP Clinical pathways
The use of clinical pathways that prescribe investigation, treatment,

and referral points can aid delivery of prompt care. They improve
reliability of care ensuring that all elements of care are considered
and delivered consistently to all patients. Prompt administration of
antibiotics is essential in patients with signs of sepsis. Arterial or
venous blood lactate is helpful in judging the severity of any shock. In
this case, the high lactate suggests the start of organ dysfunction
caused by both septic shock and dehydration.
EXPERT COMMENT
CT scanning can be extremely helpful in defining the underlying

surgical pathology and its extent. It may help distinguish between
benign and malignant disease, including the presence of metastases.
The value of CT scanning is significantly enhanced if not only is it
Page 4 of 20

reported by a specialist radiologist, but also the findings are

discussed with the surgical team.
Hospitals need to ensure there is a pathway in place that guarantees

urgent CT scanning for this group of patients. Urgent radiology
should not delay emergency surgery.
The CT scan was performed within 30 min and reported by a consultant

radiologist. The findings were discussed directly with the surgical team.
The provisional CT report identified findings consistent with a large
bowel perforation. There was evidence of a mass suggestive of an erosive
colonic tumour (Figure 9.1).
Figure 9.1
CT scan demonstrating tumour (starred) and extraluminal gas (arrows).
LEARNING POINT Emergency laparotomy: incidence

and patient outcomes
Emergency laparotomy describes a wide range of invasive abdominal

operations that are performed commonly across the globe for
potentially life-threatening conditions. An estimated 1:1100 of the
population undergo emergency laparotomy each year [1].
In developed counties, mortality at 1 month exceeds 10% and major

morbidity 30%. Sequelae may represent a significant burden to
patients and healthcare systems long after the operative period [2].
Morbidity and mortality rates are substantially higher in certain
subgroups: 30-day mortality is approximately 25% in patients aged 80
years or older and in those requiring immediate surgery, and
approximately 75% in patients with severe liver disease [3, 4].
Associations between frailty syndromes and postoperative outcomes
are currently poorly understood.
Currently, intra-abdominal malignancies are common precipitants of

emergency laparotomy and the incidence of colorectal cancers in
older people is increasing [5, 6]. In the next two decades, the
Page 5 of 20

proportion of the population aged over 65 years will markedly

increase and around 10% of patients will be aged at least 80 years.
According to the Office for National Statistics, by mid-2039, more
than 13% of the population will be 75 years and older [7]. The number
and complexity of emergency laparotomies performed is therefore
anticipated to increase dramatically over coming decades.
LEARNING POINT Perioperative care pathways in

emergency laparotomy
Evidence supports the use of care bundles comprising:
● risk assessment
● early antibiotics
● maintaining the interval between decision and operation at less
than 6 hours
● goal-directed fluid therapy (GDFT)
● postoperative admission to an intensive care unit (ICU) [8].
Standards of care support:
● sepsis bundles including prompt administration of broad-

spectrum antibiotics and timely source control
● review by a senior surgeon within 14 hours of admission
● prompt imaging and timely reporting by a consultant radiologist
● assessment and documentation of risk of death
● arrival in the operating room (OR) in a time commensurate with
operative urgency
● the presence of a consultant surgeon and anaesthetist in the OR
if estimated risk of death is 5% or greater
● postoperative level 2 or level 3 care if estimated risk of death is
5% or greater
● involvement of a care of the elderly physician in the
postoperative care of older patients [9].
EXPERT COMMENT
Frailty describes the global deterioration in strength (and

physiological reserve) that occurs with ageing. It may also occur with
chronic illness and particularly with advanced cancer. Frailty includes
loss of muscle bulk and power, termed sarcopenia, in the elderly. It is
Page 6 of 20

an area of considerable clinical importance and research interest, but

at present, while it is recognized as a clinical entity, there is a lack of
clinical consensus on definition, diagnosis, or gradation. An example
of a grading system is the Clinical Frailty Scale [10].
Frailty is particularly important in critical illness as it is a predictor of

a poor outcome. Surgery is associated with a 15–25% loss of muscle
power in the early postoperative phase and this will be dramatically
worsened by complications that prevent mobilization and increase
catabolism. Muscle weakness impacts mobilization, effective
coughing, and weaning from mechanical ventilation. Frail survivors of
critical illness experience greater impairment in health-related
quality of life compared with those who are not frail [11].
While considerable efforts are being made to address concerns

around frailty, there are currently no established treatments to lessen
its impact in the perioperative period. Preoperative exercise training
(for elective patients), early mobilization, prompt reintroduction of
nutrition, simple respiratory exercises, and avoidance of
complications (especially delirium) are likely to be of benefit [12].
LEARNING POINT National Emergency Laparotomy

Audit and care pathways
National Emergency Laparotomy Audit (NELA) is a continuous

national audit programme in England and Wales that was started in
2012. It was commissioned following evidence of high rates of
mortality and variations in organization of care and outcomes. The
programme combines an audit of structure, process, and outcome
measures for all hospitals in these countries performing emergency
laparotomy. It gained evidence from approximately 60,000 emergency
laparotomies in its first 2 years.
The first two NELA reports identified poor delivery of key processes
of care in a substantial minority of cases; this included those patients
for whom risk was not documented preoperatively [3, 9]. A principal
recommendation of the NELA reports was the routine use of care
pathways to reduce variation and improve patient outcomes.
The surgical trainee used the P-POSSUM (Portsmouth Physiological and

Operative Severity Score for the Enumeration of Mortality and Morbidity)
and SORT (Surgical Outcomes Risk Tool) tools to risk assess the patient
[13, 14, 15]. Although these risk tools were developed to calculate risk
within populations and not for individual patient decision-making, they
were used here to alert the team that they were dealing with a patient at
Page 7 of 20

high risk of perioperative morbidity and mortality. P-POSSUM estimated

the 30-day mortality for this patient at 91% and SORT at 28%.
The patient was discussed with the consultant surgeon, consultant

anaesthetist, and consultant intensivist so that the risks and benefits
could be assessed before the patient was offered surgery. The patient had
capacity and the high risk of potential complications, including death and
chronic deterioration in health quality, was discussed at length with him.
Palliative care was also explained as an alternative to surgery. The patient
wanted to pursue all active treatment options. Their next of kin was
contacted to inform them of the patient’s decision, rationale for surgery,
and the potential risks involved. The patient was consented and booked
for an emergency laparotomy.
In the OR, the patient’s data were entered into the NELA web tool.
EXPERT COMMENT
The legal framework for consent differs between countries but good
practice requires a patient-centred approach. That implies that a
patient is informed of all the risks that they would consider pertinent
before undergoing a procedure and that all relevant alternatives
(including no treatment) are also discussed. This approach is
established in UK law [16, 17]. For patients such as this with a high
mortality risk, and also a high risk of survival with a poorer quality of
life than before admission, this may require considerable explanation
and discussion, and should be led by appropriately senior members of
the team, including intensivists. The clinical condition of the patient
may make such discussions difficult and it requires careful judgement
to balance adequate provision of information against overload of
information in an acutely ill patient. Surgery will not be an
appropriate solution in all cases and as it is poor practice to offer
futile treatments. Risk assessment and discussion of an appropriate
course of action should take place before surgery is offered.
LEARNING POINT Quantifying risk
Tools for assessing risk incorporate two or more variables into a score
or equation, to stratify or estimate the likelihood of an adverse
outcome, often short-term mortality. Component variables are
independent predictors of the outcome, usually identified through an
iterative process of multivariable regression. Many are now available
online as smart phone apps.
Page 8 of 20

The American Society of Anesthesiologists (ASA) physical status tool

is widely used, easily understood, and of practical value. However, it
is highly subjective, takes little account of patient age, and wide inter-
observer variability is reported [18].
SORT uses six routinely measured variables to estimate the likelihood

of 30-day mortality [15]. These are ASA physical status, operation
type, severity and urgency, presence of malignancy, and age. It was
developed in response to recommendations from the 2011 National
Confidential Enquiry into Patient Outcome and Death study on
perioperative care, ‘Knowing the Risk’ [19]. Data from 16,788
patients in this study were used to develop and internally validate
SORT. It may require external validation in high-risk populations,
including emergency laparotomy.
P-POSSUM was derived from the original POSSUM risk prediction

tool that was developed in 2002 [13, 14]. It uses 12 physiological and
6 operative variables for its calculation. It requires operative findings
to be included, which reduces its value preoperatively, as these must
be entered based on anticipated surgical findings. It is widely used
and has been validated for use in emergency laparotomy [20],
demonstrating moderate performance in this setting. Predicted P-
POSSUM mortality has now been compared to observed mortality in
over 40,000 patients in the NELA database. This has demonstrated
that P-POSSUM over-predicts mortality almost twofold at higher
mortality rates (e.g. >25–30%). It does show good correlation below
15% predicted mortality, and is therefore useful for stratification of
risk in order to better define high-risk patients (predicted mortality
>5%) and the need for critical care and presence of a consultant.
Data from NELA has now been used to develop a bespoke risk
prediction tool for patients undergoing emergency laparotomy [21]. It
is more accurate than P-POSSUM, which has now been removed from
NELA in favour of the NELA risk prediction model.
EXPERT COMMENT
Estimation of risk of death constitutes a standard of care for all

patients undergoing surgery in the UK. It serves two purposes: to
help inform patients of the risk of surgery, and to help plan
subsequent care and the need for resources such as consultant input
and critical care.
Importantly, risk tools use population data to predict mortality (or

morbidity) in patient populations. Results from risk prediction tools
therefore describe how a large population of patients with the
inputted characteristics might be predicted to behave, but cannot
accurately predict the outcome for an individual patient—which in
Page 9 of 20

terms of mortality is dichotomous (i.e. they survive or die). As such,

they are of value for risk stratification but applying specific outputs of
risk assessments to individual patients as the sole means of decision-
making is discouraged. Risk prediction tools should be used to
support clinical decision-making in conjunction with discussion with
the patient and their family.
High-risk patients mandate the presence of senior decision-makers.

Emergency laparotomy patients are frequently very sick and can
deteriorate quickly, requiring prompt decision-making which is best
provided by experienced clinicians. This can include changing the
surgical plan mid operation, depending on changes in the patient’s
condition. For instance, in a patient with escalating inotrope
requirements, it may be appropriate to abandon plans to anastomose
the bowel, and instead provide an end stoma. Intraoperative findings
such as the presence of metastases or extensive ischaemic bowel may
make limitations on care appropriate.
The patient remained oligoanuric despite fluid resuscitation. A further

fluid bolus was prescribed and the patient was transferred urgently to the
OR.
Within 4 hours of presentation in the emergency department the patient

arrived in the OR. He was transferred directly onto the operating table.
He remained tachycardic (heart rate 130 beats/min), hypotensive (blood
pressure 85/60 mmHg), tachypnoeic (respiratory rate 28 breaths/min),
and hypoxaemic (SpO2 92% breathing 15 L/min of oxygen). He had now
become delirious.
EXPERT COMMENT
Given the patient’s dehydration and lack of urine output, it may be

tempting to delay surgery to enable fluid resuscitation. However, this
must be balanced with the overriding requirement for prompt source
control to manage his septic shock. It is easier to infuse fluids rapidly
in the OR than it is on the ward and where necessary such
resuscitation is best performed in the OR or ICU.
Critically ill patients should have anaesthesia induced in the OR

rather than in the anaesthetic room. This avoids moving a potentially
unstable patient soon after induction and the ‘monitoring gap’ that
otherwise occurs during transfer.
The anaesthetic team, led by a consultant, thoroughly pre-oxygenated the

patient while a third litre of crystalloid was infused rapidly and a radial
arterial line sited. In view of recent antiplatelet medication and the likely
Page 10 of 20

need for level 3 postoperative care, an epidural catheter was not inserted
preoperatively; instead, rectus sheath catheters were to be sited by the
surgical team before wound closure. Anaesthesia was induced with 150
mcg fentanyl (2 mcg/kg), 70 mg ketamine (1 mg/kg), and 70 mg
suxamethonium (1 mg/kg).
Volume-controlled ventilation was commenced with a lung protective

strategy: tidal volume 420 mL (6 mL/kg ideal body weight), rate 16 bpm,
inspiratory:expiratory ratio 1:2, positive end-expiratory pressure 5
cmH2O. His plateau pressure was maintained at 30 cmH2O or less.
Anaesthesia was maintained using sevoflurane titrated to bispectral index
values of 40–60 and neuromuscular blockade with boluses of atracurium.
He was intubated with an 8.0 mm inner diameter tracheal tube, with
subglottic suction, as postoperative ventilation on ICU was anticipated.
After induction of anaesthesia, an infusion of metaraminol and
intermittent boluses (0.5 mg) were required to maintain the 70 mmHg
predefined mean arterial pressure (MAP) target. An antibiotic-
impregnated, five-lumen right internal jugular central line was inserted
using full asepsis and ultrasound guidance. A noradrenaline infusion was
started and the metaraminol stopped. Cardiac output monitoring using
oesophageal Doppler showed a corrected flow time less than 450 ms,
which suggested hypovolaemia.
A midline laparotomy incision extending above the umbilicus was made.

There was extensive faecal contamination with pockets of pus. The bowel
had perforated just proximal to a suspected colonic tumour. A Hartmann’s
procedure was performed.
Intravascular filling (with crystalloid and blood products) and titration of

noradrenaline was guided by blood pressure and cardiac output
monitoring and lactate clearance. His noradrenaline requirements
escalated and hydrocortisone 50 mg four times daily was started to
potentially enable a dose reduction in noradrenaline. Intraoperatively, the
metabolic acidosis worsened, accompanied by increasing lactate value,
hyperkalaemia, and deranged clotting. Only 50 mL of urine had been
passed since catheterization. It was anticipated that renal replacement
therapy would be required so a right internal jugular dialysis catheter
was inserted under ultrasound guidance.
The surgeons anticipated postoperative ileus was likely. Before surgical

closure, a fine-bore feeding tube was passed nasally and with the help of
the surgeons was placed in the jejunum, to facilitate post-pyloric feeding
on the ICU.
EXPERT COMMENT
Currently, evidence for the use of cardiac output monitoring to guide

GDFT in emergency laparotomy is derived primarily from elective
Page 11 of 20

surgical populations. In major elective gastrointestinal surgery, GDFT

may reduce postoperative complication rates but has not been shown
to reduce mortality [22]. A UK multicentre, randomized controlled
trial of GDFT in emergency laparotomy populations was underway in
the UK in 2017 (http://www.floela.org.uk).
Patients undergoing high-risk emergency laparotomy, such as this

patent, are likely to require organ support and level 3 care on ICU
and preparations for this can be started in the OR. In patients likely
to require controlled ventilation, cardiovascular support, renal
replacement therapy, or enteral feeding (especially with prolonged
gastroparesis or ileus), this will include placing a tracheal tube with
subglottic suction, a central venous catheter, an enteral feeding tube
(especially nasojejunal), and possibly a dialysis catheter.
LEARNING POINT Epidemiology and burden of sepsis
Sepsis is defined as life-threatening organ dysfunction caused by a

dysregulated host response to infection. Septic shock is a subset of
sepsis involving profound circulatory, cellular, and metabolic
abnormalities. Patients with septic shock require a vasopressor to
maintain a MAP of 65 mmHg or greater and a serum lactate level
greater than 2 mmol/L in the absence of hypovolaemia. This
combination is associated with hospital mortality rates greater than
40% and is even higher in older patients [23]. Organ failure is the
commonest cause of short-term mortality in surgical patients.
Timeline
18.00 Arrival at hospital
+30 min Seen in emergency department resuscitation
+45 min Anaesthetic review
+1.00 CT scan
hour
+1:25 Senior surgical review

hours
+1:45 Senior anaesthetist, intensivist, and surgeon review.

hours Discussion with patient. Booked for theatre
Page 12 of 20

+3:00 Arrival in emergency theatre

hours
+3:45 Surgery
hours
+6:30 End of surgery

hours
+7:15 Admission to ICU

hours
LEARNING POINT Pre-existing susceptibility to sepsis
Sepsis is more common with increasing age [24] and increased age
and multimorbidity are associated with an increased likelihood of
developing multiple organ dysfunction [25]. Risk factors include pre-
existing organ impairment and immunosuppression, including
diabetes mellitus and hepatic cirrhosis [26].
Iatrogenic component
Medical therapies, such as use of inappropriately high tidal volumes
during mechanical ventilation, have been implicated in the
development of the acute respiratory distress syndrome and acute
kidney injury. The ‘two-hit’ hypothesis proposes that in the presence
of predisposing acute or chronic disease, a trigger (such as
mechanical ventilation or vasopressor drugs) precipitates organ
failure.
The patient remained sedated and mechanically ventilated at the end of

surgery and was admitted to the ICU. Sedation and analgesia were
maintained with propofol and fentanyl infusions and noradrenaline
continued targeting a MAP greater than 70 mmHg. Lung protective
ventilation continued.
Cardiac output monitoring continued and this indicated a reduced stroke

volume and normovolaemia. A dobutamine infusion was started to
improve myocardial contractility. Despite an adequate MAP, metabolic
acidosis worsened in the hour after ICU admission and the patient
remained oliguric, so continuous renal replacement therapy was started.
Regular gastroprotection with omeprazole was prescribed, but

thromboprophylaxis was delayed pending review of clotting function.
Page 13 of 20

Tazocin was continued and metronidazole added as per local microbiology

policy. The patient was nursed using ventilator-associated pneumonia,
central line, and pressure care bundles. Enteral nutrition was started via
the nasojejunal tube but he did not absorb this.
EXPERT COMMENT
Emergency laparotomy is a high-risk procedure: 30-day mortality is

greater than 15% rising to greater than 20% for those over 80 years
of age [3, 27, 28, 29]. A disproportionate number of patients are
elderly—approximately two-thirds of patients are aged over 60 years
and approximately 85% of deaths occur in this group. As many as half
of patients may not return to their original place of residence after
surgery [30]. Increased mortality extends beyond the hospital stay
and more than one-third of deaths occur after 1 month [28]. Despite
this, ICU admission is not mandated and varies markedly between
countries (24% Denmark, 60% UK) [3, 28].
Complications occurring after surgery are associated with prolonged

admission and increased hospital mortality [31]. Patients
experiencing postoperative complications have increased mortality
for several years, compared to patients who do not experience
complications [32]. More patients undergoing emergency laparotomy
will experience complications that delay discharge than after elective
surgery, but evidence suggests it is the patient’s and the hospital’s
response to complications that impacts outcome more than the
number of complications itself [33]. Hospitals with better outcomes
do not have lower rates of complications but rather are better at
detecting and managing those patients who are deteriorating and at
managing serious complications [34]. Older patients may not
experience more complications, but are more likely to die from them
and to experience death between 3 and 30 days postoperatively [28].
While respiratory, gastrointestinal and infective morbidity is common,
cardiovascular complications may be more important in determining
outcome [30, 33].
Admission to ICU postoperatively provides the opportunity to manage

the patient in an area with higher nurse–patient and doctor–patient
ratios, to provide optimal monitoring, and to provide monitoring,
expertise, and advanced treatments that cannot be provided on the
wards. Although there is a lack of definitive evidence that critical care
admission reduces mortality in this group of patients, it seems logical.
Regular senior multidisciplinary review, physiological optimization,
early detection and treatment of deterioration, and, where feasible,
early mobilization and intensive rehabilitation are the mainstay of
treatment. Supportive evidence of the benefit of ICU includes the
observation that hospitals with better outcomes from emergency
surgery have more ICU beds [35]. In one small study, the risk-
Page 14 of 20

adjusted standardized mortality rate of patients admitted to the ICU

after emergency laparotomy was substantially lower than that of the
patients who were sent directly to the ward [36]. Several studies have
observed that the highest mortality occurs in patients who are
initially discharged to the wards and are subsequently admitted to the
ICU [27].
Quality improvement projects that include bundles of care—including

increasing the proportion of patients admitted to the ICU—after
emergency laparotomy have had success in reducing the length of
stay and mortality in this high-risk group [37]. Several national bodies
recommend ICU admission for emergency laparotomy patients with a
predicted mortality of greater than 5 or 10% [38] and that hospitals
should have the capacity to admit all such cases to the ICU. In
practice, this includes all patients aged older than 60 years, all those
with comorbidities, and all patients with an elevated lactate. A strong
argument therefore can be made for defaulting to admission of all
patients to critical care after emergency laparotomy, thereby making
admission to the wards the exception.
On days 1–3, the patient remained on multiorgan support (sedated,

ventilated, renal replacement therapy, vasopressors, and inotrope
support).
By day 3, persistently elevated inflammatory markers and haemodynamic

instability suggested failure of source control. Exploration in the OR
demonstrated four-quadrant purulent fluid. An abdominal washout was
performed and a large-bore drain inserted.
After a further return to the OR for abdominal washout, inflammatory

markers began to decline and haemodynamic support was weaned off.
However, despite lung protective ventilation, by 72 hours the patient
fulfilled the criteria for acute respiratory distress syndrome.
After his second return to the OR, parenteral nutrition was started via a
dedicated peripherally inserted central catheter line (see Case 13). On
day 6, a percutaneous tracheostomy was sited to aid with weaning. On
day 10, he developed ventilator-associated pneumonia with a resistant
Pseudomonas infection.
EXPERT COMMENT
It is not unusual for patients to need to return to theatre. Data from

NELA suggest this ranges from 2% to 20%, and is associated with
increased mortality and longer hospital stay. In some case this may be
planned, particularly if ‘damage control’ surgery has been performed,
when the patient has been too unstable for an initial definitive
Page 15 of 20

procedure, or to close a laparostomy. Unplanned returns for

complications are also likely. This may be due to a remaining source
of sepsis, anastomotic breakdown, bowel ischaemia, or to assess
stoma viability.
The timing of a return to theatre can be problematic as patients may

be unstable due to ongoing sepsis and multiple organ failure.
Instability may preclude performing further CT scans, requiring
surgery to be undertaken with diagnostic intent.
The patient spent a long time in the ICU. Over the next 2 months, his
recovery and rehabilitation was complicated by a protracted wean from
ventilatory support because of a combination of underlying chronic lung
disease, acute pathology, and critical illness myoneuropathy.
Routine investigations excluded intrinsic and postrenal causes of his

acute kidney injury and this was attributed to sepsis. Continuous renal
replacement therapy was provided for the first month of his stay.
His intra-abdominal sepsis settled slowly and enteral nutrition was re-
established after 2 weeks. He remained weak and required intensive
chest and rehabilitative physiotherapy.
Almost 2 months after his initial surgery, the patient’s tracheostomy was
decannulated, and he was discharged to a medicine for the care of older
people ward where he remained an inpatient for a further 2 months.
Despite intensive multidisciplinary rehabilitation, he did not regain his
previous level of mobility and could walk only short distances and under
close supervision. Due to increased frailty and ongoing complex medical
needs, he was discharged to a nursing home. Four months after hospital
discharge and 8 months after his initial presentation the patient died.
Discussion
Development of multiple organ dysfunction is common in patients

admitted to ICUs. The number of impaired organ systems and severity of
their impairment may be used to quantify the severity of illness and
likelihood of subsequent morbidity and mortality.
Sepsis is the commonest cause of multiple organ dysfunction, and in this

setting outcomes are poor. Survival of older people with multiple organ
dysfunction is likely to involve a complicated and prolonged period of
recovery and often leads to a subsequent reduction of functional ability.
The relatively poor prognosis necessitates monitoring of clinical progress
and assessment of quality of survival.
In this case, pre-existing frailty and multiple morbidity not only

predisposed to the development of multiorgan failure, but also resulted in
Page 16 of 20

a critical loss of functional ability, such that the patient required nursing
care following hospital discharge [39, 40].
It is preferable for individuals to have discussed their wishes in advance

of such a scenario, whether with health professionals, friends, and family
or by formal documentation. Where possible, this information should be
actively sought out to inform these decisions and in particular to support
limitation of treatment when clinically appropriate (see Case 8).
The outcome of this case is not surprising given the systemic impact
of emergency laparotomy in an elderly patient whose pre-existing
reserve was already very limited. At present, there is very limited
data available on longer-term outcomes and quality of life following
emergency laparotomy. This can make informed discussion with
patients and family challenging. It is hoped that this may be answered
by ongoing research.
The urgent nature of emergency laparotomy means that there may be

limited time to consider some of these aspects, but it is important to
do so. These discussions impact subsequent care, and may avoid
prolonged and distressing treatment for a patient if there is a limited
chance of a successful outcome and good quality of life. These
decisions need to be individualized to each patient, and are best made
when senior clinicians from all relevant specialties are involved.
References
1. Shapter SL, Paul MJ, White SM. Incidence and estimated annual cost of
emergency laparotomy in England: is there a major funding shortfall?
Anaesthesia. 2012;67:474–8.
2. Oliver M, Grocott M, Anderson I, Murray D. The problem with

emergency laparotomies. Br J Hosp Med (Lond). 2015;76:498–9.
3. NELA Project Team. Second Patient Audit Report of the National

Emergency Laparotomy Audit. London: Royal College of Anaesthetists;
2016.
4. Hoteit MA, Ghazale AH, Bain AJ, et al. Model for end-stage liver disease
score versus Child score in predicting the outcome of surgical procedures
in patients with cirrhosis. World J Gastroenterol. 2008;14:1774–80.
5. Faiz O, Warusavitarne J, Bottle A, et al. Nonelective excisional

colorectal surgery in English National Health Service trusts: a study of
Page 17 of 20

outcomes from hospital episode statistics data between 1996 and 2007. J
Am Coll Surg. 2010;210:390–401.
6. Kesisoglou I, Pliakos I, Sapalidis K, Deligiannidis N, Papavramidis S.

Emergency treatment of complicated colorectal cancer in the elderly.
Should the surgical procedure be influenced by the factor ‘age’? Eur J
Cancer Care. 2010;19:820–6.
7. Office for National Statistics. National Population Projections: 2014-

Based Statistical Bulletin [Internet]. Office for National Statistics; 2015
[cited 2 April 2017]. Available from: https://www.ons.gov.uk/
peoplepopulationandcommunity/populationandmigration/
populationprojections/bulletins/nationalpopulationprojections/2015-10-29.
8. Huddart S, Mowat I, Sanusi S, et al. Introduction of an integrated care

pathway for emergency laparotomies saves lives. Anaesthesia.
2012;67:20.
9. NELA Project Team. First Patient Report of the National Emergency

Laparotomy Audit. London: Royal College of Anaesthetists; 2015.
10. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of

fitness and frailty in elderly people. CMAJ. 2005;173:489–95.
11. Bagshaw SM, Stelfox HT, Johnson JA, et al. Long term association
between frailty and health related quality of like among adult survivors of
critical illness: a prospective multicentre cohort study. Crit Care Med.
2015;43:973–82.
12. Cassidy MR, Rosenkranz P, McCabe K, Rosen JE, McAneny D. iCough:

reducing postoperative pulmonary complications with a multidisciplinary
patient care program. JAMA Surg. 2013;148:740–5.
13. Copeland GP, Jones D, Walters M. POSSUM: a scoring system for

surgical audit. Br J Surg. 1991;78:355–60.
14. Prytherch DR, Whiteley MS, Higgins B, Weaver PC, Prout WG, Powell
SJ. POSSUM and Portsmouth POSSUM for predicting mortality.
Physiological and Operative Severity Score for the enUmeration of
Mortality and morbidity. Br J Surg. 1998;85:1217–20.
15. Protopapa KL, Simpson JC, Smith NCE, Moonesinghe SR.

Development and validation of the Surgical Outcome Risk Tool (SORT). Br
J Surg. 2014;101:1774–83.
16. Yentis SM, Hartle AJ, Barker IR, et al. Consent for anaesthesia.
Association of Anaesthetists of Great Britain and Ireland. Anaesthesia.
2017;72:93–105.
17. Montgomery v Lanarkshire Health Board [2015]. UKSC 11.
Page 18 of 20

18. Haynes SR, Lawler PG. An assessment of the consistency of ASA

physical status classification allocation. Anaesthesia. 1995;50:195–9.
19. Findlay GP, Goodwin APL, Protopapa K, Smith NCE, Mason M.

Knowing the Risk. A Review of the Peri-Operative Care of Surgical
Patients. London: National Confidential Enquiry into Patient Outcome and
Death; 2011. Available from:http://www.ncepod.org.uk/2011report2/
downloads/POC_fullreport.pdf.
20. Oliver CM, Walker E, Giannaris S, Grocott MPW, Moonesinghe SR.

Risk assessment tools validated for patients undergoing emergency
laparotomy: a systematic review. Br J Anaesth. 2015;115:849–60.
21. Eugene N, Oliver CM, et al. Development and internal validation of a

novel risk adjustment model for adult patients undergoing emergency
laparotomy surgery: The National Emergency Laparotomy Audit risk
model. Br J Anaesth. 2018;121:739–48.
22. Pearse RM, Harrison DA, MacDonald N, et al. Effect of a

perioperative, cardiac output-guided hemodynamic therapy algorithm on
outcomes following major gastrointestinal surgery: a randomized clinical
trial and systematic review. JAMA. 2014;311:2181–90.
23. Singer M, Deutschman C, Seymour C, et al. The Third International

Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA.
2016;315:801–10.
24. Martin GS, Mannino DM, Moss M. The effect of age on the
development and outcome of adult sepsis. Crit Care Med. 2006;34:15–21.
25. Perl TM, Dvorak LA, Hwang T, Wenzel RP. Long-term survival and
function after suspected gram-negative sepsis. JAMA. 1995;274:338–45.
26. Martin G, Brunkhorst FM, Janes JM, et al. The international

PROGRESS registry of patients with severe sepsis: drotrecogin alfa
(activated) use and patient outcomes. Crit Care. 2009;13:R103.
27. Vester-Andersen M, Lundstrøm LH, Møller MH, et al. Mortality and

postoperative care pathways after emergency gastrointestinal surgery in
2904 patients: a population-based cohort study. Br J Anaesth.
2014;112:860–70.
28. Tengberg LT, Cihoric M, Foss NB, et al. Complications after

emergency laparotomy beyond the immediate postoperative period—a
retrospective, observational cohort study of 1139 patients. Anaesthesia.
2017;72:309–16.
29. Saunders DI, Murray D, Pichel AC, Varley S, Peden CJ; UK Emergency
Laparotomy Network. Variations in mortality after emergency
laparotomy: the first report of the UK Emergency Laparotomy Network.
Br J Anaesth. 2012;109:368–75.
Page 19 of 20

30. McGillicuddy EA, Schuster KM, Davis KA, Longo WE. Factors
predicting morbidity and mortality in emergency colorectal procedures in
elderly patients. Arch Surg. 200;144:1157–62.
31. Khuri SF, Henderson WG, DePalma RG, et al. Determinants of long-
term survival after major surgery and the adverse effect of postoperative
complications. Ann Surg. 2005;242:326–41.
32. Moonesinghe SR, Harris S, Mythen MG, et al. Survival after

postoperative morbidity: a longitudinal observational cohort study. Br J
Anaesth. 2014;113:977–84.
33. Howes TE, Cook TM, Corrigan LJ, Dalton SJ, Richards SK, Peden CJ.
Postoperative morbidity survey, mortality and length of stay following
emergency laparotomy. Anaesthesia. 2015;70:1020–7.
34. Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality
associated with inpatient surgery. N Engl J Med. 2009;361:1368–75.
35. Ozdemir BA, Sinha S, Karthikesalingam A, et al. Mortality of

emergency general surgical patients and associations with hospital
structures and processes. Br J Anaesth. 2016;116:54–62.
36. Clarke A, Murdoch H, Thomas MJ, Cook TM, Peden CJ. Mortality and
postoperative care after emergency laparotomy. Eur J Anaesthesiol.
2011;28:16–9.
37. Huddart S, Peden CJ, Swart M, et al. Use of a pathway quality

improvement care bundle to reduce mortality after emergency
laparotomy. Br J Surg. 2015;102:57–66.
38. The Royal College of Surgeons of England. The Higher Risk General
Surgical Patient: Towards Improved Care for a Forgotten Group. Report
of the Royal College of Surgeons of England/Department of Health
Working Group on Peri-operative Care of the Higher-Risk General
Surgical Patient. London: The Royal College of Surgeons of England;
2011. Available from: http://patientsafety.health.org.uk/resources/higher-
risk-general-surgical-patient-towards-improved-care-forgotten-group.
39. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B.

Epidemiology of multimorbidity and implications for health care,
research, and medical education: a cross-sectional study. Lancet.
2012;380:37–43.
40. Bagshaw SM, Stelfox HT, McDermid RC, et al. Association between
frailty and short- and long-term outcomes among critically ill patients: a
multicentre prospective cohort study. CMAJ. 2014;186:E95–102.
Page 20 of 20

Sedation and delirium

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Sedation and delirium
Author(s): Nim Pathmanathan
DOI: 10.1093/med/9780198814924.003.0010
Expert commentary by Paul Nixon
Case history
A 45-year-old, 80 kg male was admitted by the emergency

department (ED) trauma team following a road traffic collision. He was
intoxicated with alcohol, and had lost control while driving a car, hitting a
tree at approximately 50 miles/hour. Injuries identified in emergency
department assessment included fractured ribs 5–11 on the right with a
flail segment and haemopneumothorax, an unstable pelvic fracture, and
open fractures of the right femur, distal ulna and radius. He had an
intercostal chest drain inserted with an initial output of 500 mL of blood.
Haemodynamic stability was achieved after resuscitation with 1 L of
Hartmann’s solution, 3 units of red blood cells, and placement of a pelvic
binder (see also Case 4). He underwent a trauma series computed
tomography (CT) scan and was then transferred to the operating room.
Page 1 of 30
The patient was admitted to the intensive care unit (ICU) at 20:00
following a 4-hour operation, which involved external fixation of the
pelvis, femur, and forearm. Intraoperatively, he received paracetamol 1 g
and morphine 20 mg. His last dose of neuromuscular blocker was 2 hours
before ICU admission. In the operating room, he had been transfused 8
units of red blood cells, 4 units of fresh frozen plasma, and one adult
therapeutic dose of platelets. Low-pressure suction was applied to the
intercostal chest drain and output was 400 mL for the previous 4 hours.
The trauma surgeons planned to internally fix the pelvis, femur and
forearm in 2 days.
The patient returned to ICU intubated, his lungs were mechanically

ventilated (synchronized intermittent mandatory ventilation tidal volume
480 mL (6 mL/kg ideal body weight), respiratory rate 18 breaths/min,
positive end-expiratory pressure (PEEP) 8 cmH2O, pressure support 15
cmH2O), and his arterial blood oxygen saturation was 98% (fraction of
inspired oxygen (FiO2) 0.5). His heart rate was 110 beats/min, blood
pressure 102/56 mmHg, supported by 0.1 mcg/kg/min noradrenaline.
Urine output was 220 mL over the past 4 hours and his temperature was
36.0°C. He was sedated with propofol 200 mg/hour and morphine 6 mg/
hour. The Richmond Agitation–Sedation Scale (RASS) score was −5.
Initial blood gas values were pH 7.32, partial pressure of carbon dioxide
(PaCO2) 5.8 kPa, partial pressure of oxygen (PaO2) 14.7 kPa, bicarbonate
(HCO3−) 18.1 mmol/L, haemoglobin 88 g/L, and lactate 2.6 mmol/L.
CLINICAL TIP Sedation after transfer
Attend to the sedation strategy as soon as the patient is admitted to

the ICU. A recent longitudinal study suggested an association
between early deep sedation (within 48 hours) and increased
mortality and duration of mechanical ventilation [1]. Deep sedation is
often used following intubation in the ED or operating room in order
to facilitate safe transfer to the ICU but is often then unnecessarily
continued on admission to ICU. Examine the sedation strategy in the
ED and again on admission to ICU; stipulate and regularly review the
target level of sedation. Despite the use of sedation scales, sedation
protocols, and emerging evidence of harm from deep sedation,
patients commonly remain over-sedated [2, 3].
LEARNING POINT Sedation scoring tools
Sedation can be assessed by clinical scoring systems and by objective

measures such as bispectral index (BIS) or auditory evoked
potentials. Objective measures are no substitute for clinical scoring
systems, but are useful in assessing the depth of sedation when
Page 2 of 30

neuromuscular blockade is being used, making clinical scoring

systems impractical.
There are numerous clinical scoring systems in use. The RASS (Table
10.1) and Riker Sedation Agitation Scale (SAS; Table 10.2) are
reliable, validated in adult ICU patients, and used widely [3]. They are
the most frequently used scales in Australasia whereas the Ramsay
Sedation Scale (Table 10.3) is the most frequently used in the UK [4].
The particular tool used is less important than familiarity with it and
the quality of its implementation. Staff training is essential to
maintain adherence to sedation scoring.
Table 10.1 Richmond Agitation–Sedation Scale (RASS)
Score Scale Description
+4 Combative Violent, combative, immediate danger
+3 Very Pulls or removes tubes/lines,

agitated aggressive
+2 Agitated Non-purposeful movements, fights

ventilator
+1 Restless Anxious, not aggressive
0 Alert and
calm
−1 Drowsy Not alert, opens eyes and makes eye

contact to verbal stimulation for ≥10
seconds
−2 Light Not alert, opens eyes and makes eye

sedation contact to verbal stimulation for <10
seconds
−3 Moderate Not alert, briefly opens eyes but no eye

sedation contact to verbal stimulation
−4 Deep Not alert, opens eyes to physical

sedation stimulation
−5 Unrousable No response to verbal or physical

stimulation
Page 3 of 30

RASS +1 to +4 = agitated; RASS 0 = awake and calm; RASS −1 to

−2 = lightly sedated; RASS −3 to −5 = deeply sedated.
Table 10.2 Riker Sedation–Agitation Scale (SAS)
Score Term Descriptor
7 Dangerous Pulling at tracheal tube, trying to

agitation remove catheters, climbing over
bedrail, striking at staff, thrashing
side to side
6 Very agitated Requiring restraint and frequent

verbal reminding of limits, biting
tracheal tube
5 Agitated Anxious or physically agitated, calms

to verbal instructions
4 Calm and Calm, easily rousable, follows

cooperative commands
3 Sedated Difficult to rouse but awakens to

verbal stimuli or gentle shaking,
follows simple commands but drifts off
again
2 Very sedated Arouses to physical stimuli but does

not communicate or follow commands,
may move spontaneously
1 Unrousable Minimal or no response to noxious

stimuli, does not communicate or
follow commands
Table 10.3 Ramsay Sedation Scale
Score Description
1 Anxious, agitated or restless
2 Cooperative, oriented, tranquil
3 Responds only to verbal commands
Page 4 of 30

4 Asleep, brisk response to light stimulation
5 Asleep, sluggish response to stimulation
6 Unrousable
Procedure for RASS assessment [5]:
1. Observe patient:
● Patient is alert, restless, or agitated Score 0 to

+4
2. If not alert, state patient’s name and instruct to open eyes and
look at speaker:
● Patient awakens with sustained eye opening Score −1

and eye contact
● Patient awakens with eye opening and eye Score −2

contact but not sustained
● Patient has any movement in response to Score −3

voice but no eye contact
3. When no response to verbal stimulation, physically stimulate

patient by shaking shoulders and/or rubbing sternum:
● Patient has any movement to physical Score −4

stimulation
● Patient has no response to any stimulation Score −5
CLINICAL TIP Bolus doses
Use bolus doses of drugs before starting analgesic and sedative

infusions. Bolus doses enable rapid achievement of analgesia and
optimal sedation. Conversely, a change in an infusion rate may take
many hours to achieve a stable plasma level (and clinical effect). By
loading the patient with bolus doses, the subsequent infusion can
often be at a lower rate, which may prevent excessive drug
administration. This requires regular sedation assessment.
Page 5 of 30

The ICU plan was for stabilization overnight and consideration of

extubation in the morning. The propofol and morphine were discontinued
to target a RASS score of 0 to −2. Two hours later, the noradrenaline
infusion had been weaned off and the patient’s RASS score was −2.
However, he was grimacing and localizing to the tracheal tube and
appeared to be in pain. A 5 mg morphine bolus was administered. Pain
was regularly assessed during the subsequent hour and he required two
further boluses of morphine and subsequently an infusion at 5 mg/hour.
At 03:00 there was no evidence of pain, but he now appeared agitated,
with a RASS score of +1. A 30 mg bolus of propofol was given followed by
an infusion at 50 mg/hour. The RASS score at 04:00 was −1.
EXPERT COMMENT
Analgesics, such as an opioid, form the mainstay of sedation

protocols. Address the patient’s pain first and then target an
appropriate sedation level. Many analgesics sedate and this
secondary effect may limit the requirements of other sedative
hypnotics. If an intubated patient is pain free, alert, and calm,
additional sedation is of little benefit.
LEARNING POINT Sedation protocols
Sedation protocols are most likely to be effective when packaged with

assessment of pain and delirium.
Key points of any sedation protocol include:
● staff training in the use of the protocol

● a target sedation score is set regularly (e.g. twice daily)
● a light sedation target (e.g. RASS score 0 to −2) is the default
unless clinically contraindicated
● regular assessment of sedation scores—minimum four times per
day
● administration of boluses of sedatives and titration of infusions
accordingly
● regular audit of sedation management.
EXPERT COMMENT
Page 6 of 30

The pharmacokinetics and pharmacodynamics of drugs are often

difficult to predict in the ICU setting. Institutional and practitioner
preferences lead to widespread variation in sedation management.
Sedation protocols improve sedation practice by providing a
framework to standardize sedation strategies and by incorporating
regular patient assessment, with an algorithm for titration of
analgesic and sedative drugs.
Sedation scoring tools are most effective when they are used in
conjunction with a targeted sedation protocol. Targets are set by the
medical team or default targets applied depending on the presenting
case. Bedside nursing staff can then titrate analgesic and sedative
drugs to meet the desired sedation target. Assess frequently, up to
hourly if possible, until stability at the target level is achieved.
Frequent assessment leads to earlier achievement of the target and
may prevent excessive drug accumulation.
LEARNING POINT Strategies to minimize sedation
Acceptable ways to minimize sedation include the use of a

protocolized light sedation policy or daily sedation interruptions. A
daily sedation interruption is the reduction or cessation of sedation to
wake the patient, with the aim of reducing sedation accumulation.
Sedation interruptions are not suitable for patients receiving
neuromuscular blockers or those receiving high-level respiratory or
cardiovascular support.
LEARNING POINT Light versus deep sedation
ICU patients receiving mechanical ventilation often require sedation

and analgesia for a variety of reasons including the treatment of pain,
tolerance of the tracheal tube and mechanical ventilation, to permit
invasive procedures, to reduce physiological stress, and to enable
respite from a noisy and often distressing environment.
Historically deep sedation (e.g. RASS score −5 to −3) was thought to

be most suitable to achieve these goals and to avert longer-term
psychological consequences. However, studies have shown that deep
sedation results in prolonged duration of mechanical ventilation and
ICU length of stay [6, 7, 8, 9]. The reason for this is not clear but may
be related to complications such as ventilator-associated pneumonia,
barotrauma, airway complications, delirium, and adverse effects of
the sedating drugs including hypotension, bradycardia, reduced
Page 7 of 30

gastric motility, respiratory depression, and suppression of the cough

reflex [9].
The aim for most patients is a RASS score of −2 to 0 (or equivalent in

other scoring systems), whereby patients are comfortable, orientated,
alert or easily rousable, have good sleep architecture, and can
cooperate with interventions such as physiotherapy.
In some patients, light sedation may be harmful. Examples include

patients with intracranial injury and high intracranial pressures,
severe acute respiratory distress syndrome, or status epilepticus.
These patients require deeper sedation (e.g. RASS score of −3 to −5
or equivalent). Ensure adequate levels of sedation are maintained if
neuromuscular blocking drugs are administered. Potential side effects
of under and over sedation are shown in Table 10.4.
EVIDENCE BASE Daily interruption of sedative

infusions in critically ill patients undergoing mechanical
ventilation [7]
● Randomized controlled trial (RCT) in 128 patients in a medical

ICU.
● Daily sedation interruption until patients were awake versus
routine care.
● Median duration of mechanical ventilation reduced from 7.3
days in the control group to 4.9 days in the intervention group (P =
0.004).
● Median ICU length of stay reduced from 9.9 to 6.4 days (P =
0.02).
● In the intervention group, 9% versus 27% in the control group
underwent radiological imaging to assess neurological status (P =
0.02).
● No difference in complications (e.g. unintended tracheal tube/
central venous catheter removal).
Table 10.4 Potential adverse effects of under- and oversedation
Light sedation (RASS score at or Deep sedation (RASS score

above −2) −3 to −5)
Pain/discomfort Increased length of

mechanical ventilation
Page 8 of 30

Anxiety Increased length of admission
Agitation Increased vasopressor

requirements
Risk to patient/carer safety Decreased cooperation with

physiotherapy
Increased oxygen consumption Reduced cough and secretion

clearance
Increased energy expenditure Unnecessary radiological

investigations
Decreased tolerance of invasive Increased delirium

procedures
Risk of dislodgement of devices Disorders of sleep

including airway and vascular architecture
access devices Pressure sores
Post-traumatic stress disorder
Awareness of pain during invasive
procedures
Day 2
The patient remained lightly sedated at 08:00 with a RASS score of −1.
His oxygen requirements, however, had increased: FiO2 was 0.6, PEEP
was 12 cmH2O, with pressure support of 15 cmH2O. Tidal volumes were
in the range of 300–400 mL but he was limited by pain when asked to
take deep breaths. The intercostal chest drain remained on suction and
had drained 250 mL of haemoserous fluid over 12 hours. Repeat chest X-
ray, showed a small residual right pneumothorax and increasing
opacification throughout the right lung field. A sedation interruption was
not undertaken as extubation was not appropriate. Cardiovascular, renal,
and liver function were stable and unsupported. Delirium was assessed as
negative via the Confusion Assessment Method for the Intensive Care
Unit (CAM-ICU) tool. Pain was assessed using a numeric rating scale,
scoring 8 out of 10. A bolus of morphine 5 mg was given and the infusion
was increased to 8 mg/hour. His pain score reduced to 4 increasing to 7
on deep inspiration. Following discussion with the acute pain service a
paravertebral catheter was sited and a bolus of 0.125% bupivacaine was
given followed by an infusion; his pain subsided significantly and
respiratory variables gradually improved. His RASS score at 18:00 was
−3 and the propofol and morphine infusions were reduced to 30 mg/hour
and 4 mg/hour respectively.
Page 9 of 30

LEARNING POINT Delirium screening tools
Delirium in ICU patients is common with an incidence of up to 83%

[10]. As delirium can lead to an increased hospital length of stay,
morbidity, and even 6-month mortality [11], it is recommended that
patients are routinely monitored for delirium to enable early
detection, investigation, and treatment. However, screening for
delirium is surprisingly uncommon, only 3.7% in Canadian ICUs
surveyed in 2006 [12].
Validated methods of screening are available such as the CAM-ICU

[10] and the Intensive Care Delirium Screening Checklist (ICDSC)
[13]. On completion of both scales, delirium is either present or
absent, but no severity marker is indicated. Undertake the
assessment at least once per nursing shift or more frequently if the
patient’s behaviour changes (Figure 10.1).
Figure 10.1
CAM-ICU worksheet.
Source: data from Ely, E.W., et al. Delirium in Mechanically Ventilated

Patients Validity and Reliability of the Confusion Assessment Method
for the Intensive Care Unit (CAM-ICU). Journal of the American
Medical Association. 2001;286(21):2703–2710. Copyright © 2001
American Medical Association. All Rights Reserved.
CAM-ICU Assessment
● If RASS is −5 to −4, stop and reassess when more awake.
Page 10 of 30

● If RASS −3 to +4, proceed to delirium assessment.
Day 3
The patient’s respiratory condition improved overnight. The FiO2 was

weaned to 0.4, PEEP was 8 cmH2O, with pressure support of 10 cmH2O.
During that morning, a family meeting was undertaken and a collateral
history was obtained: the patient drank approximately 60 units of alcohol
per week, used cannabis and methamphetamine regularly, and smoked 15
cigarettes each day. Pabrinex supplements, thiamine 300 mg
intravenously (IV) three times daily, and a 21 mg nicotine patch were
started.
He returned to theatre and underwent open reduction and internal

fixation of the pelvis, right femur, and forearm. After 6 hours of surgery
he returned intubated and ventilated without cardiovascular support. He
was sedated with propofol 200 mg/hour and analgesia was provided by
morphine 10 mg/hour and the paravertebral infusion of bupivacaine. His
RASS score was −5.
Day 4
The patient’s respiratory condition improved again overnight (FiO2 of 0.3,

PEEP 8 cmH2O, and pressure support 8 cmH2O) and his sedation was
weaned to morphine 5 mg/hour and propofol 50 mg/hour. His RASS score
was +2. He denied any pain but was restless and appeared agitated. The
propofol infusion was stopped, while continuing the morphine to assess
suitability for extubation.
LEARNING POINT Pain assessment and scoring
Pain is not confined to the surgical cohort of ICU patients and

assessment is vital when addressing the patient’s analgesic and
sedation requirements. Pain can lead to tachycardia and
hypertension, and agitation, delirium, and symptoms of acute
psychological distress. Patients with pain may be agitated and can
pose a threat to themselves and the staff caring for them.
Pain can be difficult to assess in a mechanically ventilated ICU

patient. Vital signs can be an aid, but should not be used alone to
monitor pain [3]. There are many scoring systems to help clinicians
assess pain, an example being the Behavioural Pain Scale. These
scoring systems can be used in medical, postoperative patients and
trauma patients (except for the head injured). As with the assessment
Page 11 of 30

of sedation, pain assessment should be performed regularly and

treated accordingly.
CLINICAL TIP
Pay attention to procedures such as suctioning and mobilization that

can cause pain in the ICU. Consider giving a bolus of analgesic drug
before these procedures. Opioids are the analgesic of choice in the
critically ill.
During the next 30 min he became very agitated and was pulling at his
tracheal tube and intravenous lines. He was tachycardic and tachypnoeic.
Arterial blood gas analysis showed pH 7.46, PaCO2 4.0 kPa, PaO2 12.3
kPa, HCO3− 27.3 mmol/L, and lactate 1.3 mmol/L. CAM-ICU screening
was positive for delirium. Extubation was deemed unsafe and he was
administered propofol 30 mg and the infusion restarted at 50 mg/hour. A
delirium screen (see Table 10.5) was started to seek a modifiable cause.
There were no signs of infection and no modifiable causes of delirium
other than possible alcohol and drug withdrawal. Diazepam 10 mg via a
nasogastric (NG) tube was prescribed 6-hourly as per the local alcohol
withdrawal regimen. The agitation persisted, however, and he remained
CAM-ICU positive. Quetiapine 25 mg twice daily NG was prescribed. His
infusions remained relatively unchanged over the day: propofol 40 mg/
hour and morphine 4 mg/hour.
Page 12 of 30

Table 10.5 Delirium risk factors
Past medical history Acute illness Environmental Medication Social history
Age >70 years Sepsis Catheters/tubes/drains Benzodiazepines Smoker
Cardiac failure Fever Visual/hearing impairment Opioids Alcohol abuse
Hepatic failure Hypoxia Corticosteroids Malnutrition
Renal failure Hypotension Absence of visible daylight Tricyclic antidepressants Lack of visitors
Hypertension APACHE II score >15 Physical restraints Anticholinergics
Dementia Hypo/hypernatraemia Sleep deprivation Antiemetics
Epilepsy Hypo/hyperglycaemia Loss of diurnal rhythm Drug/medication

withdrawal
Depression Hypocalcaemia
Thyroid dysfunction
Acute kidney injury
Pain
APACHE II, Acute Physiology, Age, Chronic Health Evaluation II.
Page 13 of 30
and Legal Notice).
CLINICAL TIP Treating delirium
Treat reversible causes of delirium and optimize non-pharmacological

treatments before treating with drugs. Exclude withdrawal states
(e.g. alcohol, recreational drugs, antidepressants, and nicotine) and, if
appropriate, reintroduce the drug or substitutes. A commonly
overlooked cause of delirium is the abrupt cessation of prolonged
infusions of sedative medication such as benzodiazepine, opioids, or
alpha agonists. A slower tapering of the sedative medication should
be considered and alternative medications, such as clonidine, may be
instituted to dampen down the withdrawal effect.
LEARNING POINT Non-pharmacological management

of delirium
Non-pharmacological management is an integral part of the

management of delirium. Ensure visual aids are available and hearing
aids are in place and switched on. Enhance communication, where
appropriate, using aids such as word charts. Orientation should occur
including the establishment of day–night orientation and the use of
clocks. Reduce ambient lighting during night-time and keep sound to
a minimum; consider using quiet bins and reducing the volume of
telephones and avoid non-essential interventions during rest periods.
Ear plugs and eye pads may be useful as may night time melatonin to
improve sleep pattern. These non-pharmacological measures may also
lead to less sedative medication being required.
EXPERT COMMENT
There is no clear evidence guiding the optimal medication for the

treatment of delirium in the ICU. Studies have shown an association
between benzodiazepines and delirium and they should be avoided if
possible (except in the case of benzodiazepine for alcohol withdrawal
or as dose-sparing drugs in deep sedation). Based on limited data,
antipsychotics (e.g. quetiapine or haloperidol) and alpha2-receptor
agonists (e.g. clonidine and dexmedetomidine) are useful [3, 14, 15].
LEARNING POINT Pharmacological management of

delirium
Page 14 of 30

Despite lacking a strong evidence base, the mainstay of

pharmacological management of delirium is antipsychotic medication.
Examples of medications used for the treatment of delirium include
the following:
● Antipsychotics:
◦ Quetiapine 12.5–25 mg orally/NG twice daily plus 12.5–25 mg

as required (PRN) (can be titrated up to a maximum of 200 mg/
day in divided doses).
◦ Olanzapine: 2.5–5 mg orally/NG every night plus 2.5–5 mg
twice daily PRN (can be titrated to 10 mg twice daily and a
maximum daily dose of 30 mg).
◦ Haloperidol: if oral route not available or patient is acutely
agitated/delirious; 0.5–2.5 mg IV repeated after 15 min if
required. Can also be given intramuscularly if no IV access
available. For elderly/frail patients, start at half the
recommended dose and titrate slowly.
● Alpha agonists
◦ Dexmedetomidine: infusion of 0.2–1.5 mcg/kg/hour.

◦ Clonidine: 1–4 mcg/kg/hour.
Antipsychotics can all cause the long QT syndrome and neuroleptic

malignant syndrome. The newer atypical drugs (quetiapine,
olanzapine) cause these side effects less commonly than the
traditional drugs such as haloperidol. They are contraindicated in
patients with pre-existing long QT syndrome and in Parkinson’s
disease which they exacerbate. Long-term treatment is not usually
required; stop these drugs when the delirium resolves.
Day 5
Following a settled night, the patient was again assessed for suitability
for extubation. He was calm and cooperative with a RASS score of −1.
The CAM-ICU remained positive and quetiapine doses were continued.
The propofol was stopped and the patient was extubated successfully to
humidified oxygen. He was discharged to the ward the following day. The
quetiapine and diazepam were weaned off over the following 5 days.
Discussion
Both protocolized sedation and daily sedation interruptions are

acceptable strategies to minimize sedation use. In one study, the addition
of a daily sedation interruption to routine care reduced sedative use, the
duration of mechanical ventilation, and ICU length of stay [7]. More
recent trials have documented inconsistent results when daily sedation
Page 15 of 30

interruptions were compared to protocolized sedation [16, 17] and there

has been concern about patient comfort and safety and increasing
nursing workload [18].
Numerous studies have shown that the introduction of a sedation protocol

or package can reduce the duration of mechanical ventilation, ICU length
of stay, and hospital length of stay [6, 19, 20, 21]. Other studies have been
unable to reproduce these benefits [22, 23]. The reasons for this are
unclear but may be due to nursing intensity, prior experience of sedation
management, or studies being underpowered.
EXPERT COMMENT
Introducing sedation scoring protocols into an ICU requires a

complex change management process. Stakeholder buy-in is required
and education of all team members involved is essential. Staff must
be well supported and educated regularly. Regular audits and
reinforcement are required until the unit culture is adjusted.
LEARNING POINT Analgesia-first sedation
A study using daily sedation interruptions compared analgesia-only

sedation in the form of morphine with sedation using propofol or
midazolam [24]. In the analgesia-only arm, there was an increased
number of ventilator-free days and a decreased ICU and hospital
length of stay. However, more patients in the analgesia-only group
developed agitated delirium. While the results of this study do not
advocate a purely analgesia-based sedation protocol, the study shows
potential benefits of an analgesia-first protocol. By prioritizing the
treatment of pain, the reduction of co-administered hypnotic drugs
may improve outcomes.
EVIDENCE BASE Awakening and Breathing

Controlled (ABC) trial [25]
● Multicentre RCT.
● Included 336 patients who underwent either daily sedation
interruption plus a daily spontaneous breathing trial (SBT) or a
daily SBT alone.
● Patients in the daily sedation interruption plus SBT group were
discharged earlier from ICU (9.1 vs 12.9 days; P = 0.01) and
hospital (median 14.9 vs 19.2 days; P = 0.04).
Page 16 of 30

● There was an increase in self-extubation events in the daily

sedation interruption plus SBT group but no increase in the rates
of reintubation.
● One-year survival showed a mortality benefit in the daily
sedation interruption plus SBT group (Hazard ratio 0.68; 95%
confidence interval 0.50–0.92; P = 0.01).
EVIDENCE BASE Sedation Lightening and Evaluation

of A Protocol (SLEAP) trial [26]
● Multicentre RCT.
● Included 430 patients who underwent daily sedation
interruption plus protocolized sedation or protocolized sedation
alone.
● No difference in time to extubation, or ICU or hospital length of
stay.
● Higher mean doses of sedation used in the daily sedation
interruption cohort.
While light sedation increases oxygen consumption, energy expenditure,

and catecholamine release [27, 28], there is no evidence this translates
into increased rates of myocardial ischaemia or infarction [29, 30].
Similarly, there is no evidence of psychological harm from light sedation.
There is an association between amnesia in critical illness and the
development of post-traumatic stress disorder symptoms [31]; these
symptoms may be related to having delusional memories without factual
recall [32, 33]. An RCT evaluating the effect of light or deep sedation on
mental health showed that post-traumatic stress disorder symptoms were
more common in the deep sedation cohort but this was not statistically
significant. This cohort had increased rates of disturbing memories with
lower rates of factual recall [8]. Two large RCTs have also shown no
evidence of long-term psychological harm from daily sedation
interruptions [34, 35].
LEARNING POINT Analgesia and anaesthesia for

procedures
Light sedation is used to tolerate invasive ventilation and enable

respite from a distressing environment. However, this level of
sedation is often not adequate for procedures. Suctioning and
mobilization are examples that may require a prior bolus of sedation.
Page 17 of 30

More invasive procedures such as percutaneous tracheostomy require

analgesia and anaesthesia to ensure comfort and prevent awareness.
This is imperative when using neuromuscular blockade to avoid the
distress of unintended awareness during paralysis, not infrequently
identified in the ICU population [37].
Patients who are administered neuromuscular blockade are obviously

unsuitable for light sedation. Clinical scoring systems are of no use to
assess depth of sedation; monitors such as the BIS may have a role in
monitoring sedation depth and titrating sedation. There is, however, a
poor correlation of depth of sedation when assessed by clinical scoring
tools and by BIS (in patients who were not being administered
neuromuscular blockade) [36]. Furthermore, BIS is not validated in ICUs
and there is uncertainty about the level that indicates deep sedation.
There is insufficient evidence to suggest that a particular drug or

sedation strategy is superior to any other and sedation management is
often guided by individual or institutional preferences including factors
such as familiarity and cost. The commonly used medications include
propofol, benzodiazepines, and opioid analgesics. Worldwide, an opioid
plus a hypnotic such as propofol or midazolam is the most commonly used
combination. Other frequently used medications include clonidine,
dexmedetomidine, and ketamine. As sedation involves elements of
analgesia and hypnosis, combining an opioid with a hypnotic is often
beneficial. The different mechanisms of action of the drugs reduce overall
dosage and dose-dependent side effects. An overview of sedation options
is given in Table 10.6.
Page 18 of 30

Table 10.6 Overview of sedation options
Examples Mechanism of Pharmacokinetic Pharmacodynami Useful properties Adverse effects

action s cs
Propofol Thought to be due Highly protein Decreased Due to rapid Propofol infusion
to positive bound to albumin systemic vascular clearance, can be syndrome
modulation of (98%) resistance, cardiac used for frequent Pain on injection
GABA at the GABAA Fast onset and output, and blood neurological (bolus)
receptor leading to offset due to high pressure assessment of Hyperlipidaemia
hyperpolarization clearance Respiratory patients
following chloride Accumulation in depressant Anticonvulsant
influx tissue stores when Antitussive Antiemetic
used in prolonged Anxiolysis
infusions (without Amnesia
use of targeted
light sedation)
Benzodiazepines Lorazepam, Modulate the Midazolam is Dose-dependent Anticonvulsant Unpredictable and

midazolam, effect of GABA at oxidized by the respiratory Anxiolytic prolonged effect in
diazepam GABAA receptors cytochrome P450 depression Potentiate the hepatic and renal
enzyme system to Decreased heart effects of opioids failure and critical
form water-soluble rate and systemic illness
metabolites which vascular Risk of toxicity
can accumulate in resistance from propylene
renal failure and glycol (carrier for
have central lorazepam)
nervous system May prolong the
depressant effects duration of
ventilation,
Page 19 of 30
and Legal Notice).
Lorazepam is intensive care stay,

primarily and hospital stay
metabolized by May increase the
glucuronidation to incidence of
inactive delirium
metabolites Risk of withdrawal
Midazolam has a with prolonged use
higher clearance
than lorazepam
Opioids Morphine Agonist at opioid Mainly Respiratory Analgesia Tolerance and risk
Alfentanil receptors metabolized in the depression Sedation at higher of withdrawal with
Fentanyl Alfentanil is 10 liver to both Bradycardia doses prolonged use
times more potent inactive and active Antitussive May reduce dose Prolonged effect in
than fentanyl compounds that of co-administered hepatic/renal
which is 100 times are excreted in sedatives dysfunction
more potent than urine and bile Generally cheap
morphine and familiar
Remifentanil Selective mu Ultrashort-acting Bradycardia and Potent analgesic Cost

agonist opioid due to hypotension (when Renal/hepatic Chest wall rigidity
metabolism by used at higher dysfunction does (bolus)
plasma esterases doses) not prolong the
Displays a context- Respiratory duration
insensitive half- depression Sedative-sparing
time; half-life of effect
drug remains at 3– Easily titratable
4 min irrespective
of duration of
infusion
Page 20 of 30
and Legal Notice).
Alpha2 receptor Dexmedetomidine Centrally acting Highly protein Sedation Minimal Bradycardia
agonists alpha2 agonist at bound (94%) Analgesia respiratory Reduced clearance
the locus Metabolized by Bradycardia depression in hepatic failure
coeruleus glucuronidation Hypotension Cost
Affinity for alpha2: and hydroxylation
alpha1 1600:1 in the liver and
Active D-stereoiso excreted
mer of predominantly by
medetomidine the kidneys
Clonidine Centrally acting Metabolized by the Sedation Minimal May cause initial
postsynaptic alpha2 liver to inactive Analgesia respiratory hypertension via
agonist at the metabolites that Bradycardia depression alpha1 stimulation
lateral reticular are excreted by Hypotension Not commonly prior to the
nucleus of the the kidneys used as a first-line hypotensive alpha2
medulla. Leads to agent. May have a effects
reduced role as an adjunct Bradycardia
intracellular cAMP when sedation is Can cause rebound
and increases difficult to manage hypertension on
potassium ion or wean sudden cessation
conductance Useful drug in the of the drug
Stimulates alpha2 setting of
receptors in the recreational
spinal cord leading substance abuse
to increased
endogenous opiate
release
Affinity for alpha2:
alpha1 200:1
Page 21 of 30
and Legal Notice).
Ketamine Non-competitive Metabolized by the Analgesic Laryngeal reflexes Hallucinations

antagonism at the liver to the active Increased heart usually intact Uncertain effect
NMDA receptor norketamine prior rate, maintains when used for on intracranial
to further blood pressure and sedation pressure
conjugation to cardiac output No studies
inactive Bronchodilator supporting its use
metabolites which in sedation in
are excreted in the intensive care
urine Hypersalivation
Page 22 of 30
and Legal Notice).
Benzodiazepines are cheap and the most commonly used class of

sedatives worldwide. However, the American Pain, Agitation, and
Delirium Guidelines 2013 advocate using non-benzodiazepine medication
in mechanically ventilated ICU patients because benzodiazepines prolong
the duration of ventilation and ICU length of stay and increase the
incidence of delirium [3]. Benzodiazepines retain a role in alcohol
withdrawal and as dose-sparing drugs in deep sedation.
Opioids are used in most sedation regimens. There is no evidence to

suggest better outcomes for a particular opioid; morphine and fentanyl
are most commonly used. Remifentanil may offer advantages over other
opioids because it has a sedative-sparing effect, metabolism independent
of organ function, and a context-insensitive half-life where the half-life
remains at 3–4 min irrespective of infusion duration. This fast, predictable
offset time facilitates rapid neurological assessment. One of the
disadvantages of remifentanil is the rapid and total lack of analgesia once
the infusion is stopped. It is also more expensive than other opioids.
Propofol is commonly used in the ICU. It has a fast onset and a faster
offset than benzodiazepines. It has no analgesic properties and is
therefore often used in combination with an opioid. It can make blood
more lipaemic, which can interfere with some blood tests. A rare adverse
consequence is propofol infusion syndrome (PRIS).
LEARNING POINT Propofol infusion syndrome
● PRIS is a rare life-threatening condition caused by impairment

of mitochondrial oxidative phosphorylation and free fatty acid
utilization [38].
● The true incidence of PRIS is unknown, but it is much higher in
children and for this reason propofol is not licensed for sedation in
ICU patients aged less than 16 years
● Features include new or unexplained metabolic acidosis, cardiac
dysfunction, rhabdomyolysis, renal failure, hypertriglyceridaemia,
hepatomegaly, and lipaemia.
● Risk factors include young age, increasing dose and duration,
severe head injuries, sepsis, high exogenous or endogenous
catecholamine and glucocorticoid levels, and a low carbohydrate
to high lipid intake [38].
● Mortality is 18–30% in suspected cases [39, 40].
● PRIS persists after stopping the drug; prevention is imperative
and a high index of suspicion is required as only supportive
treatment is available.
● Propofol is not recommended for sedation at a dose of greater
than 4 mg/kg/hour. However, there are case reports of PRIS at
lower doses.
Page 23 of 30

● Daily monitoring of creatine kinase and triglycerides has been

proposed as surveillance when propofol is used for over 24 hours.
Dexmedetomidine is a relatively recent addition to the choice of ICU

sedatives, which can be used as a sole sedative drug for light to moderate
sedation and is thought to lead to a more cooperative patient with less
respiratory depression. The main adverse effects are bradycardia and
hypotension.
Dexmedetomidine has been compared with traditional sedatives in

several RCTs including MENDS [41] (comparator lorazepam), SEDCOM
[42] (comparator midazolam), MIDEX [43] (comparator midazolam),
PRODEX [43] (comparator propofol), and DESIRE [44, 45] (comparator
mixed sedatives). In summary, dexmedetomidine was non-inferior to all
these traditional sedatives and led to reduced rates of delirium when
compared to lorazepam [41] and midazolam [42] and a modest reduction
in mechanical ventilation time compared to midazolam [42, 43]. There
was no difference in the duration of mechanical ventilation when
compared to propofol [43]. It also allowed patients to communicate pain
more effectively when compared to both propofol and midazolam [43].
Dexmedetomidine is not suitable for use when deep sedation is required

[44]. It is also substantially more expensive than traditional sedatives and
until there is a clear benefit or a reduction in cost, it will remain a
second-line drug. It has a role in weaning sedation when sedation
management or delirium is problematic.
Clonidine has a role as an adjunct when sedation is difficult to manage or

wean and may have a role as an adjunct in the management of alcohol
withdrawal.
Ketamine is used primarily as an analgesic adjunct. Analgesia occurs at

much lower concentrations than required for sedation. It is not widely
used for sedation in ICU, nor supported by evidence. Ketamine causes
transient sympathetic nervous system stimulation and bronchodilation
with preservation of the cough reflex. It causes a degree of muscle
rigidity and is associated with distressing dreaming or hallucinations,
which may be ameliorated by co-administration of benzodiazepines.
Analgesics that are often used as adjuncts in ICU include paracetamol,

tramadol, gabapentinoids, ketamine, and clonidine. Non-steroidal anti-
inflammatory drugs are often avoided in many patients in the ICU
because of the potential for upper gastrointestinal ulceration and renal
injury. Consider using regional anaesthetic techniques such as epidural
and paravertebral analgesia when applicable.
Page 24 of 30

Delirium
Delirium is a syndrome of acute onset characterized by a fluctuation of

mental state, inattention, and either disorganized thinking or an altered
level of consciousness. It can be classified into three subtypes:
hyperactive (where patients appear agitated, restless, or paranoid),
hypoactive (where patients appear lethargic, inattentive, or apparently
pleasantly confused), and mixed (where patients fluctuate between the
two). While the symptoms of hyperactive delirium are the most
synonymous with a diagnosis of delirium, this subtype is the least
common form [46]. The pathophysiology of delirium remains poorly
understood, but current theories include an imbalance of
neurotransmitters with gamma-aminobutyric acid (GABA), acetylcholine,
and dopamine playing a role.
EXPERT COMMENT
Without the use of validated assessment tools such as the CAM-ICU,

hypoactive delirium is often missed by clinicians. Hypoactive delirium
causes the same degree of morbidity and mortality as hyperactive
delirium, and may even be worse [11]. Identification of risk factors
and non-pharmacological management are the mainstay of treatment.
It is unclear whether medications (e.g. antipsychotics) are beneficial
in the management of hypoactive delirium.
The incidence of delirium in ICU is as high as 83% depending on the

screening tool used and population studied [10]. Delirium was thought to
be a relatively benign sign of the severity of critical illness, but has been
found to be an independent predictor of increased ICU and hospital
length of stay, increased 6-month and 1-year mortality [11, 47], and it is
linked to longer-term neurocognitive disturbance in survivors [48]. The
duration of delirium also has an effect on 6-month and 1-year mortality
[49]. In the US in 2006, delirium was estimated to cost $6.9 billion per
year [50].
There is currently no conclusive evidence to support the use of

prophylactic antipsychotics to reduce the incidence of delirium and the
cornerstone of the prevention of delirium is the minimization of risk
factors [51, 52]. Limited evidence suggests that light sedation reduces the
rates of delirium and enables early assessment and detection of delirium.
It also enables early mobilization, which may reduce rates of delirium and
has numerous other benefits.
Page 25 of 30

Management of sedation in the ICU requires a team-based approach.

Validated assessment tools are available and are best used in
conjunction with a protocolized sedation algorithm. Prioritize
analgesia in any sedation process even if the patient is assumed to
have minimal discomfort. Active sedation management begins on
admission of the patient to the ICU so that unnecessary accumulation
of drugs and their subsequent side effects are prevented.
Delirium in the ICU is challenging to treat and is associated with

patient morbidity and mortality. It is important to attempt to prevent
delirium and to identify its presence early. Seek risk factors and
causes and treat appropriately. There is only limited evidence to
indicate that treatment of delirium with drugs is effective. This topic
requires further research.
References
1. Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation
predicts long-term mortality in ventilated critically ill patients. Am J
Respir Crit Care Med. 2012;186:724–31.
2. Watson PL, Shintani AK, Tyson R, Pandharipande PP, Pun BT, Ely EW.
Presence of electroencephalogram burst suppression in sedated, critically
ill patients is associated with increased mortality. Crit Care Med.
2008;36:3171–7.
3. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the
management of pain, agitation, and delirium in adult patients in the
4. Shehabi Y, Botha JA, Boyle MS, et al. Sedation and delirium in the
intensive care unit: an Australian and New Zealand perspective. Anaesth
Intensive Care. 2008;36:570–8.
5. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over

time in ICU patients. Reliability and validity of the Richmond Agitation-
Sedation Scale (RASS). JAMA. 2003;289:2983–11.
6. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented

sedation protocol on the duration of mechanical ventilation. Crit Care
Med. 1999;27:2609–15.
7. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of
sedative infusions in critically ill patients undergoing mechanical
ventilation. N Engl J Med. 2000;342:1471–7.
8. Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial of light
versus deep sedation on mental health after critical illness. Crit Care
Med. 2009;37:2527–34.
Page 26 of 30

9. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The
use of continuous IV sedation is associated with prolongation of
mechanical ventilation. Chest. 1998;114:541–8.
10. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically
ventilated patients: validity and reliability of the Confusion Assessment
Method for the Intensive Care Unit (CAM-ICU). JAMA. 2001;286:2703–10.
11. Ely EW, MD, Shintani A, Truman B, et al. Delirium as a predictor of

mortality in mechanically ventilated patients in the intensive care unit.
JAMA. 2004;291:1753–62.
12. Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of

sedatives, analgesics, and neuromuscular blocking agents in critically ill
patients. Crit Care Med. 2006;34:374–80.
13. Bergeron N, Dubois MJ, Dumont M, et al. Intensive Care Delirium

Screening Checklist: evaluation of a new screening tool. Intensive Care
Med. 2001;27:859–64.
14. Rubino AS, Onorati F, Caroleo S, et al. Impact of clonidine

administration on delirium and related respiratory weaning after surgical
correction of acute type-A aortic dissection: results of a pilot study.
Interact Cardiovasc Thorac Surg. 2010;10:58–62.
15. Reade MC, O’Sullivan K, Bates S, Goldsmith D, Ainslie WR, Bellomo R.

Dexmedetomidine vs haloperidol in delirious, agitated, intubated patients:
a randomised open-label trial. Crit Care. 2009;13:R75.
16. De Wit M, Gennings C, Jenvey WI, Epstein SK. Randomized trial

comparing daily interruption of sedation and nursing-implemented
sedation algorithm in medical intensive care unit patients. Critical Care.
2008;12:R70.
17. Nassar JAP, Park M. Daily sedative interruption versus intermittent

sedation in mechanically ventilated critically ill patients: a randomized
trial. Ann Intensive Care. 2014;4:1–2.
18. Devlin JW, Tanios MA, Epstein SK. Intensive care unit sedation:
waking up clinicians to the gap between research and practice. Crit Care
Med. 2006;34:556–7.
19. Brattebo G, Hofoss D, Flaatten H, Muri AK, Gjerde S, Plsek PE. Effect
of a scoring system and protocol for sedation on duration of patients’
need for ventilator support in a surgical intensive care unit. Qual Saf
Health Care. 2004;13:203–5.
20. Quenot JP, Ladoire S, Devoucoux F, et al. Effect of a nurse-

implemented sedation protocol on the incidence of ventilator-associated
pneumonia. Crit Care Med. 2007;35:2031–6.
Page 27 of 30

21. Marshall J, Finn CA, Theodore AC. Impact of a clinical pharmacist-

enforced intensive care unit sedation protocol on duration of mechanical
ventilation and hospital stay. Crit Care Med. 2008;36:427–33.
22. Bucknall TK, Manias E, Presneill JJ. A randomized trial of protocol

directed sedation management for mechanical ventilation in an Australian
23. Elliott R, McKinley S, Aitken LM, et al. The effect of an algorithm-

based sedation guideline on the duration of mechanical ventilation in an
Australian intensive care unit. Intensive Care Med. 2006;32:1506–14.
24. Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically

ill patients receiving mechanical ventilation: a randomised trial. Lancet.
2010;375:475–80.
25. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired
sedation and ventilator weaning protocol for mechanically ventilated
patients in intensive care (Awakening and Breathing Controlled trial): a
randomised controlled trial. Lancet. 2008;371:126–34.
26. Mehta S, Burry L, Cook D, et al. Daily sedation interruption in

mechanically ventilated critically ill patients cared for with a sedation
protocol: a randomized controlled trial. JAMA. 2012;308:1985–92.
27. Terao Y, Miura K, Saito M, Sekino M, Fukusaki M, Sumikawa K.

Quantitative analysis of the relationship between sedation and resting
energy expenditure in postoperative patients. Crit Care Med.
2003;31:830–3.
28. Plunkett JJ, Reeves JD, Ngo L, et al. Urine and plasma catecholamine
and cortisol concentrations after myocardial revascularization.
Modulation by continuous sedation. Anesthesiology. 1997;86:785–96.
29. Hall RI, Maclaren C, Smith MS, et al. Light versus heavy sedation
after cardiac surgery: myocardial ischemia and the stress response.
Anesth Analg. 1997;85:971–8.
30. Kress JP, Vinayak AG, Levitt J, et al. Daily sedative interruption in
mechanically ventilated patients at risk for coronary artery disease. Crit
Care Med. 2007;35:365–71.
31. Granja C, Gomes E, Amaro A, et al. Understanding posttraumatic

stress disorder-related symptoms after critical care: the early illness
amnesia hypothesis. Crit Care Med. 2008;36:2801–9.
32. Jones C, Grifﬁths RD, Humphris G, Skirrow PM. Memory, delusions,

and the development of acute posttraumatic stress disorder-related
symptoms after intensive care. Crit Care Med. 2001;29:573–80.
Page 28 of 30

33. Larson MJ, Lindell KW, Hopkins RO. Cognitive sequelae in acute
respiratory distress syndrome patients with and without recall of the
intensive care unit. J Int Neuropsychol Soc. 2007;13:595–605.
34. Jackson JC, Girard TD, Gordon SM, et al. Long-term cognitive and
psychological outcomes in the Awakening and Breathing Controlled trial.
Am J Respir Crit Care Med. 2010;182:183–91.
35. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The
long-term psychological effects of daily sedative interruption on critically
ill patients. Am J Respir Crit Care Med. 2003;168:1457–61.
36. Nasraway SA, Wu EC, Kelleher RM, Yasuda CM, Donnelly AM. How
reliable is the Bispectral Index in critically ill patients? A prospective,
comparative, single-blinded observer study. Crit Care Med.
2002;30:1483–7.
37. Cook TM, Andrade J, Bogod DG, et al. 5th National Audit Project
(NAP5) on accidental awareness during general anaesthesia: patient
experiences, human factors, sedation, consent, and medicolegal issues. Br
J Anaesth. 2014;113:560–74.
38. Loh NW, Nair P. Propofol infusion syndrome. Continuing Educ Anaesth
Crit Care Pain. 2013;13:200–2.
39. Roberts RJ, Barletta JF, Fong JJ, et al. Incidence of propofol-related
infusion syndrome in critically ill adults: a prospective, multicentre study.
Crit Care. 2009;13:R169.
40. Fong JJ, Sylvia L, Ruthazer R, Schumaker G, Kcomt M, Devlin JW.

Predictors of mortality in patients with suspected propofol infusion
syndrome. Crit Care Med. 2008;36:2281–7.
41. Panharipande PP, Pun BT, Herr DL, et al. Effect of sedation with
dexmedetomidine vs lorazepam on acute brain dysfunction in
mechanically ventilated patients: the MENDS randomized controlled trial.
JAMA. 2007;298:2644–53.
42. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs

midazolam for sedation of critically ill patients: a randomised trial. JAMA.
2009;301:489–99.
43. Jakob SM, Ruokenen E, Grounds RM, et al. Dexmedetomidine vs

midazolam or propofol for sedation during prolonged mechanical
ventilation. JAMA. 2012;307:1151–60.
44. Kawazoe Y, Miyamoto K, Morimoto T, et al. Effect of dexmedetomidine

on mortality and ventilator-free days in patients requiring mechanical
ventilation with sepsis: a randomized clinical trial. JAMA. 2017;317:1321–
8.
Page 29 of 30

45. Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versus

propofol/midazolam for long-term sedation during mechanical ventilation.
46. Peterson JF, Pun BT, Dittus RS, et al. Delirium and its motoric
subtypes: a study of 614 critically ill patients. J Am Geriatr Soc.
2006;54:479–84.
47. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH.
Days of delirium are associated with 1-year mortality in an older intensive
care unit population. Am J Respir Crit Care Med. 2009;180:1092–7.
48. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a

predictor of long-term cognitive impairment in survivors of critical illness.
Crit Care Med. 2010;38:1513–20.
49. Shehabi Y, Riker RR, Bokesch PM, et al. Delirium duration and
mortality in lightly sedated, mechanically ventilated intensive care
50. Inouye SK, Ferrucci L. Elucidating the pathophysiology of delirium

and the interrelationship of delirium and dementia. J Gerontol A Biol Sci
Med Sci. 2006;61:1277–80.
51. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on
the duration of delirium and coma in critically ill patients (Hope-ICU): a
randomised, double-blind, placebo-controlled trial. Lancet Respir Med.
2013;1:515–23.
52. Wang W, Hong-Liang L, Wang D, et al. Haloperidol prophylaxis

decreases delirium incidence in elderly patients after noncardiac surgery:
a randomized controlled trial. Crit Care Med. 2012;40:731–9.
Page 30 of 30

Acute-on-chronic liver failure

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Acute-on-chronic liver failure
Author(s): Tasneem Pirani
DOI: 10.1093/med/9780198814924.003.0011
Expert commentary by Julia Wendon
Case history
A 55-year-old female presented with a 10-day history of painless

jaundice and abdominal distension. She had continued to work as a nurse
until the week before when colleagues had commented on her
conjunctival discolouration. She denied weight loss or change in bowel
habit. She reported normal coloured but loose stools and dark urine. In
the last few days her urge to pass urine had reduced and she had not
passed urine for more than 12 hours.
She had a past medical history of hypertension and mild asthma. She had
no history of chronic liver disease. Her medications included irbesartan
150 mg once daily, bendroflumethiazide 2.5 mg once daily, verapamil 120
mg three times a day, and a salbutamol inhaler as required. She had no
allergies. She was a lifelong non-smoker but reported a 50 units/week
alcohol history for at least the last 15 years (Table 11.1) [1]. She denied
Page 1 of 39
significant family history, recent travel, and use of illicit or recreational

drugs. She denied use of new prescribed or over-the-counter medications
(including paracetamol and salicylates) and could not recall any courses
of antibiotics in the preceding 6 months. She had not consumed herbal
medication or nutritional/weight loss supplements.
LEARNING POINT Calculating units
Page 2 of 39

Table 11.1 Calculating alcohol units
Wine Beer/lager/cider Other drinks
Quantity Units Strength Units (can) Units (pint Drink Units

glass)
Small 125 mL 1.6 Regular 1.8 2.3 25 mL single 1

spirit/mixer (40%
ABV)
Standard 175 mL 2.3 Strong 2.2 3
Large 250 mL 3.3 Extra-strong 3.5 4 275 mL bottle of 1.5

alcopop (5.5%
ABV)
Bottle 10
One unit equals 10 mL or 8 g of pure alcohol. The number of units in a drink is based on the size of the drink as well as its alcohol strength. Most alcohol
will have an alcohol by volume (ABV) percentage on the container (ABV = how much of the total volume is alcohol). Therefore: units = strength (ABV) ×
volume (mL) ÷ 1000.
Source: data from NHS. (2012) Change4life: Alcohol units and guidance. Copyright © 2012 NHS. Contains public sector information licensed under the
Open Government Licence v3.0.
Page 3 of 39
and Legal Notice).
LEARNING POINT History and investigations
The initial meeting may be the best or only time to obtain details
before the patient deteriorates from hepatic encephalopathy (HE).
Social, medication (all antibiotics in the preceding 6 months, new
over-the-counter or prescription medication, nutritional supplements,
anabolic steroids, and recreational drugs), drug and alcohol history,
and psychiatric history are often overlooked. A full history is
especially important when a transplant centre considers feasibility for
transplantation.
It is prudent to investigate for all potential causes of acute liver

failure (ALF) (Table 11.2) [2] in a patient with no known prior history
of cirrhosis or chronic liver disease, albeit investigations may
subsequently suggest an acute-on-chronic process.
Table 11.2 Investigations
Haematology FBC, blood film
Biochemistry Renal (urea, creatinine, potassium, sodium,

corrected calcium, phosphate)
Liver (ALT, AST, GGT, ALP, conjugated and
unconjugated bilirubin, albumin), vitamin B12,
folate, thyroid function tests, ferritin, lipid
profile, creatine kinase, amylase, lactate
dehydrogenase, and glucose
Coagulation INR, prothrombin time (used in many scoring

systems), and fibrinogen
Arterial blood Lactate and ammonia

sample
Toxicology Paracetamol and salicylate levels and additional

screen if indicated
Viral screen HIV, EBV, CMV, HSV, HAV IgM, and IgG (if
travel to endemic area), HBsAg, anti-HB core
IgM, anti-HEV IgM, adenovirus, parvovirus B19,
and leptospirosis serology (if history relevant)
Metabolic Serum copper and caeruloplasmin (if age

screen appropriate)
Page 4 of 39

Autoimmune Immunoglobulins, liver autoantibodies (smooth

screen muscle antibody, antimitochondrial antibody,
liver/kidney microsomal antibody), antinuclear
antibody, and antineutrophil cytoplasmic
antibody
Radiology Liver ultrasound scan with focus on liver

parenchyma, vascular patency (hepatic artery,
hepatic veins and portal vein), and spleen size
as well as presence or absence of ascites (signs
of portal hypertension)
CT scan and/or MRI /MRCP to further
characterize the hepatic parenchyma and
patency of vessels (e.g. recanalization of the
umbilical vein suggesting a chronic disease
process). Also to assess for pancreatitis (often
reported in cases of paracetamol overdose) [2],
visualize the bile ducts, and rule out any
contraindications to transplantation such as
metastatic malignancy
ALP, alkaline phosphatase; ALT, alanine transaminase; AST,

aspartate transaminase; CMV, cytomegalovirus; EBV, Epstein–Barr
virus; FBC, full blood count; GGT, gamma-glutamyltransferase;
HAV, hepatitis A virus; HB, hepatitis B; HEV, hepatitis E virus; HIV,
human immunodeficiency virus; HSV, herpes simplex virus; IgM,
immunoglobulin M (recent infection); IgG, immunoglobulin G
(recent or past infection); MRCP, magnetic resonance
cholangiopancreatography; MRI, magnetic resonance imaging.
EXPERT COMMENT
It is always important to maintain an open mind about the cause of

acute liver dysfunction—considering presenting features, clinical
history, examination, and diagnostics. The basics of pre-hepatic,
hepatic and post-hepatic aetiologies should always be considered in a
systematic fashion.
EXPERT COMMENT
Elevated transaminases greater than 5000 IU/L raise the possibility of

hypoxic hepatitis or paracetamol-induced toxicity, while elevated
Page 5 of 39

alkaline phosphatase should raise the concern of infiltrative

processes. Liver biopsy is required occasionally (guided by
hepatological input) but only rarely alters treatment. An enlarged
liver may be seen in those with severe acute alcoholic hepatitis (AH)
but should again raise concern of infiltration.
On examination, she was obese (estimated body mass index of 43 kg/m2).

She was alert but weak and lethargic. Her Glasgow Coma Scale (GCS)
score was 15. She had a blood pressure of 98/60 mmHg and heart rate of
130 beats/min in sinus rhythm. Her jugular venous pulse was visible 2 cm
above the sternal notch. The electrocardiogram showed sinus tachycardia
and left ventricular hypertrophy. She was cool to the elbows with a
central capillary refill time of 4 seconds. Capillary blood glucose was 4.5
mmol/L and tympanic temperature was 37.9°C.
She was clinically jaundiced and had conjunctival pallor. She had spider
naevi over her anterior chest, upper back, and face. She had no rash but
did have bruises over her arms and feet. Her cardiorespiratory
examination was grossly normal, but she could not lie flat because of
shortness of breath. Her abdomen was grossly distended, with shifting
dullness and minimal tenderness in the right upper quadrant, but no
organomegaly. She had peripheral oedema to the knees.
The clinical impression was that of an index presentation with

decompensated cirrhosis secondary to alcohol. However, with no prior
history of cirrhosis, ALF or subacute liver failure were potential
differentials requiring exploration and exclusion.
Large-bore intravenous access was established and blood tests (Table

11.3), including blood cultures, sent. A urinary catheter was inserted and
urinalysis revealed trace blood but no evidence of infection. The urine
was sent for culture. The chest radiograph was normal.
Page 6 of 39

Table 11.3 Initial investigations
Arterial blood gas (FiO2 Full blood count Liver enzymes Coagulation Urea and electrolytes
0.21)
pH 7.30 Hb (g/dL) 10.1 ALT (IU/L) INR 2.2 (0.9–1.4) Na (mmol/L) 129
(7.35–7.45) (130–165) 135 (10–40) (135–145)
PaO2 (kPa) 12.1 MCV (fL) 109 AST (IU/L) 270 PT (sec) K (mmol/L) 3.3
(>10.5) (77–95) (10–50) 30 (30–40) (3.5–5.0)
PaCO2 (kPa) 3.2 Plt (×109/L) 61 ALP (IU/L) 203 Fibrinogen (g/L) Urea (mmol/L) 4.2
(4.5–6.3) (150–450) (30–130) 4.1 (1.5–4.5) (3.3–6.7)
HCO3 (mmol/L) 16.4 (22– WCC (×109/L) GGT (IU/L) 447 Cr (μmol/L) 168
28) 18.2 (4.0–11.0) (1–55) (45–120)
BE (mmol/L) –10.1 Neut (109/L) 16.9 Bili (μmol/L) Corr Ca (mmol/L) 2.1
(+2—2) (2.0–6.3) 651 (3–20) (2.15–2.6)
Glucose (mmol/L) Amy (IU/L) 70 Albumin (g/L) 26

4.8 (3.9–7.2) (<100) (35–50)
Lactate (mmol/L) PO4 (mmol/L) 0.61

3.2 (<2.0) (0.8–1.4)
CRP 80 (<5)
Page 7 of 39
and Legal Notice).
ALT, alanine transaminase; Amy, amylase; AST, aspartate transaminase; ALP, alkaline phosphatase; BE, base excess; Bili, bilirubin; Corr Ca, calcium corrected
for albumin; Cr, creatinine; CRP, C-reactive protein; GGT, gamma glutamyl transferase; Hb, haemoglobin; HCO3, bicarbonate; INR, international normalized
ratio; K, potassium; MCV, mean corpuscular volume; Na, sodium; Neut, neutrophils; PCO2, partial pressure of carbon dioxide; Plt, platelets; PaO2, partial
pressure of oxygen; PaO4, phosphate; PT, prothrombin time; WCC, white cell count.
Page 8 of 39
and Legal Notice).
The clinical history and initial investigations (temperature, white cell

count (WCC), C-reactive protein, lactate, sinus tachycardia, and relative
hypotension) raised the possibility of sepsis-related decompensation of
cirrhosis with jaundice, coagulopathy, and ascites. AH was also within the
differential diagnoses.
She was commenced on broad-spectrum antibiotics (piperacillin–

tazobactam 4.5 g three times daily) and intravenous fluid, initially as 250
mL boluses to assess the haemodynamic response. Following
approximately 2 L of 0.9% sodium chloride, an infusion of 100 mL/hour
was started. A diagnostic paracentesis was not performed because of the
risk of bleeding, but antibiotics were continued for presumed
spontaneous bacterial peritonitis (SBP). The renal impairment was
initially treated as prerenal in origin. A non-contrast CT confirmed the
presence of cirrhosis with portal hypertension and a large amount of
ascites. The hepatic vasculature appeared patent (Figure 11.1).
Figure 11.1
A coronal reconstruction CT image, after intravenous contrast, showing a
small liver with an irregular margin in keeping with cirrhosis, generalized
large volume ascites, and splenomegaly. The labelled lienorenal/
splenorenal shunt vessels are due to portal hypertension.
LEARNING POINT Nutritional deficiencies and

alcohol withdrawal syndrome
Prophylactic parenteral thiamine (3 days) followed by oral thiamine is

recommended for dependent drinkers if they are malnourished, at
risk of malnourishment, or have decompensated liver disease. Do not
Page 9 of 39

give intravenous dextrose before high-dose parenteral thiamine

because of the risk of precipitating Wernicke’s encephalopathy.
Alcohol withdrawal syndrome is a severe medical condition that can

affect alcohol-dependent patients who suddenly stop drinking. The
symptoms can occur as early as 6 hours after discontinuation and
patients admitted to hospital must be monitored for this.
The revised Clinical Institute Withdrawal Assessment of Alcohol

(CIWA-Ar) scale [3] is a 10-point score that enables clinical
quantitation of the severity of the alcohol withdrawal syndrome and
treatment tailored accordingly. Benzodiazepines are considered the
gold standard treatment for alcohol withdrawal syndrome.
In patients with advanced cirrhosis or acute AH, consider short-acting

benzodiazepines (e.g. lorazepam or oxazepam) instead of
chlordiazepoxide to avoid oversedation or worsening of HE.
EXPERT COMMENT
In the clinical context of altered GCS, neurology, or worsening

delirium, always consider metabolic causes, sepsis, dehydration, or
drug-related neurotoxicity—recognizing especially the increased
sensitivity of cirrhotic patients to opiates and benzodiazepines.
LEARNING POINT Clotting in liver disease
The liver plays a central role in the haemostatic system as it

synthesizes most coagulation factors and proteins involved in
fibrinolysis [4]. Clotting dysfunction in liver disease has been
extensively studied.
The haemostatic alterations that occur in acute and chronic liver

failure affect both procoagulant (elevated factor VIII, low
plasminogen, decreased protein C and S, and reduced antithrombin
levels) and anticoagulant (vitamin K deficiency, dysfibrinogenaemia,
and thrombocytopenia) pathways. This means that patients with
chronic liver failure are at risk of complications of both thrombosis
and bleeding.
Routine correction of coagulation abnormalities may not be necessary

for standard intensive care unit (ICU) procedures. Functional tests for
clotting (e.g. thromboelastography) are more useful as they measure
the dynamics of thrombin production, provide a global assessment of
coagulation, and can guide clinical management.
Page 10 of 39

EXPERT COMMENT
International normalized ratio (INR) does not reflect risk of bleeding

in ALF or acute-on-chronic liver failure (ACLF) as there are balanced
changes in procoagulants and anticoagulant levels. Low platelet
count and fibrinogen, usually in association with prolonged APTT
identify those at risk of bleeding. There is no evidence that
prophylactic use of coagulation support is beneficial.
Over the following 48 hours she received treatment for SBP, until an
ascitic tap showed no evidence of this. Her renal function continued to
deteriorate despite intravenous fluid resuscitation (urine output<500 mL/
day, creatinine 230 μmol/L, urea 21 mmol/L), so terlipressin and albumin
(20% human albumin solution, 100 mL twice daily) was started for type 1
hepatorenal syndrome (HRS).
The viral screen and microbiology yielded negative results. She developed
signs of confusion and agitation. She was treated for HE with lactulose 20
mL three times daily via nasogastric tube and supportive management.
Within 72 hours of admission, her GCS score decreased acutely to 3/15.

She was intubated for airway protection and transferred to the ICU via a
computed tomography (CT) scan to rule out an acute intracranial bleed or
ischaemic event. The CT head was normal.
EXPERT COMMENT
Moderate decreases in GCS score can result in microaspiration and

increase the risk of chest sepsis.
LEARNING POINT Fluids in cirrhosis
Hyponatraemia is common in cirrhosis as portal hypertension causes

the release of potent arteriolar vasodilators, such as nitric oxide,
which affect the splanchnic circulation predominantly [5, 6]. This
causes a drop in the central effective circulating volume which causes
relative hypotension and activation of the renin–angiotensin–
aldosterone, antidiuretic hormone, and sympathetic nervous systems
[7]. The net outcome of this is increased renal salt and water
reabsorption (total body salt and water overload), and accumulation
of extracellular fluid. The hyponatraemia is therefore a dilutional
hyponatraemia and total body sodium is not reduced.
Page 11 of 39

Normal saline and sodium-containing crystalloids have traditionally

been avoided in patients with cirrhosis because of concerns about
simply expanding the extravascular volume and reducing renal
perfusion without a net positive effect on effective circulating volume.
In haemodynamically unstable patients, certainly in severely ill
patients (Child–Turcotte–Pugh class B and C cirrhosis), volume
expansion reduces plasma levels of renin, suggesting some degree of
effective circulating volume expansion [8]. However, it is important to
recognize hyponatraemia and avoid crystalloids such as 5% dextrose
that worsen hyponatraemia and risk precipitation of HE.
EXPERT COMMENT
Always assess the circulating volume in patients with cirrhosis.

Oedema and ascites are not reflective of central blood volume, some
patients will be under-filled and respond to fluid therapy while others
will show central volume overload with pulmonary venous
hypertension. Giving fluids to the latter subgroup will potentially
worsen renal function through increasing renal venous pressure and
decreasing perfusion pressure.
Albumin for resuscitation and replacement of intravascular volume

deficit has been debated extensively over the years. In liver disease,
albumin has an established role in three situations:
1. Prevention of (large volume) paracentesis-induced circulatory

dysfunction.
2. Prevention of renal failure during SBP.
3. Treatment of HRS, in addition to vasoconstrictors.
There have been two recent randomized controlled trials that showed
no survival benefit in using albumin in cirrhotic patients with sepsis
other than SBP [9]. The smaller study (100 patients) did show
improved circulatory function and less kidney injury [10].
LEARNING POINT The kidneys in cirrhosis
Up to 20% of hospitalized patients with decompensated cirrhosis have

renal complications [11]. The most common causes are prerenal,
acute tubular necrosis, and HRS, but other causes such as
glomerulonephritis, diuretic or non-steroidal anti-inflammatory drug
toxicity, and abdominal compartment syndrome from tense ascites
also occur [11]. Many patients with cirrhosis have underlying
parenchymal renal disease.
Page 12 of 39

Despite the common misconception, renal dysfunction in the context

of cirrhosis is not automatically a diagnosis of HRS: rather, HRS is a
diagnosis of exclusion with a defined set of diagnostic criteria. It can
only be diagnosed when all other causes of renal failure have been
ruled out [12, 13].
Type 1 HRS is a rapidly progressive (i.e. <2 weeks) acute renal

impairment that frequently develops following a precipitating factor
that causes deterioration of liver function and other organ
dysfunction.
Type 2 HRS occurs in patients with refractory ascites and there is a

moderate but steady degree of renal impairment which is now
categorized as chronic kidney injury.
The diagnosis of type 1 HRS, previously required fulfilment of

stringent creatinine-based criteria, often delaying treatment with
vasopressor therapy. Patients with renal dysfunction and cirrhosis
who do not fulfil the diagnostic criteria of type 1 HRS have similarly
poor outcomes as those with HRS [14], so a consensus definition of
what constitutes acute kidney injury (AKI) in cirrhosis is necessary.
Serum creatinine level is a poor biomarker of renal dysfunction in

patients with cirrhosis, especially in those with ascites and muscle
wasting [15], and patients may have AKI despite normal creatinine.
The prognostic importance of small changes in serum creatinine in

cirrhosis [16] led to the International Club of Ascites defining AKI in
patients with cirrhosis as an increase in serum creatinine of at least
26.5 µmol/L within 48 hours or at least a 50% rise from a known or
presumed baseline within the preceding 7 days [17].
EXPERT COMMENT
Always consider AKI when there is a rise in creatinine. A

protein:creatinine ratio that is only moderately elevated predicts
progression and is potentially a marker for earlier interventions.
Earlier treatment with vasoactive agents, prior to profound oliguria
and marked elevation in creatinine, is more likely to preserve renal
function.
LEARNING POINT Acute on chronic liver failure

(ACLF)
Page 13 of 39

ACLF occurs in patients with pre-existing chronic liver disease (CLD)

or cirrhosis (compensated or decompensated) who develop hepatic
and extrahepatic organ failure. There are numerous identifiable
precipitants for ACLF but in up to 40% of cases no precipitant is
identified [18, 19]. Infection is the commonest precipitant, with
viruses, drugs, ischaemia, alcohol, surgery, and sepsis all common.
When no obvious cause is identified, treatment for sepsis is
appropriate.
Recognition of ACLF as a clinically and pathophysiologically distinct

syndrome from acute decompensation (AD) of compensated CLD is
important in order to initiate prompt management and reduce the
associated high 28-day mortality (Tables 11.4 and 11.5).
Table 11.4 ACLF grade as proposed by the CANONIC study
ACLF grade 1 ACLF ACLF

grade 2 grade 3
Three subgroups: 2 organ ≥3 organ

1. Kidney failure solely failures as failures as
2. Single non-renal organ defined by defined by
failure (liver, coagulation, CLIF-SOFA CLIF-SOFA
circulation, or respiration) score score
and a serum creatinine 132–
176 μmol/L (1.5–1.9 mg/dL)
and/or mild to moderate
hepatic encephalopathy
3. Single cerebral failure and
a serum creatinine 132–176
μmol/L (1.5–1.9 mg/dL)
Note: renal failure = creatinine ≥177 μmol/L (≥2mg/dL).
Source: data from Moreau, R., et al. CANONIC Study Investigators

of the EASL–CLIF Consortium: Acute-on-chronic liver failure is a
distinct syndrome that develops in patients with acute
decompensation of cirrhosis. Gastroenterology. 44(7), 1426–37.
Copyright © 2013 Elsevier Inc. All rights reserved.
Table 11.5 Mortality according to ACLF grade
ACLF grade 28-day mortality 90-day mortality

(%) (%)
Grade 0 (no organ 4.7 11

failure)
Page 14 of 39

Grade 1 22.1 40.7
Grade 2 32 52.3
Grade 3 76.7 79.1
EVIDENCE BASE CLIF Acute-on-Chronic Liver Failure

in Cirrhosis (CANONIC) study
The landmark CANONIC study [20] showed a clear difference in

mortality between simple AD (manifesting as ascites, encephalopathy,
gastrointestinal haemorrhage, and SBP) and ACLF (with additional
organ failure). The Chronic Liver Failure–Sequential Organ Failure
Assessment (CLIF-SOFA) score and definition of ACLF have been
validated in various studies internationally and are thought to be
good independent predictors of short-term mortality in patients with
ACLF [21, 22, 23]; the CLIF-SOFA may be useful in assessing
response to ICU treatment [24].
On arrival in ICU, she was anuric, with a GCS of 4T (E1, VT, M3). She
swiftly developed circulatory shock with a lactate level of 6.4 mmol/L and
this was treated with noradrenaline 0.5 mcg/kg/min and terlipressin 0.2
mg/hour. She was noted to have an ammonia level of 180 μmol/L, and
continuous venovenous haemofiltration was started at 35 mL/kg/hour
exchange. A septic screen was repeated and antibiotics were escalated by
addition of amikacin (an aminoglycoside thought to be less nephrotoxic
than gentamicin). However, there was no clear source of sepsis to explain
the systemic inflammatory response and a diagnosis of AH was thought to
be the overall underlying precipitant of ACLF.
The Maddrey score [25] was 77.3 and as a result steroid therapy was
started (hydrocortisone 50 mg 6-hourly), with a planned review in 7 days
in combination with results of the Lille score [26]. At this stage, she had
established liver, coagulation, cardiovascular, renal, and neurological
failure.
EXPERT COMMENT
Kidneys contribute to 20% of ammonia clearance and thus AKI will

decrease ammonia clearance and increase the risk of HE.
Page 15 of 39

Her Child–Turcotte–Pugh score was C [12] with a Model for End-stage

Liver Disease (MELD) score of 35, suggesting a 52.6% 3-month mortality
without transplantation.
LEARNING POINT Definition and diagnosis of

alcoholic hepatitis
AH is a distinct clinical syndrome caused by chronic alcohol abuse

and has a poor prognosis: 28-day mortality ranges from 30% to 50%
[25]. Although AH is an acute condition, approximately 50% of
patients with AH have established cirrhosis [27].
Patients have a history of alcohol excess leading up to presentation,

but a period of abstinence (up to 4 weeks) before presentation is not
uncommon, possibly due to development of symptoms. Abstinence for
longer than 3 months should raise the suspicion of cirrhosis and/or
decompensation.
The diagnosis is based on history and a high index of suspicion.

Patients typically present with non-specific symptoms such anorexia,
nausea, vomiting, and malaise. They are jaundiced and can have
features of ACLF and a systemic inflammatory response with
tachycardia and fever. Superimposed bacterial and fungal infections
are common in AH and often contribute to multiorgan failure [28].
LEARNING POINT Prognostic scores used in cirrhosis

and ACLF
Scores such as the King’s College criteria [29] and others are
specifically used to prognosticate in ALF and determine which
patients might be considered for emergency transplantation.
However, these scoring systems do not apply to patients with
cirrhosis and ACLF.
Of note, none of the scores are reliable indicators of futility and their
use early in the clinical course to determine admission to the ICU is
not appropriate. Patients with cirrhosis and organ dysfunction or
failure often warrant a trial of critical care [23].
Child–Turcotte–Pugh score
The Child–Turcotte–Pugh score was developed in 1964 to predict the
outcome after portocaval shunting surgery in patients with cirrhosis
[30] and later modified to include prothrombin time which replaced
‘nutritional status’ [19] (Table 11.6).
Page 16 of 39

Table 11.6 Variables included in the Child–Turcotte–Pugh score

and associated 1- and 2-year mortality
Measure 1 point 2 points 3 points
Albumin g/L (g/dl) >35 28–35 (2.8– <28

(3.5) 3.5) (<2.8)
Bilirubin μmol/L (mg/ 34 (<2) 34–51 (2–3) >51 (>3)

dl)
Ascites None Controlled Refractory
Hepatic None 1–2 3–4

encephalopathy
Prothrombin time <4 4–6 >6

prolongation (sec)
International <1.7 1.7–2.3 >2.3

normalized ratio
Score Class 1-year survival (%) 2-year survival (%)
5–6 A 100 85
7–9 B 81 57
10–15 C 45 35
A weakness of the Child–Turcotte–Pugh score is the inclusion of

variables based on subjective clinical assessment.
Model for End-stage Liver Disease score
Bilirubin 17.1 µmol/L = 1 mg/dL; creatinine 88.4 µmol/L = 1 mg/dL.
MELD score-associated mortality at 3 months:
● 30–39: 52.6% mortality

● 20–29: 19.6% mortality.
● 10–19: 6.0% mortality.
Page 17 of 39

The minimum score is 6 and maximum 40. Bias against people on

long-term renal replacement therapy (RRT) is taken away by a
maximum creatinine (354 µmol/L).
The MELD score [31] has been used in numerous clinical settings
including assisting decisions on referral, listing, and prioritizing for
transplantation [32] and to guide management of AH [33].
In patients with cirrhosis, an increasing MELD score indicates

worsening hepatic dysfunction and increased 3-month mortality risk.
The MELD score may be modified by inclusion of serum sodium

(UKELD, MELD-NA scores) to reflect the impact of hyponatraemia on
mortality and neurological dysfunction [34, 35].
CLIF SOFA/CLIF-C OF, CLIF-C ACLF, and CLIF-AD

scores
The CLIF-SOFA score was devised to diagnose ACLF in the CANONIC
study [20] and is a simple validated organ function scoring system
that predicts 28-day and 90-day mortality. The CLIF SOFA score
replaces platelets with INR and GCS score with grade of HE in the
original SOFA score [36] (Table 11.7).
Table 11.7 Components of the original SOFA score compared with

the CLIF-SOFA score
SOFA score (scored 0–4) CLIF-SOFA score (scored 0–4)
● PaO2/FiO2 ● PaO2/FiO2
● GCS ● HE grade
● MAP or use of ● MAP or use of vasopressors/
vasopressors/inotropes inotropes/terlipressin
● Bilirubin ● Bilirubin
● Platelets ● INR (platelets <20 = score
● Creatinine or urine 4)
output/24 hours ● Creatinine or use of RRT
Minimum score 0 and Minimum score 0 and
maximum 24 maximum 24
FiO2, fraction of inspired oxygen; HE, hepatic encephalopathy;

INR, international normalized ratio; MAP, mean arterial pressure;
PaO2, partial pressure of oxygen; RRT, renal replacement therapy.
Age and WCC were identified as independent prognostic markers by

the study and have been included in an updated scoring system, the
CLIF-C ACLF score. This score predicts 28-day mortality significantly
better at 48 hours, 3–7 days, and 8–15 days after ACLF diagnosis than
Page 18 of 39

at diagnosis [37] and is therefore useful in tracking patients’

progress.
Numerous trials have evaluated prognostic scores for cirrhotic

patients admitted to ICU. The SOFA score [36] predicts ICU mortality
better than liver-specific scores such as Child–Turcotte–Pugh and
MELD scores [38, 39]. For cirrhotic patients with AD, but without
ACLF, the CLIF Consortium Acute Decompensation score (CLIF-C
ADs) is more accurate than other liver scores in predicting prognosis
[40].
The Liver Injury Failure Evaluation score

Recently, the Liver Injury Failure Evaluation (LiFe) score [41] was
developed from a large international retrospective cohort study of
1916 patients with CLD admitted to the ICU. The score is easily
calculated from arterial lactate, total bilirubin, and INR. It predicts
short-term mortality in ACLF almost as well as SOFA and CLIF SOFA
scores.
Scores specific to alcoholic hepatitis

Maddrey discriminant function
This is used to estimate disease severity and mortality in acute AH
[25]:
A score of 32 or greater has a predicted 1-month mortality rate of 25–

45% compared with less than 10% at up to 3 months for milder AH.
Glasgow Alcoholic Hepatitis Score

See Table 11.8 [42].
Table 11.8 Variables for calculating the Glasgow Alcoholic

Hepatitis Score (GAHS). A score of 9 or greater is associated with
a higher mortality
Variable Score
1 2 3
Age <50 ≥50 –
White cell count (109/L) <15 ≥15 –
Urea (mmol/L) <5 ≥5 –
Page 19 of 39

INR <1.5 1.5–2.0 >2.0
Bilirubin (μmol/L) <125 125–250 >250
INR, international normalized ratio.
The results of this score are categorized into <9 or ≥9.

Corticosteroids improve survival in patients with a Maddrey score
≥32 and a GAHS ≥9, (59% vs 38% at 84 days), but there is no
survival benefit with a GAHS <9 [43].
Lille model
Lille score = 3.19 − 0.101 × (age in years) + 0.147 × (albumin day 0 in
g/L) + 0.0165 × (day 7 bilirubin level in μmol/L) − (0.206 × creatinine
day 0 in μmol/L) − 0.0065 × (bilirubin day 0 in μmol/L) − 0.0096 ×
(INR or prothrombin time in seconds)
The Lille score [26] is used to determine response to steroids in AH at

7 days of treatment: a score greater than 0.45 indicates non-
response. Mortality at 6 months is notably higher with a score greater
than 0.45 (75% vs 15%).
CLINICAL TIP Prognostic scoring in liver failure
All the liver scores can be calculated on calculators found on various

websites and smartphone applications.
The patient’s clinical condition remained precarious for the first week on
the ICU. Despite standard medical treatment for HE (treatment of
precipitating cause, ensuring bowels were opening regularly, and
avoidance of sedation after initial stabilization), she remained grade 4
encephalopathic. Three days after the initiation of parenteral L-ornithinine
L-aspartate (LOLA), her neurological condition improved, although she
remained myopathic. Optimal feeding was established early into her ICU
admission ensuring adequate calorie and protein provision to avoid
muscle loss.
On day 7, her Lille score was 0.38, confirming steroid response, and
prednisolone 40 mg once daily was continued for 28 days. By day 10, her
GCS was consistently 15/15, she had weaned off vasopressor support,
was undergoing ventilation wean, but still required continuous renal
replacement therapy (CRRT).
Page 20 of 39

On day 16 she developed persistent pyrexia of at least 38°C, tachycardia,

and hypotension (mean arterial pressure 50 mmHg) and soon her GCS
dropped to 6, requiring reintubation. A diagnostic paracentesis confirmed
SBP (WCC 1570 cells/microL, 90% neutrophils). Fluid resuscitation,
antibiotics, and vasopressor support were recommenced. In view of the
use of steroids and the high risk of fungal sepsis, antifungal cover using
the echinocandin, anidulafungin, was commenced. Serum beta-D-glucan
was requested while awaiting culture results.
LEARNING POINT Hepatic encephalopathy
HE is a brain dysfunction caused by liver insufficiency and/or

portosystemic shunting, causing a wide spectrum of neurological or
psychiatric abnormalities ranging from subclinical alterations to coma
[44]. Psychomotor abnormalities in overt HE can be detected by
bedside clinical tests.
Diagnosis and management of HE is a challenge. Classification is

based on four aspects: type of hepatic abnormality, time course,
presence or absence of precipitating factors, and characteristics of
neurological manifestation (Table 11.9). The presence or absence of
ACLF has been proposed as a fifth domain [45].
Page 21 of 39

Table 11.9 Classification of hepatic encephalopathy [48]
HE type Description Subcategory Subdivisions Clinical manifestation
A HE associated with Acute – – –

liver failure
B HE associated with Episodic Precipitated GCS or according to West

portosystemic Bypass or Spontaneousa Haven criteria
shunts and no evidence of Recurrentb
intrinsic liver disease
C HE associated with Persistent Mild GCS or according to West

Cirrhosis and portal Severe Haven criteria
hypertension/or Treatment dependent
portosystemic shunts
Minimal (MHE)c – Not detected clinically,

needing complex
neuropsychiatric and
psychometric testing
a
No obvious precipitating factor;
b
repeated episodes with a time interval of 6 months or less;
c
abnormal results of established psychometric or neuropsychological tests without clinical manifestations.
Page 22 of 39
and Legal Notice).
Source: data from Ferenci, P., et al. Hepatic encephalopathy - Definition, nomenclature, diagnosis, and quantification: Final report of the Working Party
at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 35(3), 716–21. Copyright © 2002 American Association for the Study of
Liver Diseases.
Page 23 of 39
and Legal Notice).
In patients with cirrhosis, HE is an event that defines

decompensation, similar to variceal bleed and ascites. Patients with
cirrhosis or CLD admitted to the ICU must be screened for alterations
in mental state at repeated intervals. HE must be distinguished from
other causes of altered mental state and neurology. Common
differentials are included in Table 11.10. Hyponatraemia and
hyperammonaemia affect neurological function synergistically and
hyponatraemia with HE has a poor prognosis [46]. HE affects 30–45%
of patients with cirrhosis and its occurrence is associated with
increased mortality: median survival with decompensated cirrhosis
and HE is approximately 2 years, compared with at least 12 years in
patients with compensated cirrhosis without HE [47].
Page 24 of 39

Table 11.10 Common differentials to be considered when faced with the non-specific symptoms of hepatic encephalopathy
Drugs and Metabolic Infection Endocrine Vascular Inflammatory Others

toxins
Alcohol Diabetic Encephalitis Hyponatraemia Intracranial Autoimmune Dementia

withdrawal or ketoacidosis haemorrhage encephalitis
intoxication
Benzodiazepines Hypoglycaemia Septic Hypercalcaemia Hypoxic Sarcoidosis Status epilepticus

encephalopathy encephalopathy
Opioids Hyperosmolar Cerebral abscess Hypothyroidism Ischaemic stroke Systemic lupus Inherited urea
hyperglycaemic erythematosus cycle disorders
state causing raised
ammonia
Wernicke’s Uraemia Space-occupying

encephalopathy lesions
Recreational drug Hypercarbia

use (sleep apnoea)
Page 25 of 39
and Legal Notice).
LEARNING POINT How to diagnose hepatic

encephalopathy
A thorough history, examination, and a high clinical suspicion on the

basis of known CLD is key to making the diagnosis. There is no
specific test for HE, and exclusion of other conditions may require CT
scanning, magnetic resonance imaging, lumbar puncture,
electroencephalography, and blood biochemistry. Seek and treat any
precipitants of HE. A response to treatment can be used to confirm
the diagnosis.
Ammonia has been postulated in the pathophysiology of HE and

circulating values can be elevated in patients with CLD, ACLF, and
ALF, as well as AD cirrhosis. Measuring ammonia concentrations
remains controversial but a normal ammonia value in a patient with
overt HE should encourage a diagnostic re-evaluation. Conversely, an
elevated ammonia alone should not be used to make the diagnosis of
HE, but it is contributory. It does not provide staging or prognostic
information for HE in patients with CLD [49]. In ALF, by contrast,
ammonia is an independent risk factor for development of high-grade
HE and intracranial hypertension secondary to cerebral oedema [50],
and treatment to lower ammonia, such as RRT, is established practice.
Despite cerebral oedema being a more common occurrence in ALF
(approximately 25% [51]), sudden increases in ammonia may be
observed alongside an inflammatory response in ACLF patients
resulting in neurological disturbances [52, 53]; a common scenario
being that of insertion of a new transjugular intrahepatic
portosystemic shunt, sepsis, and concurrent hyponatraemia.
Epileptiform activity should always be sought and treated.
There is a significant risk of intracranial haemorrhage in patients

with ACLF and high-grade HE and this diagnosis is considered in
ACLF patients with new focal neurology, or poor neurological
recovery in ICU upon sedation withdrawal [54].
Potential precipitants for HE include:
● infections (commonest precipitant)—chest, urinary tract, SBP,

and unidentified
● gastrointestinal bleed—variceal or non-variceal
● hypovolaemia
● transjugular intrahepatic portosystemic shunt procedure
● constipation
● electrolyte abnormalities—new diuretic
Page 26 of 39

● alcohol binge
● sedatives or antidepressants/antipsychotics
● hepatocellular carcinoma
● acute portal vein thrombus
● recent surgery causing acute decompensation
● non-compliance with medication
● unknown.
LEARNING POINT Management of hepatic

encephalopathy in ACLF
Management depends on the classification and severity of HE.

Management of HE in ALF is very distinct and will not be covered in
this chapter.
In HE, the aim is to induce remission and maintain remission. The

first step is to provide supportive care in a safe environment. This
may include one-to-one nursing with frequent monitoring of mental
status. Appropriate (often nasogastric) enteral feed avoids protracted
energy restriction, especially when neurology prevents normal
feeding. ICU admission for intubation and ventilation is often
required when the GCS falls and airway safety is compromised.
Specific management is focused on managing the precipitant to

prevent progression of HE, and to reduce the duration of high-grade
HE. This may include stopping implicated medication, treating sepsis,
correcting electrolytes and dehydration, and in the case of a recently
inserted portosystemic shunt for ascites or variceal haemorrhage,
consideration of downsizing the shunt. Often, no specific cause is
identified and patients receive empirical antibiotics, intravenous
hydration, and vitamin replacement in addition to supportive care.
Therapies specifically targeting HE are then initiated.
EXPERT COMMENT
None of the therapies for HE have been examined in the context of

critical illness. One study has demonstrated that in high-grade
encephalopathy, enteral nutrition was not harmful; while treatment
with albumin did not alter resolution of encephalopathy. For other
Page 27 of 39

treatments, the evidence must be extrapolated from evidence gained

in other settings.
LEARNING POINT Therapies targeting hepatic

encephalopathy
Non-absorbable disaccharides
Lactulose (beta galactosidofructose) and lactitol (beta
galactosidosorbitol) are metabolized to lactic and acetic acid in the
colon, thereby reducing the pH which results in the conversion of
ammonia to ammonium and passage of ammonia from tissues to the
colonic lumen. Colonic flora shifts from urease- to non-urease-
producing bacterial species. Their cathartic effects reduce colonic
bacterial load and may also reduce ammonia. A meta-analysis did not
support its routine use in clinical practice [55], but newer studies
suggest improved neuropsychometric and quality of life scores [56].
Current guidelines still favour the use of lactulose. The initial dose
recommendation is 25 mL orally or via nasogastric tube 4-hourly, until
soft stools, followed by further titration in order to achieve three soft
stools/day. Over-dosage can lead to severe ileus, diarrhoea and
dehydration, electrolyte imbalances such as hypernatraemia, and
even precipitation of HE [57]. Lactulose can be administered as an
enema (300 mL lactulose with 700 mL water, as a retention enema
every 4 hours as needed) if the enteral route is unavailable.
Enemas do not confer additional benefit if oral/enteral purgatives are

maintaining more than three soft motions/day.
Antibiotics
Rifaximin is used in addition to lactulose to prevent HE. It is a
semisynthetic antibiotic derived from rifamycin that has gained
popularity due to its tolerability and safe side effect profile. The
National Institute for Health and Care Excellence has recommended
rifaximin on the evidence of a large, well-conducted randomized
controlled trial [58] which showed fewer and shorter hospitalizations
related to HE in patients taking rifaximin. Plasma values of rifaximin
are negligible and the risk of bacterial resistance appears to be lower
with rifaximin than with systemic antibiotics. Rifaximin is
recommended as secondary prophylaxis for persistent HE in patients
who have had episodes of overt HE while on lactulose alone.
In patients on ICU receiving high doses of broad-spectrum antibiotics,

there is no evidence for adding rifaximin.
Page 28 of 39

L-Ornithine L-aspartate
LOLA is a compound salt of the amino acids ornithine and aspartate.

These amino acids activate the urea cycle enzymes that convert
ammonia into urea. LOLA also stimulates glutamate transaminase,
increasing glutamate levels. Ammonia is used in the conversion to
glutamate to glutamine in skeletal muscle by glutamine synthetase.
The net effect is reduction of ammonia.
LOLA (oral or intravenous) has improved ammonia values, and

various HE parameters in settings outside critical care and in low
grades of HE [59]. Some benefit has also been reported in higher
grades of HE, such as those seen in ACLF, and LOLA was safe and
associated with shorter hospital stay [60]. In the setting of ACLF,
LOLA may be considered as an adjunctive therapy if the patient does
not respond to conventional therapy. The usual dose is one 20 g
infusion/day for 7 days. Oral LOLA (6 g three times daily) can also be
used in grade 1–2 HE that persists despite resolution of the
precipitant.
CRRT with haemofiltration

In patients with ACLF, CRRT is often required for treatment of
concomitant AKI. Approximately 20% of ammonia load is excreted
renally, so AKI may increase ammonia values in liver disease [61] and
haemofiltration may improve ammonia clearance [62]. There is a
linear relationship between increasing ultrafiltration rates and
ammonia clearance, and a close correlation between ammonia and
urea clearance. Urea clearance can therefore be used as a surrogate
marker for ammonia clearance.
The use of ultra-high-volume CRRT (40–60 mL/kg/hour) has been

explored in several settings, but is generally of little benefit over
conventional CRRT (30–35 mL/kg/hour).
CLINICAL TIP Anticoagulation for renal replacement

therapy
Anticoagulation of RRT circuits may be achieved with prostacyclin,

heparin, or citrate. ACLF patients appear to tolerate citrate well
although those with profound elevation of aspartate transaminase,
INR, or lactate should be closely monitored to ensure appropriate
citrate metabolism. There was no difference in rates of severe
disturbance in pH or calcium in patients with normal, mild, or severe
liver failure in a recent multicentre prospective observational study
[63].
Page 29 of 39

LEARNING POINT Nutrition
Traditional low-protein diets to reduce intestinal ammonia production

are not needed. A normal protein diet is safe, and avoids protein
malnutrition that contributes to muscle wastage [64, 65]. Daily
targets of 35–45 kcal/g and 1.2–1.5 g/kg of protein are appropriate.
Early specialist dietetic input is vital in AD cirrhosis or ACLF to avoid

deterioration in nutritional status, which will negatively impact
recovery.
LEARNING POINT Percutaneous embolization of

large portosystemic shunts
Patients with medically refractory HE and relatively preserved liver

function should be investigated for the presence of large
portosystemic shunts (e.g. splenorenal shunts); if detected, consider
embolization by radiologists experienced in this procedure.
LEARNING POINT Molecular adsorbent recirculating

system
The molecular adsorbent recirculating system (MARS) is an

extracorporeal liver support system based on albumin dialysis. Blood
is dialysed across an albumin-impregnated membrane using 20%
albumin as dialysate. Charcoal and anion exchange resin columns in
the circuit cleanse and regenerate the albumin dialysate. MARS does
not replace the synthetic function of the liver. It does, however,
remove albumin-bound toxins such as bilirubin, bile acids, nitric
oxide, and endogenous benzodiazepines, as well as exogenous drugs
and toxins and water-soluble ammonia. These effects can improve HE,
systemic haemodynamics, and renal function. As such, it is a
promising treatment for management of liver failure in patients who
simply require additional time for recovery or potentially as a bridge
to liver transplantation.
In the ICU setting, MARS has been used for various clinical situations
(Table 11.11) [66].
Table 11.11 The main indications for MARS
Acute liver failure
Page 30 of 39

Acute-on-chronic liver failure ● Jaundice

complicated by:
● Hepatic encephalopathy
● Renal dysfunction
Acute intoxication or overdose ● E.g. benzodiazepines,

with albumin-bound and other carbamazepine, phenytoin,
protein-bound substances and valproate
Intractable pruritus in cholestatic

liver conditions
Acute liver failure after major

hepatectomy
Post transplant ● Primary non-function
● Secondary liver failure or

multiorgan failure
● Disease recurrence in
graft
Source: data from Saliba, F. The Molecular Adsorbent

Recirculating System (MARS®) in the intensive care unit: a rescue
therapy for patients with hepatic failure. Critical Care. 10(1), 118.
Copyright © 2006 BioMed Central Ltd.
A large trial comparing MARS with standard medical therapy in ACLF

showed MARS to be safe but it did not improve 90-day liver
transplant-free survival [67]. It continues to be used throughout the
world for various indications.
Overall, MARS and other artificial liver systems do not improve

mortality in ALF or ACLF but may improve HE and other biochemical
indices. American and European guidelines do not recommend MARS
for the treatment of resistant HE [44]. However, carefully chosen
patients may benefit from extracorporeal liver support either as a
bridge to transplantation or instead of transplantation.
Despite advances in the understanding of ALF and ACLF, no specific

medical treatments have been developed and liver transplantation
remains the only definitive treatment.
Page 31 of 39

The prospect of liver transplantation was raised by the patient’s next of

kin due to persistent deterioration. The current evidence for this was
provided to them.
LEARNING POINT Steroids in alcoholic hepatitis
Severe AH carries a 1-month mortality of greater than 30% in some

studies. The recent Steroids or Pentoxifylline for Alcoholic Hepatitis
(STOPAH) trial did not show a statistically significant reduction in 28-
day, 90-day, or 1-year mortality with the use of corticosteroids
compared with placebo [68]. Conversely, meta-analysis has shown a
mortality benefit with steroids, particularly in Lille responders [69].
Factors associated with increased mortality include HE, renal
impairment, infectious complications, and coagulopathy [69].
Over the following 8 days she received full supportive treatment for
multiorgan failure and eventually began making a recovery. She was
eventually discharged to the ward after a protracted 50-day ICU
admission.
EXPERT COMMENT
The characterisations and selection of patients in the STOPAH trial

has been criticized, for possibly not representing patients with severe
AH, and further research continues. In the meantime, corticosteroids
continue to be used in severe acute AH. The Lille score is used to
inform the decision to continue at 7 days.
LEARNING POINT Transplant listing and allocation in

ACLF
In acute AH patients who do not respond to or deteriorate despite

medical therapy, liver transplantation before 6 months of abstinence
has improved survival, but remains controversial. Concerns over
patient selection criteria and recidivism prevent this from being
routine practice outside of trials.
Liver transplantation is an established treatment for CLD for defined

indications that carry significant morbidity and mortality and may be
considered when the patient’s length of life or quality of life is in
question. The scarcity of organs, the high-risk surgery, the burden of
post-transplant morbidity, and the need for long term
Page 32 of 39

immunosuppression necessitate rigorous transplant assessment, to

ensure selected patients are most likely to benefit from
transplantation and have an optimal outcome.
In ACLF, the role of transplantation is uncertain and despite its high

short-term mortality in most countries, there is no priority listing for
ACLF. A single-centre study from Europe showed excellent outcomes
in ACLF patients who received liver transplantation with 1- and 5-
year survival rates of 87% and 82% respectively: comparable to non-
ACLF patients [70]. The waiting list mortality was 54%, suggesting
that timing of transplantation is essential, and that the window of
opportunity may be narrow.
Discussion
ACLF is a distinct clinical entity that carries a high mortality. Early

recognition of the condition and intensive management in order to
prevent progression to multiorgan failure may improve the short-term
prognosis.
LEARNING POINT Alternatives to transplantation
Plasma exchange and high-volume plasmapheresis
Plasma exchange is a form of extracorporeal support that simulates

some functions of the liver by removing toxic metabolites and
mediators of multiorgan failure (proinflammatory cytokines) while
replenishing potentially beneficial factors.
To date there are no large studies evaluating plasma exchange using

the current definition of ACLF and it is therefore not undertaken
routinely.
Despite full supportive care, and a marked improvement in the

understanding of the pathophysiology of ACLF, limitations of treatment
modalities persist. The mainstay of management is currently supportive,
and, in a small minority of carefully selected cases, transplantation.
AH is a cause of ACLF and carries a high short-term mortality. Use of

steroids in patients with more severe disease (Maddrey score ≥32, GAHS
≥9) has been reported to improve short-term mortality; however, ongoing
studies aim to clarify its role in long- and short-term mortality and
morbidity.
Page 33 of 39

The use of extracorporeal liver support and high-volume plasmapheresis

for ACLF varies within and between different countries. Its role as a
bridge to recovery remains unclear [71].
Transplantation has been performed on patients with ACLF with

encouraging results; given the narrow window of opportunity for success,
further understanding of the pathophysiology may make ACLF an
indication for emergency transplantation.
AH can be a cause of ACLF. Timely diagnosis, recognition of the

syndrome, and early intervention is the key to successful outcomes.
Scoring systems have been developed but should not be used to
determine who would benefit from ICU treatment, but more to
monitor progress while in critical care. Liver transplantation remains
the definitive treatment of decompensated cirrhosis; however, timing
for transplantation, patient selection, and ultimately the scarcity of
organs means that further research into pathophysiology of ACLF and
other supportive treatments is required.
References
1. National Health Service. (2012) Change4life: Alcohol Units and
Guidance [Internet]. Available from: http://www.nhs.uk/Change4Life/
Pages/alcohol-lower-risk-guidelines-units.aspx.
2. Sy-Jou C, Chin-Sheng L, Chin-Wang H, Cheng-Li L, Chia-Hung K.

Acetaminophen poisoning and risk of acute pancreatitis: a population-
based cohort study. Medicine (Baltimore). 2015;94:e1195.
3. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM.

Assessment of alcohol withdrawal: the revised Clinical Institute
Withdrawal Assessment for Alcohol Scale (CIWA-Ar). Br J Addict.
1989;84:1353–7.
4. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver

disease: evidence and clinical consequences. Blood. 2010;116:878–85.
5. Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation

hypothesis: a proposal for the initiation of renal sodium and water
retention in cirrhosis. Hepatology. 1988;8:1151–7.
6. Henriksen JH, Bendtsen F, Sorensen TI, et al. Reduced central blood

volume in cirrhosis. Gastroenterology. 1989;97:1506–13.
7. Schrier RW. Body fluid volume regulation in health and disease: a

unifying hypothesis. Ann Intern Med. 1990;113:155–9.
Page 34 of 39

8. Brinch K, Moller S, Bendtsen F, et al. Plasma volume expansion by

albumin in cirrhosis. Relation to blood volume distribution, arterial
compliance and severity of disease. J Hepatol. 2003;39:24–31.
9. Thévenot T, Bureau C, Oberti F, et al. Effect of albumin in cirrhotic

patients with infection other than spontaneous bacterial peritonitis. A
randomized trial. J Hepatol. 2015;62:822–30.
10. Guevara M, Terra C, Nazar A, et al. Albumin for bacterial infections

other than spontaneous bacterial peritonitis in cirrhosis. A randomized,
controlled study. J Hepatol. 2012;57:759–65.
11. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis.

Hepatology. 2008;48:2064–77.
12. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention

and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56:1310–
18.
13. Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome. Lancet.

2003;362:1819–27.
14. Salerno F, Cazzaniga M, Merli M, et al. Diagnosis, treatment and

survival of patients with hepatorenal syndrome: a survey on daily medical
practice. J Hepatol. 2011;55:1241–8.
15. Sherman, DS, Fish DN, Teitelbaum I. Assessing renal function in

cirrhotic patients: problems and pitfalls. Am J Kidney Dis. 2003;41:269–
78.
16. Cholongitas E, Calvaruso V, Senzolo M, et al. RIFLE classification as

predictive factor of mortality in patients with cirrhosis admitted to
intensive care unit. J Gastroenterol Hepatol. 2009;24:1639–47.
17. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute

kidney injury in patients with cirrhosis: revised consensus
recommendations of the International Club of Ascites. Gut. 2015;64:531–
7.
18. Bernal W, Jalan R, Quaglia A, Simpson K, Wendon J, Burroughs A.

Acute on chronic liver failure. Lancet. 2015;386:1576–87.
19. Pugh R, Murray-Lyon I, Dawson J, Pietroni MC, Williams R.

Transection of the esophagus in bleeding oesophageal varices. Br J Surg.
1973;60:648–52.
20. Moreau R, Jalan R, Gines P, et al. CANONIC Study Investigators of the

EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct
syndrome that develops in patients with acute decompensation of
cirrhosis. Gastroenterology. 2013;44:1426–37.
Page 35 of 39

21. Lee M, Oh S, Jang Y, et al. CLIF-SOFA scoring system accurately

predicts short-term mortality in acutely decompensated patients with
alcoholic cirrhosis: a retrospective analysis. Liver Int. 2015;35:46–57.
22. Soares e Silva P, Lazzarotto C, Ronsoni M, et al. Single-centre

validation of the EASL-CLIF Consortium deﬁnition of acute-on-chronic
liver failure and CLIF-SOFA for prediction of mortality incirrhosis. Liver
Int. 2015;35:16–23.
23. McPhail M, Shawcross D, Ables R, et al. Increased survival for

patients with cirrhosis and organ failure in liver intensive care and
validation of the Chronic Liver Failure–Sequential Organ Failure Scoring
System. Clin Gastroenterol Hepatol. 2015;13:1353–60.
24. Ferreira F, Bota D, Bross A, et al. Serial evaluation of the SOFA score
to predict outcome in critically ill patients. JAMA. 2001;286:1754–8.
25. Maddrey W, Boitnott J, Bedine M, Weber F, Mezey E, White R.

Corticosteroid therapy of alcoholic hepatitis. Gastroenterology.
1978;75:193–9.
26. Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool
for therapeutic strategy in patients with severe alcoholic hepatitis treated
with steroids. Hepatology. 2007;45:1348–54.
27. O’Shea R, Dasarathy S, McCullough A. Alcoholic liver disease.

Hepatology. 2010;51:307–28.
28. Gustot T, Maillart E, Bocci M, et al. Invasive aspergillosis in patients

with severe alcoholic hepatitis. J Hepatol. 2014;60:267–74.
29. O’Grady J, Alexander G, Hayllar K, Williams R. Early indicators of

prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439–55.
30. Child C, Turcotte J. Surgery and portal hypertension. In: Child GC (ed)
The Liver and Portal Hypertension. Philadelphia, PA: Saunders; 1964, pp.
50–64.
31. Malinchoc M, Kamath P, Gordon F, Peine C, Rank J, Borg P. A model to

predict poor survival in patients undergoing transjugular intrahepatic
portosystemic shunts. Hepatology. 2000;31:864–71.
32. Merion R, Schaubel D, Dykstra D, Freeman R, Port F, Wolfe R. The

survival benefit of liver transplantation. Am J Transplant. 2005;5:307–13.
33. Dunn W, Jamil L, Brown L, et al. MELD accurately predicts mortality

in patients with alcoholic hepatitis. Hepatology. 2005;41:353–8.
34. Londono M, Cardenas A, Guevara M, et al. MELD score and serum

sodium in the prediction of survival of patients with cirrhosis awaiting
liver transplantation. Gut. 2007;56:1283–90.
Page 36 of 39

35. Kim W, Biggins S, Kremers W, et al. Hyponatremia and mortality

among patients on the liver-transplant waiting list. N Engl J Med.
2008;359:1018–26.
36. Vincent J, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ

Failure Assessment) score to describe organ dysfunction/failure. Intensive
Care Med. 1996;22:707–10.
37. Jalan R, Saliba F, Pavesi M, et al. CANONIC study investigators of the

EASL-CLIF Consortium. Development and validation of a prognostic score
to predict mortality in patients with acute-on-chronic liver failure. J
Hepatol. 2014;61:1038–47.
38. Levesque E, Hoti E, Azoulay D, et al. Prospective evaluation of the

prognostic scores for cirrhotic patients admitted to an intensive care unit.
J Hepatol. 2012;56:95–102.
39. Saliba F, Ichai P, Levesque E, Samuel D. Cirrhotic patients in the ICU:

prognostic markers and outcome. Curr Opin Crit Care. 2013;19:154–60.
40. Jalan R, Pavesi M, Saliba F, et al. The CLIF Consortium Acute

Decompensation score (CLIF-C ADs) for prognosis of hospitalised
cirrhotic patients without acute-on-chronic liver failure. J Hepatol.
2015;62:831–40.
41. Edmark C, McPhail M, Bell M, Whitehouse T, Wendon J, Christopher

K. LiFe: a liver injury score to predict outcome in critically ill patients.
42. Forrest E, Evans C, Stewart S, et al. Analysis of factors predictive of

mortality in alcoholic hepatitis and derivation and validation of the
Glasgow alcoholic hepatitis score. Gut. 2005;54:1174–9.
43. Forrest E, Morris A, Stewart S, et al. The Glasgow alcoholic hepatitis

score identifies patients who may benefit from corticosteroids. Gut.
2007;56:1743–6.
44. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic

liver disease: 2014 Practice Guideline by the American Association for the
Study of Liver Diseases and the European Association for the study of the
Liver. Hepatology. 2014;60:715–35.
45. Cordoba J, Ventura-Cots M, Simón-Talero M, et al. Characteristics,

risk factors, and mortality of cirrhotic patients hospitalized for hepatic
encephalopathy with and without acute-on-chronic liver failure (ACLF). J
Hepatol. 2014;60:275–81.
46. Córdoba J, Gottstein J, Blei A. Chronic hyponatremia exacerbates

ammonia-induced brain edema in rats after portacaval anastomosis. J
Hepatol. 1998;29:589–94.
Page 37 of 39

47. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic

indicators of survival in cirrhosis: a systematic review of 118 studies. J
Hepatol. 2006;44:217–31.
48. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy—

Definition, nomenclature, diagnosis, and quantification: Final report of
the Working Party at the 11th World Congresses of Gastroenterology,
Vienna, 1998. Hepatology. 2002;35:716–21.
49. Lockwood A. Blood ammonia levels and hepatic encephalopathy.

Metab Brain Dis. 2004;19:345–9.
50. Bernal N, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial

ammonia and clinical risk factors for encephalopathy and intracranial
hypertension in acute liver failure. Hepatology. 2007;46:1844–52.
51. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2016;370:1170–

1.
52. Jalan R, Olde Damink S, Ter Steege J, et al. Acute endotoxemia

following transjugular intrahepatic stent-shunt insertion is associated
with systemic and cerebral vasodilatation with increased whole body
nitric oxide production in critically ill cirrhotic patients. J Hepatol.
2011;54:265–71.
53. Jalan R, Dabos K, Redhead D, et al. Elevation of intracranial pressure

following transjugular intrahepatic portosystemic stent-shunt for variceal
haemorrhage. J Hepatol. 1997;27:928–33.
54. Joshi D, O’Grady J, Patel A, et al. Cerebral oedema is rare in acute-on-

chronic liver failure patients presenting with high-grade hepatic
encephalopathy. Liver Int. 2014;34:362–6.
55. Als-Nielsen B, Gluud L, Gluud C. Non absorbable disaccharides for

treatment of hepatic encephalopathy: systematic review of randomised
trials. BMJ. 2004;328:1046–50.
56. Prasad S, Dhiman R, Duseja A, Chawla Y, Sharma A, Agarwal R.

Lactulose improves cognitive functions and health-related quality of life in
patients with cirrhosis who have minimal hepatic encephalopathy.
Hepatology. 2007;45:549–59.
57. Bajaj J, Sanyal A, Bell D, Gilles H, Heuman D. Predictors of the

recurrence of hepatic encephalopathy in lactulose-treated patients.
Aliment Pharmacol Ther. 2010;31:1012–17.
58. Bass N, Mullen K, Sanyal A, et al. Rifaximin treatment in hepatic

encephalopathy. N Engl J Med. 2010;362:1071–81.
59. Jiang Q, Jiang X, Zheng M, Chen Y. L-Ornithine-L-aspartate in the

management of hepatic encephalopathy: a meta-analysis. J Gastroenterol
Hepatol. 2009;24:9–14.
Page 38 of 39

60. Abid S, Jafri W, Mumtaz K, et al. Efficacy of L-ornithine-L-aspartate as

an adjuvant therapy in cirrhotic patients with hepatic encephalopathy. J
Coll Physicians Surg Pak. 2011;21:666–71.
61. Wright G, Noiret L, Olde Damink S, Jalan R. Interorgan ammonia

metabolism in liver failure: the basis of current and future therapies.
Liver Int. 2011;31:163–75.
62. Slack A, Auzinger G, Willars C, et al. Ammonia clearance with

haemofiltration in adults with liver disease. Liver Int. 2014;34:42–8.
63. Slowinski T, Morgera S, Joannidis M, et al. Safety and efficacy of

regional citrate anticoagulation in continuous venovenous hemodialysis in
the presence of liver failure: the Liver Citrate Anticoagulation Threshold
(L-CAT) observational study. Critical Care. 2015;19:349.
64. Cabral C, Burns D. Low protein diets for hepatic encephalopathy

debunked: let them eat steak. Nutr Clin Pract. 2011;26:155–9.
65. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for

episodic hepatic encephalopathy: results of a randomized study. J Hepatol.
2004;41:38–43.
66. Saliba F. The Molecular Adsorbent Recirculating System (MARS®) in

the intensive care unit: a rescue therapy for patients with hepatic failure.
Crit Care. 2006;10:118.
67. Bañares R, Nevens F, Larsen F, et al. RELIEF study group.

Extracorporeal albumin dialysis with the molecular adsorbent
recirculating system in acute-on-chronic liver failure: the RELIEF trial.
Hepatology. 2013;57:1153–62.
68. Thursz M, Richardson P, Allison M, et al. STOPAH trial. Prednisolone

or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372:1619–28.
69. Mathurin P, O’Grady J, Carithers R, et al. Corticosteroids improve

short-term survival in patients with severe alcoholic hepatitis: meta-
analysis of individual patient data. Gut. 2011;60:255–60.
70. Finkenstedt A, Nachbaur K, Zoller H, et al. Acute-on-chronic liver

failure: excellent outcomes after liver transplantation but high mortality
on the wait list. Liver Transpl. 2013;19:879–86.
71. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma

exchange in patients with acute liver failure: An open randomised
controlled trial. J Hepatol. 2016;64:69–78.
Page 39 of 39

Acute pancreatitis and renal replacement therapy

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Acute pancreatitis and renal replacement therapy
Author(s): Clinton Lobo
DOI: 10.1093/med/9780198814924.003.0012
Expert commentary by Kim Gupta and Matt Thomas
Case history
A 51-year-old male patient was admitted under the surgical team

with upper abdominal pain following a single alcohol binge. He had no
known medical conditions, did not take any medications, had stopped
smoking 10 years previously, and exercised regularly. On examination, he
was haemodynamically stable and had an arterial blood oxygen saturation
(SpO2) of 96% in air, but had marked tenderness and guarding in the
epigastrium. A diagnosis of acute pancreatitis was made following
identification of a raised serum amylase value, and he was admitted to
the surgical ward.
LEARNING POINT The revised Atlanta classification
Page 1 of 20
The revised Atlanta classification 2012 for the diagnosis of acute

pancreatitis [1] requires at least two from:
1. acute-onset, severe abdominal pain

2. raised serum amylase (or lipase) at least three times the
upper limit of normal
3. characteristic findings on contrast-enhanced computed
tomography (CT) scanning, magnetic resonance imaging (MRI),
or abdominal ultrasonography.
Serum amylase rises within hours of onset of acute pancreatitis,

returning to normal within 3–5 days. Serum lipase remains elevated
for 8–14 days, and therefore in late presentation (>48 hours after
symptom onset) has better diagnostic sensitivity than amylase (80%
vs 30%). The degree of enzyme elevation does not correlate with
disease severity.
An initial abdominal ultrasound scan showed a non-dilated, non-

obstructed biliary tract, with no evidence of gallstones. The pancreatitis
was considered to be secondary to the alcohol binge. A nasogastric tube
and urinary catheter were sited, and he was managed conservatively with
analgesia and enteral nutrition.
LEARNING POINT Causes of acute pancreatitis
Acute pancreatitis has many causes. Between 75% and 85% of cases
are associated with gallstones or excess alcohol, with gallstones being
the most common cause in most European and North American
studies. Fifteen per cent of cases have no clear cause (idiopathic). In
these cases, endoscopic ultrasound examination detects occult bile
duct stones or biliary sludge in approximately two-thirds of cases.
Rarer causes (<10% of cases) include drugs (e.g. valproate and
steroids), trauma, endoscopic retrograde cholangiopancreatography
(ERCP), hypertriglyceridaemia, hypercalcaemia, and viral infections
(e.g. mumps and cytomegalovirus).
CLINICAL TIP Morphine
Although there is a theoretical risk of morphine exacerbating acute

pancreatitis through spasm of the sphincter of Oddi, there is little
human evidence that this is clinically significant in acute pancreatitis,
or that any particular opioid is more likely to cause a problem.
Page 2 of 20

Over the subsequent 48 hours, his condition deteriorated, and he was

referred to the intensive care unit (ICU) with escalating oxygen
requirements and development of a metabolic acidosis. His blood tests
and arterial blood gas results are shown in Table 12.1. His Ranson score
at 48 hours was 4 (scoring for partial pressure of oxygen, urea, aspartate
transaminase, and base excess). He was admitted to the ICU for
monitoring.
Table 12.1 Blood results and arterial blood gas results 48 hours after
admission
Variable Result Reference range
Full blood count
Hb (g/L) 142 130–180
WCC (×109/L) 16.1 4–11
Neut (×109/L) 13.9 2–6.5
Platelets (×109/L) 286 150–400
Na (mmol/L) 141 135–145
K (mmol/L) 4.7 3.5–5.0
Urea (mmol/L) 14.1 3–7
Creatinine (µmol/L) 185 <110
Glucose (mmol/L) 7.6 3.5–8.5
CRP (mg/L) 285 <10
Liver function tests
Bilirubin (µmol/L) 25 3–17
ALT (IU/L) 360 3–35
AST (IU/L) 393 3–35
Page 3 of 20

Alk P (IU/L) 240 30–130
Alb (g/L) 33 35–50
Ca (mmol/L) 2.10 2.12–2.65
Amylase 1240 <100
Arterial blood gas
pH 7.24 7.35–7.45
PaCO2 (kPa) 2.9 4.4–6.1
PaO2 (kPa) 6.8 >10
Base excess (mmol/L) −8.9 ±2
Bicarbonate (mmol/L) 14.3 22–26
Lactate (mmol/L) 2.1 <2
Alb, albumin; Alk P, alkaline phosphatase; ALT, ALT, AST, aspartate

transaminase; AST, aspartate transaminase; CRP, C-reactive protein;
Hb, haemoglobin; K, potassium; Na, sodium; Neut, neutrophils; PaCO2,
partial pressure of carbon dioxide; PaO2, partial pressure of oxygen;
WCC, white cell count.
EXPERT COMMENT
Early recognition of severe disease is important to guide appropriate

allocation of ICU resources and treatment. Ranson criteria and the
Glasgow (Imrie) criteria, shown in Table 12.2, remain widely used to
assess severity, but do not provide a full score until 48 hours after
admission [2, 3]. The presence of fewer than three Ranson’s criteria
reliably represents mild disease and the presence of six or more
criteria correlates with necrosis and an increased risk of mortality.
However, the presence of three to five Ranson’s criteria is very
common, but correlates poorly with clinical severity or development
of necrosis. Many other validated scoring systems exist, based on
physiological variables, biochemical markers, or radiological
appearance, but none have shown clear superiority in balancing
predictive power with ease of use. Severity scores based on CT
imaging (e.g. Balthazar score or CT severity index) have no clear
advantage over clinical scoring systems in predicting severe disease
Page 4 of 20

or prognosis [4, 5]. Most scoring systems have limited day-to-day

value in the clinical management of patients with acute pancreatitis,
but detection of organ dysfunction using regular clinical observations
summarized into early warning scores has similar accuracy for
prediction of severity in acute pancreatitis and is of greater value in
detecting clinical deterioration.
Table 12.2 Ranson and Glasgow criteria for assessment of acute

pancreatitis severity at 48 hours
Ranson criteria Ranson criteria Glasgow

(non-gallstone (gallstone (Imrie)
pancreatitis) pancreatitis) criteria
aAge >55 years aAge >70 years Age >55

years
aGlucose >11.1 mmol/ aGlucose >12.2 Glucose

L mmol/L >10.0 mmol/
L
aWBC >16 × 109/L aWBC >18 × 109/L WBC >15 ×

109/L
aSerum AST >250 IU/L aSerum AST >250 IU/ Serum LDH
L >600 IU/L
aSerum LDH >350 IU/ aSerum LDH >400 Serum

L IU/L albumin <32
g/L
Hct fall >10% Hct fall >10% BUN >16.1

mmol/L
Fluid sequestration >6 Fluid sequestration Serum Ca2+

L >4 L <2 mmol/L
Base deficit >4 mEq/L Base deficit >5 mEq/ Arterial PO2
L <8 kPa
BUN rise >1.8 mmol/L BUN rise >0.7 mmol/

L
Serum Ca2+ <2 mmol/ Serum Ca2+ <2

L mmol/L
Page 5 of 20

Arterial PO2 <8 kPa Arterial PO2 <8 kPa
AST, aspartate transaminase; BUN, blood urea nitrogen; Hct,

haematocrit; LDH, lactate dehydrogenase; PO2, partial pressure of
oxygen; WBC, white blood cell.
a Measurements taken on admission.
Because of rapidly escalating oxygen requirements, the patient was

anaesthetized, intubated, and his lungs ventilated. A CT scan of his
abdomen and chest demonstrated pancreatic necrosis and signs of early
acute respiratory distress syndrome (Figure 12.1). He was discussed by
consultant intensivists and surgeons and the consensus was for
conservative management of the pancreatic necrosis, with the assumption
that this was not infected.
Page 6 of 20

Figure 12.1
CT scans. (a) Abdomen: pancreatitis with evidence of pancreatic necrosis
as demonstrated by the non-enhancing pancreatic body (arrow). (b)
Chest: bilateral diffuse ground-glass infiltrates consistent with acute
respiratory distress syndrome, a moderate right-sided and small left-sided
effusion.
LEARNING POINT Initial imaging in acute

pancreatitis
● Ultrasonography should be used within 24 hours of admission to

assess for the presence of gallstones and biliary tract obstruction.
● Contrast-enhanced CT is the gold standard for diagnostic
imaging in acute pancreatitis.
● Optimal timing for the initial CT scan is greater than 96 hours
after onset of symptoms.
Page 7 of 20

● Early CT assessment (<96 hours) should be obtained only for

diagnostic uncertainty or to identify other life-threatening
disorders or complications.
● Follow-up CT or MRI in acute pancreatitis is indicated only when
there is a lack of clinical improvement, clinical deterioration, or
when invasive intervention is considered.
The patient was commenced on noradrenaline to maintain a mean arterial

pressure of 65 mmHg, with intravenous fluid therapy, initially clinically
guided, and continuation of enteral feeding, but it was decided not to
commence antibiotics. His renal function and metabolic acidosis
deteriorated and, despite use of a non-invasive cardiac output monitor
incorporating pulse contour analysis to optimize fluid balance, this
continued. On day 2 he was commenced on renal replacement therapy
(RRT) using a continuous venovenous haemofiltration (CVVHF) mode, at a
rate of 30 mL/kg/h, to target a neutral fluid balance, and anticoagulated
with heparin to target an activated partial thromboplastin time ratio of
1.5.
LEARNING POINT Types of renal replacement

therapy
Peritoneal dialysis
Peritoneal dialysis (PD) involves insertion of a dialysis catheter into
the peritoneal cavity, and then filling the cavity with dialysis fluid [6].
It works on the principle that the peritoneum is a semipermeable
membrane, enabling transfer of solutes between the dialysis fluid and
the blood vessels of the peritoneum. The dialysis fluid is left for 3–4
hours to achieve solute equilibration, and is then drained and
replaced with fresh dialysis fluid.
The advantages of PD include no requirement for anticoagulation or

expensive machinery, therapy can be continuous, and the patient can
mobilize almost normally. The most serious potential risk of PD is
infection, either through external contamination or from abdominal
viscus translocation, a risk which often precludes its use in critically
ill patients [7]. It is contraindicated with most intra-abdominal
surgical pathologies (including pancreatitis), and its efficacy is
influenced by previous abdominal surgery, duration of use, and
constipation. For these reasons, and with the development of
continuous RRTs, it is only rarely used in adult critical care. PD is still
used in paediatric critical care, where vascular access and
extracorporeal circuit management can be very difficult.
Page 8 of 20

Haemodialysis
Haemodialysis (HD) also relies on the principle of solute diffusion
across a semipermeable membrane [6]. Vascular access is usually
achieved by insertion of a large-bore dual-lumen venous catheter in
the short term, or creation of a permanent arteriovenous fistula in the
long term. An extracorporeal blood circuit is separated from dialysis
fluid by a semipermeable membrane. Solute diffusion rate is
determined by the difference in solute concentration between the
blood and dialysate. This is augmented in HD by using countercurrent
flow of the dialysate to the blood.
HD is very efficient for solute clearance (particularly low-molecular-

weight solutes), and is most commonly used outside the ICU as part
of an intermittent regimen. Use of rapid intermittent regimens
minimizes patient immobility and usually precludes the need for
anticoagulation (and the associated potential complications).
However, intermittent HD is unsuitable for patients with
cardiovascular instability (due to the high blood flow rate) or cerebral
injury (due to the associated fluid shifts and the potential for cerebral
oedema), which means it is only suitable for critically ill patients who
are stable or in the convalescent phase of their illness.
Haemofiltration
Haemofiltration (HF) relies on the principle of convection for the
transport of solutes. A pressure is applied across a semipermeable
membrane, which results in the transfer of solvent (water) across the
membrane. As the solvent crosses the membrane, solutes are carried
with it, depending on the pore size of the membrane. This is known as
‘solvent drag’, and is the main principle behind HF. The
transmembrane pressure is the pressure difference between the
blood and filtrate compartments, and is directly related to blood flow
in the circuit. This pressure difference can also be adjusted by
applying a negative pressure to the filtrate side, which often becomes
necessary as the membrane degrades. As the transmembrane
pressure is directly related to the rate of blood flow, HF is a
continuous form of RRT.
During HF, water and solutes are removed from the blood, leading to
an increase in oncotic pressure. The fraction of water removed needs
to be limited to 25%, otherwise the increased oncotic pressure
counteracts the transmembrane pressure. This is achieved by
adjusting the blood pump speed according to the ultrafiltration dose.
Replacement of plasma water and additional electrolytes is required
prior to return of blood to the circulation. This replacement fluid can
be administered before or after the filtration process. Post-filtration
replacement makes the solute clearance more effective, but pre-
filtration replacement increases the life of the haemofilter (by
reducing haemoconcentration and so protein build-up on the
Page 9 of 20

membrane fibres), and so a combination of pre- and post-filtration

replacement is generally used.
Haemodiafiltration
The addition of a transmembrane pressure to the process of HD is
called haemodiafiltration, which allows solute transfer to occur by
diffusion and convection, and is the most effective method of solute
clearance.
EXPERT COMMENT
Many of the drugs used in the ICU are cleared by the kidneys. There
are often important changes to be made in dose and frequency of
these medications. There are several reference books that give advice
on changes in medication schedules in the presence of acute kidney
injury (AKI). The Renal Drug Handbook is frequently used for this and
is also available as a database (https://renaldrugdatabase.com).
The metabolic acidaemia was corrected while on CVVHF, and the

noradrenaline requirements reduced. However, on day 4 on ICU, the
patient’s inflammatory markers increased, as did the noradrenaline and
oxygen requirements. The patient also had increased respiratory
secretions and was commenced on antibiotics (piperacillin/tazobactam)
for a suspected ventilator-associated pneumonia. Enteral nutrition was
administered at a rate of 10 mL/hour, but despite the introduction of
metoclopramide and erythromycin as prokinetic drugs, the patient had
high gastric aspirates. It was decided to start post-pyloric feeding and a
nasojejunal tube was sited.
LEARNING POINT Nutrition in acute pancreatitis
● In mild acute pancreatitis, oral feeding can be started

immediately.
● In severe acute pancreatitis, oral feeding is usually inhibited by
nausea.
● Enteral nutrition is recommended in moderate and severe acute
pancreatitis as it may help preserve gut mucosal function and
reduce the risk of multiorgan failure and pancreatic infectious
complications [8, 9].
● Nasogastric and nasojejunal delivery of enteral feed appear
comparable in efficacy and safety. Nasogastric tube placement is
Page 10 of 20

easier than nasojejunal tube placement, and should be the initial,

preferred mode of delivery of enteral nutrition.
● Use parenteral nutrition if the enteral route is unavailable or not
tolerated.
On day 6, the patient’s platelet count was 73 × 109/L, having decreased

from 358 × 109/L over the preceding 2 days. He was deemed to have an
intermediate risk of heparin-induced thrombocytopenia and the decision
was made to stop his haemofilter heparin anticoagulation, and commence
an epoprostenol infusion. Fondaparinux was prescribed for venous
thromboembolism prophylaxis.
LEARNING POINT Anticoagulation during

extracorporeal renal replacement
RRT activates the clotting cascade because blood is exposed to non-

biological surfaces. This usually manifests in clots blocking the
haemofilter membrane, and will require replacement with a new filter
circuit. Anticoagulation is used to try to prevent this occurring.
The most common modes of anticoagulation for RRT are as follows:
Unfractionated heparin—the haemofilter circuit is usually flushed

with 2 L of crystalloid with 5000 IU heparin before use. Give a bolus
of 2000–5000 IU heparin followed by an infusion starting at a rate of
5–10 IU/kg/hour aiming for an activated partial thromboplastin time
ratio of 1.5–2.0 [7]. Occasionally, heparin is used for ‘regional
anticoagulation’ of the haemofilter only. This is achieved by infusing
heparin into the blood entering the haemofilter and infusing
protamine into the blood returning to the patient.
Prostacyclin (PGI2)—often used when there are contraindications to

heparin. Prostacyclin inhibits platelet aggregation and is infused at a
rate of 2.5–5.0 ng/kg/min. It is short acting and has minimal systemic
effects.
Citrate—there is growing popularity in the use of citrate as regional

anticoagulation to prolong haemofilter use. Citrate chelates calcium,
reducing activation of both the clotting cascade and platelet
aggregation. It increases haemofilter lifespan compared to using
heparin [10]. Citrate is infused into blood entering the haemofilter
and calcium is infused into blood leaving the filter so that ionized
calcium values are restored in the blood returning to the patient.
Much of the citrate is removed in the filtration process, but citrate
returning to the patient is metabolized to bicarbonate by the liver.
Page 11 of 20

Between days 8 and 10 in the ICU, the patient developed a fever and
raised inflammatory markers. The patient underwent a full line change
and septic screen. On day 10, infection of the pancreatic necrosis was
suspected as the underlying cause and the patient’s antibiotic regimen
was escalated (meropenem and vancomycin). A percutaneous
tracheostomy was undertaken in anticipation of a prolonged period of
ventilation (the patient’s platelet count had increased to 121 × 109/L).
Two radiologically guided percutaneous drains were inserted into the
pancreatic bed, enabling samples to be taken for microbiological analysis.
Surgical large-bore drains were then inserted using the percutaneous
drains as a guide. One of the large-bore drains was used to infuse warm
saline into the pancreatic bed, and the second drain was allowed to freely
drain the pancreatic bed.
These washouts continued for 4 days, during which there was a clinical
and biochemical improvement in the patient’s condition. The washouts
were then stopped and the drains left to drain freely for a further 24
hours before being removed. Daily samples of drain fluid were analysed
during this time, but did not grow any organisms.
EXPERT COMMENT
Severe acute pancreatitis causes a profound inflammatory response.

The associated elevation in inflammatory and infective markers can
make the diagnosis of coexisting infection extremely difficult, for
example, acute cholangitis on initial presentation, and infected
necrosis later in the disease process. A high index of suspicion is
required, coupled with focused imaging and targeted microbiological
sampling.
Indications for endoscopic or surgical intervention in acute

pancreatitis include [8, 9] the following:
● Patients with gallstone pancreatitis with coexisting cholangitis

or biliary obstruction should be considered for early ERCP.
● Routine early ERCP is not needed in most patients with
gallstone pancreatitis who lack clinical or biochemical evidence of
ongoing biliary obstruction.
● Patients with mild gallstone pancreatitis should undergo
cholecystectomy during their hospital admission. In severe acute
pancreatitis, this should be delayed until active inflammation
subsides and fluid collections resolve.
● Asymptomatic pseudocysts and pancreatic or extrapancreatic
sterile necrosis do not warrant intervention.
● Stable patients with infected necrosis which has not responded
to antibiotic treatment, should be considered for drainage or
resection of infected necrosis.
Page 12 of 20

● Drainage procedures can be open (via laparotomy) or minimally

invasive. In general, minimally invasive techniques approach the
necrosis via a retroperitoneal or transgastric route, and
laparoscopic, endoscopic, or percutaneous techniques
(radiologically guided, with or without lavage) are used to achieve
drainage.
● Comparative studies of different drainage techniques are few,
but minimally invasive techniques appear to be associated with
lower rates of postoperative complications (e.g. new-onset organ
failure, bleeding, visceral perforation) compared to open
necrosectomy [11].
● Drainage procedures should usually be delayed for more than 4
weeks after the onset of the pancreatitis to enable the necrosis to
become liquefied, discrete, and walled-off.
Following removal of the pancreatic bed drains, the patient continued to

clinically improve, and ventilation weaning was commenced. He started
to pass urine while undergoing CVVHF and the decision was made to stop
RRT for a trial period. During this trial period, although there was a
modest deterioration in his renal function tests, he continued to pass
urine, and did not require further RRT. Meropenem and vancomycin were
continued for 14 days, during which time there was a marked
improvement in his inflammatory markers. At day 27, the patient’s
tracheostomy was successfully decannulated, and he was discharged to
the ward the following day.
Discussion
Acute pancreatitis is a common inflammatory condition, with an

incidence of 1–4 cases per 10,000 per year in the UK [12]. Most cases are
mild and self-limiting, but approximately 20% of cases are classified as
severe, according to the revised Atlanta criteria 2012 [1, 13]. Based on
these criteria, this patient had severe acute pancreatitis because he had
organ failure lasting more than 48 hours.
Revised Atlanta criteria (2012) for severity grading of pancreatitis
Atlanta symposium—grades of severity of pancreatitis:
Mild acute pancreatitis:
● Absence of organ failure.

● Absence of local complications.
Moderately severe acute pancreatitis:
● Local complications and/or
Page 13 of 20

● Transient organ failure (<48 hours).
Severe acute pancreatitis:
● Persistent organ failure (>48 hours).
Acute pancreatitis with pancreatic necrosis has a mortality of

approximately 10% if sterile, but this rises to around 30% if the necrosis
becomes infected. The debate surrounding the use of prophylactic
antibiotics to prevent sterile pancreatic necrosis from becoming infected
is driven by this stark contrast in mortality. The lack of consensus on this
issue is due in part to the lack of consistency in variables in the antibiotic
prophylaxis trials. These include choice and duration of antibiotic, the
extent of pancreatic necrosis, and the confounding issue of treatment
antibiotics in the placebo group. A Cochrane systematic review of
available trials in 2010 did not show a significant difference in mortality
between use of prophylactic antibiotics and the control group. In this
review, only the imipenem prophylaxis subgroup demonstrated a
significant reduction in pancreatic infections, albeit without affecting the
mortality rate [14].
LEARNING POINT Indication for antimicrobials in

acute pancreatitis
● Routine use of antibiotics is not indicated in patients with acute

pancreatitis [9].
● Give antibiotics for coexistent extrapancreatic infections (e.g.
acute cholangitis, pneumonia, and urinary tract infection).
● The use of prophylactic antibiotics to prevent sterile necrosis
from becoming infected is not supported by current evidence.
● Consider a diagnosis of infected pancreatic necrosis in patients
with pancreatic or extrapancreatic necrosis who deteriorate or fail
to improve after 7–10 days of hospital treatment. In these patients,
antibiotic treatment is either guided by culture of the infected
pancreatic necrosis (usually obtained by fine-needle aspiration), or
given empirically after necessary cultures are obtained.
● In patients with infected pancreatic necrosis, antibiotics known
to penetrate pancreatic necrosis (carbapenems, quinolones, and
metronidazole) may be useful in delaying or avoiding intervention.
● Routine treatment with antifungal drugs along with prophylactic
or therapeutic antibiotics is not recommended.
Page 14 of 20

The development of renal injury is common among critically ill patients.

There are several classifications of renal injury, although the most
commonly used are the Risk, Injury, Failure, Loss, End-stage (RIFLE)
criteria and the Acute Kidney Injury Network (AKIN) criteria [15, 16].
More recently, Kidney Disease: Improving Global Outcomes (KDIGO) has
created a classification based on both these criteria (Table 12.3) [17].
Table 12.3 KDIGO classification for acute kidney injury
Stage Serum creatinine Urine output
1 1.5–1.9 times baseline <0.5 mL/kg/hour for 6–

Or 12 hours
Increase by ≥0.3 mg/dL or
≥26.5 µmol/L
2 2.0–2.9 times baseline <0.5 mL/kg/hour for

≥12 hours
3 ≥3.0 times baseline <0.3 mL/kg/hour for

Or ≥24 hours
Increase to ≥4.0 mg/dL or Or
≥353.6 µmol/L Anuria for ≥12 hours
Or
Initiation of renal replacement
therapy
AKI is usually caused by a combination of several factors, the main ones

being:
● hypoperfusion
● sepsis/systemic inflammatory response
● direct nephrotoxicity.
Hypoperfusion is addressed by treating hypovolaemia with fluid

resuscitation, and then optimizing renal perfusion with the use of
inotropes and vasopressors. There is no evidence for the use of renal
vasodilators in the management of AKI [18].
Although the systemic inflammatory response (usually caused by sepsis)

is the most common cause of AKI in critically ill patients, the
pathophysiology is not fully understood. It is generally accepted to have a
multifactorial pathway, with components including ischaemia–reperfusion
injury, direct inflammatory injury, coagulation and endothelial cell
dysfunction, and apoptosis [19]. Many treatments used in critical care can
be nephrotoxic, including antibiotics, vasoactive drugs, diuretics, and
intravenous contrast, the use of which is often unavoidable.
Page 15 of 20

EXPERT COMMENT
In AKI in critical care facilities, it is important to not forget the basic

investigations and treatments. The NCEPOD report ‘Adding insult to
injury’ showed that common tests such as renal tract imaging
(ultrasonography or CT) and urinalysis were often omitted. It is
important to perform these on the ICU [20]. This report also showed
that potentially nephrotoxic drugs are often left prescribed.
Numerous guidelines list indications for the initiation of RRT,

including those published by Acute Dialysis Quality Initiative, KDIGO,
and the UK Intensive Care Society [17, 21, 22]. These guidelines all
vary slightly, and there are no universally accepted biochemical
values at which therapy should be started. Several studies have also
attempted to determine the optimal timing for initiation of RRT. While
there are studies which demonstrate improved outcomes with early
versus late initiation of RRT [23, 24, 25, 26, 27], other studies have
failed to show a difference in outcome [28, 29], and so the timing of
initiation is still in question. Although many have attempted to
address the issues of indications and timing of RRT, there is very little
guidance for stopping this treatment. The KDIGO guidelines
recommend discontinuing RRT when it is no longer required, either
when renal function has recovered or when it is no longer consistent
with the patient’s treatment goals [17].
LEARNING POINT Indications for renal replacement

therapy
UK Intensive Care Society indications for starting RRT [22] are as

follows:
Classic ‘renal’ indications include:
● rapidly rising serum urea and creatinine or the development of

uraemic complications
● hyperkalaemia unresponsive to medical management
● severe metabolic acidosis
● diuretic resistant pulmonary oedema
● oliguria or anuria.
‘Non-renal’ indications include:
● management of fluid balance (e.g. cardiac failure)

● clearing of ingested toxins
Page 16 of 20

● correction of electrolyte abnormalities

● temperature control
● removal of inflammatory mediators in sepsis.
Whether a continuous or an intermittent mode of RRT is superior to

the other remains controversial. In ICUs in the UK, Western Europe,
and Australia, continuous RRT is the predominant mode—
approximately 90% of ICUs in the UK use continuous techniques [30].
In the US, a greater proportion of ICUs deliver intermittent RRT, as
often this is overseen by renal physicians. Proponents of continuous
RRT suggest it offers greater haemodynamic stability, leading to
fewer episodes of renal hypoperfusion and earlier renal recovery.
Data from the BEST Investigators found that although there was no
hospital survival benefit from either mode of therapy, continuous RRT
was associated with a higher incidence of renal recovery among
survivors [31]. This finding was replicated in a systematic analysis of
observational studies in 2013. However, when the analysis was
restricted to randomized controlled trials (RCTs), there was no
evidence of difference between the two forms of RRT [32].
The optimal dose of RRT is still disputed. Several studies

demonstrated an improvement in survival with higher doses of RRT
[24, 33]. The authors of a landmark, single-centre RCT observed a
reduction in mortality from 59% to 43% when the ultrafiltration dose
was increased from 20 to 35 mL/kg/hour [24]. A 2007 survey of adult
ICUs found that 49% of units using CVVHF and 67% of units using
continuous venovenous haemodiafiltration (CVVHDF) were using a
dose of at least 35 mL/kg/hour, which differed from 2003 when 88%
of units chose a dose of 14–29 mL/kg/hour [30, 34].
More recent studies have cast doubt over the optimal RRT dose. A
large US multicentre RCT found no difference in mortality between
low-intensity RRT (CVVHDF 20 mL/kg/hour or intermittent HD three
times a week) and high-intensity RRT (CVVHDF 35 mL/kg/hour or
intermittent HD six times a week) [35]. A similar large multicentre
RCT in Australia and New Zealand found no difference in mortality
between high- (40 mL/kg/hour) and low-dose (25 mL/kg/hour)
CVVHDF [36].
Pancreatitis is a common condition and is associated with

considerable morbidity and mortality. The systemic effects from
pancreatic inflammation can lead to multiple organ failure, with
patients requiring long admissions to the ICU. Decisions about
antimicrobial use and timing of surgery are not straightforward.
Optimal management involves close working between intensivists,
Page 17 of 20

microbiologists, radiologists, and surgeons as well as

multidisciplinary team working providing supportive care and long-
term rehabilitation.
References
1. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute
pancreatitis—2012: revision of the Atlanta classification and definitions
by international consensus. Gut. 2013;62:102–11.
2. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC.
Prognostic signs and the role of operative management in acute
pancreatitis. Surg Gynecol Obstet. 1974;139:69–81.
3. Blamey SL, Imrie CW, O’Neill J, Gilmore WH, Carter DC. Prognostic
factors in acute pancreatitis. Gut. 1984;25:1340–6.
4. Balthazar EJ, Ranson JH, Naidich DP, Megibow AJ, Caccavale R, Cooper
MM. Acute pancreatitis: prognostic value of CT. Radiology. 1985;156:767–
72.
5. Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis:
value of CT in establishing prognosis. Radiology. 1990;174:331–36.
6. Waldmann C, Soni N, Rhodes A. Oxford Desk Reference: Critical Care.

Oxford: Oxford University Press; 2008.
7. Hall NA, Fox AJ. Renal replacement therapies in critical care. Cont
Educ Anaesth Crit Care Pain. 2006;6:197–202.
8. Lankisch PG, Apte M, Banks P. Acute pancreatitis. Lancet.

2015;386:85–96.
9. Tenner S, Baillie J, DeWitt J, Vege SS. American College of

Gastroenterology guideline: management of acute pancreatitis. Am J Gast.
2013;108:1400–15.
10. Oudemans-van Straaten HM, Kellum JA, Bellomo R. Clinical review:

anticoagulation for continuous renal replacement therapy—heparin or
citrate? Crit Care. 2011;15:202.
11. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach
or open necrosectomy for necrotizing pancreatitis (PANTER trial). N Engl
J Med. 2010;362:1491–502.
12. Young SP, Thompson JP. Severe acute pancreatitis. Cont Educ Anaesth
Crit Care Pain. 2008;8:125–8.
13. Johnson CD, Besselink MG, Carter R. Acute pancreatitis. BMJ.

2014;349:g4859.
Page 18 of 20

14. Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis

against infection of pancreatic necrosis in acute pancreatitis. Cochrane
15. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition,

outcome measures, animal models, fluid therapy and information
technology needs: the Second International Consensus Conference of the
Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 2004;8:R204–
12.
16. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network:
report of an initiative to improve outcomes in acute kidney injury. Crit
Care. 2007;11:R31.
17. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney

Injury Work Group. KDIGO clinical practice guideline for acute kidney
injury. Kidney Int Suppl. 2012;2:1–138.
18. Belloma R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose

dopamine in patients with early renal dysfunction: a placebo-controlled
randomised trial. Australian and New Zealand Intensive Care Society
(ANZICS) Clinical Trials Group. Lancet. 2000;356:2139–43.
19. Majumdar A. Sepsis-induced acute kidney injury. Indian J Crit Care

Med. 2010;14:14–21.
20. National Confidential Enquiry into Patient Outcome and Death

(NCEPOD). Adding Insult to Injury. London: NCEPOD; 2009. Available
from: http://www.ncepod.org.uk/2009report1/Downloads/AKI_report.pdf.
21. Ronco C, Kellum JA, Mehta R. Acute Dialysis Quality Initiative (ADQI).
Nephrol Dial Transplant. 2001;16:1555–8.
22. Intensive Care Society. Standards and Recommendations for the

Provision of Renal Replacement Therapy on Intensive Care Units in the
United Kingdom. London: Intensive Care Society; 2009. Available from:
https://www.ics.ac.uk/ICS/guidelines-and-standards.aspx.
23. Gettings LG, Reynolds HN, Scalea T. Outcome in post-traumatic acute

renal failure when continuous therapy is applied early vs late. Intensive
Care Med. 1999;25:805–13.
24. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in

continuous venovenous haemofiltration on outcomes of acute renal
failure: a prospective randomised trial. Lancet. 2000;356:26–30.
25. Wang C, Lv LS, Huang H, et al. Initiation time of renal replacement

therapy on patients with acute kidney injury: a systematic review and
meta-analysis of 8179 participants. Nephrology (Carlton). 2016;22:7–18.
Page 19 of 20

26. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed

initiation of renal replacement therapy on mortality in critically ill
patients with acute kidney injury: the ELAIN Randomized Clinical Trial.
JAMA. 2016;315:2190–9.
27. Park JY, An JN, Jhee JH, et al. Early initiation of continuous renal
replacement therapy improves survival of elderly patients with acute
kidney injury: a multicenter prospective cohort study. Crit Care.
2016;20:260.
28. Xu Y, Gao J, Zheng X, Zhong B, Na Y, Wei J. Timing of initiation of renal

replacement therapy for acute kidney injury: a systematic review and
meta-analysis of randomized-controlled trials. Clin Exp Nephrol.
2017;552–62.
29. Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-

replacement therapy in the intensive care unit. N Engl J Med.
2016;375:122–33.
30. Gatward J, Gibbon GJ, Wrathall G, Padkin A. Renal replacement

therapy for acute renal failure: a survey of practice in adult intensive care
units in the United Kingdom. Anaesthesia. 2008;63 959–66.
31. Bell M, Martling C-R. Long-term outcome after intensive care: can we
protect the kidney? Crit Care. 2007;11:147–9.
32. Schneider AG, Bellomo R, Bagshaw SM, et al. Choice of renal

replacement therapy modality and dialysis dependence after acute kidney
injury: a systematic review and meta-analysis. Intensive Care Med.
2013;39:987–97.
33. Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of
acute renal failure. N Eng J Med. 2002;346:305–10.
34. Wright SE, Bodenham A, Short A, Turney JH. The provision and
practice of renal replacement therapy on adult intensive care units in the
United Kingdom. Anaesthesia. 2003;58:1063–9.
35. Pallevsky PM, Zhang JH, O’Connor TZ, et al. The VA/NIH Acute Renal
Failure Trial Network. Intensity of renal support in critically ill patients
with acute kidney injury. N Engl J Med. 2008;359:7–20.
36. Bellomo R, Cass A, Cole L, et al. The RENAL Replacement Therapy

Study Investigators. Intensity of continuous renal replacement therapy in
critically ill patients. N Engl J Med. 2009;361:1627–38.
Page 20 of 20

Feeding, access, and thromboprophylaxis

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Feeding, access, and thromboprophylaxis
Author(s): Martin Huntley
DOI: 10.1093/med/9780198814924.003.0013
Expert commentary by Ramani Moonesinghe
Case history
A 38-year-old man presented to the emergency department with a

3-day history of abdominal pain and vomiting. He had had a poor diet for
the past month because of intermittent abdominal cramps and vomiting
after eating. He had a history of fistulating Crohn’s disease that had been
treated with monoclonal antibody therapy in the past. His current
medications included mesalazine 2 g once daily, azathioprine 100 mg
once daily, lansoprazole 30 mg once daily, ferrous sulphate 200 mg three
times daily, and Calcichew D3 forte 2 tablets once daily. He had a body
mass index (BMI) of 15.2 kg/m2.
On examination, he was tachycardic, tachypnoeic, and had cool

peripheries with a capillary refill time greater than 4 seconds. His
abdomen was distended, painful on palpation with generalized guarding,
Page 1 of 27
and absent bowel sounds. His initial blood results are presented in Table
13.1.
Table 13.1 Blood results on presentation
Arterial blood gas (FiO2 0.35)
pH 7.14 (7.35–7.45)
PaCO2 (kPa) 2.7 (4.7–6)
PaO2 (kPa) 18 (>10)
BE (mmol/L) −12 (±2)
Full blood count
Hb (g/L) 82 (130–180)
MCV (fL) 74 (76–96)
Plat (×109/L) 64 (150–400)
WCC (×109/L) 3.7 (4–11)
Clotting
INR 1.6
PT (sec) 19.2 (10.7–13.6)
APTT (sec) 46 (21–34)
Fib (g/L) 0.6 (1.5–4)
Na (mmol/L) 131 (135–145)
K (mmol/L) 3.0 (3.5–5)
Urea (mmol/L) 16 (2.5–6.7)
Page 2 of 27

Cr (μmol/L) 115 (60–110)
Alb (g/L) 18 (35–50)
CRP (mg/L) 365 (<10)
Alb, albumin; APTT, activated partial thromboplastin time; BE, base

excess; Cr, creatinine; CRP, C-reactive protein; Fib, fibrinogen; FiO2,
fraction of inspired oxygen; Hb, haemoglobin; K, potassium; MCV,
mean corpuscular volume; Na, sodium; PaCO2, partial pressure of
carbon dioxide; PaO2, partial pressure of oxygen; Plat, platelets; PT,
prothrombin time; WCC, white cell count.
EXPERT COMMENT
This patient has presented with an acute crisis on the background of

severe chronic disease, as manifest by his clinical history, low BMI,
and treatment for iron deficiency anaemia (but despite this,
presenting with a microcytic anaemia). The high creatinine
concentration is particularly alarming in the context of such a low
BMI—indicating that the degree of renal impairment is much more
substantial than the blood tests alone may indicate.
After initial resuscitation with 30 mL/kg of intravenous crystalloid and

administration of broad-spectrum antibiotics, he was transferred for an
abdominal computed tomography scan. This showed gross small bowel
dilatation with mucosal thickening and free air and fluid in the peritoneal
cavity. He was transferred urgently to the operating room where he had a
right internal jugular central line and radial arterial line inserted and was
anaesthetized for an emergency laparotomy. He was found to have
multiple small bowel perforations and faecal peritonitis, and underwent
extensive adhesiolysis, small bowel resection, and formation of an end
ileostomy. He received multiple blood products intraoperatively for an
estimated blood loss of 1.3 L.
EXPERT COMMENT
Emergency laparotomy is a high-risk procedure—data from the UK’s

National Emergency Laparotomy Audit indicate a population
mortality of 11%. Although this patient is young, he has several
features which place him at very high risk of a poor outcome,
including chronic ill health, faecal peritonitis, and the requirement for
significant blood and fluid transfusion. The principles of management
Page 3 of 27

for these high-risk patients include consultant delivered care, surgery

to be conducted as soon as possible, and postoperative critical care
admission. Risk stratification at the time of diagnosis and at the end
of surgery, using an objective risk score such as P-POSSUM
(Portsmouth Physiological and Operative Severity Score for the
Enumeration of Mortality and Morbidity) or the Surgical Outcome
Risk Tool (SORT; http://www.sortsurgery.com), alongside clinical
judgement from senior anaesthetists and surgeons, will also support
decision-making and optimal management (see Case 9).
Following surgery, he is transferred to the intensive care unit (ICU) with

propofol and fentanyl sedation, mechanical ventilation, and a
noradrenaline infusion at 0.45 mcg/kg/min. Overnight he is resuscitated
with further crystalloid and blood products and is started on a
vasopressin infusion and hydrocortisone 50 mg four times daily for
persistent hypotension. On day 1, he is reviewed by the general surgical
registrar who enquires about nutritional support for the patient.
LEARNING POINT The when, what, and how of

feeding in critical illness
The catabolic state associated with critical illness can lead rapidly to
a progressive energy deficit that is associated with adverse clinical
outcomes, for example, prolonged mechanical ventilation, increased
rates of infection, poor wound healing, and loss of gastrointestinal
integrity [1, 2]. In view of this, nutritional support in critical care has
stimulated substantial interest [3]. The timing, route of delivery, and
amount and type of nutrients that are administered has been the
focus of research in this area.
The Early Parenteral Nutrition Completing Enteral Nutrition in Adult

Critically Ill Patients (EPaNIC) trial, randomized 4640 ICU patients
with insufficient enteral nutrition to either additional parenteral
nutrition within 48 hours (early) of ICU admission or after at least 7
days (late) [4]. The trial showed no difference in ICU, hospital, or 90-
day mortality between groups and a higher rate of infections,
duration of mechanical ventilation, hospital length of stay, and total
healthcare cost in the early intervention group. An important
criticism of this trial was that it consisted of low mortality-risk
patients (ICU mortality = 6.2%) and excluded malnourished patients
(BMI <17 kg/m2), which limits the ability to generalize these finding
to higher-risk ICU patients.
The initial trophic versus full enteral feeding in patients with acute
lung injury (EDEN) trial studied a more specific high-risk group of
patients with acute lung injury and found no difference in 60-day
Page 4 of 27

mortality, organ failure, or ICU-free days, or incidence of infection

between the two groups [5]. Full enteral-fed patients did experience
more gastrointestinal intolerances; however, the incidence of this was
relatively low and may have been biased by the open-label design of
the study.
The Tight Calorie Control Study (TICACOS) also evaluated higher-risk

ICU patients, and showed that providing enteral nutrition supported
by additional parenteral nutrition significantly reduced in-hospital
and 60-day mortality [6]. This suggests that meeting calorie
requirements early with additional parenteral nutrition is beneficial
and safe.
More recently, the Intensive Care National Audit and Research Centre
(ICNARC) conducted a multicentre randomized controlled trial (RCT)
of the route of early nutritional support in critically ill patients
(CALORIES) [7]. This was a pragmatic trial, which included a
heterogeneous ICU patient population who had an unplanned
admission and were expected to remain on the ICU for at least 3 days.
The trial showed no difference in 30-day mortality or infectious
complications between groups receiving enteral or parenteral
nutrition. Importantly, more than 60% of patients failed to reach their
calorie targets during the trial, which highlights a significant problem
with feeding protocols in ICU patients.
Summary points:
1. Patients commonly develop a nutritional deficit during critical

illness that increases the probability of adverse outcomes.
2. Patients receiving artificial nutrition on the ICU often fail to
reach their daily nutritional targets.
3. Current evidence favours early initiation (i.e. within 24–48
hours) of feeding in critical illness.
4. Assessment of nutritional intake should form part of the daily
multidisciplinary review of the ICU patient so that the adequacy
and most appropriate route of nutritional support can be
determined (Figure 13.1).
5. If patients are unable or unlikely to tolerate enteral nutrition,
then the parenteral route can be used safely.
EXPERT COMMENT
Previous concerns about the safety of enteral nutrition following

emergency gastrointestinal surgery, particularly where there has
been an intestinal anastomosis, have now been appeased. Principles
of enhanced recovery support early return to enteral nutrition.
However, in this patient, there are several additional factors which
Page 5 of 27

may indicate that enteral nutrition may not be successful, such as

multiple organ dysfunction, particularly with the use of vasoactive
drugs, and the requirement for sedation including opioid therapy.
Therefore, starting parenteral nutrition as opposed to enteral
nutrition seems sensible and justified by the evidence.
Figure 13.1
Suggested decision pathway for nutritional support.
The ICU team decided to start early parenteral nutrition because of his
extensive bowel surgery, pre-existing malnutrition, and likely
gastrointestinal dysfunction. A standard formula was ordered from
pharmacy and started while awaiting review by the ICU dietician.
EXPERT COMMENT
In view of his likely chronic malnutrition and his acute critical illness,
estimation of this patient’s caloric and other dietary requirements is
likely to be challenging. Thus, expert review by the dietician is
important. Although the Surviving Sepsis Campaign guidelines make
a strong recommendation against the use of early parenteral nutrition
in sepsis, the trials contributing to this systematic review either
excluded or rarely incorporated patients who were malnourished.
These patients may represent a particular subgroup where early
parenteral nutrition could be considered when enteral nutrition is not
feasible.
Page 6 of 27

LEARNING POINT Predicting caloric requirements in

critical illness
Calculating caloric requirements in critical illness is difficult and may

involve the use of either predictive formulas (e.g. Oxford, Harris
Benedict, or Schofield) or indirect calorimetry [3, 8].
Predictive formulas are simpler to use but they are not as accurate as
indirect calorimetry, especially in certain patient groups (e.g. obesity).
They are also modelled on afebrile healthy individuals, which may
limit their relevance to ICU patients.
Indirect calorimetry calculates caloric requirement by measuring the

patient’s inspired and expired gases and directly relating the
measured oxygen consumption (VO2) and carbon dioxide production
(VCO2) to the oxidation of substrate fuel. The REE can then be
calculated by using the abbreviated Weir equation:
It is a more accurate and reproducible method that has been shown

to increase the amount of nutrition received by ICU patients [6].
However, its use is limited by the technical difficulty of performing it,
and consequently most ICU dieticians use predictive formulas and
make adjustments for specific patient factors (Table 13.2).
Table 13.2 Calorie adjustments for specific patient factors
Patient factor Additive calorie adjustment
Fever ↑ by 10% for each 1°C above 37°C (max.

40°C)
Sepsis ↑ by 9%
Surgery or ↑ by 6%
trauma
Burns ↑ by 100% for any size >30%
Source: data from Bratanow, S. and Brown, S. Nutrition in the

critically ill. Update in Anaesthesia. 2012; 28, 79–87. Copyright ©
2012 World Federation of Societies of Anesthesiologists.
Page 7 of 27

EXPERT COMMENT
Indirect calorimetry measures CO2 production and O2 consumption

(using a device known as a metabolic cart) to calculate the total
energy production. In ventilated patients in critical care, the
metabolic cart interacts with the ventilator via the tracheal tube; in
spontaneously breathing patients, a face mask, canopy (hood), or
Douglas bag (inflatable airtight bag) are used. Both the respiratory
quotient and the resting energy expenditure (REE) (which can be
used to calculate 24-hour caloric requirements) are provided.
LEARNING POINT How to commence feeding in

critical illness
● It is not necessary to correct low plasma electrolyte values

before commencing feeding [9].
● Start enteral nutrition or parenteral nutrition at less than 50% of
the estimated target energy and protein needs.
● Increase to meet full needs over the first 24–48 hours according
to the metabolic and gastrointestinal tolerances.
● Provide the full requirement of fluid, electrolytes, vitamins, and
minerals from the outset of feeding.
LEARNING POINT What are the components of basic

nutritional support?
Macronutrients
These are the main sources of energy and include proteins (4 kcal/g),
lipids (9.3 kcal/g), and carbohydrates (3.75 kcal/g) [8]. The suggested
total daily calorie requirement is estimated at 25–35 kcal/kg [9]. The
contribution made to this by proteins and lipids should be calculated
first and the remainder made up by carbohydrates (Table 13.3).
Table 13.3 The daily requirement of macronutrients
Macronutrient Daily requirement
Protein 0.8–1.5 g/kg
Page 8 of 27

Lipid 40% of total calories
Carbohydrate 3–4 g/kg

2012 World Federation of Societies of Anesthesiologists.
Micronutrients
These include trace elements (e.g. zinc, copper, and selenium) and
vitamins (e.g. thiamine (B1), riboflavin (B2), and vitamin D) [8]. They
play vital roles in enzyme function and the metabolic pathways
essential to health and recovery from critical illness [10].
Micronutrient deficiencies contribute to reduced antioxidant defence
and impaired immune function resulting in increased complication
rates (e.g. infection and poor wound healing). Despite their
widespread use in ICUs, clinical trials involving several
micronutrients (e.g. selenium and vitamin D) have failed to show a
significant mortality benefit in ICU patients and they remain a
controversial area of nutritional support [11, 12].
Fluid and electrolytes

The daily maintenance requirements for fluid and electrolytes are
listed in Table 13.4. Allowances should also be made for pre-existing
deficits, extra losses (e.g. drains and fistulae), and extra input (e.g.
intravenous drugs).
Table 13.4 Daily maintenance fluid and electrolyte requirement
Fluid Electrolyte Daily requirement
Water 30 mL/kg
Sodium 1–1 mmol/kg
Potassium 0.7–1 mmol/kg
Calcium 0.1 mmol/kg
Magnesium 0.1 mmol/kg
Chloride 1–2 mmol/kg
Phosphate 0.4 mmol/kg
Page 9 of 27


2012 World Federation of Societies of Anesthesiologists; and
National Institute for Health and Care Excellence (NICE). (2006)
Guidance for nutrition support in adults: oral nutrition support,
enteral tube feeding and parenteral nutrition. Copyright © 2006
NICE.
LEARNING POINT The changing focus of nutrition
The concept of nutrition in critical care is progressively changing

from a purely ‘supportive’ to a more ‘therapeutic’ focus, where the
constituents of nutritional formulations can be altered to improve the
management of certain disease states [8, 10]. This may be through
preventing certain disease-specific complications, reducing oxidative
stress and inflammation, enhancing beneficial stress responses, or
reducing gastrointestinal dysfunction (Table 13.5).
Table 13.5 Potential formulations for specific disease states
Disease state Formulation Effect
Liver failure ↓ Na+ ↓ Ascites and

oedema
Altered amino acids ↓ Encephalopathy
Renal failure ↓ PO42− and K+ ↓ Electrolyte excess
↑ Calorie ↓ Volume
concentration (2
kcal/mL)
Respiratory ↑ Lipid: ↓ CO2 and improved

failure carbohydrate ratio weaning
Acute ↑ Micronutrients ↑ Antioxidant effect

respiratory
distress ↑ Fish and borage ↑ Anti-inflammatory
syndrome oil effect
Page 10 of 27

Surgery, ↑ Arginine and Maintains immune

trauma, and glutamine cells and facilitates
burns tissue repair
Intestinal ↓ Fibre ↓ Gut transit time

failure
↑ Hydrolysed ↑ Absorption
proteins and
medium-chain
triglycerides
↑ Probiotics ↑ Protective bowel

flora

Excellence (NICE). (2006) Guidance for nutrition support in adults:
oral nutrition support, enteral tube feeding and parenteral
nutrition. Copyright © 2006 NICE; and Hegazi, R., et al. Clinical
review: optimizing enteral nutrition for critically ill patients – a
simple data-driven formula. Critical Care 2011; 15:234. Copyright
© 2006 BioMed Central Ltd.
LEARNING POINT Summary guidelines for feeding in

critical illness
● Haemodynamically stable patients with a functioning

gastrointestinal tract who are not expected to be on a full oral diet
within 3 days should receive enteral nutrition within 24 hours of
admission.
● In patients where enteral nutrition is not feasible, there is
currently no clear benefit for commencing early parenteral
nutrition and consequently intravenous glucose should be initiated
with enteral feeds advanced as tolerated. However, malnourished
patients may represent a particular subgroup of critically ill
patients who benefit from early parenteral nutrition if enteral
nutrition is not feasible [13, 14, 15].
● In the absence of indirect calorimetry, patients should receive 25
kcal/kg/day increasing to target over the following 2–3 days.
● All patients receiving less than their targeted enteral feeding
after 2 days should be considered for supplementary parenteral
nutrition.
● All parenteral nutrition prescriptions should include a daily dose
of multivitamins and trace elements.
Page 11 of 27

● The use of gastric residual volume as a marker of intolerance to

enteral feeding and for preventing aspiration is controversial and
poorly evidence based [16].
● Traditional practice is to slow or stop enteral nutrition if residual
gastric volumes exceed 200 mL every 4 hours. Using a higher
threshold for gastric residual volume (>500 mL) improves the
provision of enteral nutrition without clearly increasing the risk of
ventilator-associated pneumonia [17, 18].
● Consider intravenous metoclopramide and/or erythromycin in
patients with high gastric residual volumes.
● Position patients receiving enteral nutrition at 30° head
elevation to reduce the risk of aspiration and ventilator-associated
pneumonia.
● There is no need to ‘rest’ patients receiving enteral feeding
overnight.
● Avoiding gastric acid suppression and allowing breaks in enteral
feeding to let gastric pH decrease help to prevent bacterial
overgrowth.
● Hyperglycaemia (glucose >10 mmol/L) should be avoided/
treated in order to minimize infectious complications.
EXPERT COMMENT
Small intestinal bacterial overgrowth is an over-proliferation of

bacteria in this part of the bowel which is usually much less colonized
than the large bowel. It can lead to abdominal bloating, pain, nausea,
vomiting/poor absorption of feed, and diarrhoea with consequent
risks of malnutrition and weight loss. In critically ill patients,
therefore, the commonest presentation will be poor absorption.
Elemental diets or cyclical antibiotic therapy may be used to treat
this.
Use of gastric acid suppression in critically ill patients is generally

considered to be unnecessary once full enteral feeding is established,
unless there is a particularly high risk of gastrointestinal bleeding. In
general hospital settings, three systematic reviews have concluded
that proton pump inhibitors (PPIs) are associated with an increased
risk of Clostridium difficile (toxin) (CDT) infection, and while a causal
link has not been established, the use of PPIs has been discouraged in
critical care, where H2 antagonists can be used as an alternative [19,
20, 21]. However, a recent meta-analysis specifically of critical care
trials found that PPIs were superior to H2 antagonists in the
prevention of significant gastrointestinal bleeding and did not lead to
a greater risk of pneumonia or mortality; however, none of the 19
Page 12 of 27

trials reported CDT infection, and therefore the concern about CDT
preponderance in critically ill patients has not been addressed [22].
While trials in this area are continuing (e.g. SUP-ICU), it may be
preferable to use H2 antagonists as first-line therapy for gastric
protection, unless the patient is on long-term PPIs or there is a reason
to consider the patient at high risk for gastrointestinal bleeding. Once
enteral feed has been fully established, gastric acid suppression can
be stopped, again unless there is an indication to continue it because
the patient is at high risk for gastrointestinal bleeding.
The central venous catheter (CVC) that was inserted in the operating
theatre did not have any sterile ports and so a peripherally inserted
central catheter (PICC) line was inserted into his right cephalic vein. The
position was confirmed on chest radiography and the administration of
parenteral nutrition was started.
EXPERT COMMENT
If a patient is likely to need parenteral nutrition within 5 days of

inserting a CVC then it is advisable to keep one lumen sterile so that
it can be used and prevent the need to obtain additional central
venous access.
This patient seems like he may require longer-term nutrition, because

of his chronic ill health; therefore, a tunnelled line might be of value.
However, until the risk of sepsis has reduced, it is likely to be more
beneficial to manage him with short-term lines.
LEARNING POINT European Society of Parenteral

and Enteral Nutrition (ESPEN) guidelines for venous
access in parenteral nutrition
Route
● A CVC should be used for most patients receiving parenteral

nutrition [23].
● Peripheral access (short cannula or midline catheter) can be
used safely for a limited period with solutions that have an
osmolarity < 850 mOsm/L.
Device
● Short term—peripheral cannula, non-tunnelled CVC, and PICC.
Page 13 of 27

● Medium term—tunnelled CVC and ports, and PICC.

● Long term—tunnelled CVC and totally implantable devices.
Vein
● The choice of vein is affected by several factors (i.e. familiarity

with technique, body habitus, risk of complications, and presence
of thrombus and/or infection).
● The subclavian vein has the lowest rate of infectious
complications, followed by the internal jugular and femoral vein.
● High approaches to the internal jugular vein restrict nursing
access and increase the risk of catheter contamination and
infection.
EXPERT COMMENT
A midline catheter is a peripherally inserted catheter which is shorter

than a PICC and does not lie in a central vein—that is, the tip usually
lies in the axillary vein. It is more secure than a short peripheral
cannula and is commonly used for prolonged antibiotic courses.
LEARNING POINT Intravascular complications of

central venous catheter insertion
In a multicentre trial published in 2015, 3027 adult ICU patients were

randomly assigned to have a non-tunnelled CVC inserted in either the
subclavian, jugular, or femoral vein [24]. A total of 3471 catheters
were inserted and the median duration of catheter use was 5 days.
Catheterization of the subclavian vein, as compared with the jugular

or femoral vein, was associated with a significantly lower risk of
catheter-related bloodstream infection (0.5% vs 1.4% vs 1.2%
respectively) and symptomatic deep vein thrombosis (DVT) (0.5% vs
1.4% vs 1.2% respectively). However, the subclavian vein was
associated with a higher risk of mechanical complications (2.1% vs
1.4% vs 0.7% respectively), which was primarily pneumothorax
(1.5%). Interestingly, the risk of catheter-related bloodstream
infection and symptomatic DVT was similar for jugular and femoral
sites.
This trial highlights the significant complication rates associated with

CVC insertion, despite the increasing use of ultrasound guidance.
This is often an underappreciated problem, which accounted for 14%
Page 14 of 27

of all litigation claims associated with intensive care treatment in

England between 1995 and 2012 [25].
LEARNING POINT Prevention and management of

catheter-related infection
Interventions to reduce the risk of catheter-related

infection
(For guidance, see references [23, 26].)
● Regular education and competence-based training of staff

involved in catheter insertion and/or care.
● Appropriate choice of catheter insertion site.
● Use of an all-inclusive catheter insertion kit and a procedural
checklist.
● Use of single-lumen catheters whenever possible.
● Use of a chlorhexidine/silver sulfadiazine or antibiotic-
impregnated catheter if it is expected to remain in place for longer
than 5 days.
● Ultrasound-guided venepuncture.
● Maximal barrier precautions during insertion.
● An appropriate hand-washing policy.
● Use of 2% chlorhexidine on the skin at insertion and for daily
washes on ICU.
● Appropriate dressing of the exit site.
● Disinfection of hubs, stopcocks, and needle-free connectors
before accessing.
● Regular change of administration sets.
● Daily review of the catheter insertion site.
● Prompt removal of catheters when central access is no longer
required.
There is no evidence to suggest that routine, scheduled replacement

of catheters reduces the risk of catheter-related infections and
therefore the decision to replace a catheter should be based on
clinical assessment and culture results [27].
Diagnosis of catheter-related infection
● Quantitative or semi-quantitative culture of the catheter tip

(after removal), or
● Paired quantitative blood cultures or paired qualitative blood
cultures from a peripheral vein and the catheter.
Page 15 of 27

Treatment of catheter-related sepsis (short-term lines)
● A short-term CVC should be removed if there are:
◦ signs of local infection at the exit site

◦ clinical signs of sepsis in the absence of other obvious sources
◦ positive paired blood cultures.
● Where there is suspicion of infection, the tip should be sent for

culture and this may assist in diagnosis of line-associated infection
and choice of appropriate antibiotics.
● Appropriate antibiotic therapy should be continued after
catheter removal.
Treatment of catheter-related sepsis (long-term lines)
● A long-term CVC should be removed if there is:
◦ tunnel infection or port abscess

◦ clinical signs of septic shock
◦ positive paired blood cultures for fungi or highly virulent
bacteria
◦ complicated infection (e.g. endocarditis, septic thrombosis).
In patients who have limited or difficult venous access, an attempt to

save the device may be tried by ‘locking’ the line with antibiotic.
Vancomycin is commonly used as empirical therapy in view of the
prevalence of methicillin-resistant Staphylococcus aureus in
healthcare settings [28].
On day 4, he became confused, hypotensive, and developed atrial

fibrillation. On examination, he had cool peripheries and reduced muscle
power. His repeat blood results are shown in Table 13.6.
Table 13.6 Repeat blood results
PO42− (mmol/L) 0.2 (0.8–1.4)
Mg2+ (mmol/L) 0.5 (0.7–1.0)
K+ (mmol/L) 2.7 (3.5–5.0)
Page 16 of 27

LEARNING POINT Refeeding syndrome
Refeeding syndrome is a potentially fatal complication that may occur

when initiating artificial nutrition in a malnourished patient [9, 29].
The characteristic biochemical feature of this syndrome is
hypophosphataemia but other fluid and electrolyte disturbances
commonly occur (Figure 13.2).
Figure 13.2
Pathophysiology and clinical manifestations of refeeding syndrome.
LEARNING POINT Identifying patients at risk of

refeeding syndrome
Patients at high risk of refeeding syndrome should be identified on

admission to the ICU. This is to ensure that close monitoring and
timely replacement of electrolytes and vitamins occurs, and if
necessary, the appropriate clinical specialists are involved in their
management at the earliest opportunity (Figure 13.3).
Page 17 of 27

Figure 13.3
Managing patients at high risk of refeeding syndrome.
Source: data from National Institute for Health and Care Excellence
(NICE) (2006). Guidance for nutrition support in adults: oral nutrition
support, enteral tube feeding and parenteral nutrition. Copyright ©
2006 NICE.
National Institute for Health and Care Excellence

criteria for patients at risk of refeeding syndrome
Patient has one or more of the following [9]:
● BMI less than 16 kg/m2.

● Unintentional weight loss greater than 15% within the last 3–6
months.
● Little or no nutritional intake for longer than 10 days.
● Low concentrations of potassium, phosphate, or magnesium
prior to feeding.
Or patient has two or more of the following [9]:
● BMI less than 18.5kg/m2.

● Unintentional weight loss greater than 15% within the last 3–6
months.
● Little or no nutritional intake for longer than 5 days.
● A history of alcohol abuse or drugs including insulin,
chemotherapy, antacids, or diuretics.
Page 18 of 27

He was given intravenous replacement of phosphate, potassium, and

magnesium and commenced on an insulin infusion to control his blood
glucose. He was also started on regular intravenous vitamin B
replacement (a 7-day course). The parenteral nutrition rate was gradually
increased over the next week during which time his electrolytes were
monitored closely. On day 9, he suddenly developed a swollen, painful,
and warm left arm and the nurse looking after him commented that she
was no longer able to aspirate blood from the PICC line. An urgent
Doppler ultrasound scan of his left arm showed a DVT involving the left
axillary and subclavian veins.
LEARNING POINT Prevention of catheter-related

central venous thrombosis
Critically ill patients exhibit several general and ICU acquired risk
factors (Table 13.7) for venous thromboembolism and the incidence of
DVT in those not treated with thromboprophylaxis can be as high as
81% [30]. In view of this, almost all ICU patients will require
pharmacological thromboprophylaxis. This presents several
challenges for the intensivist as haemorrhage, coagulopathy, and
thrombocytopenia are common in ICU patients. Furthermore, the
need for effective thromboprophylaxis often must be balanced
carefully with the need for antiplatelet therapy, for example, acute
coronary syndromes, invasive procedures and expectant surgery.
Table 13.7 Risk factors for venous thromboembolism
General ICU acquired
Increased age Sepsis
Past history of venous Vasopressor use

thromboembolism
Past history of cancer Respiratory or cardiac

failure
Immobilization Pharmacological sedation
Obesity Mechanical ventilation
Pregnancy Central venous catheter
Trauma, spinal cord injury End-stage renal failure
Page 19 of 27

Recent surgery
Stroke
Source: data from Hegazi, R., et al. Clinical review: optimizing

enteral nutrition for critically ill patients – a simple data-driven
formula. Critical Care 2011; 15:234. Copyright © 2006 BioMed
Central Ltd.
CVC insertion in ICU patients is a significant risk factor for venous

thromboembolism, with catheter-related thrombosis rates of 10–69%
with femoral catheters, 40–56% with internal jugular catheters, and
2–10% with subclavian catheters [31]. The risk of thrombosis
increases with the duration of catheter placement, but while the risk
of pulmonary embolism (PE) increases fourfold with a lower-limb DVT,
there doesn’t appear to be an increased risk of PE with an upper-limb
DVT.
Several strategies to reduce catheter-related thrombosis have been

suggested [26]:
● Use an insertion technique that limits damage to the vein, such

as:
◦ ultrasound guidance at insertion

◦ selection of the smallest calibre compatible with the required
infusion therapy
◦ positioning the tip of the catheter at or near the atriocaval
junction.
● Use of a CVC rather than a PICC. There is a higher reported rate

of upper extremity superficial venous thrombosis with PICCs,
especially in critically ill and cancer patients [32].
● Use routine thromboprophylaxis in all critically ill patients
unless contraindicated.
ICU patients should also be considered routinely for mechanical

protection against venous thromboembolism (pneumatic calf pumps
and compression stockings) and active early immobilization.
CLINICAL TIP Correct positioning of a central venous

catheter
A well-positioned CVC should be ±2 cm from the carina on the chest

radiograph, with the tip not pointing at the wall of the superior vena
cava. Other methods for establishing correct positioning include
Page 20 of 27

Peres’ height formula (height (cm)/10 for the right internal jugular
vein (IJV) and (height (cm)/10) + 4 cm for the left IJV) and the use of
electrocardiographic guidance. Catheters that are too short may
result in drug extravasation from proximal lumens that are not in the
vein, an increased risk of DVT because of slow venous flow, and poor
drug dissemination. Catheters that are too long or point directly at
the vessel wall may result in arrhythmias, damage to the tricuspid
valve, or erosion and puncture of the vessel wall (especially when
larger diameter catheters are used, e.g. Vascaths).
His parenteral nutrition was discontinued, the PICC line was removed,
and he was prescribed treatment dose low-molecular-weight heparin.
After discussion with the general surgeons and dietician, the decision was
made to commence enteral nutrition at an initial rate of 10 mL/hour. This
is increased over the next 4 days; however, he developed abdominal pain,
a high stoma output, and steatorrhoea. Because of this, he developed a
negative fluid balance and it became difficult to maintain his electrolyte
levels.
LEARNING POINT Short bowel syndrome
Short bowel syndrome is a rare condition where patients are

incapable of maintaining adequate nutrition and hydration through
oral intake because of a reduction in functional intestinal area [33].
This may be the consequence of small bowel resection, when less
than 200 cm of small bowel remains, or diseases that affect the
absorptive capacity of the intestines (e.g. radiation enteritis) [34, 35,
36]. The characteristic symptoms of short bowel syndrome are:
● abdominal pain
● diarrhoea and steatorrhoea
● fluid and micronutrient depletion (often with high stoma output)
● weight loss and malnutrition
● fatigue.
Short bowel syndrome may be permanent or temporary depending on

the ability of the remaining small bowel to increase its absorptive
capacity. Most patients with short bowel syndrome develop complex
long-term nutritional problems because of intestinal failure and
require a coordinated multidisciplinary team approach to manage
their disease during the acute ICU admission, on the general ward
and on discharge to the community (Figure 13.4) [37].
Page 21 of 27

Figure 13.4
The multidisciplinary team management of short bowel syndrome.
Over the next few days he was given further micronutrients and fluid
replacement intravenously and his enteral nutrition formula was altered
to a low-fibre feed with medium-chain triglycerides and hydrolysed
proteins. He was prescribed regular probiotic supplements and started on
codeine phosphate 30 mg four times daily. A multidisciplinary team
meeting was held to discuss his long-term nutritional support and he was
subsequently referred to the interventional radiology department for
insertion of a tunnelled CVC for supplemental parenteral nutrition.
LEARNING POINT Strategies for managing a high

output stoma (>1500 mL/day)
1. Exclude organic causes (e.g. infection, steroid withdrawal,

subacute obstruction, and sepsis).
2. Restrict oral intake to 500 mL/day.
3. Commence loperamide 4 mg four times daily.
4. Add codeine phosphate 15–60 mg four times daily.
5. Commence omeprazole 40 mg twice daily.
6. Consider a trial of antibiotics for bacterial overgrowth.
7. Commence St Mark’s glucose–electrolyte replacement
solution and consider keeping nil by mouth for 24–48 hours.
8. Increase loperamide dose to 8 mg four times daily.
9. Further increase loperamide dose by 2–4 mg.
10. Consider octreotide 200 micrograms three times daily for 3–
4 days.
Page 22 of 27

Discussion
Nutritional support is an evolving area of intensive care medicine

that has the potential to have a significant impact on mortality and
morbidity. Feeding protocols have historically been based on poor-quality
observational or single-centre studies, which have produced inconsistent
and conflicting results. There has recently been a resurgence of interest
in ICU nutrition with investment in larger multicentre RCTs investigating
both pragmatic and specific questions about nutritional support [7].
Nutrition is clearly important for recovery from critical illness [38, 39,
40]. Deciding on how to optimally provide cost-effective support in this
complex heterogeneous group of patients is a real challenge. Critically ill
patients often have gastrointestinal dysfunction and have multiple
interruptions to feeding regimens because of the need for recurrent
surgery, radiological investigations, and dislodgment/complications with
feeding tubes or vascular access. This results in a progressive energy
deficit and it is now increasingly apparent that most ICU patients
regularly fail to reach their nutritional targets [7]. This is compounded by
the fact that feeding guidelines have previously favoured enteral nutrition
because of concerns about the risks of parenteral nutrition [4, 41].
However, the increased incidence of infective complications, previously
associated with parenteral nutrition, is now less evident [6, 7]. This has
facilitated a change in practice to earlier initiation of parenteral nutrition
in patients failing to tolerate enteral nutrition and will hopefully translate
into improved levels of nutrition and patient outcomes in future.
Tailoring nutritional formulas more specifically to patient and clinical

characteristics is another area of development [10], and a wider range of
feeds, additives, and supplements is now available to support this. It is
likely that nutrition will increasingly be considered in terms of a
therapeutic option as opposed to just providing generic support. Similarly,
improved matching of the type and amount of nutritional support at the
various stages of critical illness may help to mitigate the prevalence and
effects of under- and overfeeding. This will rely on an improved
understanding of the patterns of critical illness and the establishment of
more robust mechanisms for determining optimal macro- and
micronutrient requirements. Nutrition in critical care is ultimately going
through a transition from a ‘one-size-fits-all’ approach to a more disease-
and patient-specific approach to prescribing.
A FINAL WORD FROM EXPERT
As with the rest of medicine, critical care nutrition is moving towards

a protocolized but personalized approach. Both patient- and disease-
related factors will influence the route, volume, and content of
nutritional supplementation. Thus, while there is a clear benefit in
Page 23 of 27

conducting large-scale RCTs, the need for focused evaluations in

specific groups of patients should not be overlooked, and may explain
the reason why many large trials are unable to find significant
differences between therapeutic approaches. Further, the role of
technology advancement and improvements in the prevention of
infection associated with intravenous catheterization mean that
previous concerns about parenteral nutrition can be overcome with
careful attention to detail in high-quality generic patient care. The
input of critical care dieticians is important in developing a safe and
effective approach to feeding. Gastrointestinal dysfunction can drive
both malnutrition and the risk of infectious complications, thus
vigilance and maintenance of nutrition via the parenteral route if
required are important principles of management. Future advances,
including developing approaches to measuring demand (by using
indirect calorimetry) so that supply can be more accurately matched
to nutritional demand, may present opportunities for quality
improvement in this field.
References
1. Alberda C, Gramlich L, Jones N, et al. The relationship between
nutritional intake and clinical outcomes in critically ill patients: results
of an international multi-center observational study. Intensive Care Med.
2009;35:1728–37.
2. Peuhkuri K, Vapaatalo H, Korpela R. Even low-grade inflammation

impacts on small intestinal function. World J Gastroenterol.
2010;16:1057–62.
3. Casaer M, Van den Berghe G. Nutrition in the acute phase of critical

illness. N Engl J Med. 2014;370:1227–36.
4. Casaer M, Mesotten D, Hermans, et al. Early versus late parenteral

nutrition in critically ill adults. N Engl J Med. 2011;365:506–17.
5. Rice T, Wheeler A, Thompson B, et al. Initial trophic vs full enteral

feeding in patients with acute lung injury: the EDEN randomized trial.
JAMA. 2012;307:795–803.
6. Singer P, Anbar R, Cohen J, et al. The tight calorie control study

(TICACOS): a prospective, randomized, controlled pilot study of
nutritional support in critically ill patients. Intensive Care Med.
2011;37:601–9.
7. Harvey S, Parrott F, Harrison, et al. Trial of the route of early

nutritional support in critically ill adults (CALORIES). N Engl J Med.
2014;371:1673–84.
Page 24 of 27

8. Bratanow S, Brown S. Nutrition in the critically ill. Update Anaesth.

2012;28:79–87.
9. National Institute for Health and Care Excellence (NICE). Nutrition

Support in Adults: Oral Nutrition Support, Enteral Tube Feeding and
Parenteral Nutrition. Clinical guideline [CG32]. London: NICE; 2006.
Available from: https://www.nice.org.uk/guidance/cg32.
10. Hegazi R, Wischmeyer P. Clinical review: optimizing enteral nutrition

for critically ill patients—a simple data-driven formula. Crit Care.
2011;15:234.
11. Angstwurm M, Engelmann L, Zimmermann T, et al. Selenium in

intensive Care (SIC): results of a prospective randomized, placebo-
controlled, multi-center study in patients with severe systemic
inflammatory response syndrome, sepsis, and septic shock. Crit Care
Med. 2007;35:118–26.
12. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on

hospital length of stay in critically ill patients with vitamin D deficiency:
the VITdAL-ICU randomized clinical trial. JAMA. 2014;312:1520–30.
13. Lochs H, Valentini L, Schutz T, et al. ESPEN Guidelines for adult

enteral nutrition. Clin Nutr. 2006;25:177–360.
14. Cano N, Aparicio M, Brunori G, et al. ESPEN Guidelines for adult

parenteral nutrition. Clin Nutr. 2009;28:359–479.
15. McClave S, Taylor B, Martindale R, et al. Guidelines for the provision

and assessment of nutrition support therapy in the adult critically ill
patient. JPEN J Parenter Enteral Nutr. 2016;40:159–211.
16. Reignier J, Mercier E, Le Gouge, et al. Effect of not monitoring

residual gastric volume on risk of ventilator-associated pneumonia in
adults receiving mechanical ventilation and early enteral feeding. JAMA.
2013;309:249–56.
17. Pinilla J, Samphire J, Arnold C, et al. Comparison of gastrointestinal

tolerance to two enteral feeding protocols in critically ill patients: a
prospective, randomized controlled trial. JPEN J Parenter Enteral Nutr.
2001;25:81–6.
18. Montejo J, Minambres E, Bordeje L, et al. Gastric residual volume

during enteral nutrition in ICU patients: the REGANE study. Intensive
Care Med. 2010;36:1386–93.
19. Tleyjey I, Bin Abdulhak A, Riaz M, et al. Association between proton

pump inhibitor therapy and Clostridium difficile infection: a
contemporary systematic review and meta-analysis. Plos One.
2012;7:e50836.
Page 25 of 27

20. Kwok C, Arthur A, Anibueze C, et al. Risk of Clostridium difficile

infection with acid suppressing drugs and antibiotics: meta-analysis. Am J
Gastroenterol. 2012;107:1011–19.
21. Janarthanan S, Ditah I, Adler D and Ehrinpresis M. Clostrisium

difficile—associated diarrhoea and proton pump inhibitor therapy: a
meta-analysis. Am J Gastroenterol. 2012;107:1001–10.
22. Alshamsi F, Belley-Cote E, Cook D, et al. Efficacy and safety of proton

pump inhibitors for stress ulcer prophylaxis in critically ill patients: a
systematic review and meta-analysis of randomized trials. Crit Care.
2016;20:120.
23. Pittiruti M, Hamilton H, Biffi R, et al. ESPEN guidelines on parenteral

nutrition: central venous catheters (access, care, diagnosis and therapy
complications). Clin Nutr. 2009;28:365–77.
24. Parienti J-J, Mongardon N, Megarbane B, et al. Intravascular

complications of central venous catheterization by insertion site. N Engl J
Med. 2015;373:1220–9.
25. Pascall E, Trehane S-J, Georgiou A, Cook TM. Litigation associated

with intensive care unit treatment in England: an analysis of NHSLA data
1995–2012. Br J Anaesth. 2015;115:601–7.
26. Marschall J, Leonard M, Fakih M, et al. Strategies to prevent central

line-associated bloodstream infections in acute care hospitals: 2014
update. Infect Control Hosp Epidemiol. 2014;35:772–96.
27. McGee D, Gould K. Preventing complications of central venous

catheterization. N Engl J Med. 2003;348:1123–33.
28. Mermel L, Allon M, Bouza E, et al. Clinical practice guidelines for the
diagnosis and management of intravascular catheter-related infection:
2009 update by the Infectious Diseases Society of America. Clin Infect
Dis. 2009;49:1–45.
29. Mehanna H, Moledina J, Travis J. Refeeding syndrome: what it is, and

how to prevent it. BMJ. 2008;336:1495–8.
30. Adriance S, Murphy C. Prophylaxis and treatment of venous

thromboembolism in the critically ill. Int J Crit Illn Inj Sci. 2013;3:143–51.
31. Minet C, Potton L, Bonadona A, et al. Venous thromboembolism in the

ICU: main characteristics, diagnosis and thromboprophylaxis. Crit Care.
2015;19:287.
32. Smith R, Nolan J. Central venous catheters. BMJ. 2013;347:f6570.
33. Storch K. Overview of short bowel syndrome: clinical features,

pathophysiology, impact and management. JPEN J Parenter Enteral Nutr.
2014;38:5S–7S.
Page 26 of 27

34. Pironi L, Arends J, Baxter J, et al. ESPEN endorsed recommendations.

Definition and classification of intestinal failure in adults. Clin Nutr.
2015;34:171–80.
35. O’Keefe S, Buchman A, Fishbein T, et al. Short bowel syndrome and

intestinal failure: consensus definitions and overview. Clin Gastroenterol
Hepatol. 2006;4:6–10.
36. Buchman A, Scolapio J, Fryer J. AGA technical review on short bowel

syndrome and intestinal transplantation. Gastroenterology.
2003;124:1111–34.
37. Matarese L, Jeppesen P, O’Keefe S. Short bowel syndrome in adults:

the need for an interdisciplinary approach and coordinated care. JPEN J
Parenter Enteral Nutr. 2014;38:60S–64S.
38. Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative

intravenous feeding (TPN) on outcome following major surgery evaluated
in a randomized study. Ann Surg. 1993;217:185–95.
39. Simpson F, Doig GS. Parenteral vs. enteral nutrition in the critically ill
patient: a meta-analysis of trials using the intention to treat principle.
40. Giner M, Laviano A, Mequid MM, Gleason JR. In 1995 a correlation

between malnutrition and poor outcome in critically ill patients still
exists. Nutrition. 1996;12:23–9.
41. Gramlich L, Kichian K, Pinilla J, et al. Does enteral nutrition compared

to parenteral nutrition result in better outcomes in critically ill adult
patients? A systematic review of the literature. Nutrition. 2004;20:843–8.
Page 27 of 27

Malignancy and critical illness

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Malignancy and critical illness
Author(s): Nishita Desai
DOI: 10.1093/med/9780198814924.003.0014
Expert commentary by Gary Wares
Case history
A previously fit and well 63-year-old lady presented to her general

practitioner with a 1-month history of generalized weakness and fatigue.
On examination, she had an enlarged spleen and petechiae on her legs.
Her blood tests revealed that she was anaemic, thrombocytopenic, and a
blood film revealed blast cells. She was urgently referred to the
haematology outpatient clinic and a bone marrow biopsy showed the
presence of blast cells at 35%. Subsequently, she was diagnosed with
acute myeloid leukaemia. She was admitted to hospital electively and
underwent an allogenic haematopoietic stem cell transplantation (HSCT)
from a human leucocyte antigen (HLA)-matched unrelated donor with a
reduced-intensity myeloablative preconditioning regimen comprising total
body irradiation and FMC (fludarabine, melphalan, and alemtuzumab)
chemotherapy.
Page 1 of 24
During her pre-engraftment period (defined as a period up to 30 days

post HSCT), from day 5 after HSCT she was reviewed regularly by the
critical care outreach team because of a high National Early Warning
Score (NEWS) of 5 [1]. She had a productive cough and, given the high
risk of pneumonia, was commenced on a 7-day course of intravenous
Tazocin (piperacillin/tazobactam) and clarithromycin and oral oseltamivir.
She was already taking prophylactic co-trimoxazole and fluconazole as
part of the post-HSCT regimen. On day 11 after the HSCT, due to
persistent pyrexia, tachypnoea, and an additional oxygen requirement of
4 L/min, in consultation with microbiology, her antibiotics were changed
to intravenous (IV) meropenem. On day 13 after the HSCT, her clinical
condition deteriorated further and she was reviewed urgently by the
critical care outreach team because of hypotension, a NEWS score of 7,
and a quick Sequential (Sepsis-Related) Organ Failure Assessment
(qSOFA) score of 3. At this point, she had a temperature of 38°C, a lactate
value of 2.5 mmol/L, and her blood pressure was 78/40 mmHg following
an IV infusion of 3 L of Hartmann’s solution. Following discussion with
the haematology team, the patient, and her family, the decision was made
to admit her to the intensive care unit (ICU) for further investigation and
management. Within 2 hours, the patient was transferred to the ICU.
EXPERT COMMENT
The use of HSCT for curative treatment of malignant and non-

malignant disease has increased over the last 10 years. Previously,
outcomes for patients who were admitted to ICU following HSCT
were poor, partly because ‘treatment apathy’ provoked suboptimal
treatment from the outset. Overall improvements in care through
initiatives such as the Surviving Sepsis Campaign [2] have led to an
improvement in outcomes in many centres.
During HSCT, haemopoietic stems cells are transfused into a recipient

from a donor with the intention of repopulating and replacing the
haemopoietic system. The donor cells can be the patient’s own
(autograft) or from another donor (allograft). The cells can be
harvested from bone marrow, umbilical cord blood, or peripheral
blood.
Autografts are performed using the patient’s own cells when their
cancer is in remission following chemotherapy and/or radiotherapy.
This can be days, weeks, or months following disease control, or even
after years where there has been relapse of the primary condition.
The patient undergoes a period of intensive preconditioning before
infusion of the autograft resulting in a period of profound
immunosuppression. Engraftment and return of marrow synthetic
function can take up to 25 days after the transplant and patients
remain vulnerable to infective complications during this time. During
an autograft, the patient acts as their own donor so risks of
Page 2 of 24

incompatibility, graft-versus-host disease (GvHD), and the

requirement for long-term immunosuppression are negated. There is
a low early mortality from autografts, with large-volume centres
expecting a mortality of less than 5% and a much lower long-term
morbidity profile compared to allograft HSCT. There is a risk of
repopulating the patient’s marrow with tumour cells and the risk of
recurrence in subsequent years.
Allografts involve a more intensive preconditioning regimen with

chemotherapy and/or radiotherapy causing early profound
immunosuppression to the same extent as autografts; however, the
patient’s marrow is repopulated with cells that have antigenic
properties. Donors and recipients are matched to the same HLA
profile. Cytomegalovirus (CMV) status is matched between donor and
recipient to ensure that avoidable CMV reactivation with potential for
disseminated CMV infection is minimized in the post-transplant
period. Immunosuppression is also required to prevent graft rejection
and to reduce the incidence of GvHD. Allogenic transplantation has a
high morbidity and mortality (20–40% in the early treatment phase)
and is usually offered to patients with limited comorbidities who are
younger and able to tolerate the more intensive conditioning
regimens. Because of the intensive preconditioning, early mortality in
allogenic stem cell transplant is in the order of 20%, but is sometimes
the only chance of a cure.
Having undergone HSCT, patients present many challenges to the

critical care team both during and after their initial period of
treatment. They often present diagnostic and therapeutic quandaries
for a team that may not be experienced in treating such patients. The
immunosuppression required following allograft in the presence of
systemic infection may lead to therapeutic indecision and treatment
delay. There may be treatment apathy among teams unfamiliar with
disease progress and treatment options in such patients with complex
multisystem disease. Treatment of HCST patients in high-volume
centres is associated with reduced mortality [3] and, where possible,
these patients should be transferred to the centre that provided the
initial therapy and subsequent transplant.
The patient was admitted into a side room on the ICU and reverse-barrier
nursed using protective isolation precautions. Clinical findings and
examination were consistent with septic shock [4, 5], with tissue
hypoperfusion, hypotension, and a raised serum lactate at 3.0 mmol/L,
but she had no clear evidence of organ dysfunction at this time. Blood
test results revealed the patient to be pancytopenic (Table 14.1) and
following discussion with the haematology team she was commenced on
granulocyte-colony stimulating factor (G-CSF). Following discussion with
the microbiologist, therapeutic-dose IV co-trimoxazole and anidulafungin
was started. The patient was already on IV meropenem, having already
Page 3 of 24

completed the course of IV Tazocin and clarythromycin. In view of her

deterioration and diagnosis of neutropenic sepsis, antibiotics were
escalated to include IV amikacin (requiring drug monitoring with daily
trough levels).
Table 14.1 Initial blood results
Blood test Result Reference range
Haemoglobin (g/L) 80 115–165
Platelets (× 109/L) 72 140–400
White cell count (× 109/L) 0.8 3.6–11
Neutrophils (× 109/L) 0.1 1.8–7.5
Lymphocytes (× 109/L) 0.5 1.0–4.0
Sodium (mmol/L) 141 135–145
Potassium (mmol/L) 4.7 3.5–5
Urea (mmol/L) 10 1.2–8
Creatinine (μmol/L) 108 70–100
Bilirubin (μmol/L) 10 3–22
ALP (U/L) 115 9–52
GGT (U/L) 66 12–43
AST (U/L) 55 14–36
Albumin (g/L) 18 34–48
CRP (mg/L) 200 <5
ALP, alkaline phosphatase; AST, aspartate transaminase; CRP, C-

reactive protein; GGT, gamma glutamyl transferase.
LEARNING POINT Management of neutropenic sepsis
Page 4 of 24

Mortality from neutropenic sepsis is between 45% and 50% among

critically ill patients admitted to ICUs [6] and it is therefore
considered an acute medical emergency. Neutropenic sepsis as
defined by the National Institute for Health and Care Excellence
(NICE) is an absolute neutrophil count of 0.5 × 109/L or less
(neutropenia) in association with a temperature higher than 38°C
(fever) or other signs and symptoms consistent with clinically
significant sepsis [7]. Patients are at risk of severe neutropenia and
bacterial infections in the pre-engraftment period (up to 30 days after
HSCT). It is important to identify neutropenic fever early and look for
signs and symptoms of infection and evidence of systemic
inflammation.
Low-risk patients can be discharged home with oral antibiotics and

outpatient follow-up. High-risk patients should be given IV broad-
spectrum antimicrobials within 60 min of presentation. High-risk
patients are those expected to be neutropenic for more than 7 days
with active comorbidities or ongoing organ dysfunction. Effort should
be made to conduct appropriate microbiological surveillance
including two sets of blood cultures and urine cultures before starting
antimicrobials. The patient should be isolated and full reverse-barrier
precautions should be undertaken by staff and visitors.
The choice of antimicrobial therapy will depend on several factors

including the degree of immunosuppression, infection history,
previous antimicrobial use, and local patterns of antimicrobial
exposure and resistance. There is some debate on whether initial
empirical monotherapy or combination therapy should be used.
Advantages of combination therapy include broad-spectrum coverage
and possible synergistic activity which may reduce resistant strains.
However, cost and significant side effects such as ototoxicity and
nephrotoxicity are important disadvantages to combination therapy.
No randomized controlled trial or meta-analysis has provided
evidence that adding an aminoglycoside or quinolone to a beta-lactam
is superior to broad-spectrum beta-lactam alone. Meta-analysis has
shown that initially, monotherapy with an anti-pseudomonal beta-
lactam agent should be considered [8]. In the UK, the current NICE
recommendation is piperacillin–tazobactam (Tazocin) as first-line
empirical therapy [7]. NICE and the Infectious Diseases Society of
America guidelines [9] have specific antibiotic recommendations for
high-risk patients with neutropenic sepsis (Figure 14.1). Although
most episodes of febrile neutropenia are assumed to be caused by an
infection, blood cultures are positive in less than 30% of febrile
neutropenic episodes [10]. It is important to maintain antibiotic
stewardship and switch from intravenous to oral antibiotics after 48
hours in patients whose risk of developing septic complications has
been reassessed to be low.
Page 5 of 24

Figure 14.1
Antibiotic guidelines for neutropenic sepsis based on NICE and
Infectious Diseases Society of America (IDSA) guidelines.
Source: data from NICE and IDSA.
Empirical antifungal coverage should be started in high-risk patients

who have persistent fever after 4–7 days of a broad-spectrum
antibacterial regimen and no identified source of fever. In patients
who have not been receiving antifungal prophylaxis, an echinocandin
such as caspofungin is recommended as first line. If an invasive
mould infection such as aspergillus is suspected, then voriconazole
should be considered. Antiviral agents and co-trimoxazole should be
considered on an individual patient basis.
The routine use of granulocyte-macrophage colony stimulating factors

in neutropenic patients with a fever is not recommended. The
European Organisation for Research and Treatment of Cancer [11]
suggests that G-CSF should be considered in high-risk patients. High-
risk features include expected prolonged (>10 days) or profound
(≤0.1 × 109/L) neutropenia, age over 65 years, uncontrolled primary
disease, pneumonia, hypotension, and multiorgan dysfunction,
invasive fungal infection, or being hospitalized at the time of the
developing fever.
LEARNING POINT Fungal infections
The incidence of fungal infections is 10–20% after HSCT. Allogenic

HSCT transplant recipients and patients with severe GvHD are at the
highest risk of serious invasive fungal infections from yeasts and
Page 6 of 24

moulds. Other risk factors include previous azole exposure, prior

colonization, prolonged antibiotic use, duration and severity of
neutropenia, use of corticosteroids, and gastrointestinal damage
caused by total body irradiation or chemotherapy with high-dose
cytosine arabinoside [12]. Fifty per cent of individuals are colonized
with Candida albicans and this is the most common fungal infection in
the pre-engraftment period (Figure 14.2), due to breakdown of the
gastrointestinal mucosa caused by chemotherapy or GvHD. Azoles,
such as fluconazole, are the most common prophylactic antifungal:
they reduce the number of invasive fungal infections and decrease all-
cause mortality [13]. Although mould-active prophylaxis (e.g.
voriconazole or amphotericin), compared with fluconazole
prophylaxis, significantly reduces fungal infection-related mortality in
cancer patients receiving chemotherapy or HSCT, it also increases
adverse effects and does not reduce all-cause mortality [14].
Figure 14.2
Phases of opportunistic infections and complications in allogenic
HSCT recipients. EBV, Epstein–Barr virus; HHV6, human herpes virus
6; PTLD, post-transplant lymphoproliferative disorder; TLS, tumour
lysis syndrome; TTP, thrombotic thrombocytopenia purpura; VOD,
hepatic veno-occlusive disease.
Source: data from Kedia, S. et al. Infectious Complications of

Hematopoietic Stem Cell Transplantation. Journal of Stem Cell
Research & Therapy. 2013; S3: 2. Copyright © 2013 OMICS
International—Open Access Publisher.
The engraftment period is usually from 3 weeks to 3 months. During

the immediate and late post-engraftment period, during which the T-
cells begin to recover, infection with Aspergillus spp. is the most
common. The use of prophylactic fluconazole has reduced invasive C.
albicans infection, but has led to an increase in invasive mould
infections, particularly with Aspergillus spp., Pneumocystis jirovecii
Page 7 of 24

pneumonia (PJP) occurs late after transplant and is discussed in detail

later.
Concerns over antimicrobial resistance, toxicity, drug interactions,

over-treatment, and cost have limited routine antifungal prophylaxis.
Anti-candida prophylaxis with fluconazole is recommended in selected
high risk solid-organ transplant recipients, patients with
chemotherapy-induced neutropenia, HSCT recipients with
neutropenia, and those receiving allogenic HSCT. Posaconazole,
caspofungin, and itraconazole are alternatives. Treatment with
echinocandins such as caspofungin, micafungin, and anidulafungin is
recommended for candidaemia in neutropenic patients. For patients
who are less critically ill with no previous exposure to azoles,
fluconazole is a reasonable alternative. Recommended duration of
treatment is 14 days after resolution of attributable signs and
symptoms, clearance of the bloodstream of Candida spp. and recovery
of neutropenia. Removal of indwelling catheters is recommended if
practical.
In patients who are at high risk of invasive aspergillosis (e.g. HSCT

recipients requiring high-dose steroids for GvHD or those with a
history of invasive aspergillosis), prophylaxis with a mould-active
extended spectrum azole (voriconazole or posaconazole) is
recommended. For the treatment of invasive aspergillosis,
voriconazole is recommended as first line. Liposomal amphotericin B,
caspofungin, micafungin, and posaconazole are all second line.
On admission to the ICU, an internal jugular central venous catheter

(CVC) and a radial arterial line were inserted. Following ongoing fluid
resuscitation guided by dynamic cardiac output monitoring with a LiDCO
(Lithium Dilution Cardiac Output) monitor, she was started on 0.1 mcg/
kg/min of noradrenaline to maintain her mean arterial blood pressure
(MAP) above 65 mmHg. During the first day in the ICU, her arterial blood
gases indicated worsening hypoxaemia (partial pressure of arterial
oxygen (PaO2) 7.0 kPa on 0.6 fraction of inspired oxygen (FiO2) via
facemask). Nasal high-flow oxygen was started. Alongside the initial
blood tests (Table 14.1), a full septic screen was sent to microbiology
including blood, urine and sputum cultures, and a respiratory viral
screen. A chest X-ray showed bilateral interstitial shadowing, worse bi-
basally, suggestive of severe bilateral pneumonia.
By day 3 on the ICU she had deteriorated further, now requiring an FiO2
of 0.9 with flows of 50 L/min cmH2O. She was visibly tiring, with use of
accessory muscles. Following discussion with the patient, her family, and
the haematology team, the decision was made to intubate her trachea for
airway protection, bronchial toileting, and ventilation.
Page 8 of 24

She was preoxygenated with FiO2 1.0 on continuous positive airway

pressure of 10 cmH2O, induced with a rapid sequence induction. An 8 mm
internal diameter tracheal tube with a subglottic suction port was
inserted. Mechanical ventilation was started with tidal volumes of 6 mL/
kg ideal body weight and positive end-expiratory pressure of 12 cm H2O.
She was maintained with deep sedation and an atracurium infusion was
started to eliminate respiratory effort. After a period of assessment, as
she remained hypoxaemic despite an FiO2 of 1.0 she was turned prone.
She was maintained prone for 16 hours daily and lung protective
ventilation was maintained with permissive hypercapnia and a target
peripheral capillary oxygen saturation of 88–92% [15]. This is discussed
further in Case 3.
On day 5 of admission, when she was more stable, she underwent a chest
computed tomography scan. This did not show evidence of pulmonary
embolism but there were lung parenchymal changes with ground-glass
change within the lungs bilaterally. The differential diagnosis included an
infection or a drug reaction (Figure 14.3).
Figure 14.3
Chest computed tomography scan on day 5 of admission, showing lung
parenchymal changes with ground-glass change within the lungs
bilaterally. The differential diagnosis in this case included an infection or
a drug reaction.
CLINICAL TIP Bronchoalveolar lavage
Page 9 of 24

Often microbiological cultures are negative. Consider

bronchoalveolar lavage early, if safe to do so, so that samples for PCR
and microscopy and culture can be obtained.
There were no positive microbiological cultures to date. Influenza A and B

polymerase chain reaction (PCR) assays were negative, so oseltamivir
was discontinued. Serum beta-D-glucan assay was positive at 200 pg/mL
(>80 pg/mL positive) and galactomannan serum antigen was negative
(<0.5 index). Collectively these results suggested that an invasive
aspergillus infection was unlikely but indicated the possibility of a P.
jirovecii infection. Treatment-dose IV co-trimoxazole, anidulafungin,
meropenem, and amikacin were continued.
LEARNING POINT Biomarkers for fungal infection
Invasive fungal infections can be difficult to diagnose, particularly

invasive Aspergillus spp. Inhalation of Aspergillus spp. is common, so
culture isolation from the airway does not necessarily indicate
disease: conversely, many patients with invasive Aspergillus are
culture negative. The gold standard for diagnosis is a tissue biopsy
with microscopic visualization of the organism but biopsy is
frequently not feasible, is associated with significant risks, and
microscopic examination and culture can be insensitive. While PCR
has been used for the diagnosis of P. jirovecii, Candida spp., and
Cryptococcus infections, it has shown mixed results for aspergillosis.
Imaging can be useful but again is non-specific. Serum biomarkers
may therefore provide a non-invasive approach to establishing
invasive fungal infection.
Beta-D-glucan is a cell wall component of many fungi including

Candida spp. and P. jirovecii, which makes it useful for diagnosing
invasive fungal infection with these organisms but not for invasive
aspergillosis. It has a high negative predictive value, making it useful
in excluding fungal infection, and it can also be useful when invasive
fungal infection is suspected [16]. It is sensitive for P. jirovecii and
may be used as a screening tool [17].
Galactomannan is a polysaccharide found in fungal cell walls and is a

major constituent of the Aspergillus cell wall. Galactomannan antigen
detection via enzyme immunoassay in serum or bronchoalveolar
lavage fluid is relatively specific for invasive Aspergillus [18]. Serum
screening can be used once or twice weekly to detect invasive fungal
infection before clinical signs and symptoms develop, but it has a
greater predictive value when there is a high clinical suspicion of
infection. False positives can occur in patients who are taking certain
beta-lactam antibiotics, with other organisms such as Penicillium spp.,
Cryptococcus neoformans, and Histoplasma spp. which share the
Page 10 of 24

cross-reacting antigens, in patients who may get translocation from

reduced mucosal integrity, and by contamination from ingestion of
certain foods (pasta, rice).
Maintain a high index of suspicion for the diagnosis of invasive fungal

infection and evaluate the clinical risk. The diagnostic accuracy is
improved by combining assessment of clinical risk with other
diagnostic approaches such as imaging, serial measurements of
galactomannan antigen, targeted beta-D-glucan, and serial PCRs.
LEARNING POINT Pneumocystis jirovecii pneumonia

(PJP)
P. jirovecii is a specific species of pneumocystis affecting human

lungs. It was previously called P. carinii, an organism that also infects
rats, but after determining that the organism infecting humans is
genetically and functionally distinct it was renamed P. jirovecii. It was
also previously thought to be a protozoan, until 1988 when DNA
analysis showed it was a fungus, albeit an unusual one lacking in
ergosterol and very difficult to grow in culture [19].
PJP presents classically as gradually progressive dyspnoea, with a

non-productive cough and a low-grade fever. It is commonly
associated with HIV-seropositive individuals, specifically those with a
low CD4 count or acquired immunodeficiency syndrome (AIDS). Other
risk factors include haematological malignancies (particularly acute
lymphoblastic leukaemia), HSCT (specifically allogenic),
immunosuppressive chemotherapy, and prolonged high-dose
corticosteroids. The ICU mortality of haematological patients with PJP
is approximately 30%.
Diagnosis can be made by quantitative PCR, although this should be

interpreted alongside clinical and radiological features [20]. Chest X-
rays may show bilateral proximal interstitial infiltrates (bat’s wing)
and CT shows bilateral ground-glass changes with apical
predominance and peripheral sparing. Infection beyond the lungs is
rare.
Antimicrobial prophylaxis is highly successful in preventing PJP in

immunocompromised patients at moderate to high risk. While most
antifungal drugs are ineffective against P. jirovecii, there is some
evidence that echinocandins particularly micafungin may be effective.
Co-trimoxazole (trimethoprim–sulfamethoxazole) is first line for
prophylaxis and treatment [21]. Second line drugs include dapsone,
pentamidine, clindamycin–primaquine, and atovaquone.
Page 11 of 24

High-dose steroid therapy is an effective adjunct during treatment of

AIDS-related PJP, because it blunts the inflammatory response and is
associated with reduced mortality [22]. In non-HIV-related PJP, there
are few studies exploring the use and efficacy of corticosteroids and
results are conflicting. Many patients with haematological
malignancies who develop PJP are already taking steroids but if not,
they can be given to those who develop moderate/severe PJP.
EXPERT COMMENT
Maintain a high index of suspicion for infective complications in these

patients and start broad-spectrum cover early based on the local
knowledge base of sensitivity patterns. The impact of P. jirovecii has
changed dramatically over the last 10 years and infections are
becoming rarer because of the use of prophylactic co-trimoxazole. A
beta-D-glucan assay can help to direct therapy towards PJP, although
full investigations include a bronchoalveolar lavage and PCR analysis
of the lavage fluid for PJP as well as other bacterial cultures and viral
PCR studies. High-resolution CT is useful in the investigation of
invasive pulmonary fungal disease.
Broad-spectrum antibacterial, antifungal, and, where appropriate,

antiviral therapy is started as soon as cultures have been taken; in
practice, these are often started before a full infective screen has
been completed.
Consider the CMV status of the patient and start an antiviral agent
such as ganciclovir if clinical suspicion for CMV reactivation is high.
As ganciclovir is immunosuppressive, it may have to be changed to an
alternative agent if there is bone marrow suppression. Diagnosis is
confirmed by PCR for viral antigens or CMV DNA polymerase.
On day 7 of ICU admission, oxygenation and ventilation improved.

However, hypotension, which was poorly fluid responsive, persisted and
she was vasodilated and oligoanuric. A procalcitonin (PCT) assay was
higher than 10 ng/mL, which suggested an ongoing bacterial infection.
Her CVC was changed (and cultured) and a dialysis catheter was inserted
in preparation for renal replacement therapy. Antibiotics were changed
empirically on microbiological advice to IV vancomycin, teicoplanin, and
voriconazole. Amikacin and co-trimoxazole were continued. Meropenem
was stopped.
Renal replacement therapy was started with a 35 mL/kg/hour exchange

rate for a severe metabolic acidosis and acute kidney injury (see Case 12).
A transthoracic echocardiogram showed a hyperdynamic left ventricle,
pulmonary hypertension (systolic pulmonary arterial pressure 70 mmHg),
Page 12 of 24

with moderate tricuspid regurgitation and moderate right ventricular

failure. The patient had developed acute right ventricular failure
secondary to her severe acute respiratory distress syndrome.
On day 10 of the ICU admission, the patient developed diarrhoea, stopped

absorbing her nasogastric feeds, and the plasma bilirubin increased to
150 µmol/L and gamma glutamyl transferase to 40 U/L. In view of
progressive multiorgan failure (respiratory, cardiovascular, renal, and
now gut) there was a suspicion of GvHD. Stools samples were negative
for Clostridium difficile antigen and toxin. After seeking haematological
advice, high-dose methylprednisolone was started.
CLINICAL TIP Central venous catheter-related

bloodstream infections
It is often difficult to confirm that a CVC is the source of infection in

bacteraemia or fungaemia. There may be no evidence of infection at
the insertion site, and the organisms involved are frequently part of
the normal skin flora and are common contaminants of blood
cultures. A differential quantitative blood culture using time to
positivity can be considered: blood cultures taken from the CVC will
have a higher bacterial load than those taken peripherally, and
therefore a shorter time to positivity. If central blood cultures become
positive at least 120 min before peripheral blood cultures taken
simultaneously, the CVC is the more likely source of infection [23],
though not all studies confirm this result. In the UK,
recommendations from Public Heath England [24] are that diagnosis
of catheter-related bacteraemia be based on isolation of the same
organism from the blood and purulent CVC insertion site or CVC tip.
Alternately, catheter-related bloodstream infection can be diagnosed
if there is clinical sepsis that is unresponsive to antimicrobial therapy
and that resolves on catheter removal. Routine remove of central
venous access devices as part of the initial empiric management of
suspected neutropenic sepsis is not recommended and should be
considered only if there is confirmed infection with Staphylococcus
aureus, Pseudomonas aeruginosa, or Candida spp. [10].
LEARNING POINT Procalcitonin (PCT)
The management of patients with malignancy (particularly

haematological malignancy) and fever can be challenging. It can be
difficult to determine whether the fever is related to infection or other
causes; including blood transfusions, disease burden, medications, or
other disease processes such a GvHD. Conventional markers of sepsis
such as C-reactive protein (CRP) and white cell counts can be
Page 13 of 24

challenging to interpret in patients who are immunosuppressed and

these markers lack sensitivity for bacterial infections. This can lead to
unnecessary, prolonged antimicrobial treatment which risks or
perpetuates antibiotic resistance. PCT is a useful biomarker for
detection of bacteraemia in febrile neutropenia and has a better
diagnostic value than CRP [25].
PCT is a peptide precursor of calcitonin, a hormone synthetized by

the thyroid parafollicular C cells and involved in calcium homeostasis.
It is also produced and released as an acute phase protein by the
neuroendocrine cells of the lung and intestine in response to
endotoxin and inflammatory cytokines released in response to
bacterial infections. For this reason, PCT has been considered as a
marker for the diagnosis of bacterial infection and to aid antibiotic
stewardship, by enabling earlier cessation of treatment [26]. Serum
PCT release in response to viral infections and non-infectious
inflammatory stimuli (e.g. autoimmune disease and chronic
inflammatory processes) is much less pronounced and rarely exceeds
0.5 ng/mL. It is not metabolized and has a half-life of 30 hours. A PCT-
based algorithm for antibiotic discontinuation has been shown to be a
cost-effective way of reducing antibiotic exposure [27, 28]. In patients
with sepsis, higher PCT values are associated with a greater risk of
progression to severe sepsis/septic shock and values fall with
successful treatment. Persistent or recurrent PCT elevation may
indicate secondary infection. False-positive elevated PCT levels can
be caused by massive cell death, such as burns and other microbial
infections. False negatives can be seen in early infection or localized
infection such as an abscess. PCT can therefore be a useful aid for the
diagnosis and risk stratification of bacterial sepsis, choice and timing
of the initiation of antibiotic treatment, and in deciding when to
discontinue antibiotics. Its routine use remains controversial and
further research is required before its use is adopted widely.
LEARNING POINT Graft-versus-host disease
GvHD is a multisystem disorder and a common complication of

allogenic HSCT, which classically develops in the early post-
transplant period (<100 days). It is a T-cell-mediated disease,
whereby the donor graft cells recognize the recipient host cells as
foreign. The main antigenic target of the T-cells of the graft is the
host major or minor histocompatibility complex molecules. The risk is
greater with HLA and sex disparity between recipient and donor.
Acute GvHD commonly presents with a classic maculopapular rash,
persistent nausea and/or emesis, abdominal cramps with diarrhoea,
and a rising serum conjugated bilirubin concentration [29]. The main
organs affected are the skin, gastrointestinal tract, and liver. It is
usually a diagnosis of exclusion. The differential diagnosis is wide
Page 14 of 24

especially in a critically ill patient and includes hepatic veno-occlusive

disease (VOD) (see the learning point on ‘Hepatic veno-occlusive
disease’). Diagnosis can be made by taking a biopsy of the tissue
involved. Treatment involves optimizing immunosuppression (usually
calcineurin inhibitors such as ciclosporin or tacrolimus), high-dose
methylprednisolone 2 mg/kg/day, optimizing nutrition, and use of
octreotide which may reduce the diarrhoea. Patients who are
refractory to steroids face a poor prognosis as second-line agents,
including mycophenolate mofetil and etanercept, are less effective.
EXPERT COMMENT
GvHD is unique to allogenic HSCT and typically presents with one or

more of a collection of problems related to eye, skin, intestine, liver,
or lungs. Patients often have intractable diarrhoea with ileus, nausea,
vomiting, and abdominal pain. This often results in the use of
parenteral nutrition to maintain calorific requirements. Diagnosis is
via a skin (where the patient has a maculopapular rash) or rectal
biopsy. This will distinguish between GvHD and Clostridium difficile
diarrhoea. As a last resort, a liver biopsy can be used to make the
diagnosis. Management of acute GvHD is aimed at
immunosuppression: ciclosporin, methotrexate, mycophenolate, and
methylprednisolone have all been used with variable effect.
The patient deteriorated rapidly on day 11, bilirubin and gamma glutamyl
transferase increased to 236 µmol/L and 300 U/L, respectively. She
displayed right upper quadrant abdominal tenderness during a sedation
hold. Clinically, she was grossly oedematous and her plasma albumin
concentration was 10 g/L. An ultrasound examination of the liver showed
no evidence of hepatomegaly or ascites. A blood film showed red cell
crenation and occasional red cell fragments. There was a suspicion of
hepatic VOD: defibrotide was considered but due to concerns over GvHD
and poor gut absorption, it was not started. Bone marrow trephine
showed an empty marrow with no haematopoiesis, and no engraftment
indicating graft failure.
LEARNING POINT Hepatic veno-occlusive disease
Hepatic sinusoidal obstruction syndrome or hepatic VOD is a

complication of allogenic and autologous HSCT. It is a life-threatening
condition that usually occurs within the first 30 days after HSCT and
is thought to be caused by the high-dose conditioning chemotherapy
regimens that precede HSCT. The mean prevalence of VOD is 14%
(range 0–60%) [30] and it causes significant morbidity and mortality
Page 15 of 24

with severe VOD associated with a mortality of 67–90% in the first

100 days after transplant [31]. The differential diagnosis of deranged
liver function following HSCT includes GvHD, infection, drug toxicity,
and VOD.
VOD is characterized by damage to sinusoidal and small hepatic vein

endothelium, microthrombosis, sinusoidal fibrosis, and hepatocellular
necrosis. This can lead to portal hypertension, coagulopathy,
fulminant acute liver failure, hepatic encephalopathy, and hepatorenal
syndrome, eventually leading to multiorgan failure and death. Risk
factors include pre-existing liver disease, allogenic transplant, second
transplant, and lower age. The diagnosis is usually made clinically,
based on the presence of hepatomegaly, ascites, raised bilirubin, and
weight gain. Liver biopsy is often considered too high risk in these
patients. Ultrasonography is useful to rule out other causes.
Treatment is largely supportive, through diuresis, renal replacement

therapy, and analgesia. Recent studies using defibrotide are
promising, with a complete response rate of 36–42% [31] and it has
been approved by the European Medicines Agency for this indication.
Defibrotide is an oligonucleotide that acts as a
polydeoxyribonucleotide adenosine receptor and it has
antithrombotic, anti-inflammatory, and anti-ischaemic properties. It
has a protective effect against endothelial cell injury, may stimulate
revascularization and has a protective effect against GvHD.
Defibrotide has minimal side effects and no known toxicity. Despite
reducing procoagulant activity, increasing fibrinolysis, and
modulating platelet activity, its use has not been associated with an
increased risk of systemic bleeding. Recent guidelines recommend
the use of defibrotide in the treatment of VOD at a dose of 25 mg/kg/
day [32]. Other treatments include methylprednisolone, careful fluid
balance, and, in some cases, consideration of transjugular
intrahepatic portosystemic shunt or hepatic transplantation.
In view of her continued deterioration with multiorgan failure

(respiratory, cardiovascular, gut, and renal) despite maximal medical
management, and with evidence of graft failure, her condition and
progress was discussed between the clinical teams and senior nursing
staff involved in her care. Her condition was judged to be unsurvivable. A
family discussion took place which included the haematology team, the
ICU team, and the palliative care team. After this, the decision was made
to change the direction of her care from restorative to palliative care. End
of life care and comfort measures were started and unnecessary life-
sustaining treatment was withdrawn. She died within 12 hours with her
family present.
Page 16 of 24

LEARNING POINT Outcomes in patients with

haematological and solid organ tumours admitted to the
ICU in high-volume centres
Outcomes of critically ill cancer patients have improved over the last
decade. An increasing number of patients with solid and
haematological malignancies will benefit from ICU support and this is
associated with a decreased mortality. Intensivists are increasingly
willing to admit patients with advanced cancer to the ICU [33].
Advances in cancer diagnosis, improvements in chemotherapy
regimens, better patient selection, and improved ICU care have all
contributed to better outcomes in these patients. However,
prognostication remains challenging and the prognostic significance
of certain risk factors has changed over time. Classic predictors of
mortality in this group of patients may no longer be relevant and even
those that are associated with increased mortality are often
unreliable [33, 34]. Performance status and number of organ
dysfunctions appear to be important in prognostication.
Mortality on the ICU, although improved, remains high, with cancer

patients admitted to ICU having a 25–45% mortality, which is
comparable to many other diseases. Over the last decade, some units
have reported a 15.7% reduction in hospital mortality of critically ill
cancer patients with neutropenic sepsis [35]. Patients with
haematological malignancy have the highest ICU mortality at 61% for
allograft patients and 39% for autograft patients [36], though
treatment in high-volume centres is associated with improved survival
[3].
Delayed admission to ICU of cancer patients with acute respiratory

failure is associated with increased mortality [37]. A 60% mortality
rate was reported in ventilated cancer patients who survived to day 5
on an ICU [38]. Cancer patients with acute respiratory distress
syndrome have a 55% mortality compared to 25% in those without
cancer. Longer-term outcomes following ICU admission have yet to be
evaluated but more than half of cancer patients staying longer than
16 days in an ICU survive for at least 1 year [39].
With poor prognostic certainty in many cases and ever improving

outcomes, the focus should be on early multidisciplinary decision
making and timely ICU admission when indicated, supported by good
ongoing communication between clinical teams and families, and
early diagnosis of the condition precipitating admission.
Page 17 of 24

Discussion
This case illustrates the diagnostic and therapeutic challenges in critically

ill cancer patients, focusing on high-risk patients following allogenic
HSCT for haematological malignancy. It highlights some of the
complexities of managing such patients, who are clearly at risk of
multiorgan failure with complex pathophysiological states.
Cancer Research UK reports that more than 300,000 people are newly
diagnosed with cancer every year in the UK. Overall mortality is
improving; however, there is an ageing population and the incidence of
cancer is increasing in the elderly and more are dying of cancer.
Treatment of cancer is changing with a move towards more targeted
therapy and immunotherapy with novel drugs. Over time, an improved
understanding of the pathophysiology and toxicity of the novel
chemotherapy drugs will facilitate better ICU management.
With improving outcomes and rising expectations, more cancer patients

are admitted to ICU. Studies from high-volume specialist ICUs have
shown reduced mortality and improved outcomes. Early identification of
these patients, early critical care input, understanding patient
expectations, and advanced care planning are all key components to high-
quality care.
The approach to the management of these complex patients must be

multidisciplinary. Despite optimal treatment, some of these patients will
require end of life care on the ICU; this should be planned and delivered
in a systematic, dignified, and compassionate way.
EXPERT COMMENT
Selecting which patient with cancer may benefit from ICU care is
notoriously difficult, particularly without reliable scoring systems or
clear predictors of survival. Cancer diagnosis is often associated with
clinical pessimism and ICU management in this population requires
considerable resource use, availability of which may vary between
smaller hospitals and specialist centres. Intensivists tend to be overly
pessimistic and the oncologists similarly overly optimistic. Therefore,
a multidisciplinary approach needs to be adopted, requiring excellent
communication between the clinical teams involved, not only at
admission but also during the time spent on an ICU. Increasingly
recognized is the importance of identifying patient expectations and
wishes. These require careful exploration, consideration, and
management. Equally important, all clinicians and the patient need to
understand the goals of the cancer treatment, which may include cure
or prolongation of life without cure.
Page 18 of 24

Traditional markers of cancer severity such as stage, disease burden,

spread of disease, cycle of chemotherapy, and characteristics of the
cancer are inconsistent at predicting mortality. Similarly, patient
characteristics such as age and neutropenia are no longer reliable for
assessing the potential benefits of ICU care and are not as relevant as
previously thought. Hospital mortality is likely to be better
determined by performance status, number of organ dysfunctions at
admission, and the presence of haematological malignancy. Further
research is required into the triage criteria for ICU referral, the
survival rates after full ICU management, and the survival rates after
a trial of ICU.
LEARNING POINT End of life decision-making and

prognostication
Advanced care planning before ICU admission should be instigated as

early as possible—ideally before critical illness occurs—to ensure that
planned care is appropriate and in accordance with the patient’s
values and preferences. All parties must understand the goals of ICU
care and early involvement of palliative care clinicians may be
important components of multidisciplinary approach to care.
Advanced care planning interventions may increase the frequency of

out-of-hospital and out-of-ICU care and increase compliance with
patients’ end of life wishes. Trials of ICU care lasting 1 to 4 days may
be sufficient in patients with poor-prognosis solid tumours, whereas
patients with haematological malignant neoplasms or less severe
illness seem to benefit from longer trials of ICU care.
Reappraise aggressive ICU management after a few days of full

support. Sepsis is a frequent complication of critically ill patients with
cancer: sepsis, septic shock, and the need for vasopressor use are all
independent predictors of ICU mortality in patients with
haematological malignancies. The multidisciplinary teams (intensivist,
oncologist/haematologist, palliative care) should regularly assess
treatment goals, degree of success, and suitability and where
indicated, aid in changing the goals from restorative to palliative
care. Postponing end of life decisions increases the physical and
emotional burden on patients and relatives and such care should be
timely, multidisciplinary, and focused on the patient’s autonomy,
dignity, and expectations.
Often ‘do not attempt cardiopulmonary resuscitation’ orders are

completed within the first 48 hours of admission to ICU; at this time,
patients are often too unwell to participate in such discussions. Such
Page 19 of 24

decisions should involve patients where possible, family if this is not

possible, and should be reviewed regularly.
Future therapeutic and research considerations for the critically

unwell cancer patient should include early palliative care
involvement, advanced care planning, and better prognostication.
Improvements in outcomes for many cancer patients, particularly for

those with complications of cancer treatments, mean that these
patients may often benefit from ICU admission if physiological
deterioration occurs. Prognostication is complex and imperfect so
patients require advance planning and multidisciplinary input to
determine the best management. Trials of ICU care may be
appropriate in many patients for whom it would not have been
appropriate 10 years ago. Included in the group of cancer patients in
whom outcomes have improved and in whom ICU care is often
appropriate are patients with haematological malignancies. HSCT has
transformed the outcomes from haematological malignancy, but the
risks and benefits must be considered when offering such therapy,
especially to the patient with multiple comorbidities. Because of their
complexity, these patents should ideally be managed in high-volume
centres with close multidisciplinary working practices to ensure the
best outcomes.
References
1. Royal College of Physicians (RCP). National Early Warning Score
(NEWS): Standardising the Assessment of Acute-Illness Severity in the
NHS. Report of a Working Party. London: RCP; 2012.
2. Rhodes A, Evans L, Aihazzani W, et al. Surviving sepsis campaign:

international guidelines for management of sepsis and septic shock: 2016.
3. Intensive Care National Audit and Research Centre. Annual quality

report 2015/16 for adult critical care [Internet]. 2016. Available from:
https://onlinereports.icnarc.org/Reports/2016/12/annual-quality-
report-201516-for-adult-critical-care (accessed 3 July 2017).
4. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ
failure and guidelines for the use of innovative therapies in sepsis. The
ACCP/SCCM Consensus Conference Committee. American College of
Page 20 of 24

Chest Physicians/Society of Critical Care Medicine. Chest.

1992;101:1644–55.
5. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new

definition and assessing new clinical criteria for septic shock: for the
third international consensus definitions for sepsis and septic shock
(Sepsis-3). JAMA. 2016;315:775–87.
6. Mokart D, Darmon M, Resche-Rigon M, et al. Prognosis of neutropenic

patients admitted to the intensive care unit. Intensive Care Med.
2015;41:296–303.
7. National Institute for Health and Care Excellence (NICE). Neutropenic

Sepsis: Prevention and Management in People with Cancer. Clinical
guideline [CG151]. London: NICE, 2012. Available from: https://
8. Paul M, Dickstein Y, Schlesinger A, et al. Beta-lactam versus beta-

lactam-aminoglycoside combination therapy in cancer patients with
neutropenia. Cochrane Database Syst Rev. 2013;6:CD003038.
9. Infectious Diseases Society of America (IDSA). Neutropenic sepsis

guidelines [Internet]. http://www.idsociety.org/IDSA_Practice_Guidelines
(accessed 12 December 2016).
10. Feld R. Bloodstream infections in cancer patients with febrile

neutropenia. Int J Antimicrob Agents. 2008;32:S30–3.
11. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC
guidelines for the use of granulocyte-colony stimulating factor to reduce
the incidence of chemotherapy-induced febrile neutropenia in adult
patients with lymphoproliferative disorders and solid tumours. European
Organisation for Research and Treatment of Cancer. Eur J Cancer.
2011;47:8–332.
12. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk-based,
antifungal strategy in neutropenic patients. Br J Haematol. 2000;110:273–
84.
13. Robenshtok E, Gafter-Gvili A, Goldberg E, et al. Antifungal

prophylaxis in cancer patients after chemotherapy or hematopoietic stem-
cell transplantation: systematic review and meta-analysis. J Clin Oncol.
2007;25:5471–89.
14. Ethier MC, Science M, Beyene J, Briel M, Lehrnbecher T, Sung L.

Mould-active compared with fluconazole prophylaxis to prevent invasive
fungal diseases in cancer patients receiving chemotherapy or
haematopoietic stem-cell transplantation: a systematic review and meta-
analysis of randomised controlled trials. Br J Cancer. 2012;106:1626–37.
15. Guérin C, Reignier M, Richard JC, et al. Prone positioning in severe

acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–68.
Page 21 of 24

16. Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic

adjunct for invasive fungal infections: validation, cutoff development, and
performance in patients with acute myelogenous leukemia and
myelodysplastic syndrome. Clin Infect Dis. 2004;39:199–205.
17. Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum

1,3-β-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis,
and invasive aspergillosis: systematic review and meta-analysis. J Clin
Microbiol. 2012;50:7–15.
18. Zou M, Tang L, Zhao S, et al. Systematic review and meta-analysis of

detecting galactomannan in bronchoalveolar lavage fluid for diagnosing
invasive aspergillosis. PLoS One. 2012;7:e43347.
19. Edman JC, Kovacs JA, Masur H, Santi DV, Elwood HJ, Sogin ML.
Ribosomal RNA sequence shows Pneumocystis carinii to be a member of
the fungi. Nature. 1988;334:519–22.
20. Teh BW, Azzato FA, Lingaratnam SM, Thursky KA, Slavin MA, Worth
LJ. Molecular diagnosis of Pneumocystis jirovecii in patients with
malignancy: clinical significance of quantitative polymerase chain
reaction. Med Mycol. 2014;52:427–32.
21. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis,

prophylaxis and management of Pneumocystis jirovecii pneumonia in
patients with haematological and solid malignancies, 2014. Intern Med J.
2014;44:1350–63.
22. Castro JG, Morrison-Bryant M. Management of Pneumocystis jirovecii

pneumonia in HIV infected patients: current options, challenges and
future directions. HIV AIDS (Auckl). 2010;2:123–34.
23. Garcia X, Sabatier C, Ferrer R, et al. Differential time to positivity of

blood cultures: a valid method for diagnosing catheter-related
bloodstream infections in the intensive care unit. Med Intensiva.
2012;36:169–76.
24. UK Standards for Microbiology Investigations. Issued by the

Standards Unit, Public Health England. Bacteriology. 2014;37:1–51.
25. Kim DY, Lee YS, Ahn S, Chun YH, Lim KS. The usefulness of
procalcitonin and C-reactive protein as early diagnostic markers of
bacteremia in cancer patients with febrile neutropenia. Cancer Res Treat.
2011;43:176–80.
26. Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of

infection and guide to antibiotic decisions: past, present and future. BMC
Med. 2011;9:107–16.
27. Kip MMA, Kusters R, IJzerman MJ, Steuten LM. A PCT algorithm for
discontinuation of antibiotic therapy is a cost effective way to reduce
Page 22 of 24

antibiotic exposure in adult intensive care patients with sepsis. J Med

Econ. 2015;18:944–53
28. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce

patients’ exposure to antibiotics in intensive care units (PRORATA trial): a
multi-centre randomised controlled trial. Lancet. 2000;375:463–74.
29. Dignan FL, Clark A, Amrolia P, et al. Diagnosis and management of

acute graft-versus-host disease. Br J Haematol. 2012;158:30–45.
30. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of

hepatic veno-occlusive disease after blood or marrow transplantation: a
prospective cohort study of the European Group for Blood and Marrow
Transplantation. European Group for Blood and Marrow Transplantation
Chronic Leukemia Working Party. Blood. 1998;92:3599–604.
31. Richardson PG, Ho VT, Giralt S, et al. Safety and efficacy of

defibrotide for the treatment of severe hepatic veno-occlusive disease.
Ther Adv Hematol. 2012;3:253–65.
32. Dignan FL, Wynn RF, Hadzic N, et al. British Society for Blood and
Marrow Transplantation. BCSH/BSBMT guideline: diagnosis and
management of veno-occlusive disease (sinusoidal obstruction syndrome)
following haematopoietic stem cell transplantation. Br J Haematol.
2013;163:444–57.
33. Azoulay E, Soares M, Darmon M, Benoit D, Pastores S, Afessa B.

Intensive care of the cancer patient: recent achievements and remaining
challenges. Ann Intensive Care. 2011;1:5.
34. Bird GT, Farquhar-Smith P, Wigmore T, Potter M, Gruber PC.

Outcomes and prognostic factors in patients with haematological
malignancy admitted to a specialist cancer intensive care unit: a 5 yr
study. Br J Anaesth. 2012;108:452–9.
35. Legrand M, Max A, Peigne V, et al. Survival in neutropenic patients

with severe sepsis or septic shock. Crit Care Med. 2012;40:43–9.
36. Schellongowski P, Staudinger T, Kundi M, et al. Prognostic factors for

intensive care unit admission, intensive care outcome, and post-intensive
care survival inpatients with de novo acute myeloid leukemia: a single
center experience. Haematologica. 2011;96:231–7.
37. Mokart D, Lambert J, Schnell D, et al. Delayed intensive care unit

admission is associated with increased mortality in patients with cancer
with acute respiratory failure. Leuk Lymphoma. 2013;54:1724–9.
38. Lecuyer L, Chevret S, Thiery G, Darmon M, Schlemmer B, Azoulay E.

The ICU trial: a new admission policy for cancer patients requiring
mechanical ventilation. Crit Care Med. 2007;35:808–14.
Page 23 of 24

39. Gruber PC, Achilleos A, Speed D, Wigmore TJ. Long-stay patients with
cancer on the intensive care unit: characteristics, risk factors, and clinical
outcomes. Br J Anaesth. 2013;111:1026–7.
Page 24 of 24

Major burns

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Major burns
Chapter: Major burns
Author(s): Sian Alys Moxham
DOI: 10.1093/med/9780198814924.003.0015
Expert commentary by Amber E. Young
Case history
An 18-month-old girl weighing 11.5 kg was brought into the

regional major trauma centre after becoming trapped in a house fire for
40 minutes. The child was found unconscious with burns. Assessment of
her conscious level showed a Paediatric Glasgow Coma Scale score of 6
(E1, M4, V1). She was initially managed by the prehospital team who
intubated her on scene with a size 4.0 uncuffed, uncut tracheal tube using
ketamine and fentanyl. She received two boluses of 20 mL/kg warmed
0.9% saline before hospital admission.
LEARNING POINT Upper airway injury and intubation
Page 1 of 29
Major burns
Upper airway injury is typically caused by direct thermal injury with

associated oedema that may potentially lead to tracheal obstruction
[1]. Early intubation is advised if there are signs of potential upper
airway injury, such as singed facial/nasal hairs, carbonaceous sputum,
stridor, hoarse voice, drooling, or dysphagia [2]. A child’s trachea has
a small cross-sectional area and any swelling will cause a
disproportionate increase in resistance and risk of airway obstruction.
Continuing facial swelling due to facial burns and fluid administration

may displace a tracheal tube, which therefore should be left uncut.
Tube fixation is important—attach the tracheal tube to a bony surface
or to the teeth as soon as possible after arrival at the burn service.
On arrival at the emergency department a primary survey was completed.

She was covered with soot and there were burns on her face, the entire
circumference of her thorax, and part of her abdomen.
Her arterial oxygen saturation by pulse oximetry (SpO2) was 87% despite
a fractional inspired oxygen concentration (FiO2) of 0.8. Arterial blood
gas (ABG) analysis showed a partial pressure of oxygen of 7.5 kPa and
partial pressure of carbon dioxide of 6.7 kPa. Her lungs were difficult to
ventilate; tidal volumes were small and the peak airway pressure was 45
cmH2O. She was sedated with morphine and midazolam, and given
atracurium to facilitate ventilation. Urgent thoracic escharotomy was
undertaken which restored her peak airway pressure to normal values.
Her oxygenation and carbon dioxide clearance subsequently improved.
Sedation was maintained with a combination of weight-adjusted
midazolam and morphine infusions.
EXPERT COMMENT
Burned skin leads to interstitial oedema that compresses underlying

soft tissues. Circumferential burns can cause extremity ischaemia,
elevated intra-abdominal pressures, tracheal and jugular venous
compression when the neck is involved, and respiratory compromise
when the chest and upper abdomen are involved—especially in
children [3, 4]. Circumferential chest burns will restrict chest wall
movement, leading to decreased tidal volumes and carbon dioxide
retention. Escharotomies should be undertaken aseptically in the
operating room under general anaesthesia and with blood available.
They rarely need to be undertaken outside an operating environment
or before burn service admission, unless there are predicted delays of
several hours. The exception to this is when circumferential burns
impact patient ventilation [5, 6].
Page 2 of 29

Major burns
The patient had a heart rate of 145 beats per minute. Her blood pressure
was 81/43 mmHg, capillary refill was 4 seconds, and she had cold
peripheries.
Laboratory admission bloods were unremarkable. Her admission ABG,

however, revealed a carboxyhaemoglobin (COHb) value of 36%, a lactate
concentration of 3.0 mmol/L, and a base deficit of −6 mmol/L—consistent
with carbon monoxide (CO) poisoning.
LEARNING POINT Pathology of inhalational injury
Inhalational injury can occur in isolation or in combination with a

cutaneous burn. The presence of inhalational injury is an independent
risk factor for death after burn injury [7, 8, 9]. Consider inhalational
injury in anyone exposed to a fire within an enclosed area [10].
Pulmonary parenchymal injury: toxins typically cause local

inflammation and hypersecretion which can obstruct the airways
causing alveolar collapse and hypoxaemia [11]. The gold standard for
diagnosis of inhalational injury is fibreoptic bronchoscopy, although
there is no classification system for severity [12, 13, 14]. Clinical
differentiation between direct chemical irritation of the lungs and the
systemic inflammatory response (SIR) to the cutaneous injury may
also be difficult [11]. Pulmonary parenchymal injury after inhalation is
often delayed and should be anticipated [15]. Treatment is supportive
and involves a lung protective ventilation strategy, regular pulmonary
toilet, respiratory physiotherapy, humidified oxygen, nebulized
N-acetylcysteine (a powerful mucolytic), and nebulized heparin to
decrease fibrin casts [16, 17, 18, 19].
Carbon monoxide (CO) and cyanide are two toxic chemicals that
cause severe systemic toxicity and metabolic derangement.
CO causes tissue hypoxia by reducing oxyhaemoglobin and

competitively inhibiting cytochrome oxidase enzymes thereby
interfering with normal cellular oxygen handling [20].
Carboxyhaemoglobin (COHb) can be directly measured by a blood gas
analyser that incorporates co-oximetry. Significant CO poisoning may
exist despite normal pulse oximetry. Peak COHb levels may be
underestimated on initial co-oximetry because of supplemental
oxygen given before hospital admission [21]. Symptoms are non-
specific and may not correlate with measured COHb values, but
duration of exposure is an important factor in prognosis (Table 15.1).
Values of more than 10% may be significant. The mainstay of
treatment is high-concentration oxygen, as the half-life of CO is 250
minutes in air and only 40–60 minutes when breathing 100% oxygen
[21]. Evidence is conflicting for the use of hyperbaric oxygen in the
Page 3 of 29

Major burns
treatment of CO poisoning [22]. Practical issues also limit the

applicability of this treatment [23].
Table 15.1 Symptoms and signs associated with ranges of

carboxyhaemoglobin values
COHb % Symptoms/signs
10–20 Asymptomatic, headache
20–40 Visual disturbance, tiredness, disorientation
40–60 Marked confusion, aggression, seizures, coma,

cardiovascular collapse
Cyanide uncouples the mitochondrial respiratory chain (primarily by

inhibiting cytochrome C oxidase) causing histotoxic hypoxia.
Diagnosis of cyanide poisoning may be difficult, but ST elevation on
the electrocardiograph may be suggestive along with an increased
anion gap, unexplained lactic acidosis, or raised mixed venous
saturation. A high index of suspicion is key. Treatment is with
hydroxocobalamin, sodium thiosulphate, sodium nitrate or dicobalt
edetate. Hydroxocobalamin is the preferred antidote in the UK as it is
relatively safe, easy to give, does not compromise oxygen-carrying
capacity, and does not produce hypotension, unlike sodium
thiosulphate and sodium nitrate [24, 25, 26].
EXPERT COMMENT
Early detection of bronchopulmonary injury with bronchoscopy is

important to enable appropriate treatment to be undertaken.
Inhalation injury substantially increases mortality and often requires
tracheal intubation [16, 17, 18]. However, as intubation and
ventilation will increase the incidence of nosocomial pneumonia,
patients with inhalation injury should not be prophylactically
intubated, nor should they receive prophylactic antibiotics [9].
The patient had sustained 55% total burn surface area (TBSA) deep
partial/full-thickness burns covering her head, neck, chest, parts of her
abdomen, and upper limbs.
LEARNING POINT Pathology of a burn
Page 4 of 29

Major burns
Heat denatures proteins and damages plasma membrane integrity

resulting in cell necrosis. The temperature and duration of the heat
source are synergistic contributors to injury. Necrosis is worst at the
centre of the burn, resulting in three zones of injury classically
described by Jackson [27]:
1. Zone of coagulation: no viable cells.

2. Zone of stasis: viable and non-viable cells. This is an at-risk
area that may convert to full necrosis with hypoperfusion,
oedema, and infection. In the elderly and those with significant
comorbidities, such as diabetes and chronic illness, this zone is
at higher risk of conversion to cell death [28].
3. Zone of hyperaemia: viable cells which usually recover
completely.
Protection of the zone of stasis involves adequate fluid resuscitation,

avoidance of vasoconstrictor drugs, prevention of infection, and
excision of non-viable tissue [29, 30, 31, 32].
LEARNING POINT Burns assessment and

management
Modern management of a burn relies on accurate assessment of the

size and depth of burn injury. This depends upon clinical expertise
and experience.
Burn assessment involves

1. Determination of the size of the burn (%TBSA) to guide fluid
resuscitation and future management. This is most commonly
undertaken either using the ‘rule of nines’ in adults or more
accurately, especially in children, Lund and Browder charts [33]
(Figures 15.1 and 15.2). The Mersey Burns App is a free clinical
tool which helps calculate burn percentages and fluid regimens
[34]. This has been recommended by the National Institute for
Health and Care Excellence (NICE) for speed of assessment
compared to paper- or calculator-based methods [35].
2. Determining the burn wound depth to guide surgical
management. Wounds that are not predicted to heal within 2–3
weeks (deep partial thickness and full-thickness depth) will
require surgical excision and covering with autograft or other
means to close the wound.
Page 5 of 29

Major burns
Figure 15.1
Wallace rule of nines.
Reproduced with permission from Shehan Hettiaratchy, S., and Papin,

R. ABC of burns—Initial management of a major burn: II—assessment
and resuscitation. British Medical Journal. 329(7457): 101–103.
Copyright © 2004, BMJ Publishing Group Ltd.
Page 6 of 29

Major burns
Figure 15.2
Lund and Browder chart.
Reproduced with permission from Shehan Hettiaratchy, S., and

Papini, R. ABC of burns—Initial management of a major burn: II—
assessment and resuscitation. British Medical Journal. 329(7457):
101–103. Copyright © 2004, BMJ Publishing Group Ltd.
Superficial burns are erythematous, painful, and non-blistering.

Superficial partial-thickness burns form blisters. Once the blister is
removed, the wound is red, moist, blanches with pressure, and is
hypersensitive [38]. Superficial burns and superficial partial-thickness
depth burns typically heal within 2–3 weeks without scarring and with
no impact on cosmesis or function.
Deep partial-thickness burns blister and appear mottled pink and

white immediately after injury. Full-thickness burns can be
recognized by pallor, and a leathery, firm feel. They are insensate and
non-blanching [38]. Deeper burns typically take more than 3 weeks to
heal. Burns that have longer healing times have an increased risk of
scarring, with associated contractures, and impact cosmesis and
psychological function. See Table 15.2 for a summary of the clinical
features.
Page 7 of 29

Major burns
Table 15.2 Burn type and clinical features
Burn type Tissue burnt Clinical features
Appearance Pain Capillary refill time Blisters
Superficial Epidermis Red, glistening Painful Brisk No
Partial—superficial Epidermis, upper After blistering: red, Painful Brisk Yes

dermis moist
Partial—deep Epidermis, upper and Dry, mottled pink and Dull ache Absent Yes
deep dermis white
Full thickness Epidermis, upper and Dry, pale, and Absent Absent No
deep dermis, leathery
subcutaneous tissue
Page 8 of 29
and Legal Notice).
Major burns
Burns of more than 20% TBSA will trigger a systemic inflammatory

response (SIR). Early surgical excision of the eschar with immediate
or delayed skin grafting improves outcomes in terms of organ
function, sepsis, and survival by reducing this SIR [32, 38, 40].
EXPERT COMMENT
Assessing burn depth accurately is key to future management and

prognosis. Clinical assessment of burn depth is unreliable and has
been shown to be effective only 60–75% of the time [36]. Most burns
are mixed-depth partial-thickness burns. Delayed or incorrect
diagnosis can lead to unnecessary surgical procedures, or delayed
surgery with the development of complications. Laser Doppler
imaging is an alternative technique, but uses surrogate markers of
burn depth and is limited by the time frame of use, as it cannot be
used until 48 hours after injury. In 2011, NICE supported adoption of
laser Doppler imaging for guiding treatment decisions where there is
uncertainty about the depth and healing potential of burn wounds
that have been assessed by experienced clinicians [37].
Achieving vascular access for the patient was difficult, so an intraosseous

device was placed in her proximal tibia. She was commenced on an
intravenous infusion of warmed crystalloid fluid (PlasmaLyte 148). The
rate and volume was calculated according to the Parkland formula at 4
mL/kg/%TBSA along with maintenance fluid requirement.
CLINICAL TIP Giving less than 100% calculated fluid
Children who are critically unwell, or have undergone surgery, do not

receive 100% of the traditional maintenance fluid calculation. This is
due to increased antidiuretic hormone (ADH) production, resulting in
fluid retention, and a less than perfect fluid calculation. Most
paediatric intensive care units (PICUs) give between 50% and 80% of
maintenance fluid.
The patient received a total of 3816 mL of crystalloid during the first 24

hours. This was calculated from a combination of the resuscitation fluid
according to the Parkland formula, two 20 mL/kg fluid boluses given
prehospital and 80% maintenance fluid.
Page 9 of 29

Major burns
Calculation:
Parkland: 4 mL × 11.5 kg × 55% TBSA = 2530 mL over 24 hours with

50% within 8 hours.
Bolus doses: 230 + 230 mL = 460 mL.
Maintenance fluid: (4 mL × 10 kg = 40 mL) + (1.5 kg × 2 mL) = 43 mL/
hour × 80% = 826 mL over 24 hours.
A nasogastric tube was sited, and position confirmed, with the

expectation that the maintenance fluid would be converted to enteral feed
within the first 24–48 hours.
LEARNING POINT Fluid management
Until the 1950s, patients with major burns died from hypovolaemic
shock within a few days. Resuscitation has considerably increased
survival [10].
Current recommendations are that intravenous fluid replacement

should be started after a 10% TBSA burn in children and 15% TBSA
burn in adults. Hypovolaemia associated with burn injury is
secondary to evaporative fluid loss and fluid leak from capillaries
[41]. Ventricular dysfunction seen after major burn injury can
contribute to hypotension and is caused by high concentrations of
circulating cytokines [42].
The hypovolaemia caused by burns is biphasic. In the first hour, there

is rapid oedema formation within the burned tissue, followed over the
next 24 hours, by a more gradual fluid extravasation into whole-body
non-burned tissue [43]. Release of inflammatory mediators
(stimulated by the burn injury), including histamine, bradykinin, nitric
oxide, oxygen free radicals, tumour necrosis factor, interleukins, and
arachidonic acid metabolites, increase capillary permeability, which
causes fluid extravasation [42]. Normal blood volume is not restored
until 24–36 hours post injury, even with appropriate fluid
resuscitation [44].
The Parkland formula reflects the biphasic response:
Total crystalloid fluid (a balanced electrolyte solution) volume = 2–4

mL/kg × %TBSA burn [45].
Half of this total volume is given during the first 8 hours after burn
injury and the other half infused over the following 16 hours. Fluid
resuscitation formulae are only guidelines and under- or over-
resuscitation is common. Children have low circulating blood volumes
and those with major burns require swift commencement of fluid
Page 10 of 29

Major burns
replacement as delayed fluid resuscitation will worsen outcomes [46,

47, 48].
Adequate resuscitation has been traditionally indicated by correction

of clinical condition, base deficit, lactate, and pH and achieving a
urine output of 0.5 mL/kg/hour in adults, 1 mL/kg/hour in children,
and 2 mL/kg/hour in infants [10]. However, normalizing urine output
is difficult to achieve with high levels of ADH following burn injury.
Complications of under-resuscitation include acute kidney injury,

multiorgan failure, and death [10]. However, in modern practice,
complications are more commonly associated with fluid over-
resuscitation [10] and include:
● compartment syndromes:
◦ abdominal compartment syndrome

◦ extremity compartment syndrome
◦ thoracic circumferential constriction
● wound-related complications:
◦ conversion of viable tissue to non-viable tissue within the burn

injury
◦ graft failure
● vital organ oedema:
◦ pulmonary oedema
◦ cerebral oedema
● electrolyte imbalance:
◦ hyponatraemia.
EXPERT COMMENT
Fluid overload (and associated complications) is common in the early

few days after burn injury. This is associated with rigid adherence to
guidelines for fluid administration in patients with burns, difficulties
with estimating fluid balance, fluid creep, and high levels of ADH
[49]. This hypervolaemic state is often associated with
hyponatraemia. It commonly manifests as an increased oxygen
requirement in those patients with no lung pathology, or increased
ventilator requirements in those requiring ventilation. Fluid overload
Page 11 of 29

Major burns
should be anticipated and managed early with fluid restriction and/or

diuretics as required.
In the example case described here, it is likely that this child was
over-resuscitated because of the use of the Parkland formula at 4 mL/
kg/%TBSA, resulting in respiratory dysfunction and difficulty with
positive pressure ventilation. Current research suggests that over-
resuscitation of patients with burn injuries causes significant harm
with respect to respiratory function, other organ function, depth of
burn, and mortality [48, 50]. Recent work suggests that using a more
restrictive approach to burn resuscitation (permissive hypovolaemia)
with appropriate clinical end points produces better outcomes [51,
52]. A challenge in achieving optimal fluid resuscitation for burn
patients is that the gold standard is still urine output. However, this is
unlikely to reflect hydration status accurately because of the high
ADH concentrations associated with significant burn injury
(especially in children). Aiming to achieve a ‘normal’ urine output,
will almost always result in fluid overload. Using a collection of
clinical end points measured every few hours during the resuscitation
period including clinical condition, ABG indices, and serum urea and
sodium as well as urine output will ensure the best monitor of fluid
status [53, 54].
As the regional major trauma centre was distant to the burns centre, a
referral and transfer to the burn service was required. Referral was
required because of the size of the burn and the presence of an
inhalational injury with associated CO poisoning. The patient was
transferred to the regional burn centre, where she was immediately taken
to the operating room for:
● reassessment of burn size and depth

● wound cleaning and excision
● early grafting of her deep dermal and full-thickness burns.
LEARNING POINT Referral criteria
Systems for treating severe burns will vary from country to country.
The UK is an example of a country with a dedicated network of burn
centres offering specialized care. In the UK, the Burn Operational
Delivery Networks (burn ODN) comprises a group of geographically
related hospitals; a burn centre having the capacity to treat the most
severe burn from injury to rehabilitation, along with a constellation of
burn units providing care for less complex burns. Uncomplicated
small burns may be treated in burn facilities (designated plastic
surgery services). The network provides appropriate expertise and
resources for the burned patient. There are four burn ODNs within
Page 12 of 29

Major burns
England and Wales [55]. However, not all burn centres are co-located
with major trauma centres. If the patient is multiply injured and
requires other specialist care the best location for that patient will
need to be agreed. If the burn is the predominant injury, care within a
burn service is essential.
To guide referral decisions, five criteria are considered—burn size,

depth, location, mechanism, and other factors [55]. Criteria are
different for adults and children. See Tables 15.3 and 15.4.
Table 15.3 Paediatric referral criteria
Paediatric Burn unit Burn centre
TBSA % >5% >30%

>15% if <1 year
Depth >2% full thickness >20% full

>1% full thickness if <6 thickness
months
Site Any burn to special areasa As for burn unit

Any circumferential burn
Mechanism of Chemical As for burn unit

Injury Electrical
Friction
Cold injury
Inhalational injury
Other factors Any burn not healed As for burn unit

within 2 weeks
Physiological instability
secondary to burn injury
Suspicion of non-
accidental injury
a Special areas include hands, feet, face, perineum, genitalia.
Source: data from National Network for Burn Care (NNBC) (2012).
British Burn Association National Burn Care Referral Guidance:
Version 1, 2012. Copyright © 2012 NNBC. Available at
www.britishburnsassociation.org.uk.
Table 15.4 Adult referral criteria
Adult Burn unit Burn centre
Page 13 of 29

Major burns
TBSA % 10–40% >40%
10–25% with >25% with associated

associated inhalational injury or age
inhalational injury >65 years or significant
comorbidities
Depth ≥5% As for burn unit
Site Any burn to special As for burn unit

areasa
Any non-blanching
circumferential
burn
Mechanism Chemical As for burn unit

Electrical
Friction
Cold injury
Other Any burn not healed As for burn unit

factors in 2 weeks
Physiological
instability
secondary to burn
injury
Suspicion of non-
accidental injury
Pregnancy
a Special areas include hands, feet, face, perineum, genitalia.
Source: data from National Network for Burn Care (NNBC) (2012).
British Burn Association National Burn Care Referral Guidance:
Version 1, 2012. Copyright © 2012 NNBC. Available at
www.britishburnsassociation.org.uk.
EXPERT COMMENT
Early debridement of large area, deep partial-thickness or full-

thickness burns improves survival and decreases hospital stay, blood
loss, and healthcare costs [56, 57, 58, 59, 60]. However, the definition
of ‘early’ still requires clarification. In most burn services in the UK,
Page 14 of 29

Major burns
as full a debridement as possible of the burn eschar occurs when the

patient is stable and within the first 48–72 hours.
Definitive wound cover should occur early after debridement as there

is a risk of infection until the wound is closed. However, it is the
presence of dead tissue that worsens outcomes and therefore the
urgency for debridement is more than that for wound coverage.
Choice of wound coverage depends upon the size and site of the burn.
The ideal cover is the patient’s own skin (autograft); however, this will
not be possible if the burns are of more than 40–50% TBSA. In these
cases, cadaver skin or biosynthetic dressings can be used to
temporize, until a further autograft is available or until alternative
dermal cover is provided using products such as Matriderm or
Integra [49].
After surgery, the patient was nursed in a thermally controlled ICU

isolation room with an ambient temperature of 30°C and 60% relative
humidity.
The patient became progressively more oedematous over the following

few days. It became more difficult to ventilate her lungs, with the FiO2
increasing to 0.9 and peak inspiratory pressures greater than 30 cmH2O.
A positive end-expiratory pressure of 14 cmH2O was required to maintain
adequate oxygenation. A chest X-ray showed bilateral diffuse infiltrates
consistent with acute respiratory distress syndrome caused by
inhalational injury, SIR, and exacerbated by fluid overload. Her serum
sodium concentration decreased to 130 mmol/L.
LEARNING POINT Mechanical ventilation in the burn

patient
Indications for mechanical ventilation in the patient with burns

include:
● management of direct airway injury

● nosocomial pulmonary infection
● acute respiratory distress syndrome secondary to inhalational
injury, pulmonary infection, iatrogenic pulmonary oedema, or the
SIR to severe burns
● abdominal compartment syndrome
● neurological sequelae of CO or cyanide poisoning.
Page 15 of 29

Major burns
EXPERT COMMENT
Current evidence suggests that mechanical ventilation of patients

with burns, but without inhalational injury, is independently
associated with poorer outcomes [61]. This may be due to the need to
provide more intravenous fluid purely to maintain acceptable clinical
end points in patients who are sedated and ventilated [62]. Patients
with facial burns, upper airway thermal trauma, or a large burn area
should be intubated and ventilated, if required, for transfer to
definitive care at the burn service. However, extubation should then
occur as early as possible [62, 63] and should not be postponed
because of a need for daily or alternate day surgery. This
management requires careful monitoring of ventilator requirements
and airway signs in a high-care area. If extubation is not possible,
consider an early tracheostomy and weaning from sedative drugs and
positive pressure ventilation.
Over the next day, the patient’s temperature increased to 39°C and she
became increasingly tachycardic. Propranolol was started to ameliorate
the systemic inflammatory response to the burn. Despite earlier
placement of a nasogastric tube and early enteral nutrition, absorption of
feed was inconsistent. A nasojejunal tube replaced her nasogastric tube
and oxandrolone was started once she was fully absorbing her enteral
feed.
LEARNING POINT Hypermetabolic response
Burn injuries of more than 20% TBSA cause a hypermetabolic

response, characterized by a hyperdynamic circulation, increased
body temperature, catabolism, and inefficient energy substrate
cycling. This is mediated by acute phase response cytokines and
increased secretion of catecholamines, glucocorticoids, and glucagon.
Protein is preferentially used as the main body substrate. Without
treatment, the patient will have muscle wastage, delayed
mobilization, impaired rehabilitation, and immunocompromise,
increasing the risk of sepsis [10]. Cardiac output and heart rate can
often increase by 150–200%, which can last well into the
rehabilitative stage [10]. The patient will also typically develop a
hyperglycaemic insulin-resistant state and may require insulin
supplementation, especially during episodes of sepsis.
Management of the hypermetabolic response includes

pharmacological and non-pharmacological methods [64].
Page 16 of 29

Major burns
Non-pharmacological methods include:
● early wound excision and closure (as described earlier)

● early enteral nutritional support
● environmental support: high ambient temperature and humidity
to prevent heat loss.
Early enteral feeding is essential to maintain calorific input and to

protect the integrity of the bowel mucosa [65]. Repeated operative
procedures interrupt feeding regimens and early consideration of a
nasojejunal tube is important. Excessively high-calorie feeding is
associated with increased mortality. Conversely, failure to meet
nutritional requirements impairs wound healing and increases
infection risk [66]. Many formulae have been developed but most
overestimate calorie requirement. A nutritionist/dietician is a key
member of the burn care multidisciplinary team [10].
In patients with burns, an increase in ‘normal’ central body

temperature to 38°C is linked to the hypermetabolic response.
Maintaining a warm, humid ambient environment (30–33°C and 60%
humidity respectively) prevents heat loss and ameliorates the
hypermetabolic response by decreasing resting energy expenditure
by up to 20% [64].
Pharmacological treatment includes beta blockers and anabolic

agents. Propranolol, starting at 1 mg/kg, is titrated to decrease heart
rate by 20%. Propranolol reduces cardiac work, decreases hepatic
steatosis, and reduces skeletal muscle catabolism [10]. Oxandrolone,
a non-virilizing anabolic steroid, improves efficiency of protein
synthesis and healing of the burn wound, and is started when enteral
feeding is established [67]. At a dose of 0.1 mg/kg twice daily, lean
body mass is maintained and hospital length of stay decreased [68].
Liver function tests should be monitored. Propranolol and
oxandrolone should be maintained for at least 1 year after major burn
injury [10].
EXPERT COMMENT
Burns of more than 20% TBSA cause stress and inflammatory and
hypermetabolic responses which can last up to 3 years. An ebb phase
starts immediately after injury with low cardiac output, decreased
metabolic rate, and impaired glucose tolerance and may present as
shock. The flow or hyperdynamic phase occurs after 3–5 days and
comprises increased heart rate, blood pressure, temperature and
hypermetabolism, and is associated with protein catabolism [69].
Page 17 of 29

Major burns
Research supports the safety and effectiveness of drugs such as

propranolol and oxandrolone in ameliorating this hypermetabolic
response. Propranolol is a non-selective beta blocker, and has
undergone significant testing in patients with major burns. It has
been shown to decrease heart rate, cardiac work, muscle catabolism,
and resting energy expenditure in children with severe burns [70]. A
more recent systematic review of ten clinical trials concluded that
propranolol was effective and safe for reduction of metabolic rate in
patients with burns [49, 71, 72].
Results of smaller studies support a role of the testosterone analogue

oxandrolone in reducing muscle loss and hypermetabolism and
increasing bone mineral density and promoting growth in children
recovering from burns [49, 71].
LEARNING POINT General issues for the burned

patient
Airway management
A tracheostomy should be considered in the presence of facial burns,
and to aid early weaning from ventilation if extubation is otherwise
impossible.
Vascular access
The risk of sepsis from vascular access is a constant consideration.
Avoid central venous lines if possible; but if deemed essential, site
observation is paramount and consider replacement immediately if
there are any signs of infection.
Coagulation
The burn patient is at risk of unrecognized blood loss from burn
wound ooze. However, burn patients are more commonly in a
hypercoagulable state with an increased risk of deep vein thrombosis
and other thromboembolic events. Chemical thromboprophylaxis
should be initiated as soon as bleeding risk has passed, that is, when
surgery resulting in major blood loss is unlikely.
Gastroprotection
Gastrointestinal ulcer formation is common in patients with burns
who are not fed enterally. Consider chemoprophylaxis for ulcer
prevention when enteral feeding cannot be established or fails at any
point.
Page 18 of 29

Major burns
Hypothermia
Anaesthetic and sedative drugs ablate normal thermoregulation and
the patient may need to be fully exposed to enable assessment and
surgical management. The burned patient is at high risk of
hypothermia and this may exacerbate blood loss from worsening
coagulopathy. Ventricular arrhythmias are more likely and the left
shift of the oxyhaemoglobin dissociation curve reduces peripheral
oxygen delivery, risking burn injury extension and graft failure.
During anaesthesia and sedation, core temperatures of higher than
36°C should be maintained.
Altered drug handling

The hypermetabolic state, hypoproteinaemia from capillary protein
leak, and catabolism lead to altered drug handling. Free drug
concentrations are increased for those drugs that are predominantly
protein bound.
Muscle relaxants
Do not use depolarizing neuromuscular blocking drugs (i.e.
suxamethonium) from 24 hours after injury to 2 years after burn
injury because of an increase in extrajunctional nicotinic
acetylcholine receptors. Stimulation of these extrajunctional
receptors leads to excessive potassium release with the risk of
arrhythmias and cardiac arrest. Burn patients are also relatively
insensitive to non-depolarizing neuromuscular blocking drugs.
Pain
High doses of opioids are commonly used for long periods leading to
tolerance and subsequent withdrawal unless managed carefully.
Consider multimodal analgesia including gabapentinoids. Early
involvement of an age-appropriate acute pain service is crucial.
After a week in ICU, the patient was extubated. On one dressing change,
the surgeon noticed a green discharge from a burn site and skin graft on
her torso. Her dressing change was more painful than usual,
necessitating ketamine along with Entonox. Her white cell count
decreased and C-reactive protein (CRP) increased. Her temperature
increased to 40.1°C. She was taken back to the operating room for wound
debridement of a likely infected wound site. Broad-spectrum antibiotics
were started. After the results of wound swabs and blood cultures were
available, the antibiotic spectrum was narrowed to treat identified
pathogens.
LEARNING POINT Infection
Page 19 of 29

Major burns
Burn patients are susceptible to infection because of:
1. loss of skin integrity

2. cellular and humoral immunosuppression due to the SIR
3. a requirement for central vascular access and urinary
catheters
4. prolonged hospital stay and invasive procedures.
Bacterial infections are a consequence of endogenous flora and

environmental contaminants including airborne microorganisms [10].
Burned patients commonly acquire multidrug-resistant microbes or
fungal infection due to long hospitalization, high carer/patient contact
load, and frequent antibiotic therapy. Because of the high incidence of
septic episodes and risk of bacterial resistance, prophylactic
antibiotics should not be used.
Preventative measures include [10]:
1. patient isolation
2. hand washing
3. disposable waterproof full gowns, gloves, and masks
4. regular cleaning of isolation rooms with antibacterial solutions
5. regular wound, urinary catheter, and venous line inspection
plus wound and blood cultures if indicated.
Diagnosis of invasive burn wound infection can be difficult as the

standard criteria for sepsis is mimicked by the hypermetabolic
response in the non-infected burn patient. Although prophylactic
antimicrobial treatment is not appropriate in burn patients, there
needs to be scrupulous screening for infection and prompt treatment
when there is evidence of active infection.
The American Burn Association developed consensus guidelines to aid

diagnosis of sepsis in the burn patient. The trigger for diagnosis of
sepsis includes at least three of the following features as detailed in
Table 15.5 as well as ‘documented infection’ (defined in Table 15.5).
Table 15.5 Features of sepsis in the burn patient
Children Adults
Temperature >39°C or <36.5°C
Progressive >2 SD above age- >110 bpm

tachycardia specific norms
Progressive >2 SD above age- a. >25

tachypnoea specific norms breaths per
Page 20 of 29

Major burns
minute if not
ventilated.
b. Minute
volume >12
L/min if
ventilated
Thrombocytopenia <2 SD below age- <100 × 109/L

specific norms
Hyperglycaemia a. Blood sugar >20 mmol/L, if

untreated
b. >7 insulin IU/hour or >25%
increase in insulin requirement in a
24-hour period, if supplementation
used
Gastrointestinal a. Abdominal c. Enteral

stasis distension feed
b. Uncontrolled intolerance
diarrhoea
c. Enteral feed
intolerance
>24 hour:
aspirates >150
mL/hour
Documented a. Culture positive

infection b. Pathological tissue source
c. Clinical response to antimicrobials
bpm, beats per minute; SD, standard deviation.
Treatment involves source control (usually aggressive surgical

debridement of infected wounds) and targeted antimicrobial therapy.
Wound infection leading to systemic sepsis is potentially catastrophic

for the burn patient because it may lead to multiorgan failure,
haematogenous spread to distant sites, and/or graft failure. A high
index of suspicion is key. Organisms cultured during pneumonia often
reflect the flora of the burn wound [10].
Page 21 of 29

Major burns
EXPERT COMMENT
Diagnosis of burn wound infection and/or sepsis is difficult in the

patient with burns during the acute period after burn injury. The signs
of sepsis are identical to those of systemic inflammation except for
the presence of blood-borne bacteria. Diagnosis relies on a high index
of suspicion. The presence of pyrexia, changes in white blood cell
count, and CRP alone, may indicate either state. Intolerance of
enteral feed is more helpful, as is glucose instability. Evidence for the
use of procalcitonin as a biomarker of sepsis in patients with burns is
inconclusive.
If there are signs of sepsis in patients with burns, blood cultures,

wound swabs, and urgent assessment of the burn wound are
essential. Broad-spectrum antibiotics are started until cultures give
definitive results.
Toxic shock syndrome (TSS), usually secondary to the TSST1 toxin of

Staphylococcus aureus, should always be considered in the child with
signs of sepsis after burn injury. Specific management requires anti-
staphylococcal antibiotic treatment and wound cleaning. However,
management must also include anti-toxin treatment with intravenous
immunoglobulin (IVIG) or fresh frozen plasma (FFP). FFP is obtained
from adults and contains the anti-TSST1 toxin antibody which is low
in children of less than 4 years of age compared to older children and
adults. FFP is more commonly used than IVIG in the treatment of
TSS, although the evidence supporting this use is limited.
The patient was discharged from ICU after 2 weeks. Her total hospital
stay was 130 days because she required ongoing dressing changes and
further rehabilitation. National benchmarks for length of stay (healing)
are related to the size of the burn and are set at 2 days/%TBSA. Following
discharge, she will require regular reconstructive surgery for
contractures as she continues to grow during childhood and puberty.
LEARNING POINT Psychosocial aspects
There is increasing interest in the impact of major burn injury on a

patient’s psychosocial function [10]. Most patients now survive the
burn injury, because of improved burn and critical care management.
The resultant psychosocial impact has become increasingly apparent.
Communication and social interaction may be affected by altered skin
and disfigurement, with a resultant impact on social identity
(particularly in the adult population). Depressive symptoms, anxiety,
hopelessness, and emotional lability (and regressive behavioural
Page 22 of 29

Major burns
patterns in the paediatric patient) are normal reactions to the burn

injury during the recovery phase [10].
Some patients develop acute stress disorder (ASD) and post-traumatic

stress disorder (PTSD) from the initial burn injury and from multiple
medical interventions. The incidence of ASD is 19%, typically
occurring immediately following the trauma, and lasting up to 4
weeks. ASD is a predictor of PTSD, but PTSD is the most common
psychiatric disorder seen in burn survivors, occurring in
approximately 45%. Age-appropriate psychologists are key members
of the burns multidisciplinary team.
Burns cases can be complicated by the suspicion of non-accidental

injury (NAI) which is not uncommon in children with burns. Burns
account for 6–8% of all paediatric abuse cases annually and abuse-
associated burns have worse clinical outcomes including higher
mortality. The vulnerable adult may also be at risk of NAI. The wider
family should be considered, for example, any other siblings who may
need emergency social care during any NAI investigation. Clinical
notes should be detailed, factual, and objective, and the appropriate
safeguarding team involved at an early stage.
Discussion
Death from burn injury has reduced during the twentieth and the
early part of the twenty-first century. In the 1940s, a child with 50% TBSA
burns had an expected mortality of over 50%. Currently, the same child,
has an expected mortality of 16% and survival in children with burns of
greater than 80% is now possible [54]. However, this improvement in
survival is not reflected in the elderly population; the mortality rate for a
50% TBSA burn is 68% in those older than 60 years. This is most likely
because of comorbidities [10]. The difficulty with achieving meaningful
estimates for mortality includes varying burn care management,
standardizing the burn type, presence of inhalation injury, comorbidity,
and agreeing the mortality calculation. Sepsis and multiorgan failure
remain the leading causes of death after burn injury [54].
The most important advance in the surgical care of patients with large
area burns is early excision of the burn eschar with subsequent wound
coverage. This should ideally be from autografting or dermal replacement
in larger area burns. This removes the stimulus for the systemic
inflammatory and hypermetabolic responses, decreases the incidence of
sepsis, and improves survival along with cosmetic and functional outcome
[32].
Improved critical care including early and appropriate fluid resuscitation

(with a trend towards limiting fluid replacement to ‘just enough’),
amelioration of the hypermetabolic response, and strict prevention and
Page 23 of 29

Major burns
treatment (but not prophylaxis) of infection have also reduced mortality.

Positive pressure ventilation should be used with caution and only when
essential. Early extubation of all patients with burns (including those with
facial burns) is key to good outcomes.
Incidence and management of inhalational injury remains a major

determinant of burn survival. Diagnosis is still a challenge. The aims of
critical care management in inhalational injury are early diagnosis, a
protective ventilation strategy, conservative fluid management, and
pharmacological treatment/prevention of complications.
Burn care is improving with advances in surgery, critical care,

microbiology, and psychological care. Good outcomes are now
possible despite the most severe injuries, although these
improvements in outcome have been limited in the elderly. Quality
evidence is improving, although multicentre randomized controlled
trials with consistent outcome reporting are still limited, with
associated difficulties in evidence synthesis.
Areas of research include wound coverage for large area burns

(dermal preservation and replacement), improvement of wound
healing, early detection of infection with new point-of-care
technology, limitation and accuracy of fluid replacement with a clear
understanding of clinical end points, the role of ventilation in burn-
injured patients, and standardization of care to enable audit of care
pathways across services.
The importance of physical and psychological rehabilitation starting

early after injury for burns of all sizes is now clear. An understanding
of the importance of expert, experienced multidisciplinary teamwork
is also clear, as is the need to provide the best outcomes by
centralizing care into a few specialized centres for the rare major
burns in both adults and children.
References
1. Moritz A, Henriques F, McLean R. The effects of inhaled heat on the air
passages and lungs: an experimental investigation. Am J Pathol.
1945;21:311–31.
2. Madnani D, Steele N, de Vries E. Factors that predict the need for

intubation in patients with smoke inhalation injury. Ear Nose Throat J.
2006;85:278–80.
Page 24 of 29

Major burns
3. Hobson K, Young K, Ciraulo A, et al. Release of abdominal

compartment syndrome improves survival in patients with burn injury. J
Trauma. 2002;53:1129–34.
4. Tsoutsos D, Rodopoulou S, Keramidas E, et al. Early escharotomy as a

measure to reduce intraabdominal hypertension in full-thickness burns of
the thoracic and abdominal area. World J Surg. 2003;27:1323–8.
5. Asch M, Flemma R, Pruitt B Jr. Ischemic necrosis of tibialis anterior

muscle in burns patients: report of three cases. Surgery. 1969;66:846–69.
6. Hettiaratchy S, Papini R. Initial management of a major burn: II—

assessment and resuscitation. BMJ. 2004;329:101–3.
7. Palmieri T. Inhalation injury: research progress and needs. J Burn Care

Res. 2007;28:549–54.
8. Shirani K, Pruitt B Jr, Mason A Jr. The influence of inhalation injury and
pneumonia on burn mortality. Ann Surg 1987;205:82–7.
9. Jeschke M, Herndon D. Burns in children: standard and new

treatments. Lancet. 2014;383:1168–78.
10. Herndon D. Total Burn Care, 4th edn. Amsterdam: Elsevier Health
Sciences; 2012.
11. Demling R. Smoke inhalation lung injury: an update. Eplasty

2008;8:e27.
12. Hunt J, Agee R, Pruitt B Jr. Fiberoptic bronchoscopy in acute

inhalation injury. J Trauma. 1975;15:641–9.
13. Muehlberger T, Kumar D, Munster A et al. Efficacy of fiberoptic

laryngoscopy in the diagnosis of inhalation injuries. Arch Otolaryngol
Head Neck Surg. 1998;124:1003–7.
14. Cancio L. Airway management and smoke inhalation injury in the

burn patient. Clin Plast Surg. 2009;36:555–67.
15. Woodson L. Diagnosis and grading of inhalation injury. J Burn Care

Res. 2009;30:143–5.
16. Fu Z, Yang Z, Liu L, et al. The influence of N-acetyl-L-cysteine on

pulmonary injury and oxygen stress after smoke inhalation injury.
Zhonghua Shao Shang Za Zhi. 2002;18:152–4.
17. Desai M, Micak R, Richardson J, et al. Reduction in mortality in

paediatric patients with inhalation injury with aerosolized heparin/N-
acetlycystine [correction of acetylcystine] therapy. J Burn Care Rehabil
1998;19:210–12.
Page 25 of 29

Major burns
18. Miller A, Elamin E, Suffredini A. Inhaled anticoagulation regimens for

the treatment of smoke inhalation-associated acute lung injury: a
systematic review. Crit Care Med. 2014;42:413–19.
19. Walker P, Buehner M, Wood L, et al. Diagnosis and management of

inhalation injury: an updated review. Crit Care. 2015;19:351.
20. Kealey G. Carbon monoxide toxicity. J Burn Care Res. 2009;30:146–7.
21. Dries D, Endorf F. Inhalation injury: epidemiology, pathology,

treatment strategies. Scand J Trauma Resusc Emerg Med. 2013;21:31.
22. Buckley N, Juurlink D, Isbister G, et al. Hyperbaric oxygen for carbon

monoxide poisoning. Cochrane Database Syst Rev. 2011;4:CD002041.
23. Villanueva E, Bennett M, Wasiak J, et al. Hyperbaric oxygen therapy

for thermal burns. Cochrane Database Syst Rev. 2004;3:CD004727.
24. Murray L, Little M, Pascu O, et al. Toxicology Handbook, 3rd edn.

Sydney: Elsevier Australia: 2015.
25. Borron S, Baud F, Mégarbane B, et al. Hydroxocobalamin for severe

acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med.
2007;25:551–8.
26. Fortin J, Giocanti J, Ruttimann M, et al. Prehospital administration of

hydroxocobalamin for smoke inhalation associated cyanide poisoning: 8
years of experience in the Paris Fire Brigade. Clin Toxicol (Phila).
2006;44:37–44.
27. Jackson D. The diagnosis of the depth of burning. Br J Surg.

1953;40:588–96.
28. Zawacki B. Reversal of capillary stasis and prevention of necrosis in

burns. Ann Surg. 1974;180:98–102.
29. Shupp J, Nasabzadeh T, Rosenthal D, et al. A review of the local

pathophysiologic bases of burn wound progression. J Burn Care Res.
2010;31:849–73.
30. Knabl J, Bauer W, Andel H, et al. Progression of burn wound depth by

systemical application of a vasoconstrictor: an experimental study with a
new rabbit model. Burns 1999;25:715–21.
31. Rico R, Ripamonit R, Burns A, et al. The effect of sepsis on wound

healing. J Surg Res. 2002;102:193–7.
32. Cope O, Langohr J, Moore F, et al. Expeditious care of full-thickness

burn wounds by surgical excision and grafting. Ann Surg. 1947;125:1–22.
33. Hettiaratchy S, Papini R. ABC of burns: initial management of a major

burn: II – assessment and resuscitation. Br Med J. 2004;329:101–3.
Page 26 of 29

Major burns
34. St Helens and Knowsley Teaching Hospitals NHS Trust. Mersey Burns
App [Internet]. 2013. Available from: https://www.merseyburns.com
(accessed 11 April 2017).
35. National Institute for Health and Care Excellence (NICE). Mersey
Burns for Calculating Fluid Resuscitation Volume when Managing Burns.
NICE Medtech Innovation Briefing [MIB58]. London: NICE; 2016.
Available from: https://www.nice.org.uk/advice/mib58/chapter/
Introduction.
36. Heimbach D, Afromowitz M, Engrav L, et al. Burn depth estimation—

man or machine. J Trauma. 1984;24:373–8.
37. National Institute for Health and Care Excellence (NICE). MoorLDI2-
BI: A Laser Doppler Blood Flow Imager for Burn Wound Assessment.
NICE Medical Technologies Guidance [MTG2]. London: NICE; 2011.
Available from: https://www.nice.org.uk/guidance/MTG2/chapter/1-
Recommendations.
38. Waldmann C, Soni N, Rhodes A. Oxford Desk Reference: Critical Care.

Oxford: Oxford University Press; 2008.
39. Tompkins R, Remensnyder J, Burke J, et al. Significant reductions in

mortality for children with burn injuries through the use of prompt eschar
excision. Ann Surg. 1988;208:577–85.
40. Herndon D, Barrow R, Rutan R, et al. A comparison of conservative

versus early excision. Therapies in severely burned patients. Ann Surg.
1989;209:547–53.
41. Cope O, Moore F. The redistribution of body water and fluid therapy of
the burned patient. Ann Surg. 1947;126:101–45.
42. Youn Y, LaLonde C, Demling R. The role of mediators in the response

to thermal injury. World J Surg. 1992;16:30–6.
43. Demling R, Mazess R, Witt R, et al. The study of burn wound edema
using dichromatic absorptiometry. J Trauma. 1978;18:124–8.
44. Cioffi W Jr, Vaughan G, Heironimus J, et al. Dissociation of blood

volume and flow in regulation of salt and water balance in burns patients.
Ann Surg. 1991;214:213–18.
45. Baxter C. Fluid volume and electrolyte changes in the early postburn
period. Clin Plast Surg. 1974;1:693–703.
46. Wolf S, Rose J, Desai M, et al. Mortality determinants in massive

pediatric burns: an analysis of 103 children with > or = 80% TBSA burns
(> or = 70% full thickness). Ann Surg. 1997;225:554–69.
47. Barrow R, Jeschke M, Herndon D. Early fluid resuscitation improves

outcomes in severely burned children. Resuscitation. 2000;45:91–6.
Page 27 of 29

Major burns
48. Klein M, Hayden D, Elson C, et al. The association between fluid

administration and outcome following major burn: a multicenter study.
Ann Surg. 2007;245:622–8.
49. Porter C, Tompkins R, Finnerty C, et al. The metabolic stress response

to burn trauma: current understanding and therapies. Lancet.
2016;388:1417–26.
50. Saffle J. The phenomenon of “fluid creep” in acute burn resuscitation.

J Burn Care Res. 2010;28:382–95.
51. Arlati S, Storti E, Pradella V, et al. Decreased fluid volume to reduce

organ damage: a new approach to burn shock resuscitation? A
preliminary study. Resuscitation. 2007;72:371–8.
52. Walker T, Rodriguez D, Coy K, et al. Impact of reduced resuscitation

fluid on outcomes of children with 10–20% body surface area scalds.
Burns. 2014;40:1581–6.
53. Paratz J, Stockton K, Paratz E, et al. Burn resuscitation—hourly urine

output versus alternative endpoints: a systematic review. Shock.
2014;42:295–306.
54. Henschke A, Lee R, Delaney A. Burns management in ICU: quality of

the evidence: a systematic review. Burns. 2016;42:1173–82.
55. National Network for Burn Care (NNBC). National Burn Care Referral
Guidance: Version 1 [Internet]. 2012. Available from: http://
www.britishburnsassociation.org.uk (accessed 11 April 2017).
56. Pietsch J, Netscher D, Nagaraj H, et al. Early excision of major burns

in children: effect on morbidity and mortality. J Pediatr Surg.
1985;20:754–7.
57. Hernson D, Parks D. Comparison of serial debridement and

autografting and early massive excision with cadaver skin overlay in the
treatment of large burns in children. J Trauma. 1986;26:149–52.
58. Muller M, Herndon D. The challenge of burns. Lancet. 1994;343:216–

20.
59. Tompkins R, Remensnyder J, Burke J, et al. Significant reductions in

mortality for children with burn injuries through the use of prompt eschar
excision. Ann Surg. 1988;208:577–85.
60. Desai M, Hernson D, Broemeling L, et al. Early burn wound excision

significantly reduces blood loss. Ann Surg. 1990;211:753–9.
61. Galeiras R, Lorente J, Pértega S, et al. A model for predicting

mortality among critically ill burn victims. Burns. 2009;35:201–9.
62. Mackie D. Inhalation injury or mechanical ventilation: which is the

true killer in burn patients? Burns. 2013;39:1329–30.
Page 28 of 29

Major burns
63. Holst J, Sauaia A, Ivashchenko A, et al. Indications for intubation of

the patient with thermal and inhalational burns. Am J Respir Crit Care
Med. 2015;191:A1619.
64. Williams F, Jeschke M, Chinkes D, et al. Modulation of the

hypermetabolic response to trauma: temperature, nutrition, and drugs. J
Am Coll Surg. 2009;208:489–502.
65. McDonald W, Sharp C Jr, Deitch E. Immediate enteral feeding in burn

patients is safe and effective. Ann Surg. 1991;213:177–83.
66. Lee J, Benjamin D, Herndon D. Nutrition support strategies for

severely burned patients. Nutr Clin Pract. 2005;20:325–30.
67. Demling R, Orgill D. The anticatabolic and wound healing effects of

the testosterone analog oxandrolone after severe burn injury. J Crit Care.
2000;15:12–17.
68. Jeschke M, Finnerty C, Suman O, et al. The effect of oxandrolone on

the endocrinologic, inflammatory, and hypermetabolic responses during
the acute phase post burn. Ann Surg. 2007;246:351–60.
69. Henig O, Avni T, Herndon D et al. Beta adrenergic antagonists for

hospitalized burned patients. Cochrane Database Syst Rev.
2015;6:CD011713.
70. Herndon D, Hart D, Wolf S, et al. Reversal of catabolism by beta-

blockade after severe burns. N Engl J Med. 2001;345:1223–9.
71. Porter C, Tompkins R, Finnerty C, et al. The metabolic stress response

to burn trauma: current understanding and therapies. Lancet.
2016;388:1417–26.
72. Flores O, Stockton K, Roberts J, et al. The efficacy and safety of

adrenergic blockade after burn injury: a systematic review and meta-
analysis. J Trauma Acute Care Surg. 2016;80:146–55.
Page 29 of 29

Prolonged mechanical ventilation and delayed
weaning

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Prolonged mechanical ventilation and delayed weaning
Chapter: Prolonged mechanical ventilation and delayed weaning
Author(s): Patrick B. Murphy
DOI: 10.1093/med/9780198814924.003.0016
Expert commentary by Nicholas Hart
Case history
A 67-year-old retired lecturer was referred from his local intensive

care unit (ICU) to a specialist weaning, rehabilitation, and home
mechanical ventilation service. The patient had contracted poliomyelitis
when 5 years old and had required respiratory support with ‘iron lung
tank ventilation’ for 4 months during his acute illness. Following this, he
made a full respiratory recovery, with no need for ongoing ventilatory
support. He did, however, have limited recovery of lower limb strength
and the development, despite a spinal brace, of a significant scoliosis. He
regained only limited walking with callipers and required a wheelchair for
mobility. He worked as a lecturer but noticed progression of his weakness
from the age of around 50, which was consistent with post-polio
syndrome. Despite this progression, he lived with his wife in an adapted
flat with a comprehensive care package and was first reviewed by the
home mechanical ventilation and ‘post-polio’ service aged 57, 10 years
Page 1 of 28
weaning
before this referral. He had no symptoms of sleep-disordered breathing,

normal overnight oximetry, and a vital capacity of 1.9 L (Figure 16.1).
Figure 16.1
Overnight oximetry study showing oxygen saturations (upper panel) and
pulse rate (lower panel). Periods of limited desaturations occurring
intermittently throughout the night coincide with rapid eye movement
sleep or supine position. The study shows no evidence of rapid repetitive
desaturation and resaturation consistent with upper airways obstruction
and obstructive sleep apnoea or significant prolonged desaturations to
suggest clinically significant hypoventilation.
LEARNING POINT Indication for overnight non-

invasive ventilation in neuromuscular disease and chest
wall deformity: monitoring respiratory function and
screening for sleep-disordered breathing
Progressive neuromuscular disease (NMD) may lead to respiratory

muscle weakness. Respiratory muscle weakness and chest wall
deformity can result in a restrictive ventilatory deficit and chronic
respiratory failure, which can often be overlooked. Evidence supports
the use of long-term non-invasive ventilation (NIV) to improve
mortality in patients with NMD or chest wall deformity [1, 2].
Assessments of respiratory impairment secondary to NMD and chest
wall disease can encompass a simple assessment of breathlessness,
through to sitting and supine spirometry, to direct measurement of
respiratory muscle strength using inspiratory and expiratory mouth
pressures as well as sniff nasal pressures [3].
While established chronic respiratory failure is an obvious indicator of

the need for ventilatory support, it is ideal to pre-empt this event and
initiate NIV prior to the occurrence of diurnal respiratory failure, but
not so early as to burden the patient unnecessarily. Assessment of
ventilation during sleep offers an ideal opportunity to detect patients
at risk of decompensation, in the near future or in the event of a
respiratory infection, as the normal physiological changes during
sleep [4] stress the respiratory system and identify the need for
Page 2 of 28

weaning
domiciliary NIV [5, 6]. Such at-risk patients should therefore be

closely assessed at presentation with acute illness for features of
respiratory muscle weakness and sleep-disordered breathing that
places them at risk of sleep hypoventilation and thus subsequent
decompensation.
He was admitted to his local hospital with a 10-day history of a productive

cough and worsening breathlessness, despite a course of broad-spectrum
antibiotics in the community. On admission, he was febrile with right
basal crackles. A chest X-ray showed right lower lobe consolidation and
sputum culture isolated a sensitive Klebsiella species. Despite Tazocin 4.5
g three times daily started on admission he developed acute respiratory
failure within 48 hours, which was managed initially with NIV. Over the
next 24 hours, his lower airways secretion load increased and
hypoxaemia worsened, requiring emergency tracheal intubation for
invasive ventilation, oxygenation, and regular bronchial toileting.
LEARNING POINT Predicting failure of non-invasive

ventilation/selection for non-invasive ventilation
NIV is increasingly used in acute decompensated hypercapnic

respiratory failure within the critical care unit and on the general
medical wards. The indications for NIV have expanded over the past
20 years and it is considered first-line therapy in many clinical
situations [7]. However, while there is robust evidence supporting its
use in patients with acute respiratory acidosis secondary to
exacerbations of chronic obstructive pulmonary disease (COPD) [8, 9],
the data supporting its use in other situations are less compelling.
There have been no randomized controlled trials demonstrating
superiority of NIV to invasive ventilation in obesity-related acute
hypercapnic respiratory failure, but there is observational evidence to
support its use [10]. However, as NIV failure is associated with a poor
prognosis in numerous clinical contexts [11, 12, 13, 14], it is essential
to use NIV appropriately, targeting the patients who will benefit most,
such as those with pre-existing chronic respiratory disease and
considering carefully which patients should be managed within
critical care to facilitate rapid escalation to intubation when
appropriate (Table 16.1).
Table 16.1 Factors associated with non-invasive ventilation failure
Patient factors Poor nutrition
Confusion with agitation
Page 3 of 28

weaning
High upper and lower airways secretion

load
Lobar consolidation on the chest

radiograph
Intervention Poor patient–ventilator synchrony

factors
Excessive mask leak
Insufficient ventilator pressures
Outcome factors Failure to improve respiratory rate or

acidosis within 1 hour of initiating NIV
An experienced multidisciplinary team is vital to the success of acute

NIV. Despite the widespread use of NIV including on the ward, its use
requires education and training [15]. Regular clinical exposure is
important in maintaining skills and use of NIV in multiple clinical
settings can lead to dilution of expertise with subsequent erosion of
skills whereas consolidation of NIV skills in a single setting, such as a
respiratory intermediate care unit, can be both clinically and cost-
effective [16].
Over the following 7 days, and despite numerous attempts with differing
strategies, he was unable to be weaned from invasive ventilation. After
discussion with the respiratory unit which had been undertaking his long-
term monitoring, he was transferred to an ICU with an attached weaning,
rehabilitation, and home mechanical ventilation centre. This was to
facilitate direct input from specialist clinicians to manage his complex
neuromuscular condition and likely requirement for prolonged
mechanical ventilation.
LEARNING POINT Simple weaning from mechanical

ventilation
Page 4 of 28

weaning
The process of weaning from mechanical ventilation can only occur

when patients have sufficient physiological reserve to respond to the
increase in work of breathing that will occur on reduction and
withdrawal of ventilator support. ‘Readiness to wean’ is the term used
to describe assessment of a patient’s suitability for a trial of weaning.
Weaning in this context may involve either a spontaneous breathing
trial (SBT) or reduction in pressure support. Criteria for readiness
testing are:
● improving clinical picture

● adequate oxygenation (e.g. partial pressure of oxygen (PaO2) ≥8
kPa breathing a fraction of inspired oxygen (FiO2) ≤0.4 and
positive end-expiratory pressure (PEEP) ≤10 cmH2O)
● cardiovascular stability (e.g. heart rate ≤120 beats/min (bpm),
stable blood pressure, and minimal or no vasopressors)
● afebrile
● no significant respiratory acidosis
● adequate haemoglobin (e.g. haemoglobin concentration ≥70 g/
L)
● adequate mentation (e.g. Glasgow Coma Scale score ≥12)
● adequate cough function to allow secretion clearance
● stable metabolic state.
The rapid shallow breathing index (RSBI) has been used as a weaning
predictor in patients who are deemed ready to wean [17]. The RSBI is
performed in spontaneously breathing, awake patients with minimal
respiratory support. This involves monitoring respiratory parameters
during a short period (2 min) of self-ventilation using a T-piece. The
second minute of the test is used to calculate the RSBI which is the
respiratory frequency divided by the average tidal volume. The use of
a T-piece most accurately reflects post-extubation work of breathing,
with the use of PEEP or pressure support reducing the discriminatory
value of the test. A value of greater than 100 breaths/min/L indicates
a high risk of extubation failure (95%) with a value less than 100
breaths/min/L indicating an 80% chance of extubation success [17].
Although it has sensitivity to predict weaning failure, it has poor

specificity and its routine use has not been shown to improve
outcomes [18]. Other weaning predictors have been used including
oxygenation, minute ventilation, occlusion pressure, and work of
breathing [19, 20, 21, 22]. However, and not surprisingly, each of
these single predictors has insufficient power to discriminate between
weaning success and failure in daily clinical practice. Although
integrated measures have been suggested, they have also failed to be
translated into a useful clinical tool [23], highlighting that weaning
from mechanical ventilation is a complex task. Patients deemed ready
to wean but at high risk of extubation failure can be supported after
Page 5 of 28

weaning
extubation with NIV. The use of NIV in these high-risk patients can
reduce the risk of reintubation and improve hospital survival [24].
More recent data suggest that high-flow, humidified nasal oxygen
therapy demonstrates equivalent benefits to NIV in the high-risk post-
extubation simple weaning group, although interestingly the NIV arm
had significant rates of therapy failure (approximately 50%),
emphasizing the importance of skill and experience in applying this
intervention [25].
LEARNING POINT Predicting failure to wean and

prolonged mechanical ventilation
Prolonged mechanical ventilation, incorporating weaning failure, is

defined as the provision of ventilator support for greater than 21
days, although there are subtle differences between the UK and other
international consensus definitions [26, 27]. The UK definition is
based on days of invasive ventilation, whereas international
consensus incorporates days of invasive ventilation and the number of
failed SBTs.
International consensus categorization of weaning
● Simple: progression from weaning to successful extubation at

first attempt.
● Difficult: up to three SBTs or 7 days from first SBT prior to
extubation.
● Prolonged: failure to extubate after at least three SBTs or more
than 7 days following first SBT.
Early identification of patients who are likely to undergo prolonged

mechanical ventilation and weaning failure will enhance decision-
making and care planning. Factors associated with an increased risk
of prolonged mechanical ventilation include admission with
pneumonia, acute respiratory distress syndrome, COPD, restrictive
lung disease, NMD, poor nutritional state, and severe acute
physiological derangement at presentation to ICU [28]. Patients with
chronic respiratory failure due to COPD, NMD (pre-morbid or ICU
acquired), or obesity are at high risk of prolonged mechanical
ventilation and weaning failure and often will require transition to
NIV [29]. Generalized skeletal muscle weakness can be assessed by
the Medical Research Council (MRC) sum score; this is a manual
technique and involves a clinician using opposing force to rate the
strength of a patient’s peripheral muscle groups. The sum score is
calculated by the cumulative score provided by testing the power of
three upper and three lower limb groups each rated from 0 to 5
(maximum 60). The MRC sum score has been used to identify
potential respiratory muscle weakness and thus risk for extended
Page 6 of 28

weaning
ventilation, but the test is poorly repeatable in the clinical setting and
thus unreliable [30, 31]. Furthermore, the individual predictive power
of any of these clinical factors is low and so prognostic assessments
are unreliable [28]. Patients who undergo prolonged mechanical
ventilation have a high mortality with around half of patients not
surviving to 12 months—deaths occur both during and after weaning
[32, 33]. Many survivors will have impairment to physical, cognitive,
and psychosocial aspects of quality of life [34]. However, the severity
of these impairments will be most related to the number of
comorbidities and presence of chronic disease, rather than duration
of mechanical ventilation [34].
Following transfer, as the patient exhibited agitated delirium, he was

sedated with propofol at 100 mg/hour. A size 8.0 mm internal diameter
tracheal tube was in place. The ventilatory mode was changed to bi-level
pressure control with an inspiratory pressure of 22 cmH2O and an
expiratory pressure of 7 cmH2O, a back-up rate of 12 breaths/min,
inspiratory time (Ti) of 1.4 seconds with a FiO2 of 0.50. Arterial blood gas
(ABG) analysis showed pH 7.53, partial pressure of carbon dioxide
(PaCO2) 5.9 kPa, PaO2 16.9 kPa, base excess 13 mmol/L, and standard
bicarbonate (sHCO3−) 35.6 mmol/L. His heart rate was 57 bpm in sinus
rhythm and blood pressure was 97/57 mmHg. He had extensive pitting
oedema to the knees bilaterally and was being fed via a nasogastric tube
and had a urinary catheter in situ. A chest X-ray showed resolution of the
original consolidation which was replaced by widespread alveolar
shadowing, and with the reduction in inflammatory markers indicated
fluid overload and pulmonary oedema rather than a recurrent or
persistent respiratory infection (Figure 16.2). The patient was agitated
and biting the tube.
Page 7 of 28

weaning
Figure 16.2
Chest radiograph performed following transfer. The image shows
extensive bilateral perihilar airspace shadowing consistent with
pulmonary oedema.
EXPERT COMMENT
Patients with chronic respiratory failure have elevated serum

bicarbonate levels to metabolically compensate for the respiratory
acidosis caused by the elevated PaCO2. If aggressive ventilation is
pursued in such patients with a view to achieving normocapnia, then
the inevitable result is a metabolic alkalosis. This acts to blunt the
respiratory centre’s response to carbon dioxide and may leave the
patient prone to central apnoeas and respiratory centre instability
resulting in periodic breathing. The target carbon dioxide values in
patients with chronic respiratory failure should be based on the
admission bicarbonate values or, if available, the pre-admission
PaCO2.
LEARNING POINT Identify causes of prolonged

ventilation
Patients who meet the criteria for prolonged mechanical ventilation

and weaning failure should have a careful review by an experienced
critical care physician to identify potential barriers to weaning.
Assuming the initial reversible cause of ventilatory failure has
resolved, then further causes can be considered that contribute to
Page 8 of 28

weaning
failure to wean by causing an imbalance in the load–capacity–drive

relationship of the respiratory system.
Increased respiratory load
● Airways disease, such as COPD, results in expiratory flow

limitation and increased threshold load (dynamic lung
hyperinflation) and elastic load (bronchospasm and secretion load)
of the respiratory system. Ventilator setting must accommodate a
prolonged expiratory time to prevent hyperinflation.
● Obesity contributes to decreased pulmonary compliance and
increased threshold load due to intrinsic PEEP and also
contributes to increased elastic load [35]. High intra-abdominal
pressure reduces lung volume placing the patient on an inefficient
part of the respiratory pressure–volume curve [36]. Obesity also
confers a significant increase in work of breathing, placing further
demands on the respiratory muscles [37].
● Chest wall deformity, such as scoliosis and kyphosis, can often
be overlooked as a cause of increased work of breathing and may
contribute to chronic respiratory failure.
Reduced respiratory muscle capacity
● Chronic respiratory muscle weakness secondary to established

NMD (e.g. myotonic dystrophy and Duchene muscular dystrophy)
is likely to be diagnosed before admission. However, adults may
present de novo to critical care with an acute decompensation
complicating progressive respiratory muscle-predominant
neurological diseases such as motor neuron disease or late-onset
Pompe’s disease. Features of NMD should therefore be assessed
on all slowly weaning subjects with attention paid to generalized
muscle and tongue fasciculation, loss of muscle bulk, evidence of
diaphragmatic weakness or history prior to admission of bulbar
dysfunction, features of respiratory muscle weakness, gait
abnormalities, or falls.
● Prolonged critical illness can be associated with critical illness
polymyoneuropathy which can lead to significant general and
respiratory muscle weakness contributing to weaning delays.
● Metabolic derangements and malnutrition are corrected to
ensure optimal respiratory muscle function. Magnesium
supplementation may augment diaphragmatic function, although
whether this is clinically beneficial in the critical care population is
unproven [38].
Reduced neural respiratory drive
● Patients presenting with acute ascending radiculopathies, such

as Guillain–Barré syndrome and its variants, will have profound
Page 9 of 28

weaning
generalized and respiratory muscle weakness. While acute

treatment with steroids or intravenous immunoglobulin and
plasmapheresis may lead to rapid improvement in some, many
patients require prolonged weaning because of a profound
reduction in respiratory drive and respiratory muscle capacity. The
duration of recovery may be many months and is best coordinated
across the multidisciplinary team with clear rehabilitation as well
as respiratory targets.
● Obesity-related chronic respiratory failure is increasingly
common within ICUs, yet it is often undiagnosed [39]. In addition
to increased work of breathing, compared to their counterparts
with ‘simple obesity’ these patients also have a marked reduction
in ventilatory drive with further suppression in response to an
increased FiO2 [40]. Evidence of chronic respiratory failure, such
as elevated base excess and bicarbonate on admission, assists in
setting appropriate physiological targets.
● Less commonly, disorders of the neuromuscular junction, such
as myasthenia gravis or botulinum toxin poisoning, can impair the
ability to transmit respiratory drive from the cortex to the
respiratory muscles contributing to weaning failure and, as
potentially reversible causes, should be considered, investigated,
and when present treated.
In addition to impediments to weaning caused by imbalance in the

respiratory muscle load–capacity–drive relationship, non-respiratory
factors may inhibit weaning. Severe cardiac dysfunction whether in
isolation or comorbid to congenital muscular dystrophies may prevent
weaning [41, 42, 43]. Left ventricular failure and subsequent
pulmonary oedema can contribute to increased work of breathing and
the beneficial cardiac effects of positive airway pressure may render
patients ventilator dependent. A cardiology review is recommended in
these patients.
Optimal fluid management along with treatment of any reversible

ischaemia and residual heart failure is required to progress weaning.
Patients with established cardiac disease have negative physiological
consequences of weaning ventilator pressures with one study
showing an increase in pulmonary wedge pressure during weaning
trials and subsequent improvement of weaning success following
diuresis [41]. In some patients, weaning may be facilitated by
coronary revascularization [44]. More radical approaches such as the
use of cardiac resynchronization devices or long-term inotropes, such
as levosimendan, may offer potential salvage therapy for patients with
few alternative avenues for liberation from mechanical ventilation.
There is experimental evidence that levosimendan, a calcium-
sensitizing agent, may have a direct beneficial effect on diaphragm
function in these patients [45]. However, recent data in patients with
septic shock demonstrated no advantage of levosimendan on
sequential organ dysfunction score (the study primary outcome) and
Page 10 of 28

weaning
interestingly demonstrated delayed weaning in the treatment

compared to placebo group [46]. It must be realized when
interpreting these data that the patient group were not weaning
failure patients and that chronic cardiac dysfunction, despite
optimization of other therapy, was not a prerequisite for trial entry.
However, these data suggest the indiscriminate use of levosimendan
cannot be supported, and it should be reserved for carefully evaluated
patients with weaning failure and evidence of cardiac dysfunction.
EXPERT COMMENT
Patients with profound cardiac dysfunction but without comorbid

chronic respiratory disease or NMD may be unable to be liberated
from mechanical ventilation. These patients may often be
normocapnic with the ability to achieve spontaneous ventilation on
modest continuous positive airway pressure (CPAP) support but will
rapidly decompensate following its withdrawal. This can be
demonstrated by removal of positive pressure at the bedside with a
clinical evidence of a fall in cardiac output such as cooling of the
peripheries and associated respiratory distress.
A comprehensive case review was undertaken, the issues contributing to

delayed weaning were considered in full, and a weaning strategy was
developed. A major contributor to the patient’s failure to wean was
ongoing delirium, exacerbated by poorly controlled musculoskeletal pain,
sleep deprivation, and poor positioning in bed because of his significant
skeletal deformity. Fentanyl analgesia was added with the aim of reducing
the propofol infusion. The goal was a Richmond Agitation Sedation Scale
(RASS) score of −1 to 0 (i.e. alert and calm or minimally drowsy). His
fluid overload was managed with a daily negative fluid balance target of
−750 to −1000 mL. When sedation, analgesia, and diuresis led to relative
hypotension, vasopressor support was commenced. Lorazepam 0.5 mg 8-
hourly was added, enabling gradual reduction of propofol dose and
negating the requirement for vasopressor support.
The weaning strategy led to a decrease in ventilatory support (Table

16.2).
Page 11 of 28

Table 16.2 Observation chart demonstrating weaning of ventilator pressures over 4 days
Day 7 Day 8 Day 9 Day 10
Time 06:00 22:00 06:00 22:00 06:00 22:00 06:00 22:00
Ventilator BiPAP BiPAP BiPAP BiPAP BiPAP BiPAP BiPAP BiPAP

mode
FiO2 0.30 0.30 0.28 0.28 0.25 0.25 0.25 0.25
Pressure 18 16 14 14 14 14 12 12
support (cmH2O
)
PEEP/CPAP 8 8 8 8 6 6 5 5
(cmH2O)
Ti (s) 1.0 0.9 0.9 0.8 0.7 0.7 0.7 0.7
Set 16 18 20 20 22 20 20 18
respiratory
rate
Minute 7.3 7.7 8.9 8.3 10.8 9.3 10.6 8.9

ventilation (L/
min)
Page 12 of 28
and Legal Notice).
BiPAP, bi-level positive airway pressure; CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure;
Ti, inspiratory time.
Page 13 of 28
and Legal Notice).
weaning
Despite clinical improvements in fluid overload, agitation, and delirium

control, secretion management remained problematic and a tracheostomy
was planned to facilitate weaning and respiratory physiotherapy. After
family discussion, a size 9.0 mm internal diameter, non-fenestrated,
cuffed percutaneous tracheostomy tube was inserted without
complication on day 10 of mechanical ventilation. Insertion of the
tracheostomy tube facilitated reduction in sedation with cessation of
propofol and fentanyl by day 12.
LEARNING POINT Timing of tracheostomy and

weaning modes of ventilation
For the majority of ICU patients, resolution of the acute illness is

timely and simple weaning strategies with a protocolized approach,
daily sedation holds, and SBT is successful [47]. Patients who are
more complex or in whom this approach fails are likely to benefit
more from a bespoke plan that addresses the underlying causes of
failure to wean. The data supporting protocolized weaning are subject
to debate with the control group in the landmark trials being weaned
in a synchronous mandated mode of ventilation, which would not be
considered standard practice today [48, 49].
There is a lack of robust evidence of improved mortality and reduced

ICU length of stay with early (<10 days) compared with late
tracheostomy (>10 days) [50, 51]. Despite this, current practice
within critical care is not to delay tracheostomy and most units
perform tracheostomies within the first 2 weeks of invasive
ventilation [52, 53]. Early tracheostomy facilitates withdrawal of
sedation and promotes communication and bulbar function. There are
no data to suggest patients, even those with high risk for prolonged
mechanical ventilation, benefit from very early tracheostomy [54]. In
these high-risk patients, thought should be given to early aggressive
management of the disease process that precipitated critical care
admission with a view to early extubation to NIV to avoid the
complications of prolonged mechanical ventilation.
Ventilator settings have a significant impact on ability to wean

patients from mechanical ventilation and need to be actively managed
both during and between weaning trials. Settings need to alleviate
work of breathing and provide rest for respiratory muscles while
avoiding iatrogenic injury. Thought is commonly given to pressure
support, PEEP, and back-up rate settings to provide the patient with
adequate tidal volume (6–8 mL/kg ideal body weight) and ventilation
(6–12 L/min) and to control arterial CO2. However, attention also
needs to be given to settings such as inspiratory time, ventilator
mode, trigger method, and trigger sensitivity which all influence
efficacy of ventilation. The use of flow triggering (rather than
pressure triggering) is associated with reduced work of breathing in
Page 14 of 28

weaning
both pressure support and intermittent mandatory modes of

ventilation. In patients with expiratory flow limitation (e.g. COPD,
asthma), settings should enable sufficient expiratory time and applied
PEEP should be optimized to offset intrinsic PEEP and improve
respiratory mechanics (see Case 8).
Weaning trials should initially involve a staged reduction in pressure

support during daytime with return to full respiratory support at
night. Care is taken to provide an appropriate stimulus to the
respiratory muscles for training while avoiding respiratory muscle
fatigue, recovery from which can take longer than 24 hours. When the
patient can tolerate larger reductions in respiratory support, CPAP
trials can be considered. In some patients with good ventilatory
reserve but difficulty with oxygenation, high-flow, humidified oxygen
can be considered via tracheostomy, although little data is available
on its effectiveness.
Mechanical insufflation–exsufflation (MIE), using a cough assist device

attached to a tracheostomy tube catheter mount, was used to assist
secretion clearance. The tracheostomy tube was downsized on day 18 to a
size 8.0 mm internal diameter tracheostomy tube.
CLINICAL TIP Assisting phonation
The reduction in the external diameter of the tube facilitates airflow

around the tube assisting phonation during cuff down trials. Standard
critical care dual-limb ventilators are often intolerant of this
‘unintentional’ leak and so the use of a single-limb circuit ventilator
with leak compensation is preferred.
At this point, the patient was transferred from the ICU to the weaning,
rehabilitation, and home mechanical ventilation centre. Cuff down trials
facilitated weaning and communication, which demonstrated persistent
delirium that required regular reorientation therapy and ongoing use of
low-dose lorazepam (0.5 mg three times daily). During cuff down trials,
bulbar function was fully assessed by the multidisciplinary team,
including speech and language therapists, allowing sensitization of the
larynx and pharynx, which facilitated both upper and lower airway
secretion management by improving swallow and cough function. The
weaning process was delayed by an intercurrent ventilator-associated
pneumonia, during which weaning was suspended. Once cuff deflation
was tolerated for greater than 24 hours without problems, the
tracheostomy was changed to a size 7.5 mm internal diameter, non-
fenestrated cuffless tube. Weaning progressed from day 18 to day 25 with
stepwise daytime reduction in pressure support (1–2 cmH2O per day as
Page 15 of 28

weaning
tolerated) with a speaking valve in circuit (Passy-Muir Valve) to promote

phonation and self-management of secretion clearance. Independence
and self-management was encouraged and the patient was able to cough
his secretions to his mouth and remove with suction. From day 25, the
patient progressed to daytime CPAP trials at 8 cmH2O with a speaking
valve in circuit, initially intermittently and then for the duration of the
day. From day 30, the patient started daytime self-ventilation trials with
the speaking valve attached to the tracheostomy tube and heated
humidification provided by the tracheostomy mask.
EXPERT COMMENT
The use of a speaking valve adds to the respiratory load and therefore
the patient’s work of breathing. However, the use of speaking valves
facilitates communication and enables improved goal setting and
patient motivation during prolonged weaning. The additional load can
be used for a training effect on the respiratory muscles. Training
should emulate the desired effect on muscle function (i.e. patients
require an endurance method for training during weaning with
duration of weaning interventions of >20 min) .
In conjunction with daytime respiratory weaning, daily goal-directed

physical rehabilitation sessions were performed with a specialist
multidisciplinary team including respiratory, rehabilitative, and post-polio
physiotherapy, occupational therapy, dietetic therapy, and speech and
language therapy. The aim of rehabilitation was to direct full recovery and
return the patient to his baseline physical function.
By day 36, he had progressed to self-ventilation during the daytime and

invasive ventilatory support at night (Table 16.3).
Page 16 of 28

Table 16.3 Observation chart demonstrating weaning of daytime support from daytime CPAP to intermittent daytime CPAP with interspersed self-ventilating
periods over 3 days with return to invasive bi-level ventilation via tracheostomy during night-time
Day 33 Day 34 Day 35 Day 36
Ti 06 10 14 18 22 02 06 10 14 18 22 02 06 10 14 18 22 02 06 10 14 18 22
m : : : : : : : : : : : : : : : : : : : : : : :
e 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
Ve PC CP CP CP PC PC PC CP SV CP PC PC PC SV CP SV PC PC PC SV SV SV PC
nti V AP AP AP V V V AP AP V V V AP V V V V
lat
or
m
od
e
Fi 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.
O2 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21
Pr 13 13 13 13 13 13 13 13 13 13 13
es
su
re
su
pp
ort
(c
m
Page 17 of 28
and Legal Notice).
H2
O)
CP 5 10 10 10 5 5 5 10 10 5 5 5 10 5 5 5 5
AP
(c
m
H2
O)
Se 16 16 16 16 16 16 16 16 16 16 16
t
re
spi
rat
or
y
rat
e
Ti 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1.
(S) 3 3 3 3 3 3 3 3 3 3 3
CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; PCV, pressure control ventilation; SV, self-ventilation; Ti, inspiratory time.
Page 18 of 28
and Legal Notice).
weaning
Daytime trials of NIV were started with the aim of establishing nocturnal
NIV to manage rapid eye movement sleep alveolar hypoventilation (a
consequence of the patient’s restrictive ventilatory defect secondary to
previous poliomyelitis and chest wall deformity). By day 42, the patient
was established on nocturnal NIV, with the tracheostomy tube capped off
at night and speaking valve applied during the daytime. To manage
persistent, high-volume secretions, the tracheostomy tube was replaced
with a size 4.0 mm internal diameter mini-tracheostomy tube.
EXPERT COMMENT
Following tracheostomy insertion, the use of NIV can be limited by

excessive leak from the tracheostomy stoma making the use of
‘bridging’ NIV more complex with the need to accept high levels of
leak. Downsizing of tracheostomies during weaning facilitates bulbar
function and communication. Once patients can self-ventilate during
the day and are tolerating NIV with adequate control of nocturnal
hypoventilation at night then decannulation can be considered.
However, frequently patients still have excessive secretions that are
not fully mobilized by MIE alone and require suction to clear.
Movement of secretions from the lower airway into the mouth for
clearance is partly impeded by a large tracheostomy. The use of a
mini-tracheostomy enables ongoing access to the lower respiratory
tract but reduces the size of obstruction in the trachea and although
not evaluated in randomized controlled trials improves secretion
management in high-risk patient groups [7]. Ventilator support cannot
be provided by the mini-tracheostomy; therefore, the team need to be
confident that the respiratory requirements can be met non-
invasively.
LEARNING POINT Cough augmentation
Sputum retention and airway plugging can cause significant

respiratory distress with associated morbidity and should be avoided
by proactive chest physiotherapy. A tracheostomy facilitates airway
toileting. In patients with neuromuscular disorders and ineffective
cough, secretion clearance can be a barrier to decannulation. Cough
function requires several steps, with lung inflation, closure of the
glottis, and forced expiration against the closed glottis followed by
rapid glottic opening resulting in an explosive expiratory effort. This
complex process requires adequate inspiratory and expiratory muscle
strength as well as bulbar function [55]. Measurement of a cough
peak expiratory flow rate (PEFR) while ventilated, along with clinical
assessment of respiratory muscle function and cough adequacy, may
identify patients in whom secretion clearance is a barrier to weaning.
Page 19 of 28

weaning
Cough PEFR may be difficult to measure but a value of less than 160
L/min indicates the need for additional support for effective secretion
management [56].
The use of MIE devices, often referred to as cough assist devices,

provides additional support to the respiratory muscles and aids
secretion clearance [57]. MIE devices can be used during weaning via
a tracheostomy or via a face mask following decannulation. The
optimal settings for an individual patient vary greatly: pressure
swings from +40 to −40 cmH2O have traditionally been used but both
larger and smaller pressure swings may be effective [57, 58]. In the
acutely unwell patient, care needs to be taken to avoid lung
derecruitment caused by the large negative intrathoracic pressure.
Although MIE devices improve cough force and flow, there are no
data showing improvement in hard clinical outcomes. Although an
MIE device can assist in secretion mobilization it cannot compensate
for poor bulbar function which may still prevent adequate secretion
clearance following extubation or decannulation.
Nocturnal NIV was delivered by a full facemask, with circuit

humidification and an FiO2 of 0.21 (room air).
LEARNING POINT Success of transition from invasive

to non-invasive ventilation
Many patients with chronic respiratory disease can wean from

daytime ventilatory support but may not have sufficient respiratory
reserve to tolerate the challenges posed to the respiratory system
during sleep. Patients with established or presumptive diagnoses of
sleep-disordered breathing and chronic respiratory failure often
require long-term NIV following successful weaning [33]. The
transition from invasive ventilation to NIV requires careful
management, as the reinstitution of invasive respiratory support
following decannulation can be traumatic and is associated with
significant morbidity. Once suitable patients have been established as
self-ventilating via tracheostomy during daytime they can be
introduced to NIV with a capped tracheostomy. This should occur
after they have been taught the rationale for the transition to NIV, as
understanding of the importance of this step towards decannulation
and return to home maintains motivation. Patients can often find the
pressure and interfaces used for NIV uncomfortable and so a period
of daytime acclimatization at low pressures may be required. The
choice of interface depends on patient preference, underlying
diagnosis, and estimated final NIV pressures but can include nasal
pillows, nasal mask, oronasal mask, total face mask, or hood.
Although nasal masks can be used to provide adequate ventilation in
Page 20 of 28

weaning
patients with NMD they are unsuitable for higher inflation pressures
and excessive mouth leak can cause sleep disruption during use [59].
When patients are able to tolerate periods of NIV overnight, limited
sleep studies are performed with transcutaneous carbon dioxide
monitoring to ensure adequate control of sleep hypoventilation [60].
Progression can be made towards decannulation if the results of the
respiratory sleep study demonstrate satisfactory control.
Over the next 10 days, discharge plans were made alongside ongoing
multidisciplinary rehabilitation and secretion management. Nocturnal
NIV was optimized with overnight oximetry and capnometry. A
mechanical cough assist device was used three times daily. This enabled
clearing of lower airway secretions to the large airways and cough assist
directing secretions to the mouth for suctioning. This facilitated removal
of the mini-tracheostomy tube. The patient was discharged home on day
60, with a reinstatement of his original home care package as he had
returned to his premorbid level of function.
Discussion
Approximately 5–10% of ICU patients will require prolonged

mechanical ventilation (>21 days) and these patients account for a
disproportionate number of ICU bed days [61]. Although protocolized
weaning strategies, with daily SBTs or a gradual reduction in pressure
support ventilation, have been adopted by many centres to prevent
delayed extubation and subsequent tracheostomy formation [62, 63],
these protocolized strategies have limited utility with the patient
requiring prolonged mechanical ventilation. The heterogeneous nature of
patients with delayed weaning and prolonged mechanical ventilation
requires a more bespoke plan that addresses the underlying causes of
failure to wean.
The goal of weaning and rehabilitation is to achieve prompt recovery of

independent function and minimize the development of acute skeletal
muscle wasting [64] and other long-term complications of mechanical
ventilation. For this reason, weaning and rehabilitation should start early,
when the patient is in the recovery stage of their illness and is
progressing towards clinical stability.
Patients who are unable to wean despite correction of the initial

physiological insult will require prolonged mechanical ventilation and the
development of a dynamic and bespoke weaning plan involving multiple
disciplines [65]. This is achieved by goal-directed physical, respiratory,
speech and language, and occupational therapy rehabilitation combined
with nutritional support.
Such complex patients also require psychological and cognitive support

as these are common contributors to weaning delay and failure in
patients undergoing prolonged mechanical ventilation. Communication of
Page 21 of 28

weaning
the weaning strategy to the patient and caregivers is essential as part of a

holistic approach to care. This approach also includes focusing on areas
such as sleep quantity, quality, and timing as well as stimulation and
motivation of the patient [66].
While many patients will be liberated from mechanical ventilation, up to

25% of patients undergoing prolonged mechanical ventilation will require
transition to NIV and around 20% will require intermediate or long-term
tracheostomy ventilation due to irreversible, progressive, or slowly
reversible neurological conditions, chronic lung disease, or obesity-
related respiratory failure [67].
As these long-term tracheostomy-ventilated patients progress to clinical

stability, they will be suitable for transfer to specialized community
nursing facilities and a small proportion will be suitable for discharge
home, with a comprehensive care package. This is usually not an option
for patients with COPD because they tend to have frequent exacerbations.
The provision of long-term acute care for long-term ventilated

patients (an established strategy in the US driven principally by
economic pressures to move patients out of acute care facilities) is
wholly distinct from cost-effective specialist weaning centres [33, 68].
Facilities accommodating long-term tracheostomy-ventilated patients
in the community need ongoing multidisciplinary support from the
weaning centre to enable clinical stability in the community. A
competency-based process of education and training of the
community care team is essential for the management of these
complex patients.
As most of these patients have a high level of comorbidity in addition

to their respiratory needs, decisions about escalation of care during
future hospitalization should be considered and discussed when
appropriate. Patients and their relatives may have unrealistic
expectations of the potential for long-term survival, and consideration
should be given to all aspects of the patient’s outcome which will
include both their quality of life and functional ability.
References
1. Bourke SC, Tomlinson M, Williams TL, et al. Effects of non-invasive
ventilation on survival and quality of life in patients with amyotrophic
lateral sclerosis: a randomised controlled trial. Lancet Neurol.
2006;5:140–7.
Page 22 of 28

weaning
2. Buyse B, Meersseman W, Demedts M. Treatment of chronic respiratory

failure in kyphoscoliosis: oxygen or ventilation? Eur Respir J.
2003;22:525–8.
3. Lyall RA, Donaldson N, Polkey MI. Respiratory muscle strength and

ventilatory failure in amyotrophic lateral sclerosis. Brain. 2001;124:2000–
13.
4. Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW. Respiration
during sleep in normal man. Thorax. 1982;37:840–4.
5. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in

Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2000;161:166–
70.
6. Ward S, Chatwin M, Heather S, Simonds AK. Randomised controlled

trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in
neuromuscular and chest wall disease patients with daytime
normocapnia. Thorax. 2005;60:1019–24.
7. Davidson AC, Banham S, Elliott M, et al. BTS/ICS guideline for the

ventilatory management of acute hypercapnic respiratory failure in
adults. Thorax. 2016;71 Suppl 2:ii1–35.
8. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for

acute exacerbations of chronic obstructive pulmonary disease. N Engl J
Med. 1995;333:817–22.
9. Bott J, Carroll MP, Conway JH, et al. Randomised controlled trial of

nasal ventilation in acute ventilatory failure due to chronic obstructive
airways disease. Lancet. 1993;341:1555–7.
10. Carrillo A, Ferrer M, Gonzalez-Diaz G, et al. Noninvasive ventilation in

acute hypercapnic respiratory failure caused by obesity hypoventilation
syndrome and chronic obstructive pulmonary disease. Am J Respir Crit
Care Med. 2012;186:1279–85.
11. Lemyze M, Taufour P, Duhamel A, et al. Determinants of noninvasive

ventilation success or failure in morbidly obese patients in acute
respiratory failure. PLoS One. 2014;9:e97563.
12. Duarte AG, Justino E, Bigler T, Grady J. Outcomes of morbidly obese

patients requiring mechanical ventilation for acute respiratory failure.
Crit Care Med. 2007;35:732–7.
13. Carrillo A, Gonzalez-Diaz G, Ferrer M, et al. Non-invasive ventilation

in community-acquired pneumonia and severe acute respiratory failure.
14. Honrubia T, Garcia Lopez FJ, Franco N, et al. Noninvasive vs

conventional mechanical ventilation in acute respiratory failure: a
multicenter, randomized controlled trial. Chest. 2005;128:3916–24.
Page 23 of 28

weaning
15. Ballard E, McDonnell L, Keilty S, Davidson AC, Hart N. Survey of

knowledge of health care professionals managing patients with acute
hypercapnic exacerbation of COPD requiring non-invasive ventilation.
Thorax. 2007;62:A90.
16. Confalonieri M, Gorini M, Ambrosino N, Mollica C, Corrado A.

Respiratory intensive care units in Italy: a national census and
prospective cohort study. Thorax. 2001;56:373–8.
17. Yang KL, Tobin MJ. A prospective study of indexes predicting the
outcome of trials of weaning from mechanical ventilation. N Engl J Med.
1991;324:1445–50.
18. Tanios MA, Nevins ML, Hendra KP, et al. A randomized, controlled
trial of the role of weaning predictors in clinical decision making. Crit
Care Med. 2006;34:2530–5.
19. Krieger BP, Ershowsky PF, Becker DA, Gazeroglu HB. Evaluation of
conventional criteria for predicting successful weaning from mechanical
ventilatory support in elderly patients. Crit Care Med. 1989;17:858–61.
20. Meade M, Guyatt G, Cook D, et al. Predicting success in weaning from

mechanical ventilation. Chest. 2001;120:400S–24S.
21. Montgomery AB, Holle RH, Neagley SR, Pierson DJ, Schoene RB.
Prediction of successful ventilator weaning using airway occlusion
pressure and hypercapnic challenge. Chest. 1987;91:496–9.
22. Levy MM, Miyasaki A, Langston D. Work of breathing as a weaning

parameter in mechanically ventilated patients. Chest. 1995;108:1018–20.
23. Delisle S, Francoeur M, Albert M, et al. Preliminary evaluation of a

new index to predict the outcome of a spontaneous breathing trial. Respir
Care. 2011;56:1500–5.
24. Burns KE, Meade MO, Premji A, Adhikari NK. Noninvasive positive-
pressure ventilation as a weaning strategy for intubated adults with
respiratory failure. Cochrane Database Syst Rev. 2013;12:CD004127.
25. Hernandez G, Vaquero C, Colinas L, et al. Effect of postextubation

high-flow nasal cannula vs noninvasive ventilation on reintubation and
postextubation respiratory failure in high-risk patients: a randomized
clinical trial. JAMA. 2016;316:1565–74.
26. Boles JM, Bion J, Connors A, et al. Weaning from mechanical

ventilation. Eur Respir J. 2007;29:1033–56.
27. MacIntyre NR, Epstein SK, Carson S, et al. Management of patients

requiring prolonged mechanical ventilation: report of a NAMDRC
consensus conference. Chest. 2005;128:3937–54.
Page 24 of 28

weaning
28. Seneff MG, Zimmerman JE, Knaus WA, Wagner DP, Draper EA.
Predicting the duration of mechanical ventilation. The importance of
disease and patient characteristics. Chest. 1996;110:469–79.
29. Garnacho-Montero J, Amaya-Villar R, Garcia-Garmendia JL, Madrazo-

Osuna J, Ortiz-Leyba C. Effect of critical illness polyneuropathy on the
withdrawal from mechanical ventilation and the length of stay in septic
30. De Jonghe B, Bastuji-Garin S, Durand MC, et al. Respiratory weakness

is associated with limb weakness and delayed weaning in critical illness.
Crit Care Med. 2007;35:2007–15.
31. Connolly BA, Jones GD, Curtis AA, et al. Clinical predictive value of
manual muscle strength testing during critical illness: an observational
cohort study. Crit Care. 2013;17:R229.
32. Scheinhorn DJ, Hassenpflug MS, Votto JJ, et al. Ventilator-dependent

survivors of catastrophic illness transferred to 23 long-term care
hospitals for weaning from prolonged mechanical ventilation. Chest.
2007;131:76–84.
33. Pilcher DV, Bailey MJ, Treacher DF, et al. Outcomes, cost and long
term survival of patients referred to a regional weaning centre. Thorax.
2005;60:187–92.
34. Chatila W, Kreimer DT, Criner GJ. Quality of life in survivors of

prolonged mechanical ventilatory support. Crit Care Med. 2001;29:737–
42.
35. Steier J, Jolley CJ, Seymour J, et al. Neural respiratory drive in obesity.
Thorax. 2009;64:719–25.
36. Steier J, Lunt A, Hart N, Polkey MI, Moxham J. Observational study of

the effect of obesity on lung volumes. Thorax. 2014;69:752–9.
37. Sharp JT, Henry JP, Sweany SK, Meadows WR, Pietras RJ. The total
work of breathing in normal and obese men. J Clin Invest. 1964;43:728–
39.
38. Johnson D, Gallagher C, Cavanaugh M, Yip R, Mayers I. The lack of

effect of routine magnesium administration on respiratory function in
mechanically ventilated patients. Chest. 1993;104:536–41.
39. Marik PE, Desai H. Characteristics of patients with the ‘malignant

obesity hypoventilation syndrome’ admitted to an ICU. J Intensive Care
Med. 2013;28:124–30.
40. Hollier CA, Harmer AR, Maxwell LJ, et al. Moderate concentrations of
supplemental oxygen worsen hypercapnia in obesity hypoventilation
syndrome: a randomised crossover study. Thorax. 2014;69:346–53.
Page 25 of 28

weaning
41. Lemaire F, Teboul JL, Cinotti L, et al. Acute left ventricular

dysfunction during unsuccessful weaning from mechanical ventilation.
Anesthesiology. 1988;69:171–9.
42. Chatila W, Ani S, Guaglianone D, et al. Cardiac ischemia during

weaning from mechanical ventilation. Chest. 1996;109:1577–83.
43. Jubran A, Mathru M, Dries D, Tobin MJ. Continuous recordings of

mixed venous oxygen saturation during weaning from mechanical
ventilation and the ramifications thereof. Am J Respir Crit Care Med.
1998;158:1763–9.
44. Demoule A, Lefort Y, Lopes ME, Lemaire F. Successful weaning from

mechanical ventilation after coronary angioplasty. Br J Anaesth.
2004;93:295–7.
45. Doorduin J, Sinderby CA, Beck J, et al. The calcium sensitizer

levosimendan improves human diaphragm function. Am J Respir Crit Care
Med. 2012;185:90–5.
46. Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the
prevention of acute organ dysfunction in sepsis. N Engl J Med.
2016;375:1638–48.
47. Scheinhorn DJ, Chao DC, Stearn-Hassenpflug M, Wallace WA.

Outcomes in post-ICU mechanical ventilation: a therapist-implemented
weaning protocol. Chest. 2001;119:236–42.
48. Esteban A, Frutos F, Tobin MJ, et al. A comparison of four methods of

weaning patients from mechanical ventilation. Spanish Lung Failure
Collaborative Group. N Engl J Med. 1995;332:345–50.
49. Brochard L, Rauss A, Benito S, et al. Comparison of three methods of

gradual withdrawal from ventilatory support during weaning from
mechanical ventilation. Am J Respir Crit Care Med. 1994;150:896–903.
50. Gomes Silva BN, Andriolo RB, Saconato H, Atallah AN, Valente O.
Early versus late tracheostomy for critically ill patients. Cochrane
51. Siempos II, Ntaidou TK, Filippidis FT, Choi AM. Effect of early versus
late or no tracheostomy on mortality and pneumonia of critically ill
patients receiving mechanical ventilation: a systematic review and meta-
analysis. Lancet Respir Med. 2015;3:150–8.
52. Krishnan K, Elliot SC, Mallick A. The current practice of tracheostomy

in the United Kingdom: a postal survey. Anaesthesia. 2005;60:360–4.
53. Kluge S, Baumann HJ, Maier C, et al. Tracheostomy in the intensive

care unit: a nationwide survey. Anesth Analg. 2008;107:1639–43.
Page 26 of 28

weaning
54. Young D, Harrison DA, Cuthbertson BH, Rowan K. Effect of early vs

late tracheostomy placement on survival in patients receiving mechanical
ventilation: the TracMan randomized trial. JAMA. 2013;309:2121–9.
55. Bach JR. Amyotrophic lateral sclerosis: predictors for prolongation of

life by noninvasive respiratory aids. Arch Phys Med Rehabil. 1995;76:828–
32.
56. Bach JR, Saporito LR. Criteria for extubation and tracheostomy tube
removal for patients with ventilatory failure. A different approach to
weaning. Chest. 1996;110:1566–71.
57. Bach JR. Mechanical insufflation-exsufflation. Comparison of peak

expiratory flows with manually assisted and unassisted coughing
techniques. Chest. 1993;104:1553–62.
58. Chatwin M, Ross E, Hart N, et al. Cough augmentation with

mechanical insufflation/exsufflation in patients with neuromuscular
weakness. Eur Respir J. 2003;21:502–8.
59. Teschler H, Stampa J, Ragette R, Konietzko N, Berthon-Jones M. Effect

of mouth leak on effectiveness of nasal bilevel ventilatory assistance and
sleep architecture. Eur Respir J. 1999;14:1251–7.
60. Storre JH, Magnet FS, Dreher M, Windisch W. Transcutaneous

monitoring as a replacement for arterial PCO(2) monitoring during
nocturnal non-invasive ventilation. Respir Med. 2011;105:143–50.
61. Esteban A, Alia I, Ibanez J, Benito S, Tobin MJ. Modes of mechanical

ventilation and weaning. A national survey of Spanish hospitals. The
Spanish Lung Failure Collaborative Group. Chest. 1994;106:1188–93.
62. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired
sedation and ventilator weaning protocol for mechanically ventilated
patients in intensive care (Awakening and Breathing Controlled trial): a
randomised controlled trial. Lancet. 2008;371:126–34.
63. Kollef MH, Shapiro SD, Silver P, et al. A randomized, controlled trial of
protocol-directed versus physician-directed weaning from mechanical
ventilation. Crit Care Med. 1997;25:567–74.
64. Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle

wasting in critical illness. JAMA. 2013;310:1591–600.
65. Creagh-Brown B, Steier J, Hart N. Prolonged weaning. In: Stevens RD,

Hart N, Herridge M (eds) Textbook of Post-ICU Medicine. Oxford: Oxford
University Press; 2014, pp. 559–71.
66. Jubran A, Lawm G, Kelly J, et al. Depressive disorders during weaning

from prolonged mechanical ventilation. Intensive Care Med. 2010;36:828–
35.
Page 27 of 28

weaning
67. Mifsud Bonnici D, Sanctuary T, Warren A, et al. Prospective

observational cohort study of patients with weaning failure admitted to a
specialist weaning, rehabilitation and home mechanical ventilation
centre. BMJ Open. 2016;6:e010025.
68. Kahn JM, Benson NM, Appleby D, Carson SS, Iwashyna TJ. Long-term
acute care hospital utilization after critical illness. JAMA. 2010;303:2253–
9.
Page 28 of 28

Pandemic planning and critical care

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Pandemic planning and critical care
Author(s): Lucinda Gabriel
DOI: 10.1093/med/9780198814924.003.0017
Expert commentary by Jeremy Farrar
Case history
A 46-year-old Caucasian man with a body mass index (BMI) of 40

kg/m2 and a history of asthma was admitted to the medical unit following
an unintentional paracetamol overdose. He provided a 5-day history of
flu-like symptoms: generalized myalgia, fatigue, cough, and sore throat.
He had a raised creatinine kinase and was lymphopenic on admission.
The initial chest X-ray was unremarkable.
On day 2 of his hospital admission, he developed right-sided abdominal

pain and became acutely hypoxaemic with a partial pressure of oxygen of
5.6 kPa on 15 L/min oxygen by facemask necessitating admission to the
intensive care unit (ICU) for respiratory support. Based on his
presentation, and a history of flu-like illness in his close contacts, he was
transferred to an isolation room and droplet precautions were instituted.
Page 1 of 30
LEARNING POINT Variability of presentation/risk

factors
There is much concern about the appearance of new influenza A virus

subtypes (H5N1 in 1997, H1N1 in 2009, and H7N9 in 2013), and
novel corona viruses (severe acute respiratory syndrome (SARS) in
2002 and Middle Eastern respiratory syndrome (MERS) in 2012).
These outbreaks of pandemic influenza have varied widely in
pathogenicity and potential for transmission [1] with major
implications for how pandemic planning is approached. While there
has been considerable learning from each of these episodes, there is a
fundamental error in drawing learning directly from past events.
The case history illustrates that the clinical picture in severe cases of
pandemic influenza is markedly different from that seen during
epidemics of seasonal influenza (Table 17.1). Often there is a
protracted period of illness prior to patients presenting to hospital,
followed by a short period of acute respiratory deterioration. Patients
with H1N1 experienced symptoms for an average of 6 days prior to
hospital presentation, but rapidly worsened after hospital admission
and generally required ICU admission within 1–2 days. Moreover, the
clinical presentation of each pandemic influenza subtype also varies.
Measures taken between pandemics to improve preparedness (inter-
pandemic planning) are vital but require flexibility to enable
responses that are appropriate to the variables of disease aetiology
and local clinical context.
Table 17.1 Characteristics and underlying conditions of reported

hospitalized patients with 2009 pandemic influenza A (H1N1)
Patient details Risk factors
General Median age (37–41)

characteristics Current smoker
Female
Underlying Any chronic respiratory disease (e.g.

conditions asthma, chronic obstructive pulmonary
disease)
Morbid obesity
Diabetes
Other metabolic disease
Pregnancy
Cancer
Immunodeficiency
Cardiovascular disease
Page 2 of 30

Chronic hepatic disease or renal

insufficiency
Haemoglobinopathy or anaemia
Cognitive dysfunction or seizures
Asplenia
Neuromuscular disease
Treatment with aspirin
LEARNING POINT Infection control and patient

cohorting
In the initial stages of infection, pandemic influenza closely resembles

that of seasonal influenza. Poor specificity of presenting features
inevitably contributes to overdiagnosis and overloading of isolation
facilities, especially where such facilities have competing demands
[2]. Moreover, many infected individuals (including healthcare
workers) are largely asymptomatic: during seasonal influenza
epidemics, 10–40% of healthcare workers have been shown to have
asymptomatic infection [1]. While prompt diagnosis is essential for
effective and safe cohorting, rapid diagnostic testing tools have poor
sensitivity and specificity, which limits their utility for identifying and
excluding potentially infected patients. The potential for acquisition of
infection by staff who care for patients in the ICU and by patient
visitors, is therefore of great concern.
Infection control decisions are often made with limited evidence,

perhaps largely extrapolated from experience of seasonal influenza in
ambulant patients. The duration of patient isolation and use of
personal protective equipment (PPE), and the risks associated with
cohorting of patients with suspected/confirmed infection (or solely
confirmed cases where isolation capacity has been exceeded), are
often unknown, particularly in the early phase of an emerging
epidemic.
The use of non-invasive ventilation is a risk factor for transmission of

infectious disease by droplet/aerosol spread [2, 3]. Inadvertent
disconnection of ventilator circuits and open tracheal suction pose a
similar infection threat. However, experience of the 2009 H1N1
pandemic showed staff infection to be rare. Whether this reflected the
widespread and effective use of PPE or indicated that the virus had
low transmissibility within an ICU environment is unclear.
Importantly, the implications for appropriate infection control extend

beyond the confines of the ICU. During epidemic surges, clinicians
need to engage with infection control specialists, microbiology staff,
public health experts, and other stakeholders to maintain quality of
Page 3 of 30

care and to receive and respond to rapidly evolving infection control

advice. Local and more widespread education programmes should be
implemented on appropriate use of PPE, decontamination, and
disposal procedures. As the pandemic becomes recognized, public
awareness campaigns should target the wider community to
encourage home quarantine where appropriate, clear personal
hygiene, and social distancing advice to reduce household and
community transmission.
On admission to the ICU he was given a trial of high-flow nasal cannula

(HFNC) oxygen at 50 L/min and a fraction of inspired oxygen of 0.8–1.0.
Despite this, he continued to deteriorate rapidly. Three hours after ICU
admission he underwent tracheal intubation for worsening hypoxaemia.
Nasopharyngeal viral swabs were taken following intubation. He was
eventually stabilized using a tidal volume-guaranteed pressure control
mode of ventilation. A pre-intubation chest radiograph showed
generalized lung field shadowing but no gross consolidation (Figure
17.1a).
Page 4 of 30

Figure 17.1
Chest X-ray (a) on admission to the ICU, (b) 3 days after ICU admission.
LEARNING POINT Presentation of pandemic

influenza
The clinical features of the illness associated with different infective

agents will vary with each pandemic. However, a major lesson from
the 2009 H1N1 pandemic was the widespread variation in presenting
features of critically ill patients with H1N1. In addition to a typical
viral pneumonitis and acute respiratory distress syndrome (ARDS)
(approximately 50% of ICU admissions), critically ill patients with
H1N1 also presented with primary lobar pneumonia and pleural
effusions. Pulmonary embolus was a common finding, being a
frequent finding at postmortem. Secondary infection with bacteria
(20–30%) and fungi was also common. Finally, patients, particularly
children, also presented more atypically with acute abdomen, acute
Page 5 of 30

kidney injury, myocarditis, encephalitis, diabetic ketoacidosis,

multiorgan failure, or septic shock. A high level of clinical suspicion is
required to detect relevant cases in view of the multiplicity of possible
presentations.
He was started on co-amoxiclav, clarithromycin, and a 5-day course of 75

mg oseltamivir twice daily. A beta-glucan assay was sent to exclude a
fungal coinfection.
LEARNING POINT Guidelines for the treatment of

confirmed or suspected influenza
While vaccination remains the mainstay of influenza prevention,

antiviral medications can provide a useful second-line defence in the
treatment of illness when indicated.
Empiric antiviral treatment, when indicated, should be started as

early as possible and ideally within 48 hours of symptom onset (Table
17.2). However, treatment may still provide some benefit in
hospitalized patients when started later. Data obtained from
randomized controlled trials and observational studies show that
early antiviral treatment in people with influenza can lessen illness
severity, shorten time of illness, and reduce serious flu-related
complications such as pneumonia in outpatients and death in
hospitalized patients [4].
Table 17.2 Indications for antiviral treatment in influenza
Indications for starting empiric antiviral treatment of

patients with influenza
1 Illness requiring hospitalization
2 Children <2 years of age
3 Persons ≥65 years of age
4 Pregnant women and up to 2 weeks post partum (including

after miscarriage)
5 Chronic pulmonary, cardiovascular, renal, hepatic,

haematological, and metabolic disorders, neurological and
neurodevelopmental conditions
Page 6 of 30

6 Immunosuppressive conditions, including secondary to

medication or HIV infection
7 Persons <19 years receiving long-term aspirin therapy
8 Morbid obesity (BMI >40 kg/m2)
9 Residents of nursing home or long-term care facilities
10 Progressive, severe, or complicated illness, irrespective of

previous health status
Source: data from Centers for Disease Control and Prevention

(CDC). (2016) 2016-2017 Influenza Antiviral Recommendations.
Copyright ©2016 CDC. Available at https://www.cdc.gov/h1n1flu/
recommendations.htm.
When a definitive diagnosis is indicated, request definitive diagnostic

tests (real-time reverse transcriptase polymerase chain reaction
(PCR) and viral culture) rather than rapid tests (rapid influenza
diagnostic test and direct immunofluorescence assay). However,
treatment should not be delayed while waiting for laboratory
confirmation of influenza.
It may be prudent to extend the duration of treatment in those

patients who remain critically unwell (Table 17.3). Oseltamivir
resistance can arise from a change in the neuraminidase (NA)
proteins of the virus which prevent the drug binding to and inhibiting
the function of the NA protein. Antiviral resistance patterns did not
change significantly in 2015–2016 compared with the previous
season. In both seasons, oseltamivir resistance was found in only a
few H1N1 viruses as per the US Centers for Disease Control and
Prevention and the Advisory Committee on Immunization Practices.
Resultantly, the 2016–2017 guidance on the use of influenza antiviral
drugs remained unchanged.
Table 17.3 Antiviral agent recommendations; dose and frequency

of administration
Dominant Dominant
circulating strain circulating strain
has a lower risk of has a higher risk of
oseltamivir oseltamivir
resistance, eg resistance, eg
A(H3N2), influenza A(H1N1)pdm09*
B*
Page 7 of 30

Uncomplicated oseltamivir PO and zanamivir INH

influenza clinical follow up. (Diskhaler®)
Commence therapy Commence therapy
within 48 hours of within 48 hours of
onset (or later at onset (36 for
clinical discretion) children) or later at
clinical discretion OR
if unable to take
inhaled preparation
use oseltamivir PO
and clinical follow up.
Commence therapy
within 48 hours of
onset (or later at
clinical discretion)
Complicated 1st line: oseltamivir zanamivir INH++

influenza PO/NG
2nd line: zanamivir Commence therapy

INH++ within 48 hours of
onset (36 for
children) or later at
clinical discretion
Consider switching ++Consider

to zanamivir if: Zanamivir IV if
● Poor clinical patients:
response ● cannot use
● evidence of inhaled Zanamivir
gastrointestinal ● have severe
dysfunction complicated
● Subtype testing illness such as
confirms a strain multi-organ failure
with potential ● note: commence
oseltamivir as soon as possible
resistance, eg and usually within
A(H1N1)pdm09 6 days.
(see right)
*= also applicable if this is the strain known to be infecting

patient; treatment however, should not be delayed while waiting
for test results.
PHE guidance on use of antiviral agents for the treatment and

prophylaxis of influenza (2019–20). Version 10.0 Public Health
Page 8 of 30

England. September 2019. © Crown copyright 2019. Contains

public sector information licensed under the Open Government
Licence v3.0. http://www.nationalarchives.gov.uk/doc/open-
government-licence/version/3/
Dose adjustment of oseltamivir is recommended for patients with

chronic kidney disease stages 3–5.
Page 9 of 30

Treatment Premature 0—12 months >1—12 years: Does according to weight below Adults (13
(less than 36 (36 weeks years and
weeks post post 10–15 kg >15–23 kg >23–40 kg >40 kg over)1
conceptional conceptional
age) age or
greater)
Oseltamivir PO 1 mg/kg/dose 3 mg/kg/dose 30 mgBD 45 mgBD 60 mgBD 75 mgBD 75 mgBD

(treatment BDUnlicensed BD
course: 5 days)
Zanamivir INH Not licensed for children <5 years old. Children >5 years: 10 mg BD 10 mgBD
(treatment
course: 5 days)
1
If a person in this age group weighs 40 kg or less, it is suggested that the >23–40 kg dose for those aged >1–12 years, is used.
PHE guidance on use of antiviral agents for the treatment and prophylaxis of influenza (2019–20). Version 10.0 Public Health England. September 2019.
© Crown copyright 2019. Contains public sector information licensed under the Open Government Licence v3.0. http://www.nationalarchives.gov.uk/
doc/open-government-licence/version/3/
Page 10 of 30
and Legal Notice).
At 48 hours after admission to ICU, the results of the viral swabs

confirmed influenza infection. Beta-glucan results provided no indication
of fungal coinfection. On day 3 of the patient’s admission, two other
patients were admitted to ICU with respiratory failure and a similar
history of flu-like symptoms. The first, a 35-year-old woman with asthma
and type 2 diabetes presented with a 2-day history. The other, a 30-year-
old pregnant woman at 20 weeks’ gestation, had a 4-day history of a mild
respiratory illness, now worsening. These patients occupied the
remaining two isolation rooms in the ICU.
On day 4, intermittent decreases in arterial oxygen saturation down to

60% occurred in the index patient. Neuromuscular blockade, recruitment
manoeuvres (inflation to 40 cmH2O for 40 seconds), and increases in
positive end-expiratory pressure only improved arterial oxygen saturation
to 80% breathing 100% oxygen. His chest X-ray showed extensive
consolidation and widespread alveolar shadowing (Figure 17.1b). He was
taken for a computed tomography scan of his chest which showed
consolidation, ground-glass shadowing, and several small pulmonary
emboli (Figure 17.2). On return to the ICU he was anticoagulated, and he
was turned prone for 18-hour periods in an attempt to improve
oxygenation.
Figure 17.2
Computed tomography scan of the chest showing consolidation, and
ground-glass shadowing.
Page 11 of 30

On day 5, a nurse who had been a primary carer for the patient during his
ward admission became unwell and was admitted to the high dependency
unit for observation and HFNC oxygen. PPE had not been implemented
when the index patient was admitted because an infective cause of his
illness was not initially considered.
In the ICU, stocks of N95 masks and protective gloves and gowns were
rapidly being exhausted and suppliers had been notified urgently.
LEARNING POINT Personal protective equipment
PPE should be used for all aerosol/droplet-generating procedures in

the ICU. PPE includes not only face masks but also gowns, visors or
goggles, and gloves (Table 17.4). In most influenza epidemics PPE use
is not burdensome and particular attention is focused only on aerosol/
droplet-generating procedures (Figure 17.3). Safe donning, removal,
and disposal of PPE, and staff decontamination is an essential
component of infection control. In the setting of epidemics of high
virulence (e.g. SARS, MERS, avian influenza, and Ebola), these
requirements may include double gloving, double gowning, and
meticulous disinfection. Staff may have to work in pairs to achieve
this and it may have a significant impact on staffing requirements,
ability to provide timely and immediate care, and unit workload
(Figure 17.4).
Page 12 of 30

Table 17.4 Personal protective equipment requirements
Clinical activity Mask Protective eyewear Gown Gloves
No direct patient contact No
Entering patient room Surgical mask Yes As per standard precautions
Respiratory sampling Surgical mask Yes
Aerosol-generating P2 or N95 Yes

procedures
Page 13 of 30
and Legal Notice).
Figure 17.3
Fit testing of PPE to ensure adequate protection against aerosol-
generating procedures.
Reproduced courtesy of Professor Tim Cook.
Figure 17.4
Nursing critically ill influenza patients.
Over the course of the week, five further patients had been admitted to
the ICU with flu-like symptoms and subsequent respiratory compromise.
This surge in admissions stretched resources immediately and rapidly
overwhelmed available space, exhausted supplies, required provision of
additional staffing, and created challenges in preventing cross
contamination and isolation of potentially highly contagious patients. A
decision was made to use the ICU exclusively for confirmed and
suspected influenza patients. This facilitated use of the high dependency
unit and operating theatre recovery room for non-infectious patients
Page 14 of 30

requiring critical care. Staffing was a significant challenge and required

diversion of anaesthesia and nursing staff from other clinical areas to
assist in management of the increased critical care workload. The
additional level 3 ICU patients and the expansion into other clinical areas
necessitated cancellation of most elective surgery in the hospital.
LEARNING POINT Surge capacity: the 4 S’s
There are four key elements which limit surge capacity. These are
availability of staff, consumables and essential equipment, bed-
spaces, and management systems (‘staff, stuff, space, and systems’)
[5]. Historically, hospital surge capacity has focused on mass casualty
events characterized by many cases presenting over a relatively short
period followed by the prevalence declining rapidly over the ensuing
days. In contrast, pandemics occur in waves (surges), with the
increase in numbers of cases persisting for weeks to months and
many patients requiring prolonged ICU care. Critical care units often
operate at nearly 100% of capacity and are therefore at particularly
high risk of being impacted by a pandemic surge. Importantly, the
normal requirement for critical care also continues and the only part
of the workload that can be controlled is by deferring non-urgent
surgery where postoperative ICU care was planned. A relatively small
surge in ICU demand soon creates a crisis in ICU capacity and this
rapidly progresses from a local to a regional and then national
problem. The crisis requires increasing capacity or a significant
deviation from usual care, with the implementation of tiered staffing
models and rationalization of equipment, which may adversely impact
on morbidity and mortality [6] (Table 17.5). The proportion of ICU
beds occupied by H1N1 patients peaked at 9% in Australia and 19%
in New Zealand [7]. Elsewhere services exceeded surge capacity
requiring ventilation of patients outside the ICU [8]. A severe
pandemic would vastly exceed ICU capacity in all countries [5, 9].
Table 17.5 Spectrum of surge capacity
Conventional Contingency Crisis
Magnitude Minor Moderate Major
% 20% 100% 200%

Increase
capacity
Staff Regular staff Reallocation of Trained staff

plus on call to staff, deferred unavailable
cover leave, modified or too few to
adequately
Page 15 of 30

scheduled tasks/ care for

leave responsibilities volume of
patients,
reliance on
upskilling
and
retraining or
supervision
of less
trained staff
Stuff Normal Conservation, Critical

stocked adaptation, supplies
inventory of substitution of increasingly
supplies, supplies, and unavailable
conserve and occasional leading to
substitute reuse reuse and
reallocation
Space Use of normal Other Low acuity

patient care monitored and non-
space locations patient care
repurposed for areas used.
patient care Triage in
(e.g. critical place.
care unit,
theatre
recovery,
theatres)
Systems Usual care Equivalent care Crisis

standards
As surge increases, the demand–resource imbalance worsens. With an

increasing magnitude of pandemic surge, response strategies
increasingly depart from the usual standard of care until patient
mortality increases and effective delivery of critical care is no longer
possible.
Staff
The availability of nursing and medical staff trained in the care of
critically ill patients can be a key limitation to managing surge
capacity. Simple solutions, including amendments to rostering,
cancellation of leave, increasing effective full-time quotas, altering
nurse–patient ratios, and implementing overtime to meet demands
can alleviate staff shortages (Table 17.6). Nurses with prior ICU
experience and those working in anaesthesia, surgery, and emergency
departments may have the skills to manage the ventilated critically ill
Page 16 of 30

patient temporarily and can potentially be reallocated. However, this

usually requires structured refresher training, retraining, or
upskilling and necessitates significant support of less skilled staff by
regular ICU staff. Efforts must be made to ensure appropriate
isolation and care of suspected and proven cases, and staff reassured
that this will occur.
Table 17.6 Strategies to augment surge capacity in staffing
Phase Management
strategy
Preparation (inter- Model staffing needs for staged

pandemic phase) surge conditions and formulate a
plan to meet this need
Define required skill sets
Map critical-care staff competencies
against required skillsets
Maintain an up-to-date database of
staff
Allocate staff according to clinical
need and appropriate skillset
Refresh, cross-train, and upskill
remaining staff
Refresh standard operating
procedures
Promote use of incident reporting
systems to improve practice
Acute (early surge) Recall staff on leave/rostered off

Stop non-essential activities (e.g.
elective procedures)
Redeploy staff to support critical
care services
Consider extending working hours
Chronic (prolonged or Provide accommodation to staff

subsequent surges) Mitigate fatigue (rotating rosters)
Provide transport
Mental health support services
Maintain a safe working environment
Encourage collaboration and team
work
Staff shortages may be compounded by a desire to be available to

care for affected relatives. The low virulence of H1N1, in contrast to
SARS and Ebola virus, mitigated against this being a major problem
[10]. The risk of community-acquired infection is universal; however,
Page 17 of 30

staff at high risk of occupational infection (e.g. pregnancy, medical

comorbidities) should be reassigned to other clinical duties. In a
severe surge, staff illness and fear of infection is likely to increase
absenteeism. Antivirals and vaccines should be made readily
available. In some settings, it may be desirable or necessary to
provide additional remuneration to staff at significant risk, including
compensation for death or disability. The provision of counselling
should not be overlooked during the planning phase [11]. The
psychological well-being of healthcare workers has implications both
for current and any future pandemic waves, so there may be benefit
in continuing this support beyond the pandemic surge.
Stuff: consumable and equipment availability

Pharmaceutical stockpiling of antivirals by health facilities may be
advantageous and an early increase in production is essential to the
pandemic response. Nevertheless, adequate supplies of routine
medications used in ICU care may also become exhausted [12].
PPE should be rationalized. Simple surgical masks can be used where

patients’ lungs are ventilated using closed circuits, but N95 masks
are required for aerosol-generating procedures.
Oxygen, suction, clean water, electricity, and reliable emergency

generators are integral to patient care. There are many potential
points of failure within these systems and while lower-income
countries are more susceptible, equipment capacity can be rapidly
overwhelmed even in higher-income settings.
Many hospitals have numerous older or unused ICU ventilators, and

ventilators used for anaesthetic care may be suitable for ICU care in a
surge situation. Identification of this resource and a staged plan for
escalation should take place in the inter-pandemic period. Should
demand exceed resource capacity (e.g. ventilators), with no transfer
possible, pre-identified triage processes should be implemented while
trying to maintain acceptable standards of care. Where lack of
equipment necessitates triage, inclusion and exclusion criteria should
be based on incremental probability of survival. The threshold for
excluding patients will vary depending on the scale of the incident
and severity of disease and may vary over time [13].
In the inter-pandemic period, equipment, such as monitors and

ventilators, may be standardized and stockpiled where feasible.
Preventative measures should not be overlooked; currently the annual
capacity of influenza vaccine production is barely sufficient to cover
one-third of the global population [14].
Space: bed space availability

In developed countries, the availability of beds to care for critically ill
patients is least likely to be the major limiting factor in surge
Page 18 of 30

capacity, at least initially [5, 9]. A 300% expansion target for bed
capacity has been suggested, but in practice few facilities would
reach this goal. Recommissioning of closed bed spaces, converting
high dependency beds into ICU beds, and using anaesthesia recovery
units, coronary care units, and operation rooms to care for patients
are effective means of creating additional space.
Cohorting of patients with confirmed infection in a single location

isolates infectious patients and helps to concentrate resources and
appropriately trained staff. When considering an appropriate location,
factors such as the availability of antechambers to enable staff to don
and doff PPE, and provision of ventilation exhaust outputs should be
considered.
It is essential not to overlook that patients requiring ICU care for

reasons unrelated to the surge will continue to present during the
pandemic phase. Planning must accommodate these patients too.
Systems—standards of care
Each organization should ensure that it is able to respond to a
pandemic in a scalable manner [5]. ICU resources vary in quantity
and complexity and in the setting of a pandemic surge the necessary
stringent infection control measures inevitably contribute to an
increased workload. As individual hospitals and organizations can be
rapidly overwhelmed, there is a need for responsiveness on a much
larger scale.
Surveillance centres have a role in early detection of a pandemic,

coordination of an early response, and networking with appropriate
stakeholders to determine a wider strategic response based on the
severity of the incident. Regional coordinating centres should be
established which align with patterns of disease transmissibility
rather than local geography. This may be difficult given variations in
surveillance and testing strategies between countries, and the
prevalence of subclinical infection. Effective communication between
a hospital-based incident reporting system and a wider local,
regional, and national framework is essential. This should be
supported by regular communication between regulatory bodies and
national and inter-regional health agencies. Critical care clinicians
around the world have been heavily involved with developing
operational protocols, supported by standard operating procedures,
to support this. This enables rapid and efficient communication of
clinical and logistical information and facilitates contingency
planning.
The inter-pandemic period is of particular importance with respect to

optimizing management systems. A coordinated global effort is
required to establish superior surveillance, agreements on virus and
Page 19 of 30

vaccine sharing, to develop improved antiviral agents, more effective

vaccines, greater production capacity, and faster throughput [14].
The opportunities for applying mobile technologies have yet to be

fully explored. The literature suggests that implementing emergency
medical systems using mobile technology is often given a low priority.
However, in the future these will undoubtedly enhance
communication, facilitate strategic mapping, coordinate logistics, and
improve local and international responses in a timely and cost-
effective manner. To date, low-income and lower middle-income
countries have shown the highest uptake of surveillance activities
using mobile technologies. For example, a coalition of partners in
eastern Pakistan—the Indus Hospital Research Centre, a national
mobile phone provider, and the Massachusetts Institute of Technology
Media Lab—enables a pneumonia surveillance programme in Karachi
[15].
EXPERT COMMENT
In the H1N1 pandemic of 2009, after some delay, international

collaboration rapidly brought together a network of frontline
clinicians (particularly intensivists), clinical and laboratory
microbiologists and virologists, epidemiologists, pharmacologists,
public health experts, researchers, health policy experts, and non-
governmental senior administrators. This group shared early clinical,
laboratory, and epidemiological experience of the pandemic leading to
shared understanding about the nature and size of the surge and
enabling identification of key problems and potential solutions. Local,
national, and international strategic responses were informed by this
information sharing, enabling dramatically accelerated development
and cascading of clinical and governmental responses. Such
coordinated global responses are now an integral response to
emerging pandemic threats.
On day 7, the patient became febrile and nasopharyngeal swabs and

blood cultures were repeated as part of a complete septic workup at that
time. Viral swabs showed no evidence of persisting infection; however,
blood cultures grew Staphylococcus aureus and antibiotic cover was
rationalized, to vancomycin, after consultation with the microbiologists.
CLINICAL TIP Limitations of diagnostic testing during

a surge
Page 20 of 30

The significant increase in the number of tests performed during a

surge can create major logistical problems for laboratories,
compounded by increased demand for refrigeration and appropriate
storage of specimens. Turnaround times may become prolonged,
limiting clinical decision-making. This can lead to extended isolation
for some patients and increase the risk of cross infection. In addition,
accuracy of diagnosis can be difficult. Nasopharyngeal aspirates
(NPA) are superior to nose–throat swabs, and the speed of rapid
antigen tests is appealing. However, the utility of these tests is limited
in the clinical setting due to logistical practicalities relating to
transport and storage for NPAs, and poor assay characteristics for
nose–throat swabs [1, 16, 17]. During the H1N1 pandemic, NPA swabs
often returned negative results while tracheal aspirate samples were
positive in many cases with pneumonia. It became routine for paired
specimens to be sent and subsequent patient surveillance to be
performed using the specimen that had yielded the positive result
[12]. In many regions, nucleic acid testing was unavailable and rapid
point-of-care tests had insufficient sensitivity to reliably diagnose and
inform isolation decisions [1]. As the laboratory demands of the H1N1
pandemic increased, in many jurisdictions, only the seriously ill and
healthcare workers were subjected to investigation. In most patients,
treatment was commenced empirically and patients were tested only
based on clinical suspicion [1].
In addition to activating the hospital surge capacity plan, local and

regional authorities and neighbouring health facilities were notified.
National and international consultation between networks became critical
in limiting the spread of disease. National responses included various
decisions around travel restrictions in consultation with expert
stakeholders.
On a local level, patients remained cohorted according to illness severity

in designated departments within healthcare facilities. Of the patients
admitted to the local hospital one patient developed resistant hypoxaemia
and was considered a candidate for extracorporeal membrane
oxygenation (ECMO) at a nearby tertiary centre. A pregnant patient
required urgent transfer to the maternity unit and subsequent caesarean
section further complicating patient cohorting.
LEARNING POINT Extracorporeal membrane

oxygenation and severe influenza
ECMO can support gas exchange in patients with severe ARDS, as is

characteristic of severe influenza infection. The therapy, which is
independent of mechanical ventilation, may provide a rescue
intervention or minimize ventilator-associated lung injury and its
Page 21 of 30

associated multiple organ dysfunction, both crucial determinants of

survival for patients. A cohort study was conducted of all ECMO-
referred patients with H1N1-related ARDS referred, accepted, and
transferred to one of the four adult ECMO centres in the UK during
the H1N1 2009 pandemic [18]. The ECMO-referred patients were
matched with non-ECMO-referred patients using data from a
concurrent, longitudinal cohort study (Swine Flu Triage study) of
critically ill patients with suspected or confirmed H1N1. Transfer to
an ECMO centre for patients with H1N1-related ARDS was associated
with lower hospital mortality compared with matched non-ECMO-
referred patients. However, limited ECMO capacity and significant
associated costs, which are estimated to be double the routine ICU
costs, would preclude widespread use in the event of a pandemic.
EXPERT COMMENT
Experience with previous pandemics shows the critical role

leadership plays in addressing the challenges in delivering critical
care. Leadership involves using existing infrastructures and
strengthening the capacity of national and international surveillance
systems, in ways that ensure accurate detection of suspected human
cases, reliable laboratory confirmation, effective field investigation,
and complete reporting in a timely manner. The ICU generates
information about the evolving pandemic and has the potential to
communicate this in real time. Open and active lines of
communication between the ICU, the hospital, and the wider health
system enable partnerships to be established with governmental
organizations and governments, regulatory authorities,
agriculturalists, academic institutes, and industry. Decisions can then
be made about containment of the outbreak, maximizing surge
capacity and accelerating research and development.
Once a pandemic has been declared, national health authorities

collaborate with the World Health Organization’s Global Outbreak
Alert and Response Network. Various research consortia (e.g. the
International Severe Acute Respiratory and Emerging Infection
Consortium (https://isaric.tghn.org/about/) and the International
Forum for Acute Care Trialists (http://www.infactglobal.org/
About.aspx)) have been established during the inter-pandemic period
to facilitate collaboration and preparedness [19].
Leadership extends beyond the boundaries of the healthcare system.

Leaders must provide guidance to all stakeholders, especially the
media, to deliver accurate information about the pandemic. The
media play a crucial role in communicating important health
information. During the H1N1 pandemic, it proved difficult for the
media to develop messages that incorporated both the mild nature of
Page 22 of 30

the illness in most patients and the potential for severe disease in
only a minority. As a result, community doctors’ offices and hospital
emergency departments were crowded with anxious, minimally
unwell individuals, at times impairing the assessment and
management of more seriously ill patients and potentially increasing
the risk of transmission [8]. At the same time the ‘mild disease’
message proved inappropriate for particular high-risk populations,
such as the obese and pregnant women [5].
Over the course of the patient’s admission he developed multiorgan

dysfunction, including worsening ARDS, acute kidney injury,
hypernatraemia, elevated liver enzymes, and international normalized
ratio values. He was commenced on continuous venovenous
haemofiltration. This reduced his serum sodium concentration and
achieved a negative fluid balance which helped to optimize his respiratory
function.
At this point his family were approached to consent the patient for
participation in a clinical trial. The hospital’s ethics committee had
expedited ethical approval of a trial of convalescent serum; approval of
trials involving treatment algorithms remained pending. Given the patient
remained intubated and sedated, and unable to provide consent,
surrogate consent was attained.
LEARNING POINT Research
A case report is often the first document describing an atypical

infection and highlighting unique clinical or epidemiological features
of the disease. However, publication of such cases will lag temporally.
While considered weak evidence, these case reports may have a role
in drawing attention to abnormal clusters of severe cases in specific
patient groups and alerting health authorities [20].
Role of clinical research

Clinical research conducted during a pandemic has the potential to
positively impact the pandemic trajectory (Figure 17.5). Hospitals
and critical care units are in a unique position to generate
information about incidence, case presentation, infection control,
resource utilization, optimal care, and outcomes. This crucial
information can inform clinical and public health decision-making [14]
but there are multiple challenges in performing such research.
Page 23 of 30

Figure 17.5
Conceptual time course of public health severity of a major outbreak
without (upper panel) and with (lower panel) an early effective
clinical research response that provides information to clinicians on
optimal diagnosis and management as well as information to public
health authorities.
Reproduced with permission from Gabriel, L. and Webb, S. Preparing

ICUs for pandemics. Current Opinion in Critical Care. 19(5), 467–473.
Copyright © 2013 Wolters Kluwer Health, Inc.
When planning research related to a pandemic, time is critical

because if research is not initiated rapidly the opportunity will be lost,
and future patients may come to avoidable harm. Research questions
should focus on the most important and impactful projects. The type
of study will depend on the local context. For confined outbreaks
where the data set is complete, cohort studies may be ideal. Whereas
for larger outbreaks, a case series of those patients exhibiting clinical
symptoms may be more appropriate. Case–control studies can help
identify patients and environments associated with disease and thus
risk factors associated with poor outcomes.
Creation of generic case report forms that can be tailored to local

requirements and easily translated into other languages may facilitate
early data collection. Appropriate case definitions and careful
categorization of patients into confirmed, probable, or suspected
disease enables greater accuracy in defining clinical cases
retrospectively.
The availability of research personnel is also critical to conducting

research during a pandemic. This will be affected by similar
constraints as the availability of other healthcare workers. There will
Page 24 of 30

be pressure on clinicians who usually participate in research to

increase clinical workload and research staff, particularly nurses, may
be required to return to clinical duties. However, it is important that
research is prioritized as well as clinical care.
EXPERT COMMENT
Research conducted during a pandemic should be held to the same

scientific and ethical standards as that conducted at non-emergent
times. It should aim to advance knowledge or improve health, be
methodologically sound, scientifically valid, and the benefits to both
society and the individual should outweigh any harm. The 2015 West
African Ebola epidemic provided vital lessons in the challenges of
delivering ethical research practices during a pandemic where
mortality rates are high and no cure exists [21]. The challenges
included balancing the randomization of patients to untested
interventions with unknown risk–benefit profiles and navigating the
moral hazard of reconciling collective interests with those of the
individual. Novel vaccine trials have highlighted a collective
international multidisciplinary endeavour to conduct accelerated
clinical trials, testing unproven potentially lifesaving interventions
and challenging the existing principles of therapeutic research. There
must be appropriate oversight and timely ethics approval.
Historically, these approvals have been delayed until after the initial
wave of the pandemic has passed, thus precluding data collection.
While the ethics application and study protocol routinely take 2–3
months to be prepared and approved, ideally the response should
take hours or days.
EXPERT COMMENT
Critically ill patients are vulnerable, and the ethical integrity of

informed consent is challenging even in those who have the capacity
to provide prospective permissions [22, 23, 24]. Critical illness by its
very nature diminishes a patient’s capacity to provide informed
consent. With this in mind, several models are used to facilitate the
ethical conduct of emergency or critical care research, namely
deferred consent, third-party consent, and waived consent [25, 26].
Observational studies, involving the collation of de-identified data
obtained during routine clinical care, should not require patient or
surrogate consent. In fact, such consent processes can be associated
with authorization bias and invalid results [27]. Interventional designs
and even the collection of patient samples external to routine care,
may involve negligible risk to the patient and a ‘no consent’ or
Page 25 of 30

‘deferred model’ may be suitable. Hybrid models that proportionate

to the level of risk, that take account of the patient’s condition and
the availability of surrogate decision makers are essential.
Finally, all the usual challenges to conducting clinical research

remain [28].
On day 8, as his condition improved, the patient was weaned to a

spontaneous mode of ventilation. Hepatic and renal function began to
improve. He was extubated at day 11, was free of renal support by day
14, and was discharged from ICU on day 17. In the longer term he made
a good recovery without any major sequelae.
Of the seven other patients with suspected pandemic influenza admitted

to the ICU during the patient’s stay, three were confirmed using PCR and
two were positive for the viral antigen. All seven patients required
invasive ventilation. Two were without risk factors while those with risk
factors included one pregnant woman, two patients with asthma, one with
a raised BMI, and one who was also an insulin-dependent diabetic.
These patients spent a cumulative 67 days in the ICU; two died, while the
others made a good recovery with minimal long-term morbidity.
With the pandemic in its infancy and the virulence of the organism
unknown, there were efforts made to provide a prophylactic course of
oseltamivir to contacts of the patient, hospital staff, and family members.
Initially these people were then followed for onset of symptoms, but this
soon became unrealistic given the magnitude of the task and instead
regional health authorities instituted educational campaigns.
Discussion
A pandemic represents the global spread of a new, or re-emergent,

disease. Pandemics arise because of the emergence of an antigenically
novel virus (i.e. for which there is no prior immunity), usually with a
mixture (reassortment) of previously human and animal viral genomes.
These viruses often arise in developing countries where animal and
human contact is close.
Animal reservoirs, particularly birds and pigs, are a genetic mixing bowl
for antigenic variation. Presumably, the number and proximity of animals
drive the amount of genetic mixing. In this regard, it is notable that over
the past 45 years, the population of farmed pigs in China has increased
from 5.2 million to at least 500 million, and the number of domestic
poultry has increased from 5.2 million to 6 billion. The 2009 influenza
pandemic was a new strain of H1N1 resulting when a previous triple
reassortment of bird, swine, and human flu viruses further combined with
a Eurasian pig flu virus. Now, with the popularity of global airline travel,
a new strain will spread within days to weeks. Arguably, the capacity to
Page 26 of 30

form new strains to which humanity is immunologically naïve, which have

pandemic potential, is greater than ever in history.
The critical feature of all pandemics is uncertainty [1, 2]; uncertainty

surrounding pathogenicity, age-specific incidence of critical illness,
mortality rate, risk factors, and transmissibility. Historically, the
predominant form of critical illness associated with pandemics has been
pneumonia, either primary viral influenza, or secondary bacterial [3].
During an influenza pandemic it has been shown that 12–30% of the
population will develop clinical illness (compared with 5–15% for seasonal
influenza), with approximately 4% of those patients requiring hospital
admissions and at least one in five of those requiring critical care [4].
With more patients with atypical aetiology requiring intubation and
mechanical ventilation, the ICU becomes a satellite surveillance centre,
the so-called canary in the coal mine. The ICU therefore has the potential
to play a unique role in mapping the impact of the pandemic and
disseminating that information outwards.
When a large portion of the population is infected, even if the proportion

that goes on to develop severe disease is small, the total number of
severe cases can overwhelm the healthcare system. As a result, the
provision of critical care poses many challenges in terms of preparedness,
encompassing surge capacity, management systems, infection control,
and clinical leadership. ICU admissions of H1N1 influenza in Australia
were 15 times greater than for viral pneumonitis in recent seasonal
influenza outbreaks with one in seven of those admitted dying [5].
Preparedness to rapidly conduct high-quality clinical research to guide
effective and efficient care is also critical and highlights existing barriers
to conducting research in the acute care environment.
Pandemics will continue to challenge clinicians, policymakers, and

public health leaders in critical care. They are unexpected but
inevitable events and are characterized only by their uncertain scope,
duration, and effect. Any preparedness plan should encompass both
local and international coordination in order to function more
efficiently with the finite resources available.
Vulnerabilities in global, national, and local public health capacities;

limitations of scientific knowledge; difficulties in decision-making
under conditions of uncertainty; complexities in cooperation between
relevant stakeholders; and challenges in communication among
experts, policymakers, and the public need to be addressed now (6).
Deaths resulting from a new pandemic will be regrettable. Those that
result from insufficient planning, inequitable allocation of resources,
and inadequate preparation will be especially tragic [7].
Page 27 of 30

References
1. Kotsimbos T, Waterer G, Jenkins C, et al. Influenza A/H1N1_09:
Australia and New Zealand’s winter of discontent. Am J Respir Crit Care
Med. 2010;181:300–6.
2. Fowler RA, Lapinsky SE, Hallett D, et al. Critically ill patients with
severe acute respiratory syndrome. JAMA. 2003;290:367–73.
3. Hui DS, Hall SD, Chan MT, et al. Non-invasive positive pressure
ventilation: an experimental model to assess air and particle dispersion.
Chest. 2006;130:730–40.
4. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of

neuraminidase inhibitors in reducing mortality in patients admitted to
hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of
individual participant data. Lancet Respir Med. 2014;2:395–404.
5. Hota S, Fried E, Burry L, et al. Preparing your intensive care unit for
the second wave of H1N1 and future surges. Crit Care Med.
2010;38;e110–19.
6. Hick JL, Christian MD, Sprung CL. Chapter 2. Surge capacity and
infrastructure considerations for mass critical care. Intensive Care Med.
2010;36:S11–20.
7. The ANZIC Influenza Investigators. Critical care services and 2009

H1N1 Influenza in Australia and New Zealand. N Engl J Med.
2009;361:1925–34.
8. Dominguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill

patients with 2009 influenza A(H1N1) in Mexico. JAMA. 2009:302:1880–7.
9. Gabriel LE, Webb SA. Preparing ICUs for pandemics. Curr Opin Crit
Care. 2013;19:467–73.
10. Wise ME, De Perio M, Halpin J, et al. Transmission of pandemic H1N1

(2009) influenza to healthcare personnel in the United States. Clin Infect
Dis. 2011;52:S198–204.
11. Gomersall CD, Joynt JM, Ho OM, et al. Transmission of SARS to

healthcare workers. The experience of a Hong Kong ICU. Intensive Care
Med. 2006;32:564–9.
12. Funk DJ, Siddiqui F, Wiebe K, et al. Practical lessons from the first
outbreaks; clinical presentation, obstacles, and management strategies
for severe pandemic (pH1N1) 2009 influenza pneumonitis. Crit Care Med.
2010;38:e30–7.
13. Christian MD, Sprung CL, King MA, et al. Triage: care of the critically
ill and injured during pandemics and disasters: CHEST consensus
statement. Chest. 2014;146:e61S–74S.
Page 28 of 30

14. Fineberg H. Pandemic preparedness and response—lessons from the

H1N1 influenza of 2009. N Engl J Med. 2014;370;1335–42.
15. World Health Organization (WHO). mHealth: New Horizons for Health
in Mobile Technologies. Global Observatory for eHealth Series, Volume 3.
Geneva: WHO; 2011. Available from: http://www.WHO.int/goe/
publications/goe_mhealth_web.pdf.
16. Cheng AC, Dwyer DE, Kotsimbos ATC, et al. Summary of the
Australian Society for Infectious Diseases and the Thoracic Society of
Australia and New Zealand guidelines: treatment and prevention of H1N1
09 (human swine influenza) with antiviral agents. MJA. 2009;191:142–5.
17. Faix DJ, Sherman SS, Waterman SH. Rapid-test sensitivity for novel
swine-origin influenza A (H1N1) virus in humans. N Engl J Med.
2009;361:728–9.
18. Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal
membrane oxygenation center and mortality among patients with severe
2009 influenza A(H1N1). JAMA. 2011;306:1659–68.
19. The ANZIC Influenza Investigators. Critical care services and 2009
H1N1 influenza in Australia and New Zealand. N Engl J Med.
2009;361:1925–34.
20. Wiwanitkit V. The usefulness of case reports in managing emerging

infectious disease. J Med Case Rep. 2011;5:194.
21. Calain, P. The Ebola clinical trials: a precedent for research ethics in
disasters. J Med Ethics. 2018;44:3–8.
22. Gobat NH, Gal M, Francis NA, et al. Key stakeholder perceptions
about consent to participate in acute illness research: a rapid, systematic
review to inform epi/pandemic research preparedness. Trials.
2015;16:591.
23. Annane D, Outin H, Fisch C, et al. The effect of waiving consent on

enrollment in a sepsis trial. Intensive Care Med. 2004;30:321–4.
24. Davies H, Shakur H, Padkin A, et al. Guide to the design and review of
emergency research when it is proposed that consent and consultation be
waived. Emerg Med J. 2014;31:794–5.
25. The NICE-SUGAR Study Investigators. Intensive versus conventional

glucose control in critically ill patients. N Engl J Med. 2009;360:1283–97.
26. Tu JV, Willison DJ, Silver FL, et al. Impracticability of informed

consent in the registry of the Canadian Stroke Network. N Engl J Med.
2004; 350:1414–21.
Page 29 of 30

27. Fowler RA, Webb SA, Rowan KM, et al. Early observational research
and registries during the 2009–2010 influenza A pandemic. Crit Care
Med. 2010;38:e120–32.
28. Schuchat A, Bell BP, Redd SC. The science behind preparing and
responding to pandemic influenza: the lessons and limits of science. Clin
Infect Dis. 2011;52:S8–12.
Page 30 of 30

Organ donation and transplantation

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Chapter: Organ donation and transplantation
Author(s): Andrew Ray
DOI: 10.1093/med/9780198814924.003.0018
Expert commentary by Alex Manara
This case discussion is based on a patient admitted to an intensive care

unit (ICU) in the UK and much of the discussions relating to professional,
ethical, and legal issues are based on UK law and guidance from UK
professional and regulatory bodies. While many other countries practising
deceased donation will have broadly similar guidance, there may be
significant differences in some aspects of practice. The reader should not
necessarily extrapolate these interpretations of legal, ethical, and
professional guidance to what is acceptable in their own country.
Case history
An 81-year-old man was admitted to hospital following a collapse

on the golf course at 12:45. A medical emergency response team was
dispatched along with a paramedic crew. On initial assessment, the man
had a patent airway and was self-ventilating with a respiratory rate of 14
breaths/min and arterial blood oxygen saturation of 95% breathing air.
Page 1 of 23
His blood pressure was 182/94 mmHg, his heart rate was 76 beats/min,
and he was in atrial fibrillation. His Glasgow Coma Scale score was 4/15
(E1, V1, M2) and he had a fixed, dilated right pupil. His trachea was
intubated at the scene and he was transferred to the nearest emergency
department (ED). On arrival, he underwent an urgent computed
tomography scan of his brain. This demonstrated a large, right-sided
parietal intraparenchymal haemorrhage extending into the subdural
space, subarachnoid space, and ventricular system (Figure 18.1). By this
time, his wife had been contacted and had arrived in the hospital. She
confirmed that he was usually fit and active with a relatively minimal past
medical history. He was a treated hypertensive and had chronic atrial
fibrillation for which he was taking apixaban for stroke prophylaxis.
Figure 18.1
Computed tomography scan of head showing right parietal
intraparenchymal haemorrhage extending into the subdural space,
subarachnoid space, and ventricular system with a significant midline
shift.
The patient was discussed with the neurosurgical team who reviewed his
scans and concluded that this was an unsurvivable brain injury and that
withdrawal of life-sustaining treatment (WLST) should be considered. The
ED team and the ICU team who were managing the patient had two
possible options for ongoing management. The first was to undertake
WLST in the ED with a plan to transfer to a medical ward for continued
end of life care. Organ donation would not have been a possibility as the
patient did not meet the criteria for the determination of death using
neurological criteria. The other option was for the patient to be
transferred to ICU and follow a devastating brain injury pathway (Figure
18.2) [1] providing time for better prognostication and to facilitate
Page 2 of 23

optimization of his end of life care. After a frank and honest discussion
with his wife regarding the expected outcomes and the high likelihood
that he would continue to deteriorate and die, it was agreed to admit him
to ICU for continued observation and end of life care. This allowed time
for the patient’s three children to travel from elsewhere in the UK and
abroad to see their father and to support their mother at this difficult
time. It also enabled further exploration of the patient’s preferences and
values, with his family, including the option of WLST in view of the
hopeless prognosis. The specialist nurse in organ donation (SN-OD,
commonly known as a donor coordinator in many countries) was notified
of the patient’s admission to consider whether organ donation could be a
possible component of his end of life care.
Figure 18.2
Suggested pathway for intubated patients with devastating brain injury [1]
. DBD, donation after brain death; DCD, death after cardiovascular death;
EOL end of life; WLST, withdrawal of life-sustaining treatment.
Reproduced with permission from Manara, AR., et al. A Case for Stopping
the Early Withdrawal of Life Sustaining Therapies in Patients with
Devastating Brain Injuries. Journal of Intensive Care Society. 17(4), 295–
301. Copyright © 2016 SAGE.
LEARNING POINT Devastating brain injury pathways
Recommendations for the critical care management of devastating

brain injury have been published recently by the Neurocritical Care
Society [2]. Devastating brain injury pathways are being introduced
in some hospitals for patients admitted with life-threatening brain
insults (subarachnoid haemorrhage, trauma, intracerebral
haemorrhage) and where an early decision to undertake WLST is
being considered. The primary intervention is to delay the WLST to
Page 3 of 23

provide more time for physiological stabilization and continued

observation of the patient. This has the benefits of increasing
prognostic certainty, allowing more time to explore the patient’s
preferences and wishes which can then be incorporated into a
bespoke end of life care plan. Finally, it allows more time for the
consideration of organ donation.
EXPERT COMMENT
Devastating brain injury pathways already exist for the management

of hypoxic-ischaemic brain injuries following out-of-hospital cardiac
arrest, and are associated with improved outcomes. It is likely that
professional guidance will be provided on the development of similar
pathways for other causes of devastating brain injury.
LEARNING POINT Background of organ donation and

transplantation
There are currently nearly 7000 patients on an organ transplant

waiting list in the UK. Approximately 3400 organs are transplanted in
the UK each year. The demand for organs for transplantation
continues to outstrip the supply in virtually every country practising
organ transplantation, including all those in the developed world.
Since the first successful kidney transplant in 1954, surgical
techniques, immunosuppressant therapies, and intensive care have
advanced significantly to enable transplantation of other solid organs
such as the liver, lungs, heart, pancreas, and small bowel. Until more
recently, all deceased organ donors were patients confirmed as dead
using neurological criteria (donation after brain death (DBD)),
However the first heart transplant performed by Christian Barnard
was retrieved from a donor whose death was confirmed using
circulatory criteria (donation after circulatory death (DCD)). The
continued demand for organs for transplantation has led to the
reintroduction of DCD programmes in many countries including
Australia, the Netherlands, the US, Spain, and the UK.
While more than 500,000 people die each year in the UK, only around
1% (i.e. approximately 5000) of them do so in circumstances where
organ donation could be possible. There has been an increase of
almost 70% in the number of deceased organ donors (from 809 to
1364) between the publication of the Organ Donation Taskforce
Report [3] in 2008 (whose purpose was to address all barriers to
organ donation and transplantation) and 2016. This increase in donor
numbers was primarily due to increased identification and referral of
Page 4 of 23

potential donors from ICUs and EDs. DCD accounted for

approximately 75% of the increase in organ donors so that DCD now
accounts for just over 40% of all deceased donors and 35% of all
transplants in the UK. The transplant programmes of other countries,
particularly the Netherlands and Australia, also rely on a large
proportion of DCD donors. There has been little change in the consent
versus refusal rate. However there remains a substantial shortfall in
the number of organs available for transplantation, the number of
patients dying on the transplant waiting list has not decreased, and
access to the transplant waiting list is restricted by stringent criteria.
Efforts to ensure that all potential donors are given the best
opportunity to donate their organs after death is a cornerstone of the
National Health Service (NHS) Blood and Transplant and the UK
Health Departments’ strategy ‘Taking Organ Transplantation to 2020
[4].
EXPERT COMMENT
The increase in donors over the past 8 years has been primarily
driven by staff in ICUs and EDs identifying and referring more
potential donors and thus more families being approached for
donation. The current 2020 strategy [4] recognizes that further
increases in donors requires further contributions from NHS
commissioners, society, and individuals as well as from hospital
donation and transplantation teams.
LEARNING POINT Identifying and referring potential

donors
The General Medical Council’s (GMC) guidance states that, when a

patient is close to death, doctors should explore the patient’s
donation wishes with the relatives and that they should follow any
national recommendations on the identification and referral of
potential donors [5]. The UK National Institute for Health and Care
Excellence (NICE) published guidance on the referral and
identification of potential donors to SN-ODs [6] and recommends that
early referral is based upon three easily applied clinical triggers:
● An intention to diagnose death using neurological criteria

(brainstem death) or
● A decision to withdraw life-sustaining treatments or
Page 5 of 23

● Admission of a patient with a severe brain injury of such severity

that one or more brainstem reflexes have been lost and the
Glasgow Coma Scale score is 3 or 4.
The guidance also emphasizes the need to avoid premature treatment

limitation/withdrawal decisions until the possibility of donation and
the wishes of the patient have been explored. It is important that the
referral is timely since this may reduce distressing delays for the
family while awaiting organ recovery. The UK Donation Ethics
Committee states that there is no ethical dilemma in discussing a
patient with a SN-OD before a formal decision to WLST has been
discussed with the relatives [7]. Despite this advice, individual
clinicians continue to feel conflicted if they contact a SN-OD to
discuss the suitability for organ donation before they have discussed
the WLST with the family.
EXPERT COMMENT
The guidance from the GMC, NICE, and the Donation Ethics
Committee tells doctors what can and should be done. Strategy
documents such as ‘Timely identification and referral of potential
organ donors: A strategy for implementation of best practice’ [8] can
be more helpful in telling doctors how to implement these
recommendations in practice.
The SN-OD confirmed that the patient’s age was a contraindication to

DCD, but also recognized that the severity of the brain injury was such
that the clinical condition could progress to the point where confirmation
of death using neurological criteria may be possible, in which case the
patient would be suitable for DBD. By the following morning, the patient
had not received any further sedation, had fixed pupils, no responses, and
was not making respiratory efforts. The patient met all the preconditions
for confirming the diagnosis of death using neurological criteria. The
family were now all present, and were told that the ICU team suspected
that the patient had already died but that further clinical tests were
needed to confirm this. The family were invited to observe the testing and
accepted this offer. The tests were performed twice by two ICU
consultants and the patient was declared dead using neurological criteria.
EXPERT COMMENT
The transition from a devastating brain injury to brain death

increases over time after admission to hospital. Only 20% of those
Page 6 of 23

who progress to brain death do so in the first 24 hours after

admission compared to 70% by 72–96 hours [9].
LEARNING POINT Diagnosing death using

neurological criteria (brainstem death testing)
Death is defined as irreversible loss of the capacity for consciousness

and the capacity to breathe and can occur due to cessation of
brainstem function or cessation of cardiorespiratory function [10].
When brain death is suspected, the patient should be formally tested
by two medical practitioners who are competent in making the
diagnosis. Both must have been registered for more than 5 years and
one must be a consultant. Two sets of tests must be completed. This is
usually achieved with the two doctors working together: the first
doctor conducting the first set of tests while the second doctor
observes; and the second doctor conducts the second set of tests with
the first doctor observing. There is no prescribed time interval
between the tests. Some prefer to conduct the second set of tests
immediately after the first set, while others prefer to allow various
time intervals between tests.
The following criteria must be satisfied before undertaking the

clinical tests:
● The patient must be deeply comatose, unresponsive, apnoeic,

and dependent on mechanical ventilation.
● There should be no doubt that brain damage is irreversible and
the underlying aetiology must be known.
● Reversible causes of coma must be excluded:
◦ Residual effects of sedative drugs.

◦ Hypothermia—the core temperature must be greater than
34°C.
◦ Residual neuromuscular blockade.
◦ Cervical spinal cord injury.
◦ Reversible metabolic, endocrine, and circulatory
disturbances. The Academy of Medical Royal Colleges’ report ‘A
code of practice for the diagnosis and confirmation of death’
recommends testing within the following parameters:
■ Mean arterial pressure greater than 60 mmHg

■ Partial pressure of carbon dioxide (PaCO2) less than 6.0
kPa
■ Partial pressure of oxygen (PaO2) greater than 10 kPa
■ pH 7.35–7.45
Page 7 of 23

■ Na+ 115–160 mmol/L

■ K+ greater than 2 mmol/L
■ Mg2+ and PO4 0.5–3.0 mmol/L
■ Serum glucose 3.0–20 mmol/L.
Once the preconditions have been met, the clinical tests can be
undertaken to confirm death:
● Pupils bilaterally fixed and unresponsive to light (direct and

consensual responses).
● Absent corneal reflexes bilaterally.
● Absent oculovestibular reflexes—no eye movements in response
to 50 mL of ice cold water being injected in each ear in turn
(confirm that the ear canals are clear before testing).
● No cranial nerve motor response to the application of
supraorbital pressure.
● Absent cough reflex on tracheal suctioning.
● Absent gag reflex on stimulation of the posterior pharynx.
● No respiratory movement on disconnection from mechanical
ventilation. This test takes place last and only after demonstrating
the absence of all other reflexes. It is conducted as follows:
◦ Increase the patient’s fraction of inspired oxygen to 1.0.

◦ Reduce minute ventilation to achieve a PaCO2 greater than
6.0 kPa and a pH lower than 7.40.
◦ Ensure an adequate blood pressure is maintained throughout.
◦ Next, disconnect the patient from the ventilator.
◦ Maintain oxygenation by delivering oxygen at 5 L/min via a
tracheal catheter or a Mapleson C breathing system. Monitor
oxygen saturation by pulse oximetry throughout.
◦ Confirm the absence of respiratory effort for a minimum of 5
min.
◦ Repeat an arterial blood gas analysis to demonstrate an
increase in PaCO2 of greater than 0.5 kPa from the starting
value.
◦ Perform a recruitment manoeuvre on completion of the
apnoea test, reconnect the ventilator, and adjust ventilation to
achieve a normal PaCO2 and pH.
CLINICAL TIP Practicalities of testing
Page 8 of 23

Ensuring that the preconditions are fully satisfied is the crucial and
occasionally more challenging part of diagnosing death using
neurological criteria. When this is done and the clinicians proceed to
the clinical test, the criteria are then satisfied in 98.5% of patients.
The diagnosis of death using neurological criteria is only made

approximately 1500 times a year in the UK—that is, fewer than six
per year per ICU and considerably fewer in non-neurosurgical ICUs—
meaning that this is an unusual procedure for many individual
consultants. Forms endorsed by the UK’s Faculty of Intensive Care
Medicine and the Intensive Care Society are available to guide
doctors to undertake the tests in accordance with national guidance
and help standardize the procedure [11].
EXPERT COMMENT
The diagnosis of death using neurological criteria should ideally be

made whenever it is a possibility, as suggested by the UK Donation
Ethics Committee [12] rather than simply as a means of facilitating
organ donation. As in this case, the diagnosis of death can provide the
family with the certainty they need. The diagnosis of death using
neurological criteria is accepted by the law courts and protects
doctors from any potential criticism about the more subjective
decisions regarding the WLST (a diagnosis versus a prognosis).
Once the second set of tests were completed, a further discussion was
had with the relatives to inform them that the patient had died and to
confirm their understanding of the diagnosis. The family was grateful for
the certainty of a diagnosis of death rather than a decision to WLST based
on prognostication. The relatives were then offered a short break before
meeting again to discuss what happens next. In the meantime, the SN-OD
had established that the patient was not on the organ donor register, but
that he should be considered for DBD since the abdominal organs would
be suitable for transplantation. The approach to the relatives for organ
donation was planned and conducted collaboratively with the SN-OD
present. Further discussions of a medical nature were led by the ICU
consultant. The discussions leading to an approach for organ donation
was led by the SN-OD. The family were firmly of the opinion that organ
donation was consistent with the patient’s values and preferences. After
further information was given to the relatives they consented to organ
donation.
LEARNING POINT Suitability for donation
Page 9 of 23

Absolute exclusion criteria for donation of solid organs in the UK

include:
● age greater than 80 for DCD

● age greater than 85 for DBD
● known or suspected Creutzfeldt–Jakob disease
● disseminated malignancy
● known patient refusal.
Most transplant organizations no longer provide lists of relative

contraindications as these are unhelpful, ever changing, and often
organ specific, which does not preclude donation of other organs. All
donors are considered individually and potential donors with
conditions that were absolute or relative contraindications may now
be accepted on a case-by-case basis, for example, in the past, HIV-
positive patients were not considered for donation but now they may
be able to donate their organs to an HIV-positive recipient. The SN-
OD will request several investigations to assess the suitability of an
individual to donate their organs, and others to determine the
suitability of individual organs for transplantation. These generally
include tissue typing, tests to exclude the presence of transmissible
disease, blood urea and electrolytes, estimated glomerular filtration
rate, liver function tests, chest radiography, electrocardiography,
echocardiography, and imaging to exclude damage to organs being
considered for donation.
Once consent has been obtained from the family, the individual
organs are offered to transplant centres to assess suitability for
transplantation in any of the centre’s potential recipients. The kidney
offering system is undertaken centrally by the organ procurement
organization. All other organs are offered by the SN-ODs sequentially
to transplant centres.
EXPERT COMMENT
Whether organs are considered suitable for transplantation depends

on recipient factors and circumstances as well as donor factors. While
intensivists have an obvious role in informing SN-ODs if they are
concerned about the suitability of any potential donor, the decision to
accept organs for transplantation can be made only by the transplant
teams who hold information on potential recipients. The best
approach is to discuss with a SN-OD all patients meeting the referral
triggers.
Page 10 of 23

LEARNING POINT Approaching organ donation with

families
Approaching a family for organ donation should be planned, and

undertaken only after they have understood and accepted the
determination of death using neurological criteria or the reasons for
WLST and the inevitability of death. It is good practice to separate
the approach for organ donation from the conversations about
prognosis and potential WLST [13]. The coroner needs to be informed
of many patients before donation can proceed since the causes of
death that that are most commonly associated with organ donation
are reportable to a coroner. These include causes of sudden death
such as subarachnoid and intracerebral haemorrhage and death
following trauma including severe head injury. While coroners are
generally supportive of organ donation, there are occasions when
they may only allow certain organs to be donated, and other
occasions when they will not allow donation to proceed at all. These
situations most commonly occur when the patient’s death is likely to
be followed by a criminal investigation by the police and forensic
pathologists.
While the wish of a patient to be an organ donor after death is

occasionally known, it is more common to have to explore their
preferences and wishes regarding organ donation with their relatives.
Opinion polls have suggested that around 90% of the UK population
support organ donation, yet only 62% of families approached for
donation will give their consent or authorization for organ donation to
proceed. Efforts should be made to support families by providing
appropriate information in a suitable environment and enabling them
to understand the potential benefit of organ donation. It is good
practice to use a collaborative approach between the SN-OD and the
ICU team when approaching families (Figure 18.3). SN-ODs are
specifically trained in supporting families through this decision-
making process and can provide all the detailed and accurate
information required by families. Also, the involvement of a SN-OD in
the family approach is associated with significantly higher rates of
consent to organ donation [14].
Page 11 of 23

Figure 18.3
The three stages recommended in approaching a family for organ
donation. ODR, organ donation register; SN-OD, specialist nurse in
organ donation.
Reproduced from NHS Blood and Transplant (2013). Approaching the

families of potential organ donors. Best practice guidance. Copyright
© 2013 NHS. Contains public sector information licensed under the
Open Government Licence v3.0. Available at: http://www.odt.nhs.uk/
pdf/family_approach_best_practice_guide.pdf.
Apart from the involvement of the SN-OD in the family approach, the
other factors significantly associated with consent are the patient’s
ethnicity and a prior knowledge of a patient’s wish to donate after
death (Figure 18.4) [14]. When a patient’s wish to donate is already
known, some 90% of families will agree to organ donation. The other
10% will, however, override the wish of their relative and will not
consent to donation. While it is common practice to accept the wishes
of the family, it is also important to explore their reasons for not
respecting that individual’s wishes, as it is possible they may regret
their decision in the future.
Page 12 of 23

Figure 18.4
Odds ratio for the effect of various factors on the consent rate in
donation after brain death (DBD) and donation after circulatory death
(DCD). White ethnicity, general ICU, no known donation wish,
approach before the first set of brain death tests, no mention of
donation before family approach, presence of a specialist nurse in
organ donation (SN-OD) and a SN-OD-only approach was used as the
baseline for comparison (odds ratio 1). Error bars indicate 95%
confidence intervals (CIs).
Reproduced with permission from Hulme, W., et al. Factors
influencing the family consent rate for organ donation in the UK.
Anaesthesia. 2016(71), 1053–1063. Copyright © 2016 The Association
of Anaesthetists of Great Britain and Ireland.
In 2015, Wales implemented legislation to introduce a soft opt-out

system whereby the population is deemed to have agreed to donate
unless they have previously expressed or registered a desire not to do
so [15]. The potential impact of this strategy on donor numbers will
Page 13 of 23

be monitored closely and may well prompt legislation reviews in other

countries of the UK.
EXPERT COMMENT
While various factors are associated with increased consent rates for
organ donation, the one that is most easily modifiable by the ICU and
ED staff is how they plan and execute the approach to the family. This
means involving a trained requestor in the family approach. This is
almost always the SN-OD. The SN-OD can also provide more up-to-
date information, answer all the family’s questions on donation, and
almost invariably has more time to support the family through the
process than the busy clinical team.
EXPERT COMMENT
When a potential donor is on the organ donor register or subject to

the Welsh opt-out legislation and deemed to have given consent, then
it is appropriate that a presumptive approach is made to the family.
The approach assumes that consent has already been given by the
patient and the conversation is primarily about how to make their
wish a reality.
The SN-OD offered the organs to the transplant teams who accepted the
kidneys, liver, and pancreas for transplantation. While awaiting the
arrival of the organ retrieval team, the patient’s further management
changed to a strategy to optimize the function of the organs to be
transplanted and avoid any damage that can result from the physiological
changes that accompany brainstem death [16]. Initially the patient
developed diabetes insipidus which was manged with intermittent doses
of intravenous desmopressin. The patient’s hypotension was managed
with fluids and an infusion of vasopressin to maintain mean arterial
pressure.
EXPERT COMMENT
Vasopressin was used instead of noradrenaline as the vasoconstrictor

of choice because it improves the outcomes of transplanted kidneys
and also treats the diabetes insipidus the patient had developed.
Page 14 of 23

EXPERT COMMENT
The results of transplantation are not only dependent on the number

of organs available but more importantly on the quality of the organs
recovered. Management of a potential DBD donor is in effect the
provision of high-quality intensive care management. Intensivist-led
management of potential DBD donors can increase the number of
organs successfully recovered and transplanted, particularly lungs
[17] .
He was actively warmed to maintain normothermia and insulin was

infused to manage hyperglycaemia. A lung protective ventilation strategy
was continued. The patient was transferred to the operating theatre
where he was manged by a senior anaesthetist who continued the
vasopressin infusion, fluids, and ventilatory strategy used on the ICU but
also administered neuromuscular blocking drugs and opioids during the
3-hour retrieval procedure. This was carried out by a single abdominal
surgical retrieval team. On this occasion, a second thoracic retrieval team
was not required as the heart and lungs were not suitable for
transplantation. The kidneys and liver were successfully transplanted into
three recipients, while the pancreas was used for research. The use of
retrieved organs for research purposes when they are not transplanted is
a routine component of the consent process. The SN-ODs later wrote to
the patient’s relatives to thank them for the gift the patient had made and
to provide them with anonymized details of the patients who had
benefited from the organ transplants.
EXPERT COMMENT
In the future, management of the potential DBD donor may include

induced hypothermia rather than maintaining normothermia as it has
been shown to improve the outcomes of renal transplantation [19].
LEARNING POINT Physiological support of the donor
There are several physiological changes that occur following brain

death. Many can cause damage to organs being considered for
transplantation. The incidence of these changes is:
● hypotension 80%
● diabetes insipidus 65%
● disseminated intravascular coagulation 30%
Page 15 of 23

● cardia arrhythmias 30%

● pulmonary oedema 20%
● metabolic acidosis 10%.
Managing these physiological changes appropriately can increase the

chances of organs being transplanted successfully [16]. Donor care
bundles are increasingly used to guide the optimization of potential
DBD donors and to set appropriate physiological targets to aim for. A
donor care bundle in common use in the UK is provided by NHS
Blood and Transplant (Figure 18.5) [18].
Figure 18.5
A donor optimization bundle.
Reproduced from NHS Blood and Transplant. (2013) Donor
Optimisation Guidance Around Selecting Potential DBD Donors.
Copyright © NHS. Contains public sector information licensed under
the Open Government Licence v3.0. Available at https://
www.odt.nhs.uk/deceased-donation/best-practice-guidance/donor-
optimisation/.
Page 16 of 23

LEARNING POINT Donation after circulatory death
DCD describes recovery of organs after death has been confirmed

using circulatory criteria. In the US, Australia, the Netherlands, and
the UK, controlled DCD is the DCD pathway practised. It is the only
deceased donation pathway where the patient is still alive and
awaiting the WLST when donation decisions are made and
antemortem interventions to maintain donation potential are applied.
All aspects of this form of donation and many of its ethical, legal, and
professional challenges have been reviewed in detail [22]. DCD was
primarily a kidney-only recovery pathway with data showing that
transplanted DCD kidneys had the same long-term outcome as DBD
kidneys. Today, DCD is a multiorgan recovery pathway enabling
successful transplantation of kidneys, liver, pancreas, lungs, and
recently also the heart.
Patients suitable for controlled DCD are generally those with

devastating brain injuries who do not meet the criteria for testing for
brain death and a decision to undertake WLST has been reached once
ongoing treatment is no longer deemed to be in the patient’s best
interests. In these circumstances, the suitability of the patient for
donation is discussed with a SN-OD, and then the family are
approached for consent to donation before the WLST. If the family
agree to donation, the WLST is delayed and physiological stability is
maintained until the retrieval team is on site and prepared in the
operating theatre. The WLST is undertaken in a location close to or
within the theatre complex to reduce the warm ischaemic damage to
organs after asystole. Death is confirmed in a timely manner after 5
min of continuous coma, apnoea, and absence of the circulation as
recommended by national guidance [10]. The patient is then rapidly
transferred to the operating theatre for the organ recovery
procedure. In general, the donation process is stopped if the time
from WLST to death exceeds 2–3 hours. The main concern from the
transplantation perspective is the damage caused by the warm
ischaemic time. This is the time that the organ remains at body
temperature without adequate perfusion. It is measured as the period
between a sustained drop in systolic blood pressure to less than 50
mmHg until the start of cold perfusion and must be kept to a
minimum to maximize the chance of successful organ transplantation.
Development of new technologies such as normothermic regional
perfusion, to reduce warm ischaemic damage, will continue to
improve the outcomes of transplanted organs recovered from DCD
donors (Figure 18.6). Normothermic regional perfusion involves the
insertion of catheters with balloons to isolate the circulation of organs
to be transplanted. The organs are reperfused with warm oxygenated
blood for, usually, 2 hours after the cardiac arrest before cold
perfusion is commenced, although the optimal duration remains to be
defined. Normothermic regional perfusion does not reduce the
Page 17 of 23

functional warm ischaemia time but reverses some of the damage

done, allows further evaluation of donor organs before a decision to
transplant is made, and appears to improve transplant outcomes.
Figure 18.6
The use of regional normothermic perfusion with blood to reduce the
damage caused by the warm ischaemic time (WIT) before the onset of
organ perfusion with cold solutions. The acceptable functional WIT
varies for different organs and ranges from 30 min for the liver and
pancreas to 60 min for kidneys and lungs. SaO2, oxygen saturation of
arterial blood; SBP, systolic blood pressure.
Despite the success of DCD programmes, the gold standard pathway

for deceased donation remains DBD since more organs are retrieved
and transplanted from DBDs than DCDs and the outcomes are often
considered better. Also, DBD is the more efficient deceased donation
pathway as 45% of potential DBD donors become actual donors
compared to only 10% of potential DCD donors who become actual
donors. Potential DBD donors are patients whose clinical condition is
suspected to fulfil the criteria for confirming death using neurological
criteria. Potential DCD donors are patients in whom cardiorespiratory
arrest is anticipated to occur after the WLST within a time frame that
will enable organ recovery.
Overall, DBD is the preferred model for organ donation—because it

increases rates of organ retrieval and successful transplantation. As
the number of DCD donors in the UK has increased each year since
2002 (and now accounts for 42% of all deceased organ donors), there
has been concern that this increase is at the expense of DBD because
of WLST in patients who might otherwise be DBD donors. However,
the evidence indicates that DCD donors are an additional pool of
organ donors, and the pool of DBD donors has not decreased. Despite
this, it is estimated that the common practice of early WLST decisions
in the UK and other northern European countries prevents around a
quarter of DCD donors progressing to brainstem death and the
potential for DBD donation [23]. Modification of end of life practices
Page 18 of 23

has the possibility of increasing the chances of meeting the stated

wishes of patients who will not survive, to donate their organs after
their death.
Discussion
Organ donation may not be a common occurrence in many

hospitals, but should always be considered as a routine part of end of life
care for all patients dying in the ICU or ED. The deceased donation
pathway that a patient follows will depend on the circumstances (Figure
18.7) [20]. Only DBD and controlled DCD are routinely practised in the
UK and the Netherlands, which is a reflection of the greater frequency
with which WLST is practised in northern Europe compared with
southern European countries such as Spain, Italy, and Portugal. In these
southern European counties, WLST is much less frequent and thus the
incidence of brain death is about four times more common, while
uncontrolled DCD is more common. While not all patients will be suitable
for organ donation and not all families will consent to or authorize
organs, any potential for organ donation is lost immediately if potential
organ donors are not identified and referred by the ICU or ED team.
Figure 18.7
A comparison of the three-principle deceased donation pathways.
Reproduced with permission from Citerio, G., et al. Organ donation: a

critical care perspective. Intensive Care Medicine. 2016;42:305–315.
Copyright © Springer-Verlag Berlin Heidelberg and ESICM 2015.
In the case described in this chapter, routine practice in many hospitals

would have been to explore the option of organ donation in the ED when
a decision to WLST had been reached. Since the patient was older than
80 years, which excludes DCD, and because he still had brainstem
reflexes excluding consideration of DBD, it is likely that he would have
been extubated in the ED, and end of life care continued there or on a
general medical ward. However, by transferring him to the ICU as part of
Page 19 of 23

a devastating brain injury pathway, it enabled his family members to

attend the hospital, giving them more time to come to terms with his
diagnosis and to explore the patient’s preferences and values to create a
bespoke end of life care plan [21], which on this occasion included the
potential for organ donation. It also provided the opportunity for the
family to witness the clinical tests to confirm death, helping them
understand the absolute futility of ongoing organ support. In doing so, the
patient was also able to become a DBD and donated his kidneys,
pancreas, and liver. Furthermore, the likelihood of his wife agreeing to
authorize DCD without her family being present and without the support
of a SN-OD is significantly less than the prospect of her authorizing DBD.
Finally, admitting the patient to ICU also enabled best practice to be
followed in the key steps of the organ donation pathway including timely
referral, approaching the family, confirming death using neurological
criteria, and optimizing the donor’s physiology.
This case demonstrates best practice applied to each step of the

donation pathway, particularly those where donation potential is most
likely to be lost. There is guidance from our professional and
regulatory bodies on the identification and referral of potential
donors using clinical triggers, confirming death using neurological or
circulatory criteria, assessing suitability for donation, approaching
the relatives for organ donation, gaining consent/authorization, and
optimization of the potential donor to maximize the number and
quality of organs to be transplanted. All this best practice is endorsed
by the Intensive Care Society and Faculty of Intensive Care Medicine
in the section on organ donation in their Guidelines for the Provision
of Intensive Care Services [24]. While in the past some may have
perceived many of these recommendations as being in the best
interests of the recipient rather than the donor, those views are based
on a narrow interpretation of only the patient’s medical best interests
and are inconsistent with the more current interpretation of best
interests as enshrined within the UK’s Mental Capacity Act 2005 [25].
This requires those making decisions on behalf of an adult lacking
competence to consider the person’s past and present wishes and
feelings, the beliefs and values that would be likely to influence that
person’s decision if they had capacity, and the other factors that they
would be likely to consider if they were able to do so. A patient’s wish
to donate should therefore be considered when making decisions on
their behalf. This case is possibly even more challenging because the
patient was admitted to the ICU as part of a devastating brain injury
pathway despite a very poor prognosis and before establishing the
patient’s wishes about organ donation. The ambitions of such
pathways (which include improving accurate prognostication,
improving end of life care for the patient and their relatives, and
Page 20 of 23

enabling exploration and facilitation of their end of life choices,

including organ donation) can also be interpreted as being in that
individual patient’s best interests.
References
1. Manara AR, Thomas I, Harding R. A case for stopping the early
withdrawal of life sustaining therapies in patients with devastating brain
injuries. J Intensive Care Soc. 2016;17:295–301.
2. Souter MJ, Blissitt PA, Blosser S, et al. Recommendations for the

critical care management of devastating brain injury: prognostication,
psychosocial, and ethical management. A position statement for
healthcare professionals from the neurocritical care society. Neurocrit
Care. 2015;23:4–13.
3. Department of Health. Organs for Transplants: A Report from the

Organ Donation Taskforce. London: Department of Health; 2008.
Available from: https://webarchive.nationalarchives.gov.uk/
20130105051141/http://www.dh.gov.uk/en/Publicationsandstatistics/
Publications/PublicationsPolicyAndGuidance/DH_082122.
4. NHS Blood and Transplant and the UK Departments of Heath. Taking

Organ Transplantation to 2020. A UK Strategy [Internet]. Available from:
https://www.nhsbt.nhs.uk/tot2020/the-strategy/ (accessed 29 November
2016).
5. General Medical Council. Treatment and Care Towards the End of Life:
Good Practice in Decision Making. London: General Medical Council;
2010. Available from: http://www.gmc-uk.org/static/documents/content/
Treatment_and_care_towards_the_end_of_life_-_English_1015.pdf.
6. National Institute for Health and Care Excellence. Organ Donation for
Transplantation: Improving Donor Identification and Consent Rates for
Deceased Organ Donation. Clinical guideline [CG135]. London: National
Institute for Health and Care Excellence; 2011. Available from: https://
7. Academy of Medical Royal Colleges Donation Ethics Committee

Consultation Document. An Ethical Framework for Controlled Donation
after Circulatory Death [Internet]. 2011. Available from: http://
www.aomrc.org.uk/wp-content/uploads/2016/05/
Controlled_donation_circulatory_death_consultation_0111.pdf (accessed
29 November 2016).
8. NHS Blood and Transplant. Timely Identification and Referral of

Potential Organ Donors: A Strategy for Implementation of Best Practice
[Internet]. 2012. Available at: http://www.odt.nhs.uk/pdf/timely-
Page 21 of 23

identification-and-referral-potential-donors.pdf (accessed 29 November

2016).
9. Sanchez-Ibanez J. Potential and evolution of organ donation in Galicia

(Spain) 2006–2012. Transplant. 2013;96:S165–280.
10. Academy of Medical Royal Colleges. A Code of Practice for the

Diagnosis and Confirmation Death [Internet]. 2008. Available from: http://
www.odt.nhs.uk/pdf/code-of-practice-for-the-diagnosis-and-confirmation-
of-death.pdf (accessed 29 November 2016).
11. Faculty of Intensive Care Medicine. Form for the Diagnosis of Death
using Neurological Criteria (abbreviated guidance version) [Internet].
2016. Available from: https://www.ficm.ac.uk/sites/default/files/
Form%20for%20the%20Diagnosis%20of%20Death%20using%20Neurolog
ical%20Criteria%20-%20Abbreviated%20Version%20%282015%29_0.pdf
(accessed 29 November 2016).
12. Academy of Medical Royal Colleges Donation Ethics Committee. An

ethical framework for donation after confirmation of death using
neurological criteria (DBD) [Internet]. 2016. Available from: http://
www.aomrc.org.uk/wp-content/uploads/2016/07/
Ethical_framework_donation_after_confirmation_death_using_neurologica
l_criteria-2.pdf (accessed 29 November 2016).
13. NHS Blood and Transplant. Approaching the Families of Potential

Organ Donors: Best Practise Guidance [Internet]. 2013. Available from:
http://www.odt.nhs.uk/pdf/family_approach_best_practice_guide.pdf
14. Hulme W, Allen J, Manara AR, et al. Factors influencing the family
consent rate for organ donation in the UK. Anaesth. 2016;71:1053–63.
15. Human Transplantation (Wales) Act 2013 [Internet]. Available from:

http://www.legislation.gov.uk/anaw/2013/5/pdfs/anaw_20130005_en.pdf
16. McKeown DW, Bonser RS, Kellum JA. Management of the heartbeating
brain-dead organ donor. Br J Anaesth. 2012;108:i96–107.
17. Singbartl K, Murugan R, Kaynar AM, et al. Intensivist-led

management of brain-dead donors is associated with an increase in organ
recovery for transplantation. Am J Transplant. 2011;11:1517–21.
18. NHS Blood and Transplant. Donor Optimisation Guideline for

Management of the Brain-Stem Dead Donor [Internet]. 2012. Available
from: http://odt.nhs.uk/pdf/donor_optimisation_guideline.pdf (accessed 29
November 2016).
19. Niemann CU, Feiner J, Swain S, et al. Therapeutic hypothermia in

deceased organ donors and kidney-graft function. N Engl J Med.
2015;373:405–14.
Page 22 of 23

20. Citerio G, Cypel M, Dobb GJ, et al. Organ donation: a critical care
perspective. Intensive Care Med. 2016;42:305–15.
21. Manara A. Bespoke end-of-life decision making in ICU: has the tailor
got the right measurements? Crit Care Med. 2015;43:909–10.
22. Manara AR, Murphy PG, O’Callaghan GO. Donation after circulatory
death. Br J Anaesth. 2012;108:i108–21.
23. Broderick AR, Manara A, Bramhall S, Cartmill M, Gardiner D,

Neuberger J. A donation after circulatory death program has the potential
to increase the number of donors after brain death. Crit Care Med.
2016;44:352–9.
24. Manara A, Gardiner D. Specialised critical care: organ donation. In:

Faculty of Intensive Care Medicine and The Intensive Care Society (eds)
Guidelines for the Provision of Intensive Care Services. London: Faculty
of Intensive Care Medicine and The Intensive Care Society; 2015, pp.
138–41. Available from: https://www.ficm.ac.uk/sites/default/files/
gpics_ed.1.1_-_2016_-_final_with_covers.pdf.
25. UK Parliament. Mental Capacity Act 2005 [Internet]. 2005. Available

from: http://www.legislation.gov.uk/ukpga/2005/9/pdfs/
ukpga_20050009_en.pdf (accessed 29 November 2016).
Page 23 of 23

Index

and Jerry Nolan

DOI: 10.1093/med/
9780198814924.001.0001
Index
Tables, figures and boxes are indicated by t, f and b following the page
number
0.9% saline see normal saline

0.9% Saline versus Plasma-Lyte 148 for ICU fluid Therapy (SPLIT) trial
[link]b
1-deamino-8-d-arginine vasopressin (DDAVP) [link], [link]b
12-lead ECG [link], [link]b, [link]
A
abbreviated Weir equation [link]b
ABC trial [link]b
abdominal CT
acute pancreatitis [link], [link]f
feeding [link]
multiple organ support [link]
sepsis [link]
abdominal ultrasound [link]
abuse [link]b
Academy of Royal Colleges [link]b
N-acetylcysteine [link]b
acquired immune deficiency syndrome (AIDS) [link]b
activated partial thromboplastin time (APTT) [link]b
Page 1 of 47
Index
ACURASYS study [link]b

acute coronary syndrome (ACS) [link]b
Acute Dialysis Quality Initiative [link]b
acute exacerbation of chronic obstructive pulmonary disease (AECOPD)
case history [link]–[link]
causes [link]b
management [link]b
mechanical ventilation [link]b
invasive [link]b
non-invasive [link]b
oxygen therapy [link]b
scoring systems [link]b
acute heart failure [link]–[link]
aetiology investigations and severity assessment investigations [link]b
classification [link]t
clinical examination [link]b
defined [link]b
dilated cardiomyopathy [link]b
early referral to ECMO or VAD centre [link]b
echocardiography [link]b, [link]b
history taking [link]b
IABP-SHOCK II trial [link]b
inotropes [link]b, [link], [link]b, [link]
intra-aortic balloon pump [link], [link]b
laboratory tests [link]t
mechanical devices [link]b, [link]b
myocarditis [link]b
non-invasive ventilation [link]b
pathophysiology [link]b
rate control [link]b
transplantation [link]b
ultrafiltration [link]b
VA ECMO [link]–[link], [link]f, [link]f
acute kidney injury (AKI)
acute-on-chronic liver failure [link]b, [link]b, [link]b
aetiology [link]–[link]
fluid resuscitation [link]b
investigations and treatments [link]b
malignancy [link]
medication schedule changes [link]b
pandemic influenza [link]
sepsis [link]
Acute Kidney Injury Network (AKIN) criteria, renal injury [link]
acute liver failure (ALF) [link]b, [link]t, [link]b
acute lung injury [link]b, [link]b
acute myeloid leukaemia [link]–[link]
acute-on-chronic liver failure (ACLF) [link]–[link]
Page 2 of 47

Index
acute kidney injury [link]b, [link]b

aetiology [link]b
alcohol units, calculation of [link]t
alcohol withdrawal syndrome [link]b
alcoholic hepatitis
definition and diagnosis of [link]b
steroids in [link]b
anticoagulation for RRT [link]b
CANONIC study [link]t, [link]b
clotting dysfunction [link]b
grading [link]t
mortality [link]t
high-volume plasmapheresis [link]b
history [link]b
investigations [link]b, [link]t
molecular adsorbent recirculating system [link]b, [link]t
nutrition [link]b
nutritional deficiencies [link]b
plasma exchange [link]b
portosystemic shunts [link]b
prognostic scores [link]b, [link]t, [link]t, [link]b
STOPAH trial [link]b
transplantation [link]b see also cirrhosis; hepatic encephalopathy
acute-on-chronic respiratory failure [link]–[link]
advance decisions [link]b
best interests of patient [link]b
capacity assessment [link]b
end of life care [link]b
high-flow nasal oxygenation [link]b
Independent Mental Capacity Advocate [link]b
invasive mechanical ventilation [link]b, [link]–[link]b
mechanical ventilation
dyssynchrony [link]b
non-invasive [link]b, [link]b, [link]b
weaning [link]b, [link]b
withdrawal [link]b
treatment limitations [link]b see also acute exacerbation of chronic
obstructive pulmonary disease; chronic obstructive pulmonary disease
acute pancreatitis [link]–[link]
acute kidney injury
investigations and treatments [link]b
KDIGO classification [link]t
antibiotic indications [link]b
causes [link]b
Page 3 of 47

Index
indications for endoscopic or surgical intervention [link]b

initial imaging [link]b
morphine [link]b
nutrition [link]b
revised Atlanta classification [link]b, [link]–[link]
severity assessment [link]b, [link]t
acute respiratory distress syndrome (ARDS) [link]b, [link]
aetiology [link]b
Berlin definition [link]b, [link]t, [link]
burns [link]
diagnosis [link]b
fluid management, conservative approach [link]b
invasive mechanical ventilation [link]b
lung protective strategy [link]b
malignancy [link], [link]b
management [link]
mortality [link]
multi-trauma [link]b
pandemic influenza [link]b, [link], [link]b
rescue therapies
neuromuscular blockade [link]b
prone positioning [link]b
sedation [link]b
sepsis [link]b
acute respiratory failure [link]–[link]
causes [link]b, [link]t
chest CT [link], [link]f
chest X-ray [link]b, [link]f
defined [link]b
fluid management, conservative approach [link]b
key studies [link]b
lung trauma [link]b
management principles [link]b
mechanical ventilation [link]
oxygenation determinants [link]b
sepsis [link]b, [link]b, [link]b
ventilator establishment [link]b, [link]t
weaning from mechanical ventilation [link], [link]b see also acute
respiratory distress syndrome; pneumonia
acute stress disorder (ASD) [link]b
acute traumatic coagulopathy [link]b
adrenaline [link]b, [link]b, [link], [link]
Adults with Incapacity (Scotland) Act 2000 [link]b
advance decisions/statements [link]b
Advisory Committee on Immunization Practices [link]b
AIDS [link]b
Page 4 of 47

Index
airway management, burns patients [link]b

airway pressure release ventilation [link]b
AIRWAYS-2 trial [link]b
AKIN criteria, renal injury [link]
ALBIOS trial [link]b
albumin [link]b, [link]b, [link], [link]b, [link]b
Albumin Italian Outcomes Study (ALBIOS) trial [link]b
alcohol
excess, and acute pancreatitis [link], [link]b
units, calculation of [link]t
withdrawal [link], [link]b, [link]b, [link], [link], [link]b
alcoholic hepatitis (AH) [link]b, [link]
case history [link]
corticosteroids [link]b, [link]
definition [link]b
diagnosis [link]b
liver transplantation [link]b
prognostic scores [link]b
alfentanil
acute respiratory failure [link], [link], [link]
cardiac arrest [link], [link]b
sedation [link]t
sepsis [link]
traumatic brain injury [link]
alpha agonists [link]b, [link]b, [link]t
ALVEOLI study [link]b
American Burn Association [link]b
American College of Chest Physicians [link]b
American Heart Association (AHA) [link]b
American Pain, Agitation, and Delirium Guidelines 2013 [link]
American Society of Anesthesiologists (ASA) [link]b
American Thoracic Society [link]b
amikacin [link], [link], [link], [link]
aminoglycosides [link]b, [link]f
aminophylline [link]
amiodarone [link]
amoxicillin [link]
amphotericin [link]b, [link]b
anaemia [link]b, [link]b, [link]b
anaesthesia
burns [link]b
multiple organ support [link]b, [link]
for procedures [link]b
analgesia
burns [link]b
hepatic veno-occlusive disease [link]b
mechanical ventilation, prolonged [link]
Page 5 of 47

Index
multi-trauma [link]b, [link]b

before painful procedures [link]b, [link]b
sedation and delirium [link]b, [link]b, [link], [link], [link]
sepsis [link]b
subarachnoid haemorrhage [link]
aneurysmal subarachnoid haemorrhage [link]b
cardiac abnormalities [link]b
delayed cerebral ischaemia [link]b, [link]f
digital subtraction angiography [link]f
fluid balance and electrolyte derangements [link]b
management protocol [link]b, [link]f
rebleeding [link]b
treatment [link]b, [link]b, [link]–[link]
coiling vs clipping [link]b
vasospasm [link]b
angiotensin-converting enzyme [link]
angiotensin-converting enzyme (ACE) inhibitors [link], [link]b, [link],
[link]b
anidulafungin [link], [link], [link]b, [link]
anthracyclines [link]b
antibacterials [link]b
antibiotics
acute-on-chronic liver failure [link], [link], [link]b
acute-on-chronic respiratory failure [link]b
acute pancreatitis [link], [link], [link], [link]b
burns [link], [link]b, [link]b
feeding [link], [link]b, [link], [link]b
malignancy [link]b, [link]b, [link]b
case history [link], [link], [link]
resistance [link]
sepsis [link], [link]b, [link], [link]b, [link], [link]b
small intestinal bacterial overgrowth [link]b
stewardship [link], [link]b
streptococcal pneumonia [link]
anticoagulation [link]t, [link]b, [link], [link]b
anticonvulsants [link]b
antidepressants [link]b
antidiuretic hormone (ADH, vasopressin) [link], [link]b, [link], [link]b
antiepileptics [link]b
antifibrinolytics [link]b
antifungals [link], [link]b, [link]b, [link]b
antiplatelets [link], [link]b, [link]b, [link]b
antipsychotics [link]b, [link], [link]b
antivirals [link]b, [link]b, [link]b, [link]t, [link]t, [link]b
Page 6 of 47

Index
apixaban [link]
ARDS Network trial [link]b
arginine vasopressin/argipressin (vasopressin) [link], [link]b, [link], [link]b
ARISE study [link]b
arrhythmogenic right ventricular cardiomyopathy [link]b
ascites [link]b, [link]b
aspergillus infection [link]b, [link]b, [link]b, [link]b
aspirin [link]
Association for Palliative Medicine [link]b
atorvastatin [link]
atovaquone [link]b
atracurium [link], [link], [link], [link]
atrial fibrillation [link]t
auditory evoked potentials [link]b
avian influenza [link]b
Awakening and Breathing Controlled (ABC) trial [link]b
azathioprine [link]
azoles [link]b, [link]b
B
Balthazar score, acute pancreatitis [link]b
barbiturates [link]b
Barnard, Christian [link]b
bed space availability in pandemics [link]b
Behavioural Pain Scale [link]b
Benchmark Evidence from South American Trials: Treatment of
Intracranial Pressure (BEST:TRIP) study [link]b, [link]
bendroflumethiazide [link]b, [link]
benzodiazepines
cardiac arrest [link]b
sedation and delirium [link]b, [link], [link]t, [link]
traumatic brain injury [link]b
ventilation withdrawal [link]b
withdrawal [link]b
benzyl penicillin [link]
BEST Investigators [link]b
BEST:TRIP study [link]b, [link]
beta2 agonists [link]
beta blockers
acute coronary syndrome [link]b
acute heart failure [link]b, [link]b, [link]
burns [link]b
cardiac arrest [link], [link]
beta-d-glucan [link]b, [link]b
beta galactosidofructose [link]b
beta galactosidosorbitol [link]b
beta lactams [link], [link]b
Page 7 of 47

Index
beta-type natriuretic protein (BNP) [link]b

bi-level positive airway pressure (BiPAP) [link]b, [link]b
biomarkers
bacteraemia in febrile neutropenia [link]b
cardiac [link]b, [link], [link]b, [link]
fungal infection [link]b
renal dysfunction in cirrhosis [link]b
sepsis in burns patients [link]b
bisoprolol [link]
bispectral index (BIS) [link]b, [link]b, [link]
blood transfusion
multi-trauma [link], [link]b, [link]
sedation and delirium [link]
subarachnoid haemorrhage [link]b
BODE Index [link]b
body mass index (BMI) [link]b, [link]b
bolus doses [link]b
botulinum toxin poisoning [link]b
brain injury see devastating brain injury; traumatic brain injury
brain parenchymal oxygen tension (PbtO2) [link]b
brainstem death
approaching organ donation with families [link]b
testing [link]b, [link]–[link]
transition from devastating brain injury to [link]b
Brain Trauma Foundation [link]b, [link]
British Thoracic Society [link]b, [link]b
bronchoalveolar lavage [link]b, [link]b
bupivacaine [link], [link]
Burn Operational Delivery Networks (burn ODN) [link]b
burns [link]–[link]
airway management [link]b
altered drug handling [link]b
assessment [link]b
caloric adjustments [link]t
carboxyhaemoglobin values, associated symptoms and signs [link]t
circumferential [link]b
coagulation [link]b
fluid overload [link]b
gastroprotection [link]b
hypermetabolic response [link]–[link]b
hypothermia [link]b
infection [link]b, [link]b
inhalational injury
intubation [link]b
pathology [link]b
Lund and Browder chart [link]f
management [link]b
early debridement [link]b
Page 8 of 47

Index
fluids [link]–[link]b
wound coverage [link]b
mechanical ventilation [link]–[link]b
muscle relaxants [link]b
pain [link]b
pathology [link]b
psychosocial aspects [link]b
referral criteria [link]b, [link]t
sepsis [link]b, [link]b, [link]t, [link]b, [link]
types and clinical features [link]t
upper airway injury and intubation [link]b
vascular access [link]b
Wallace rule of nines [link]f
C
Calcichew D3 forte [link]
calcineurin inhibitors [link]b
caloric requirements, prediction in critical illness [link]b
calorie adjustments for specific patient factors [link]t
CALORIES trial [link]b
cancer see malignancy
Cancer Research UK [link]
Candida spp. infection
catheter-related [link]b
diagnosis [link]b, [link]b
after haematopoietic stem cell transplantation [link]b, [link]b
CANONIC study [link]t, [link]b, [link]b
CAOS [link]b
capacity [link]b, [link]b
carbapenems [link]b, [link]f
carbohydrate requirements [link]b, [link]t
carbon monoxide (CO) poisoning [link], [link]b, [link]
carboxyhaemoglobin (COHb) [link]b, [link]t
cardiac arrest [link]–[link]
best practice guidelines [link]b
coronary angiography timing [link]b
outcomes
classifying [link]b
predicting [link]b
post-cardiac arrest syndrome [link]b
prognostication [link]b, [link]–[link]
algorithm [link]f
biomarkers [link]b
EEG [link]b, [link]–[link]f
evoked potentials [link]b
neuroimaging [link]b
sedation [link]b
Page 9 of 47

Index
seizures [link]b
supraglottic airways [link]b
targeted temperature management [link]–[link]b
therapeutic hypothermia [link]b
induction and maintenance [link]b
side effects [link]b
cardiac arrhythmias [link]t, [link], [link]b
cardiac contusions [link]b
cardiac dysfunction [link]–[link]b
cardiac output
acute heart failure [link]b, [link]b
fluid responsiveness [link]t
multiple organ support [link], [link]b, [link]
sepsis [link]b, [link]b
cardiac resynchronization devices [link]b
cardiac ultrasound [link]
cardiogenic shock [link]b, [link]b
cardiopulmonary resuscitation [link], [link]b, [link]b
care pathways, emergency laparotomy [link]b, [link]b
care standards, pandemics [link]b
caspofungin [link]b, [link]b
CCO [link]b
cefepime [link]f
Centers for Disease Control and Prevention, US [link]b
central venous catheter (CVC)
bloodstream infections [link]b
case history [link], [link]
correct positioning [link]b
ESPEN guidelines [link]b
infection prevention and management [link]b
intravascular complications [link]b
malignancy [link], [link], [link]b
sterile lumen [link]b
venous thromboembolism [link]b
central venous oxygen saturation (ScvO2) [link]b, [link]b
central venous pressure (CVP) [link]t, [link]b
cerebral blood flow [link]b
cerebral microdialysis [link]b
cerebral performance categories (CPCs) [link]b
cerebral perfusion pressure (CPP) [link]b, [link]b, [link], [link], [link],
[link]f
cerebral salt wasting (CSW) [link]b, [link]t, [link]b, [link]b, [link]t
cerebrospinal fluid (CSF) drainage [link]b, [link]f
cerebrovascular pressure reactivity index (PRx) [link]b
cervical spine immobilization [link], [link]b
chest CT
acute pancreatitis [link], [link]f
acute respiratory failure [link], [link]f
Page 10 of 47

Index
acute-on-chronic respiratory failure [link], [link]f

cardiac arrest [link]b, [link]b
malignancy [link], [link]f, [link]b
Pneumocystis jirovecii pneumonia [link]b
chest drains
multi-trauma [link]b, [link]b
sedation and delirium [link], [link]
chest echocardiography [link]b
chest injury [link]b, [link]b, [link]b
chest physiotherapy [link]b
chest ultrasonography [link]b
chest wall deformity, indication for NIV [link]b
chest X-ray (CXR)
acute heart failure [link]
acute-on-chronic respiratory failure [link], [link]f
acute respiratory failure [link]b, [link]f
burns [link]
cardiac arrest [link]
mechanical ventilation [link], [link], [link]f
pandemic influenza [link], [link]f, [link], [link], [link]f
Pneumocystis jirovecii pneumonia [link]b
pneumothorax [link]
sepsis [link], [link]
Child–Turcotte–Pugh score [link], [link]b, [link]t
chlordiazepoxide [link]b
cholecystectomy [link]b
chronic heart failure [link]b, [link]b
chronic kidney injury [link]b
chronic liver disease (CLD) [link]b, [link]b, [link]b see also acute-on-
chronic liver failure
chronic obstructive pulmonary disease (COPD) [link]b
acute respiratory acidosis [link]b
BODE Index [link]b
mechanical ventilation [link]–[link]b, [link]
failure to wean [link]b
invasive [link]b
non-invasive [link]b, [link]b
prolonged [link]b, [link]b
ventilator dyssynchrony [link]b
weaning [link]b
pulmonary embolus [link]b see also acute exacerbation of chronic
obstructive pulmonary disease
chronic respiratory failure
Page 11 of 47

Index
mechanical ventilation [link]b, [link]b, [link]b

metabolic acidosis [link]b
obesity-related [link]b
ciclosporin [link]b
circulatory shock [link]
circumferential burns [link], [link]b
cirrhosis [link]b
case history [link]
diagnosis [link]b
fluids in [link]b
hepatic encephalopathy [link]b
kidneys [link]b
nutrition [link]b
prognostic scores [link]b
sensitivity to opiates and benzodiazepines [link]b
cisatracurium [link]b
citrate [link]b, [link]b
clarithromycin [link], [link], [link], [link], [link]
clazosentan [link]b
CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study [link]t,
[link]b, [link]b
CLIF Consortium Acute Decompensation score (CLIF-C ADs) [link]b
CLIF Consortium Acute on Chronic Liver Failure (CLIF-C ACLF) score
[link]b
CLIF SOFA score [link]b, [link]t
clindamycin–primaquine [link]b
Clinical Effect of the Association of Noninvasive Ventilation and High
Flow Nasal Oxygen Therapy in Resuscitation of Patients with Acute Lung
Injury (FLORALI) study [link]b
Clinical Frailty Scale [link]b
Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) scale
[link]b
clinical pathways [link]b
clinical research, and pandemics [link]
time course [link]f
clonidine [link], [link], [link]b, [link]b, [link], [link]t, [link]
clopidogrel [link]
Clostridium difficile (toxin) infection [link]b, [link]b
clotting dysfunction in liver disease [link]b
coagulation, in burns patients [link]b
coagulopathy, in multi-trauma [link]b
co-amoxiclav [link], [link], [link]
Cochrane reviews
acute-on-chronic respiratory failure [link]b, [link]b
antibiotic prophylaxis in acute pancreatitis [link]
traumatic brain injury [link]b, [link]b
codeine phosphate [link], [link]b
Page 12 of 47

Index
cohorting of patients in pandemics [link]b, [link]b

colloids [link]b
colorectal cancer [link], [link]b, [link]f, [link]
community-acquired pneumonia [link]
aetiology [link]b
epidemiological conditions [link]b
non-resolving [link]b
pathogens [link]b
risk factors [link]b
compression bandages/stockings [link]b, [link]
computed tomography (CT)
acute pancreatitis [link]b
acute-on-chronic liver failure [link], [link]f, [link]
multiple organ support [link]b see also abdominal CT; chest CT; head CT;
neck CT; spinal CT; whole-body CT
computed tomography angiogram (CTA) [link], [link]f, [link]b
Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)
acute respiratory failure [link]
sedation and delirium [link], [link]b, [link], [link], [link]b
worksheet [link]f
congestive heart failure [link]b
consent [link]b
organ donation [link]b, [link], [link], [link]b
influencing factors [link]b, [link]f
opt-out legislation [link]b
pandemics [link], [link]b
continuous positive airway pressure (CPAP) [link]b
acute heart failure [link]b
cardiac dysfunction [link]b
case history [link]
heart failure [link]b
interfaces [link]b
spontaneous breathing trials [link]b
trials [link]b
weaning [link]t
continuous renal replacement therapy (CRRT) [link], [link]b
continuous venovenous haemofiltration (CVVHF)
acute-on-chronic liver failure [link]
acute pancreatitis [link], [link], [link], [link]b
COPD and Asthma Outcome Study (CAOS) [link]b
coronary angiography [link], [link]b
corona viruses [link]b
coroners, and organ donation [link]b
Corticosteroid Randomization After Significant Head injury (CRASH)
trials (CRASH/CRASH-2/CRASH-3) [link]b
corticosteroids
acute-on-chronic liver failure [link], [link], [link]b, [link]
before extubation [link]b
Page 13 of 47

Index
malignancy [link]b, [link]b, [link]b

sepsis [link]b
Corticosteroid Therapy of Septic Shock (CORTICUS) trial [link]b
CORTICUS trial [link]b
co-trimoxazole [link], [link], [link]b, [link], [link], [link]b
cough augmentation [link], [link]b, [link]
CRASH/CRASH-2/CRASH-3 trials [link]b
Creutzfeldt–Jakob disease [link]b
Crohn’s disease [link]
cryptic shock [link]b
Cryptococcus infection [link]b
crystalloids [link]b
acute-on-chronic liver failure [link]b
acute respiratory failure [link], [link]
burns [link]
contraindications [link]b
feeding [link]
multiple organ support [link], [link]
sepsis [link], [link]b
CT severity index, acute pancreatitis [link]b
cyanide poisoning [link]b, [link]b
cytomegalovirus (CMV) [link]b, [link]b
cytosine arabinoside [link]b
D
damage control surgery [link]b
dapsone [link]b
daunorubicin [link]b
DDAVP [link], [link]b
death, diagnosing using neurological criteria [link]b
approaching organ donation with families [link]b
potential donors, identifying and referring [link]b
DECAF score [link]b
decision-specific capacity [link]b
Decompressive Craniectomy (DECRA) trial [link]b
deep vein thrombosis (DVT)
burns [link]b
catheter-related [link]b, [link], [link]b, [link]b
prophylaxis see thromboprophylaxis
defibrotide [link], [link]b
degloving injury [link]
dehydration
multiple organ support [link]b, [link]b, [link]b
sepsis [link]
Page 14 of 47

Index
traumatic brain injury [link]b, [link]t

delayed cerebral ischaemia (DCI) [link]b
causes [link]f
diagnosis [link]b
euvolaemia [link]b
prevention [link]b
temperature control [link]b
treatment [link]b
delirium [link]–[link]
hypoactive [link]b
management [link]b
non-pharmacological [link]b
pharmacological [link]b
mechanical ventilation, prolonged [link], [link]
risk factors [link]t
screening tools [link]b, [link]f
demeclocycline [link]b
DESIRE [link]
desmopressin [link]
devastating brain injury
donation after circulatory death [link]b
pathways [link]–[link], [link]f, [link]b, [link]
transition to brain death [link]b
dexamethasone [link], [link]
dexmedetomidine [link]b, [link], [link]t, [link]
dextrose [link]b, [link]b
diabetes insipidus
organ donation [link]b, [link], [link]b
traumatic brain injury [link], [link]b, [link]f, [link]t
diagnostic testing in pandemics [link]b
diamorphine [link]
diazepam [link], [link], [link]t
dicobalt edetate [link]b
digital subtraction angiography [link]f
dilated cardiomyopathy [link]b, [link]b
disseminated intravascular coagulation [link]b
diuretics
sepsis [link]b, [link], [link]b
diverticulitis [link]
dobutamine [link]b, [link]b, [link]b, [link]b, [link], [link]
donation after brain death (DBD) [link]b, [link]–[link]b, [link]
donor management [link]b, [link]b
Page 15 of 47

Index
donor optimization bundle [link]b, [link]f

pathway [link]t
donation after circulatory death (DCD) [link]b, [link]b, [link]f, [link]
contraindications [link]
pathway [link]t
Donation Ethics Committee, UK [link]b, [link]b
donor coordinator see specialist nurse in organ donation
do not attempt cardiopulmonary resuscitation orders [link]b
dopamine [link]b
Doppler
oesophageal [link]t
transcranial [link], [link], [link]b
doxapram [link]b
doxorubicin [link]b
Duchenne muscular dystrophy [link]b
E
Early Albumin Resuscitation for Sepsis and Septic Shock (EARSS) trial
[link]b
early goal-directed therapy (EGDT), sepsis [link], [link]b, [link]b
Early Parenteral Nutrition Completing Enteral Nutrition in Adult
Critically Ill Patients (EPaNIC) trial [link]b
early warning scores (EWS) [link]b, [link]b
EARSS trial [link]b
Ebola [link]b, [link]b, [link]b
echinocandins [link]b, [link]b, [link]b
echocardiogram
acute heart failure [link], [link]b, [link]b, [link]b, [link]
acute-on-chronic respiratory failure [link]b, [link]
cardiac arrest [link]b, [link]
chest [link]b
fluid responsiveness [link]t, [link]b
multi-trauma [link], [link]b
sepsis [link], [link]b, [link]
subarachnoid haemorrhage [link], [link]b
transthoracic [link], [link]
EDEN trial [link]b
electrocardiogram (ECG)
acute heart failure [link]b, [link]b, [link]
cardiac arrest [link], [link]b, [link]
cyanide poisoning [link]b
subarachnoid haemorrhage [link], [link], [link]b, [link], [link]b
electroencephalogram (EEG), cardiac arrest
case history [link]
prognostication [link]b, [link]–[link]f, [link]–[link]
Page 16 of 47

Index
status epilepticus [link]b

electrolytes, daily maintenance requirement [link], [link]t
emergency laparotomy [link]
cardiac output monitoring [link]b
care pathways [link]b
perioperative [link]b
case histories [link], [link], [link]–[link], [link], [link]
incidence [link]b
National Emergency Laparotomy Audit [link]b
patient outcomes [link]b
postoperative complications [link]b
presentation and clinical findings [link]b
riskiness [link]b, [link]b, [link]b, [link]b
endocardial biopsy [link]b, [link]
end of life care
devastating brain injury [link]–[link]
malignancy [link], [link], [link]b
organ donation [link]
endoscopic retrograde cholangiopancreatography (ERCP) [link]b
endothelin-A antagonists [link]b
enoximone [link]b
enteral nutrition [link], [link], [link]
acute pancreatitis [link], [link], [link]b
burns [link], [link], [link]b, [link]b
commencement [link]t
decision pathway [link]f
EDEN trial [link]b
EPaNIC trial [link]b
gastric acid suppression [link]b
multi-trauma [link]
and non-invasive ventilation [link]b
safety issues [link]b
sepsis [link]
summary guidelines [link]b
TICACOS trial [link]b
Entonox [link]
environmental pollution [link]b
epoprostenol [link]
erythromycin [link], [link]b
erythropoietin [link]b, [link]b
escharotomies [link]b
Page 17 of 47

Index
etanercept [link]b
ethical research practices [link]b
European Medicines Agency [link]b, [link]b
European Organisation for Research and Treatment of Cancer [link]b
European Resuscitation Council (ERC) [link]b, [link], [link]f
European Society of Cardiology [link]b, [link]t
European Society of Intensive Care Medicine (ESICM) [link]b, [link]b,
[link], [link]b, [link], [link]f
European Society of Parenteral and Enteral Nutrition (ESPEN) [link]b
European Study of Therapeutic Hypothermia (32–35°C) for Intracranial
Pressure Reduction after Traumatic Brain Injury (Eurotherm3235) [link]b
euvolaemia [link]b, [link]b, [link]b, [link]b, [link]b
evoked potentials [link]b, [link]
expiratory positive airway pressure (EPAP) [link]b
Expiratory Pressure (Express) study [link]b
extended Glasgow Outcome Scale (eGOS) [link]b, [link]t, [link]b
external ventricular drains (EVDs) [link]b
extracorporeal liver support [link]
extracorporeal membrane oxygenation (ECMO) [link], [link], [link]b
extradural monitors [link]b
extrication of multi-trauma patients [link], [link]b
F
FACTT [link]b
Faculty of Intensive Care Medicine [link]b, [link]
faecal peritonitis [link]
falls [link]b, [link]b
fasudil [link]b
feeding [link]–[link]
calorie adjustments for specific patient factors [link]t
catheter-related ventral venous thrombosis, prevention [link]b
changing focus [link]b
commencement [link]f
fluid and electrolytes [link]b, [link]t
high output stoma, management strategies [link]b
macronutrients [link]b, [link]t
micronutrients [link]b
potential formulations for specific disease states [link]t
refeeding syndrome [link]b
clinical manifestations [link]f
identifying at-risk patients [link]b
managing at-risk patients [link]f
pathophysiology [link]f
Page 18 of 47

Index
requirements
estimation [link]b
prediction [link]b
sepsis [link]b
short bowel syndrome [link]b
multidisciplinary team management [link]f
small intestinal bacterial overgrowth [link]b
venous thromboembolism risk factors [link]t
when, what, and how [link]b see also enteral nutrition; parenteral
nutrition
femur fracture [link]–[link], [link], [link]
fentanyl
burns [link]
feeding [link]
sedation [link], [link]t
ferrous sulphate [link]
fever
acute pancreatitis [link]
malignancy [link]b, [link]b
neutropenic sepsis [link]b
fibula fracture [link]–[link]
flail chest [link]b
FLORALI study [link]b
FloTrac [link]t
flow time corrected (FTc) [link]t
fluconazole [link], [link]b, [link]b
fludrocortisone [link]b, [link]b
fluid, daily maintenance requirement [link], [link]t
fluid challenge
sepsis [link]b, [link]b
fluid management
acute respiratory failure [link]b
burns [link]b, [link], [link]b, [link]b, [link]
conservative approach [link]b
mechanical ventilation weaning [link]b
sepsis [link]
Page 19 of 47

Index
subarachnoid haemorrhage [link], [link]b

fluid responsiveness [link]b, [link]t
fluid resuscitation
feeding [link]
multiple organ support [link]b
sepsis [link]b, [link]b, [link], [link]b, [link], [link]b
Fluids and Catheters Treatment Trial (FACTT) [link]b
FMC chemotherapy [link]
focal metabolism [link]b
fondaparinux [link]
Food and Drug Administration, US [link]b
fraction of inspired oxygen (FiO2) [link]b
PEEP/FiO2 combination [link]b, [link]t
frailty [link], [link]b, [link]
Frank–Starling curve [link]b, [link]b
fresh frozen plasma (FFP) [link]b, [link]b, [link], [link]b
functional residual capacity (FRC) [link]b
fungal infections [link]b, [link], [link]b, [link]b, [link]b
furosemide [link]b, [link], [link]
G
gabapentinoids [link], [link]b
galactomannan antigen [link]b
gallstone pancreatitis [link]b
indications for endoscopic or surgical intervention [link]b
Ranson criteria [link]t
ganciclovir [link]b
gastric acid suppression [link]b
gastroprotection, burns patients [link]b
gelatin [link]b
General Medical Council [link]b, [link]b
gentamicin [link], [link]
giant cell myocarditis [link]–[link], [link]b
Glasgow Alcohol Hepatitis Score (GAHS) [link]t
Glasgow Coma Scale (GCS)
acute-on-chronic liver failure [link]b, [link]b
organ donation [link]b
subarachnoid haemorrhage [link], [link]b, [link], [link]t
traumatic brain injury [link]b, [link]t
Glasgow (Imrie) criteria, acute pancreatitis [link]b, [link]t
Glasgow Outcome Scale (GOS) [link]b, [link]t
glycaemic control [link]b, [link]b
glycopeptides [link]f
goal-directed fluid therapy (GDFT) [link]b
graft-versus-host disease (GvHD) [link]b, [link]b
Page 20 of 47

Index

defibrotide [link]b
fungal infections [link]b
granulocyte-colony stimulating factor (G-CSF) [link], [link]b
Guillain–Barré syndrome [link]b
H
H1N1 pandemic see influenza, pandemic
H2 antagonists [link]b
haematological tumours, patient outcomes [link]b
haematopoietic stem cell transplantation (HSCT) [link]b, [link]
case history [link]
graft-versus-host disease [link]b
haemodiafiltration [link]b
haemodialysis (HD) [link]b
haemodilution [link]b
haemofiltration (HF) [link]b
CVVH see continuous venovenous haemofiltration
haemorrhage control in multi-trauma [link]b
Haldane effect [link]b
haloperidol [link]b
Hartmann’s procedure [link]
Hartmann’s solution [link], [link]b, [link]b
headache [link], [link]b
head CT
cardiac arrest [link]b, [link], [link]b, [link]b
devastating brain injury [link], [link]f
subarachnoid haemorrhage [link], [link]b, [link], [link]f, [link]b
traumatic brain injury [link], [link]b, [link]f, [link]
head injury [link]b see also devastating brain injury; traumatic brain
injury
head MRI [link]b
healthcare workers
organ retrieval team [link]
pandemics [link]b, [link], [link]
research [link]b
surge capacity [link]b, [link]t see also specialist nurse in organ
donation
Health Department, UK [link]b
heart failure
acute see acute heart failure
acute-on-chronic respiratory failure [link]b, [link]b, [link]b
chronic [link]b, [link]b
congestive [link]b
Page 21 of 47

Index
non-invasive ventilation [link]b see also acute heart failure

heart rate (HR) [link]t
heart transplantation [link]b, [link]b
hemiparesis [link]
heparin
acute pancreatitis [link], [link]
burns [link]b
low-molecular-weight [link], [link]b, [link], [link]
renal replacement therapy [link]b
unfractionated [link]b
heparin-induced thrombocytopenia [link]
hepatic dysfunction [link]b
hepatic encephalopathy (HE) [link]b
acute kidney injury [link]b
case history [link]
classification [link]t
common differentials [link]t
diagnosis [link]b
history [link]b
management [link]b
molecular adsorbent recirculating system [link]b, [link]b
hepatic veno-occlusive disease (VOD) [link], [link]b
hepatorenal syndrome (HRS) [link]b, [link]b
type 1: [link], [link]b
type 2: [link]b
high-flow nasal oxygenation (HFNO) [link]b, [link], [link], [link], [link]b
high-volume plasmapheresis [link], [link]b
HIV [link]b, [link]b
homicide [link]b
human immunodeficiency virus [link]b, [link]b
hydrocephalus [link], [link]b, [link]f, [link]b
hydrocortisone
feeding [link]
sepsis [link], [link]b
subarachnoid haemorrhage [link]b, [link]b
hydroxocobalamin [link]b
hydroxyethyl starch (HES) [link]b
hyperactive delirium [link]
hyperammonaemia [link]b, [link]b
hyperbaric oxygen [link]b
hypercapnia [link]b, [link]b
hyperglycaemia [link]b, [link]b, [link]
hyperlactataemia [link]b
hypermetabolic response, burns [link]–[link]b, [link]b, [link]
hypernatraemia [link]b, [link]
hyperosmolar therapy [link]b
hyperoxia [link]b
Page 22 of 47

Index
Hyperoxia and Hypertonic Saline in Patients with Septic Shock

(HYPERS2S) trial [link]b
hyperoxia-induced ventilation/perfusion (V/Q) mismatch [link]b
HYPERS2S trial [link]b
hypertension
passive leg raise [link]b
sepsis [link], [link], [link]b
subarachnoid haemorrhage [link]b, [link]b, [link], [link]b, [link]b, [link]b
hyperthermia
rebound [link]b
hypertonic saline (HS) [link]b, [link], [link]b, [link]b
hyperventilation [link]b
hypervolaemia [link]b, [link]b
hypoactive delirium [link], [link]b
hypocapnia [link]b
hypoglycaemia [link]b, [link]b
hyponatraemia
acute-on-chronic liver failure [link]b, [link]b
burns [link]b
subarachnoid haemorrhage [link], [link]–[link]b, [link]t
hypotension
feeding [link]
malignancy [link]
organ donation [link], [link]b
sepsis [link]b, [link]b, [link]b, [link]b, [link]b, [link]
hypothermia
burns [link]b
sepsis [link]
therapeutic see therapeutic hypothermia
triad of death [link]b
hypotonic saline [link]b
hypovolaemia [link]b, [link], [link]b, [link]b
hypovolaemic shock [link]b
hypoxaemia [link], [link], [link]
hypoxia [link]b, [link]b
hypoxic drive, loss of [link]b
hypoxic hepatitis [link]b
I
IABP-SHOCK II trial [link]b
i-gel [link], [link]b
Page 23 of 47

Index
imipenem [link]
IMPACT model, traumatic brain injury [link]b
Impella [link]b
Independent Mental Capacity Advocates (IMCAs) [link]b
indirect calorimetry [link]b
infection
burns patients [link]b, [link]b, [link]
central venous catheter [link]b
fungal [link]b, [link], [link]b, [link]b, [link]b
pandemic influenza [link]b
Infectious Diseases Society of America (IDSA) [link]b, [link]f
inferior vena cava distensibility/collapsibility index [link]t
inferior vena cava filters [link]b
influenza, pandemic [link]
coordinated response [link]b
diagnostic testing, limitations [link]b
extracorporeal membrane oxygenation [link], [link]b
hospitalized patients, characteristics [link]t
nursing [link]f
presentation [link]b
variability [link]b
surge capacity [link]b, [link]b
treatment
antivirals [link]b, [link]t, [link]t
guidelines [link]b
vaccination [link]b
informed consent [link]b
inhalational injury [link]
case history [link]
intubation [link]b
pathology [link]b
inotropes
acute heart failure [link]b, [link], [link]b, [link]
sepsis [link]b, [link]b, [link], [link]
inspiratory positive airway pressure (IPAP) [link]b
insulin [link], [link], [link], [link]
Integra [link]b
Intensive Care Delirium Screening Checklist (ICDSC) [link]b
Intensive Care National Audit and Research Centre (ICNARC) [link],
[link]b
Intensive Care Society [link]b, [link]b, [link]
intention myoclonus [link]b
intermittent compression devices [link]b, [link], [link]b
International Club of Ascites [link]b
International Forum for Acute Care Trialists [link]b
Page 24 of 47

Index
International Liaison Committee on Resuscitation (ILCOR) [link]b

International Mission for Prognosis and Analysis of Clinical Trials
(IMPACT) [link]b
international normalized ratio (INR) [link]b, [link]
International Severe Acute Respiratory and Emerging Infection
Consortium [link]b
International Subarachnoid Aneurysm Trial (ISAT/ISAT 2) [link]b
intra-aortic balloon pump (IABP) [link], [link]b
Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial
[link]b
intracranial pressure (ICP)
monitoring devices [link]b
sedation [link]b
subarachnoid haemorrhage [link]b, [link]
tiered approach to management of raised [link]b, [link]t
BEST:TRIP study [link]b
case history [link], [link], [link], [link], [link]
guidelines [link]b
hyperthermia [link]b
hyperventilation [link]b
hypothermia [link]b
osmotherapy [link]
waveforms [link]b, [link]f
intraparenchymal monitors [link]b
intravenous immunoglobulin (IVIG) [link]b
invasive aspergillosis [link]b, [link]b, [link]b
invasive ventilation
acute-on-chronic respiratory failure [link], [link]b, [link], [link]
transition to NIV [link]b
weaning [link], [link], [link]–[link]
inverse ratio ventilation [link]b
ipratropium [link]
irbesartan [link]
iron deficiency anaemia [link]b
ISAT/ISAT 2: [link]b
isotonic saline see normal saline
itraconazole [link]b
J
jugular bulb oxygenation saturation (SjvO2) [link]b
K
KDIGO see Kidney Disease: Improving Global Outcomes
ketamine
Page 25 of 47

Index
acute respiratory failure [link], [link]b

burns [link], [link]
multi-trauma [link], [link]b, [link], [link]b
sedation [link], [link]t, [link]
Kidney Disease: Improving Global Outcomes (KDIGO)
classification of acute kidney injury [link], [link]t
renal replacement therapy guidelines [link]b
kidneys
acute injury see acute kidney injury
chronic injury [link]b
cirrhosis [link]b
drug clearance [link]b
transplantation
history [link]b
offering system [link]b
outcomes [link]b, [link]b
King’s College criteria, acute liver failure prognosis [link]b
Klebsiella [link]
kyphosis [link]b
L
lactate [link]b
lactitol [link]b
lactulose [link], [link]b
lansoprazole [link]
laparotomy see emergency laparotomy
laryngoscopy [link], [link]b
lasting power of attorney (LPA) [link]b
Latin American Sepsis Institute [link]b
laxatives [link], [link]b
leadership role in pandemics [link]b
left ventricular failure [link]b
leukaemia, acute myeloid [link]–[link]
levetiracetam [link]b, [link]b, [link]b
levosimendan [link]b, [link]b, [link]b
LiDCO/LiDCO rapid [link]b
LiFe score [link]b
Lille score [link], [link], [link]b, [link]b
Lindegaard ratio [link]b
lipid requirements [link]b, [link]t
lithium [link]b
liver biopsy [link]b
liver failure see acute-on-chronic liver failure
Page 26 of 47

Index
Liver Injury Failure Evaluation score (LiFe) [link]b

liver transplantation [link]
case history [link]
history [link]b
listing and allocation [link]b
molecular adsorbent recirculating system [link]b
organ donation [link], [link]b
long QT syndrome [link]b
loperamide [link]b
lorazepam
sedation and delirium [link], [link]t, [link]
l-ornithine l-aspartate (LOLA) [link], [link]b
LOV study [link]b
low- and middle income countries [link]b, [link]b
low-molecular-weight heparin [link], [link]b, [link], [link]
lumbar drain [link]b
lumbar puncture [link]b, [link]b
Lund and Browder chart [link]b, [link]f
Lung Open Ventilation (LOV) study [link]b
lung protective ventilation strategy [link]b
burns [link]b
key studies [link]b
malignancy [link]
multiple organ support [link], [link], [link]
multi-trauma [link]b, [link]
neuromuscular blockade [link]b
sepsis [link]b, [link]
lung transplantation [link]b, [link]b
lung trauma [link]b
M
macronutrients [link]b, [link]t
Maddrey discriminant function [link], [link]b
magnesium [link]b, [link]b
magnetic resonance imaging (MRI)
head [link]b
neck [link]b
spine [link]b
major trauma centres (MTCs) [link]b, [link]t, [link]b, [link]b
Page 27 of 47

Index
malignancy [link]–[link]
bronchoalveolar lavage [link]b
central venous catheter-related bloodstream infections [link]b
colorectal cancer [link], [link]b, [link]f, [link]
disseminated, as organ donation contraindication [link]b
end of life decision-making [link]b
biomarkers [link]b
phases [link]f
graft-versus-host disease [link]b
haematological and solid organ tumours, outcomes [link]b
haematopoietic stem cell transplantation [link]b
neutropenic sepsis, management [link]b, [link]f
patient selection for ICU care [link]b
Pneumocystis jirovecii pneumonia [link]–[link]b
procalcitonin [link]b
prognostication [link]b, [link]b, [link]
mannitol [link], [link]b
Matriderm [link]b
mean arterial pressure (MAP)
cardiac arrest [link], [link]b, [link], [link]
sepsis [link]b, [link], [link], [link]b, [link]b
mechanical assist devices, acute heart failure [link]b, [link]b
mechanical insufflation–exsufflation (MIE) [link], [link]b, [link]b
mechanical ventilation [link]–[link]
acute-on-chronic respiratory failure [link]–[link]b, [link]b
ventilator dyssynchrony [link]b
acute respiratory distress syndrome [link]
case history [link]
establishment [link]b, [link]t
lung trauma [link]b
weaning [link], [link]b
burns [link]b, [link], [link]–[link]b, [link]
cardiac dysfunction [link]b
chronic respiratory failure [link]b
cough augmentation [link]b
malignancy [link]
phonation [link]b
positive pressure [link]b
Page 28 of 47

Index
prolonged
causes [link]b
prediction [link]b
sedation and delirium [link], [link]b, [link]b, [link], [link], [link]
speaking valves [link]b
ventilator-associated lung injury [link]b
ventilator-associated pneumonia [link], [link]b, [link], [link], [link]
volume-controlled [link]
weaning
failure prediction [link]b
international consensus categorization [link]b
observation charts [link]t, [link]t
simple [link]b
spontaneous breathing trials [link]b
timing [link]t, [link]
withdrawal [link]b see also invasive ventilation; lung protective ventilation
strategy; non-invasive ventilation
media role in pandemics [link]b
Medical Research Council (MRC)
CRASH trial [link]b
sum score [link]b
MELD score [link], [link]b
MENDS [link]
Mental Capacity Act 2005 [link]b, [link]b, [link]
meropenem [link], [link], [link], [link], [link], [link], [link]
Mersey Burns App [link]b
mesalazine [link]
metabolic acidosis [link]b, [link], [link]b, [link]b
metabolic cart [link]b
metaraminol [link]
methotrexate [link]b
methylprednisolone [link], [link]b, [link]b
methylxanthines [link]b
metoclopramide [link], [link]b
metolazone [link]b
metronidazole [link], [link], [link]b
micafungin [link]b, [link]b
microcirculation, in sepsis [link]b
microcytic anaemia [link]b
micronutrients [link]b
midazolam
burns [link]
Middle Eastern respiratory syndrome (MERS) [link]b, [link]b
midline catheter [link]b
Page 29 of 47

Index
milrinone [link]b, [link]b, [link]b

mineralocorticoids [link]b, [link]b
Model for End-stage Liver Disease (MELD) score [link], [link]b
modified Rankin score (mRS) [link]b
molecular adsorbent recirculating system (MARS) [link]b
indications [link]t
morphine
burns [link]
sedation and delirium [link]b, [link], [link]t
case history [link], [link], [link], [link]–[link]
motor neuron disease [link]b
multimodality monitoring (MMM) [link], [link]f
multiple organ support [link]–[link]
consent [link]b
CT scans [link]b
delayed presentation [link]b
emergency laparotomy
cardiac output monitoring [link]b
care pathways [link]b, [link]b
incidence [link]b
National Emergency Laparotomy Audit [link]b
patient outcomes [link]b
return to theatre [link]b
risk [link]b
frailty [link]b
interpretation of observations and blood results [link]b
risk quantification [link]b
sepsis
burden of [link]b
epidemiology [link]b
pre-existing susceptibility to [link]b
surgery [link]b
multi-trauma [link]–[link]
acute traumatic coagulopathy [link]b
analgesia and sedation [link]b, [link]b
blood transfusion [link]b
cardiac contusions [link]b
cervical spine immobilization [link]b
chest trauma [link]b
cyclists’ vulnerability [link]b
extrication [link]b
gut perfusion [link]b
haemorrhage control [link]b
Page 30 of 47

Index
hypothermia [link]b
lung injury [link]b
lung protective ventilation [link]b
major trauma centres [link]b, [link]t, [link]b, [link]b
missed injuries [link]b
needle decompression [link]b
packaging [link]b
pelvic injuries [link]b
rehabilitation [link]b
spinal precautions [link]b
splenic injury [link]b
surgery
tertiary [link]b
timing [link]b
tension pneumothorax [link]b
thoracostomy [link]b
thromboprophylaxis [link]b
tourniquets [link]b
trauma activation team [link]b
whole-body CT [link]b
muscle relaxants, burns patients [link]b
muscular dystrophies [link]b
myasthenia gravis [link]b
mycophenolate mofetil [link]b
myocardial dysfunction, sepsis-induced [link]b
myocarditis [link]b
giant cell [link]–[link], [link]b
VA ECMO referral [link]b
myoclonic status epilepticus [link]b, [link]b
myotonic dystrophy [link]b
N
nasogastric tubes [link]b
National Confidential Enquiry into Patient Outcome and Death (NCEPOD)
[link]b, [link]b
National Early Warning Score (NEWS)
malignancy [link]
sepsis [link]t, [link]b, [link], [link]b, [link]
National Emergency Laparotomy Audit (NELA) [link], [link]b, [link]b,
[link], [link]b
National Health Service (NHS)
Blood and Transplant Department [link]b, [link]b
trauma networks [link]b
National Institute for Health and Care Excellence (NICE)
acute heart failure [link]b, [link]
acute-on-chronic respiratory failure [link]b, [link]b, [link]b
burns [link]b, [link]b
Page 31 of 47

Index

multi-trauma [link]b, [link]b, [link]b
neutropenic sepsis [link]b, [link]f
sepsis [link]b, [link]b, [link]
traumatic brain injury [link]t, [link]t
neck CT [link]b
neck MRI [link]b
needle decompression [link]b, [link]b
Neuroanaesthesia Society of Great Britain and Ireland [link]b
Neurocritical Care Society [link], [link]b, [link]b
neurogenic stunned myocardium (NSM) syndrome [link]b
neuroleptic malignant syndrome [link]b
neuromuscular blockers in early acute respiratory distress syndrome
(ACURASYS study) [link]b
neuromuscular blocking drugs (NMDBs)
acute respiratory failure [link], [link]b, [link]
burns [link]b
sedation and delirium [link], [link]b, [link], [link]b
neuromuscular disease (NMD) [link]b, [link]b, [link]b, [link]b
neuron-specific enolase (NSE) [link]b
neuroprotective agents [link]b
neutropenic sepsis [link], [link]b, [link]f, [link]b, [link]b
nicardipine [link]b
nicotine withdrawal [link], [link]b
nimodipine [link], [link]b, [link]b, [link]b, [link]b
nines, rule of [link]b, [link]f
non-accidental injury (NAI) [link]b
non-invasive ventilation (NIV) [link]
acute heart failure [link], [link]b
AECOPD [link]b
case history [link]–[link], [link], [link], [link]
indications [link]b
interfaces [link]b
nasogastric tubes [link]b
obesity hypoventilation syndrome [link]b
successful initiation [link]b
weaning [link]b
failure prediction [link]b, [link]t
Page 32 of 47

Index
indication in neuromuscular disease and chest wall deformity [link]b

pandemic planning [link]b
selection for [link]b
tracheostomy stoma leak [link]b
transition from invasive ventilation [link]b
non-steroidal anti-inflammatory drugs (NSAIDs) [link]
noradrenaline
cardiac arrest [link]b, [link]
feeding [link]
malignancy [link]
sepsis [link], [link], [link]b, [link]b, [link]b, [link]
subarachnoid haemorrhage [link]b, [link], [link]
normal saline (isotonic saline, 0.9% saline) [link]b
burns [link]
normocapnia [link]b
normothermic regional perfusion, donation after circulatory death [link]b,
[link]f
nutrition see feeding
nutritional deficiencies [link]b
O
obesity
acute hypercapnic respiratory failure [link]b
caloric requirements, prediction in critical illness [link]b
failure to wean [link]b
prolonged [link]b, [link]b
obesity hypoventilation syndrome [link]b
octreotide [link]b, [link]b
oesophageal Doppler monitor (ODM) [link]t
Office for National Statistics [link]b
olanzapine [link]b
omeprazole [link], [link]b
opiates [link]b
opioids
burns [link]b
Page 33 of 47

Index

before painful procedures [link]b
sedation and delirium [link], [link]t
withdrawal [link]b
OPTIME CHF trial [link]b
organ donation [link]–[link]
approaching families [link]–[link]b, [link]f
background [link]b
brainstem death testing [link]b
after circulatory death [link]b, [link]f
guidance [link]b
odds ratio for consent rate [link]b
optimization bundle [link]f
pathways [link]f
physiological support of donor [link]b
register [link], [link]f, [link]b
suitability for [link]b
Organ Donation Taskforce Report [link]b
organ retrieval team [link]
oseltamivir [link], [link], [link], [link], [link]b, [link]t, [link]
osmotherapy [link]b
osmotic demyelination syndrome [link]b, [link]b
oxandrolone [link], [link]b, [link]b
oxazepam [link]b
oxygen therapy
acute-on-chronic respiratory failure [link], [link]b, [link]b
high-flow nasal oxygenation (HFNO) [link]b, [link], [link], [link], [link]b
hyperbaric oxygen [link]b
sepsis [link]b
oxygenation determinants [link]b
P
pabrinex [link]
packaging, in multi-trauma [link]b
pain
assessment [link]b
burns [link]b
scoring [link]b
sedation and delirium [link], [link], [link] see also analgesia
palliative care see end of life care
Page 34 of 47

Index
pancreas transplantation [link], [link], [link]b

pancreatic necrosis [link], [link]f, [link], [link], [link]b
pancreatitis see acute pancreatitis
pancytopenia [link]
pandemic planning [link]–[link]
diagnostic testing, limitations [link]b
infection control [link]b
informed consent [link]b
leadership [link]b
patient cohorting [link]b
personal protective equipment [link]b, [link]f
requirements [link]t
research [link]–[link]b
time course [link]f
surge capacity [link]b
spectrum [link]t
staffing, augmentation strategies [link]t see also influenza, pandemic
papaverine [link]b
paracetamol [link], [link], [link]b
parenteral nutrition [link]
catheter-related ventral venous thrombosis, prevention [link]b
central venous catheter [link]b
correct positioning [link]b
infection prevention and management [link]b
intravascular complications [link]b
commencement [link]t
ESPEN guidelines for venous access [link]b
safety issues [link]b
venous access [link]b
Parkinson’s disease [link]b
Parkland formula [link], [link]b
passive leg raise (PLR) [link]b, [link]b, [link]f
sepsis [link]
Passy-Muir Valve [link]
patient handling, in multi-trauma [link]b
pelvic binders [link]b, [link]b
pelvic injuries [link]–[link], [link]b
and traumatic brain injury [link]b
Page 35 of 47

Index
pentamidine [link]b
percutaneous coronary intervention (PCI) [link], [link]b, [link]
Peres’ height formula [link]b
perfusion indicators [link]b
peripherally inserted central catheter (PICC)
ESPEN guidelines [link]b
venous thromboembolism [link]b
peritoneal dialysis (PD) [link]b
personal protective equipment (PPE) [link]b, [link]f
pandemic influenza [link]b, [link]b, [link]
requirements [link]t
surge capacity [link]b, [link]b
phenylephrine [link]b
phenytoin [link]b, [link]b, [link]b
phonation [link]b, [link]
PiCCO [link]b, [link], [link]
piperacillin–tazobactam (Tazocin)
malignancy [link], [link]
neutropenic sepsis [link]b, [link]f
plasma exchange [link]b
Plasma-Lyte 148: [link]b, [link]
platelets
sepsis [link]b
transfusion [link]b, [link]
Pleth variability index (PVI) [link]t
Pneumocystis jirovecii pneumonia [link]b, [link], [link]–[link]b
pneumonia [link]
aetiology [link]b
burns [link]b
defined [link]b
epidemiological conditions [link]b
investigations [link]b
malignancy [link]
non-resolving [link]b
causes [link]b
diagnostic approach [link]b
pandemics [link]b, [link]b, [link]
pathogens [link]b
Pneumocystis jirovecii [link]b, [link], [link]–[link]b
ventilator-associated [link], [link]b, [link], [link], [link]
pneumothorax
Page 36 of 47

Index

signs and symptoms [link]b
tension [link]b, [link]b
POLAR study [link]b
poliomyelitis [link]
polymerase chain reaction (PCR) [link], [link]b, [link]b, [link]b, [link]b,
[link]
Pompe’s disease [link]b
portosystemic shunts [link]b, [link]b, [link]b
Portsmouth Physiological and Operative Severity Score for the
Enumeration of Mortality and Morbidity (P-POSSUM) [link], [link]b,
[link]b
posaconazole [link]b
positive end-expiratory pressure (PEEP) [link]
positive end-expiratory pressure (PEEP)/FiO2 combination [link]b, [link]t
positive pressure ventilation [link]b
post-cardiac arrest syndrome [link]b, [link]
post-extubation stridor [link]b
postoperative non-invasive ventilation [link]b
post-polio syndrome [link]
post-traumatic stress disorder (PTSD) [link], [link]b
P-POSSUM [link], [link]b, [link]b
prednisolone [link], [link], [link]b, [link]
preoxygenation [link], [link]b
pressure support ventilation [link]–[link], [link]b
procalcitonin (PCT) [link], [link]b, [link]b
ProCESS study [link]b
PRODEX [link]
progesterone [link]b
ProMISe study [link]b
prone positioning [link]b, [link]
prone positioning in severe acute respiratory distress syndrome
(PROSEVA study) [link]b
Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury
(POLAR) [link]b
propofol
acute respiratory failure [link], [link]b, [link], [link]
cardiac arrest [link], [link]b, [link]b
feeding [link]
mechanical ventilation, prolonged [link], [link], [link]
case history [link], [link], [link], [link], [link], [link]
sepsis [link]
traumatic brain injury [link], [link]b
propofol infusion syndrome (PRIS) [link]b, [link], [link]b
propranolol [link], [link]b, [link]b
PROSEVA study [link]b
prostacyclin [link]b, [link]b
Page 37 of 47

Index
protein requirements [link]b, [link]t

proton pump inhibitors (PPIs) [link]b, [link]b
Pseudomonas aeruginosa infection [link]b
Public Health England [link]b
pulmonary artery occlusion pressure (PAOP) [link]t
pulmonary embolism
pandemic influenza [link]b
pulmonary oedema
mechanical ventilation [link], [link]f, [link]b
non-invasive ventilation [link]b
sepsis [link]–[link], [link]b
pulmonary parenchymal injury [link]b
pulse contour cardiac output see PiCCO
pulse pressure variation (PPV) [link]t
pyruvate hydrogenase [link]b
Q
quetiapine [link], [link], [link], [link], [link]b
quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA)
[link]b, [link]b, [link]b, [link]
quinolones [link]b, [link]b
R
radius fracture [link], [link]
ramipril [link]
Ramsay Sedation Scale [link]b, [link]t
Randomised Evaluation of Surgery with Craniectomy for Uncontrollable
Elevation of Intracranial Pressure (RESCUE-ICP) trial [link]b
Ranson criteria, acute pancreatitis [link], [link]b, [link]t
rapid sequence induction [link], [link]b
rapid shallow breathing index (RSBI) [link]b
readiness to wean [link]b
rebound hyperthermia [link]b
recombinant activated protein C [link]b
recreational drugs [link], [link]b
clinical manifestations [link]f
identifying at-risk patients [link]b
managing at-risk patients [link]f
pathophysiology [link]f
rehabilitation
burns [link], [link]
Page 38 of 47

Index
mechanical ventilation [link], [link]

remifentanil [link]b, [link], [link]t
renal replacement therapy (RRT)
anticoagulation [link]b, [link]b
guidelines [link]b
indications [link]b
sepsis [link]b
types [link]b
RESCUE-ICP trial [link]b
research
pandemics [link]
time course [link]f
respiratory failure see acute-on-chronic respiratory failure; acute
respiratory failure; chronic respiratory failure
resting energy expenditure (REE) [link]b
restrictive lung disease [link]b
rib fracture [link]
Richmond Agitation–Sedation Scale (RASS) [link], [link]b, [link]t, [link],
[link], [link], [link], [link]
mechanical ventilation, prolonged [link]
rifaximin [link]b
RIFLE criteria, renal injury [link]
right heart failure [link]b, [link]b, [link]
Riker Sedation–Agitation Scale (SAS) [link]b, [link]t
Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria, renal injury [link]
risk quantification [link]b
Rivers’ EGDT protocol [link]b
road traffic injuries [link]b
case histories
multi-trauma [link]–[link]
traumatic brain injury [link]–[link]
pelvic injuries [link]b
rocuronium [link]
rotation thromboelastometry (ROTEM) [link]b
rule of nines [link]b, [link]f
S
S100 beta [link]b
SAFE trial [link]b, [link]b
Page 39 of 47

Index
salbutamol [link], [link]

saline see hypertonic saline; hypotonic saline; normal saline
Saline versus Albumin Fluid Evaluation (SAFE) trial [link]b, [link]b
sarcopenia [link]b
scoliosis [link], [link]b
Scottish Intercollegiate Guidelines Network (SIGN) [link]t, [link]t
sedation [link]–[link]
acute-on-chronic respiratory failure [link]
anaesthesia [link]b
analgesia [link]b, [link]b
Awakening and Breathing Controlled (ABC) trial [link]b
bolus doses [link]b
burns [link], [link]b
cardiac arrest [link], [link], [link]b, [link], [link]b
feeding [link]
interruptions [link]b, [link], [link]b
light vs deep [link]b, [link]t
prolonged [link], [link]
minimization strategies [link]b
options [link]t
propofol infusion syndrome [link]b
protocols [link]b, [link]b, [link]–[link]
scoring tools [link]b, [link]–[link]t, [link]b, [link]b
Sedation Lightening and Evaluation of A Protocol (SLEAP) trial [link]b
sepsis [link]b, [link]
subarachnoid haemorrhage [link], [link]
after transfer [link]b
traumatic brain injury [link], [link]b
Sedation Lightening and Evaluation of A Protocol (SLEAP) trial [link]b
SEDCOM [link]
seizures [link]b, [link], [link]b, [link]b, [link]b
sepsis [link]–[link]
acute kidney injury [link]
acute-on-chronic liver failure [link]b, [link]b, [link]
acute respiratory failure [link]b, [link]b
burden [link]b
burns [link]b, [link]b, [link]t, [link]b, [link]
defining [link]b, [link]b
emergency laparotomy [link]b
Page 40 of 47

Index
epidemiology [link], [link]b

feeding [link]b, [link]b, [link]b
fluid responsiveness monitoring methods [link]t
fluid resuscitation [link]b, [link]b, [link], [link]b, [link], [link]b
iatrogenic component [link]b
identifying [link]b, [link]b
initial management [link]b
inotropes [link]b, [link]b
malignancy [link]b, [link]b
catheter-related bloodstream infection [link]b
neutropenic [link], [link]b, [link]f, [link]b, [link]b
procalcitonin [link]b
microbiology [link]b
multiple organ support [link]b, [link]b, [link], [link]
National Early Warning Score (NEWS) [link]t, [link]b, [link], [link]b, [link]
neutropenic [link]b, [link]f
passive leg raise [link]b
pathogenesis [link]
pathophysiology [link]–[link]
perfusion and treatment adequacy indicators [link]b
pre-existing susceptibility to [link]b
risk stratification tool [link]t, [link]b
supportive therapies [link]b
treatment difficulties [link]
UK Sepsis Trust clinical toolkit [link]b, [link]f
vasopressors [link]b
Sepsis-3 [link]b, [link]b, [link]b
Sepsis Occurrence in Acutely ill Patients (SOAP) study [link]
Sepsis Six [link]f, [link]b, [link]b
Sepsis Trust [link]b, [link]f, [link]b
septic shock [link]b, [link]b, [link]b
case history [link]
corticosteroids [link]b
fluid resuscitation [link]b, [link]b
lactate [link]b
malignancy [link], [link]b, [link]b
multiple organ support [link]b
vasopressors [link]b
venous blood oxygen saturation [link]b
Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score
[link]b, [link]b, [link]b, [link]b, [link]b
comparison with CLIF SOFA score [link]b, [link]t
severe acute respiratory syndrome (SARS) [link]b, [link]b, [link]b
sevoflurane [link]
short bowel syndrome [link]b
multidisciplinary team management [link]f
Page 41 of 47

Index
sinus bradycardia [link]

SLEAP trial [link]b
small bowel
bacterial overgrowth [link]b
perforations [link]
SOAP study [link]
Society of British Neurological Surgeons [link]b
Society of Critical Care Medicine [link]b, [link]b
sodium chloride see normal saline
sodium nitrate [link]b
sodium thiosulphate [link]b
sodium valproate [link]b
SOFA score [link]b, [link]b, [link]b, [link]b, [link]b
comparison with CLIF SOFA score [link]b, [link]t
solid organ tumours, patient outcomes [link]b
somatosensory evoked potentials (SSEPs) [link]b, [link]
SORT see Surgical Outcome Risk Tool
speaking valves [link], [link]b
specialist nurse in organ donation (SN-OD)
approaching organ donation with families [link]–[link]b, [link]f
case history [link], [link], [link], [link], [link]
suitability for donation [link]b
NICE guidance [link]b
spinal CT [link]b, [link]b, [link]t
spinal injury [link]b
spinal MRI [link]b
spinal precautions, in multi-trauma [link]b
spinal X-ray [link]b, [link]t
spironolactone [link]b, [link]b
splenectomy [link]b
splenic injury [link]–[link], [link]b
SPLIT trial [link]b
spontaneous bacterial peritonitis (SBP) [link], [link], [link]
spontaneous breathing trials (SBTs) [link]b, [link]b, [link]b, [link]b, [link]b
staff see healthcare workers
standards of care, pandemics [link]b
Staphylococcus aureus infection [link]b, [link]b, [link]
statins [link], [link]b, [link], [link]b
status epilepticus [link]b, [link]b, [link]b, [link]b
steroids see corticosteroids
Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial [link]b
STITCH(Trauma) study [link]b
stoma
high output [link]b
tracheostomy leak [link]b
STOPAH trial [link]b
streptococcal pneumonia [link]
stress ulcer prophylaxis [link]b
Page 42 of 47

Index
stroke volume variation (SVV) [link]t

subarachnoid haemorrhage (SAH) [link]–[link]
aetiology [link]b
aneurysms
fluid balance and electrolyte derangements [link]b
management protocol [link]b, [link]f
treatment [link]b
cardiac complications [link]–[link]b
clinical grading [link]b, [link]t
delayed cerebral ischaemia [link]b, [link]f
diagnosis [link]b
early brain injury [link]
euvolaemia [link]b
hydrocephalus [link]b
hyponatraemia [link]–[link]b, [link]t
ICU management principles [link]b
rebleeding [link]b, [link]b
transfer to neuroscience centre [link]b
vasospasm [link]b
suicide [link]b
supraglottic airways [link], [link]b
surge capacity, pandemic planning [link]b
spectrum [link]t
staffing, augmentation strategies [link]t
Surgical Outcomes Risk Tool (SORT) [link], [link]b
emergency laparotomy [link]b
Surgical Trial in Traumatic Intracerebral Haemorrhage
(STITCH[Trauma]) study [link]b
SURVIVE trial [link]b
Surviving Sepsis Campaign (SSC) [link]b, [link]b, [link]b, [link]b, [link]b
central venous oxygen saturation [link]b
fluid resuscitation [link]b
haematopoietic stem cell transplantation [link]b
lactate levels [link]b
parenteral nutrition [link]b
Sepsis Six [link]b
target MAP [link]b
suxamethonium [link], [link]b
Swine Flu Triage study [link]b
Symbicort [link]
synchronized intermittent mandatory ventilation [link], [link]
syndrome of inappropriate antidiuretic hormone secretion (SIADH)
hyponatraemia [link]b, [link]t
subarachnoid haemorrhage [link]b, [link]b, [link]t
systemic inflammatory response (SIR) [link]b, [link]
systemic inflammatory response syndrome (SIRS) [link]b, [link], [link]b,
[link]–[link]
Page 43 of 47

Index
T
tacrolimus [link]b
‘Taking Organ Transplantation to 2020’ strategy [link]b
TandemHeart [link]b
targeted temperature management (TTM) [link]b, [link]b
case history [link]
inducing and maintaining hypothermia [link]b see also therapeutic
hypothermia
Tazocin see piperacillin–tazobactam
teicoplanin [link]
tension pneumothorax [link]b, [link]b
terlipressin [link], [link]
therapeutic hypothermia [link]b
inducing and maintaining hypothermia [link]b
side effects [link]b
thiamine [link], [link]b
thiopentone [link]b, [link]
thoracostomy [link], [link]b, [link]b
thromboelastography [link]b
thromboembolic disease stocking [link]b
thrombolytic agents [link]b
thromboprophylaxis
burns [link]b
catheter-related central venous thrombosis [link]b
sepsis [link]b
tibia fracture [link]–[link]
ticagrelor [link]
Tight Calorie Control Study (TICACOS) [link]b
TOPCAT trial [link]b
tourniquets [link]b
toxic shock syndrome (TSS) [link]b
tracheal intubation
burns [link]b
cardiac arrest [link], [link]b, [link]b, [link]
tracheostomy
acute-on-chronic respiratory failure [link], [link]b
burns [link]b, [link]b
Page 44 of 47

Index

prolonged [link]–[link], [link]
transition from invasive to non-invasive ventilation [link]b
stoma leak [link]b
timing [link]b
TracMan trial [link]b
tramadol [link], [link]
tranexamic acid [link]b, [link], [link]b
transcranial Doppler (TCD) [link], [link], [link]b
transplantation [link]–[link]
background [link]b
results [link]b
waiting list [link]b see also haematopoietic stem cell transplantation;
heart transplantation; kidneys: transplantation; liver transplantation; lung
transplantation; pancreas transplantation
transthoracic echocardiogram [link], [link]
Trauma Audit and Research Network (TARN) [link]b
trauma networks [link]b, [link]t, [link]b
traumatic brain injury (TBI) [link]–[link]
cerebral perfusion pressure [link]b
cervical spine scanning indications [link]t
DECRA trial [link]b
Eurotherm3235 [link]b
focal metabolism monitoring [link]b
hypocapnia/hyperventilation [link]b
ICM+ software [link]f
imaging after [link]b, [link]t
BEST:TRIP trial [link]b, [link]
monitoring devices [link]b
tiered approach to management of raised [link]b, [link]t
waveforms [link]b, [link]f
lesion progression [link]f
mannitol vs hypertonic saline [link]b
multimodality monitoring [link], [link]f
neuroprotective agents [link]b
nutritional support [link]b
osmotherapy [link]b
oxygenation monitoring [link]b
post-traumatic seizures [link]b
primary injury [link]
prognosis [link]b
RESCUE-ICP trial [link]b
scoring systems [link]b, [link]t
secondary injury [link]–[link]
Page 45 of 47

Index
sedation [link]b
sodium [link]b, [link]f, [link]t
spinal clearance in unconscious patient [link]b
STITCH(Trauma) [link]b
surgical management [link]b
systemic complications [link]b
temperature management [link]b
venous thromboembolism prophylaxis [link]b
triad of death [link]b
triage in multi-trauma [link]b, [link]b
tricuspid annular plane systolic excursion (TAPSE) [link]b
trimethoprim–sulfamethoxazole see co-trimoxazole
triple-H therapy [link]b
troponin
acute coronary syndrome [link]b
multi-trauma [link]
subarachnoid haemorrhage [link]
TTM2 study [link]b
tube thoracocentesis [link]b
U
UK Health Department [link]b
UK Intensive Care National Audit & Research Centre [link]
UK Intensive Care Society [link]b, [link]b, [link]
UK Sepsis Trust [link]b, [link]f, [link]b
ulna fracture [link], [link]
ultrafiltration [link]b
ultrasound
abdominal [link]
cardiac [link]
central venous catheter insertion [link]b
chest [link]b
unfractionated heparin [link]b
upper airway injury [link]b
US Centers for Disease Control and Prevention [link]b
US Food and Drug Administration [link]b
V
vancomycin [link], [link], [link]b, [link], [link]
vascular access, burns patients [link]b
vasopressin [link], [link]b, [link], [link]b
vasopressin-2 receptor antagonists [link]b
vasopressors [link]b, [link], [link]b, [link], [link]
Page 46 of 47

Index
vasospasm [link], [link]b, [link]b, [link]b

venoarterial extracorporeal membrane oxygenation (VA ECMO) [link]–
[link], [link]f, [link]b, [link]f, [link]b
weaning [link]
venous blood oxygen saturation (SvO2) [link]b
venous thromboembolism
prophylaxis see thromboprophylaxis
risk factors [link]t see also deep vein thrombosis; pulmonary embolism
ventilator-associated lung injury [link]b
ventilator-associated pneumonia [link], [link]b, [link], [link], [link]
ventilatory support see mechanical ventilation
ventricular assist device [link]b, [link], [link]
ventricular fibrillation (VF) [link]
verapamil [link]b, [link]
volume-controlled ventilation [link]
voriconazole [link]b, [link]b, [link]
W
Wallace rule of nines [link]b, [link]f
warfarin [link]t
Weir equation, abbreviated [link]b
Wernicke’s encephalopathy [link]b
whole-body CT [link], [link]b, [link]b
withdrawal of life-sustaining treatment (WLST) [link]
devastating brain injury pathways [link]b
donation after circulatory death [link]b, [link]–[link]b
families [link]b
subjective decisions [link]b
withdrawal states [link], [link]b, [link]b, [link], [link]
World Federation of Neurosurgical Societies (WFNS) [link], [link]b, [link]t
World Health Organization, Global Outbreak Alert and Response Network
[link]b
X
X-ray see chest X-ray; spinal X-ray
Z
zanamivir [link]t
Page 47 of 47


Challenging Concepts in Critical Care

Uploaded by

Copyright:

Available Formats

Challenging Concepts in Critical Care

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Challenging Concepts in Critical Care

Uploaded by

Copyright:

Available Formats

Foreword

Challenging Concepts in Critical Care:

Publisher: Oxford University Press Print Publication Date: Dec 2019

Author(s): Mervyn Singer

‘Challenging Concepts in Critical Care’ moves away from the traditional

Mervyn Singer MB BS MD FRCP(Lon) FRCP(Edin) FFICM

Professor of Intensive Care Medicine

University College London

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

Challenging Concepts in Critical Care:

Publisher: Oxford University Press Print Publication Date: Dec 2019

Challenging Concepts in Critical Care:

Publisher: Oxford University Press Print Publication Date: Dec 2019

Clinical Director, Professor of Respiratory and Critical Care Medicine,

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

Consultant in Intensive Care and Emergency Medicine, Addenbrooke’s

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

Challenging Concepts in Critical Care:

Publisher: Oxford University Press Print Publication Date: Dec 2019

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

withdrawal of life-sustaining treatment

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

Challenging Concepts in Critical Care:

Publisher: Oxford University Press Print Publication Date: Dec 2019

Author(s): Laith Malhas

Expert commentary by Ron Daniels

A 68-year-old man was brought into the emergency department

On initial assessment in the ED, his lungs were clear on auscultation,

His observations were as follows:

A. Oxygen saturation by pulse oximetry (SpO2) 99% on room air.

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford

Respiratory rate ≤8 9–11 12–20 21–24 ≥25

Oxygen ≤91 92–93 94–95 ≥96

Any extra Yes No

Temperature ≤35.0 35.1–36.0 36.1–38.0 38.1–39.0 ≥39.1

Systolic blood ≤90 91–100 101–110 111–219 ≥220

Heart rate ≤40 41–50 51–90 91–110 111–130 ≥131

A, alert; P, pain; U, unresponsive; V, voice.

Initial management involved placement of an 18-gauge peripheral venous

His results returned at 20:00 and were as follows:

Venous blood gas

PaCO2 (kPa) 6.6 (4.7–6)

PaO2 (kPa) 3.9 (>10)

HCO3− (mmol/L) 18.8 (22–28)

BE (mmol/L) −6.7 (±2)

Lactate (mmol/L) 5.5 (0.5–2)

Full blood count

Plat (×109/L) 118 (150–400)

WCC (×109/L) 18.2 (4–11)

Liver function and clotting

Bili (μmol/L) 8 (3–20)

Alk Phos (U/L) 131 (30–130)

ALT (U/L) 27 (10–40)