Anaesthesiology For Pancreatic Cancer

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com/esps/ World J Gastroenterol 2014 March 7; 20(9): 2304-2320

[email protected] ISSN 1007-9327 (print) ISSN 2219-2840 (online)
doi:10.3748/wjg.v20.i9.2304 © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
TOPIC HIGHLIGHT
WJG 20th Anniversary Special Issues (14): Pancreatic cancer

Anaesthetic perioperative management of patients with
pancreatic cancer
Lesley De Pietri, Roberto Montalti, Bruno Begliomini
Lesley De Pietri, Bruno Begliomini, Division of Anaesthesiol- performance of major gastrointestinal surgeries with
ogy and Intensive Care Unit, Azienda Ospedaliero-Universitaria acceptable morbidity and mortality rates. In this review,
di Modena-Policlinico, 41100 Modena, Italy we sought to provide simple daily recommendations to
Roberto Montalti, Transplantation Surgery, Azienda Os- the clinicians who manage pancreatic surgery patients
pedaliero-Universitaria Ospedali Riuniti di Ancona, 60126
to make their work easier and suggest a joint approach
Modena, Italy
Author contributions: De Pietri L conceived and designed the between surgeons and anaesthesiologists in daily deci-
review; Montalti R drafted the article; Begliomini B revised the sion making.
manuscript.
Correspondence to: Dr, Lesley De Pietri, Division of An- © 2014 Baishideng Publishing Group Co., Limited. All rights
aesthesiology and Intensive Care Unit, Azienda Ospedaliero- reserved.
Universitaria di Modena-Policlinico, No. 71 via del Pozzo, 41100
Modena, Italy. [email protected] Key words: Pancreatic cancer; Pancreatic surgery; Peri-
Telephone: +39-59-4225864 Fax: +39-59-4223765 operative anaesthesia management
Received: October 10, 2013 Revised: January 6, 2014
Accepted: January 20, 2014
Published online: March 7, 2014
Core tip: Currently, the only curative treatment for pan-
creatic cancer is surgical resection. However, this type
of surgery is still burdened by considerable morbidity
due to its complexity and to the type of referred pa-
tients (elderly and with many co-morbidities). We be-
Abstract lieve that anaesthetic management with proper surgical
Pancreatic cancer remains a significant and unresolved approaches can play a key role in the outcome of the
therapeutic challenge. Currently, the only curative patient. Simple perioperative precautions in anaesthetic
treatment for pancreatic cancer is surgical resection. management (patient risk assessment, fluids manage-
Pancreatic surgery represents a technically demand- ment, prevention of surgical site infection, thrombo-
ing major abdominal procedure that can occasionally prophylaxis, intraoperative ventilation, and intensive
lead to a number of pathophysiological alterations re- postoperative management) can help to ensure that
sulting in increased morbidity and mortality. Systemic, these surgical operations are performed with reason-
rather than surgical complications, cause the majority able assurance.
of deaths. Because patients are increasingly referred to
surgery with at advanced ages and because pancreatic
surgery is extremely complex, anaesthesiologists and De Pietri L, Montalti R, Begliomini B. Anaesthetic periopera-
surgeons play a crucial role in preoperative evaluations tive management of patients with pancreatic cancer. World J
and diagnoses for surgical intervention. The anaesthe- Gastroenterol 2014; 20(9): 2304-2320 Available from: URL:
tist plays a key role in perioperative management and http://www.wjgnet.com/1007-9327/full/v20/i9/2304.htm DOI:
can significantly influence patient outcome. To optimise http://dx.doi.org/10.3748/wjg.v20.i9.2304
overall care, patients should be appropriately referred
to tertiary centres, where multidisciplinary teams (sur-
gical, medical, radiation oncologists, gastroenterolo-
gists, interventional radiologists and anaesthetists)
work together and where close cooperation between
INTRODUCTION
surgeons and anaesthesiologists promotes the safe Pancreatic cancer (PC) is the fourth leading cause of
WJG|www.wjgnet.com 2304 March 7, 2014|Volume 20|Issue 9|

De Pietri L et al . Anaesthetic management in pancreatic cancer surgery
Table 1 A schematic representation of the integrated management of perioperative patients undergoing surgery for pancreatic cancer
Preoperative Intraoperative Postoperative

Informed patient consent Combined general and epidural analgesia Early nasogastric tube, catheter and drain
removal
Preoperative risk assessment Prevention of surgical site infection: Early oral nutrition/glycaemic control/goal-
Antimicrobial prophylaxis directed fluid therapy
Avoid hypothermia Pain relief/non-opioid oral analgesia
Glucose control
Evaluation and optimisation of preoperative physical Blood transfusion management Intensive postoperative ambulation and
conditions and medications prevention of venous thromboembolism
Nutritional status Intraoperative fluid management Intensive respiratory rehabilitation
Risk stratification, rationale for thromboprophylaxis, and Optimisation of intraoperative ventilation Intensive postoperative management
recommendations Intraoperative thromboprophylaxis
Modified from Grade et al[10].
cancer-related death in the United States and the sixth in postoperative care, pancreatic surgery remains associated
Europe, with the lowest survival rate for any solid cancer with high morbidity and mortality. Postoperative compli-
worldwide[1]. It is the most lethal type of digestive cancer cations such as primarily pancreatic fistula, haemorrhage,
and exhibits a five year survival rate of 5% with a range abscess, and delayed gastric emptying still occur at a fre-
that is correlated with staging and location. The main quency of 30% to 60%, resulting in a mortality rate of 1%
reason for this extremely poor prognosis is that less than to 5%[11]. For this reason and due to the lethality of the
15% of patients are diagnosed with resectable tumours[2]. pancreatic cancer despite surgical treatment, the patient
Currently, the only curative treatment for PC is surgical re- should be informed about the therapeutic procedure and
section, although even for resectable tumours, cure is still any potential complications or disabilities to facilitate a
rare (5-year survival rate of approximately 15%-20%)[3]. conscious involvement in the decision-making process.
Pancreatic surgery represents a challenging and tech- In the case of patients of advanced age who require
nically demanding major abdominal procedure that occa- pancreatic surgery, formal mental status testing can help
sionally results in a number of pathophysiological altera- determine whether a patient can be considered capable
tions during the early postoperative period that account of making this type of decision.
for increased rates of morbidity and mortality. Dementia is an extreme predictor of poor outcome,
Systemic, rather than surgical complications, cause exhibiting surgical mortality rates that are increased by
the majority of PC-related deaths[4]. More than 80% of 52%[12]. The decision to classify an elderly patient eligible
PCs are diagnosed in patients older than 65 years. Many for surgery cannot exclude preoperative mental status.
PC patients are or have been heavy smokers [5,6], and
nearly 80% of PC patients have either frank diabetes or
Preoperative risk assessment
impaired glucose tolerance[7]; venous thromboembolism
A complete history, physical, laboratory examinations,
remains a major complication of PC[8]. For these reasons,
PC patients who undergo a major abdominal surgery are and an assessment of the surgical risks should be includ-
at increased anaesthesiological risk. In the light of these ed in the preoperative evaluation of an elective surgery.
issues, it is important to refer these patients to centres Currently, the definition of preoperative risk remains
with a high volume of operations where a multidisci- vague and difficult to standardise, as it is influenced by
plinary approach is applied to improve the overall out- many variables attributed to patient- and surgery-specific
come. Moreover, careful patient selection is fundamental. variability[13]. Recently, a variety of scoring systems has
In this setting, the anaesthesiologist plays a crucial been developed, and the Physiologic and Operative Se-
role during preoperative evaluation, which together with verity Score for the Enumeration of Mortality and mor-
a proper surgical approach and a concerted effort with bidity (POSSUM) model by Copeland et al[14] was recog-
medical physicians, radiation oncologists, gastroenter- nised as the most effective for general surgery[15]. This
ologists and interventional radiologists is crucial for a model, which uses scores relating to 12 physiological and
favourable perioperative outcome[9]. Patient outcome can 6 operative variables, was developed to postoperatively
be significantly influenced by anaesthesiological manage- predict 30-d mortality and morbidity. The application of
ment (Table 1), starting with patient stratification and the predictive POSSUM and P-POSSUM (Portsmouth
selection, continuing throughout the surgical operation modification of POSSUM)[16] models to cases of pancre-
and finishing with postoperative care [intensive care unit atic surgery has generated conflicting results. The imple-
(ICU), recommendations for the ward][10]. mentation of this scoring system in the routine practice has
proven to be difficult, and a recent review by Wang et al[17]
has found POSSUM to overpredict postoperative mortal-
PREOPERATIVE MANAGEMENT ity. Despite these limitations, there is still a role for POS-
Informed patient consent SUM as a useful tool in pancreatic surgery. Individual
Despite recent developments in operative technique and POSSUM scores should not preclude pancreatic resec-

tion in clinical practice but might help surgeons modify Prophylactic perioperative β-blockade: In general, car-
expectations of postoperative outcomes[18]. diovascular medication should not be discontinued prior
Due to the limitations of the POSSUM model, more to surgery. In the perioperative setting, β-blockers are not
trials are needed to adequately evaluate this scoring sys- contraindicated in patients with diastolic heart failure and
tem in predicting postoperative mortality for pancreatic should be continued in patients with systolic heart failure.
surgery. However, caution is warranted with the acute adminis-
tration of β-blockers in situations of decompensating
Evaluation and optimisation of preoperative physical systolic heart failure. Nonetheless, given the risk of acute
conditions and medications withdrawal, β-blockade in patients with coronary artery
A growing number of old patients benefits from a surgi- diseases or coronary artery disease risk factors should not
cal procedure[19]. Age is an independent risk factor of be discontinued preoperatively. Rather, perioperatively
postoperative mortality and postoperative complications increasing the dosage of the patient’s β-blockade regimen
and can cause a gradual progressive loss in the biological would most likely be beneficial[28-30].
reserves for maintaining physiological homeostasis un- If a patient who is scheduled for elective pancreatic
der stress. In addition, an increasing number of patients surgery requires a new prescription, it should be started
present with one or more age-related chronic conditions, at least 1 mo prior to the procedure to allow for dose ad-
which further decrease their ability to respond to stress. justment[31,32].
Cardiac and pulmonary diseases are the most frequently
observed co-morbidities that anaesthetists and surgeons Pulmonary risk evaluation: Pulmonary complications
must manage during this complex surgery. such as pneumonia, failure to wean, and postextubation
A complete history of prior medical and surgical respiratory failure represent the second most frequent
conditions and a full medication list are particularly types of postoperative complication following wound
important[20,21]. infection, with an estimated incidence rate ranging from
2.0% to 5.6% following surgery[33,34]. Pulmonary disease
Cardiovascular risk evaluation: Cardiovascular com- increases the risk of postoperative complications, ac-
plications are among the most common and significant counting for 40% of postoperative complications and
postoperative problems in elderly patients. A practical 20% of deaths[35]. Age-related changes, such as increased
guideline for perioperative cardiovascular evaluation for closing volumes and decreased expiratory flow rates can
non-cardiac surgery has been proposed by the American predispose older patients to pulmonary complications.
College of Cardiology and American Heart Association Some postoperative pulmonary complication (PPC)
Task Force[22]. Patients should be assessed using an ap- predictors after pancreatic surgery are summarised in
proach that considers clinical predictors, the risk of the Table 2 (modified from Canet et al[36]).
proposed operation and the functional capacity. Identifying the patients who are at high risk for PPCs,
Ageing is accompanied by increased vascular and ven- can help the anaesthetist to design individually tailored
tricular stiffness, diastolic dysfunction and an increased management approaches[37-39]. Pharmacologic measures
risk of heart failure[23]. Diastolic dysfunction even with for managing these complications are either unavailable
a normal or supranormal ejection fraction might elicit or limited, and as a result, treatments must be based on
a significant effect on the perioperative outcome and physical therapy and respiratory support ventilation.
management of elderly patients[12]. Diastolic dysfunction Finally, the ability to predict PPCs would enable cli-
might significantly affect perioperative haemodynamics, nicians to give patients more precise risk assessments,
response to fluid shifts, anaesthetic drugs and other peri- thereby facilitating their decision making.
operative medications.
Patients with cardiovascular diseases are sensitive to Nutritional status and mechanical bowel preparation
haemodynamic instability and often require increased The prevalence of malnutrition is high in patients who
filling pressures to generate an adequate cardiac output. are submitted for surgery and ranges from 35% to almost
The anaesthetist must carefully manage fluids during the 60%[40]. Malnutrition has been consistently associated
operation to avoid overload or rapid volume administra- with impaired immunity[41] and can lead to increased
tion. Moreover, the anaesthetist must maintain a normal complications, such as pressure ulcers, delayed wound
haemoglobin value (Nair et al[24] demonstrated that anae- healing, increased risk of infections, impaired muscular
mia was strongly associated with diastolic dysfunction in and respiratory functions[42], as well as increased mortality
patients with coronary artery disease) and, if possible, and poor clinical outcomes.
must choose volatile anaesthetics that appear to improve Nutritional status should be determined because nu-
diastolic parameters (in contrast to propofol, which elicits tritional deficiencies are common in patients who have
the opposite effect) as measured by echocardiography[25]. undergone pancreatic resection for malignant tumours.
Thoracic epidural analgesia should be strongly suggested, Because malnutrition is potentially reversible with ap-
not only for pain management and for decreasing respi- propriate nutritional support, the early identification of
ratory complications but also because its use appears to high-risk patients is crucial, and preoperative malnutrition
improve cardiac function by improving the diastolic char- screening is required to identify and to treat the malnutri-
acteristics of the left ventricle[26,27]. tion[43]. Recently, the routine screening of patients to iden-

Table 2 Perioperative clinical predictors of postoperative

from clinical practice in pancreatic surgery. A recent
pulmonary complication in pancreatic oncological surgery review examined and compared the application of FT
protocols with standard care in elective liver and pancre-
Patient-related factors Surgery-related factors Preoperative testing- atic surgeries, showing that FT programmes can enhance
related factors
post-operative recovery and reduce the length of hospital
Congestive heart failure Abdominal surgery Serum albumin stays with no increase in adverse events, such as re-admis-
concentration
sions, morbidity or mortality[53,54]. The avoidance of MBP,
< 2.5 g/dL
ASA score > 2 Surgery duration > 3 h Anaemia together with other measures including the application
(Hb < 10 g/dL) of epidural analgesia, the prevention of intra-operative
Age > 65 yr General anaesthesia Low SpO2 hypothermia, fluid restriction, post-operative nutritional
Chronic obstructive Transfusions Chest X ray care and early mobilisation, collectively represent essential
pulmonary disease
Functional dependence Prolonged hospitalisation
elements of a FT programme that is warranted for com-
Weight loss plex surgical operations such as pancreatic resection[55,56].
Impaired sensorium In our experience FT programmes for hepatopancreatic
Cigarette smoking resections appear to be safe and associated with a reduc-
Respiratory infections
tion in the length of hospital stays.
within the past month
Modified from Canet et al[36]. ASA: American Society of Anesthesiologists.

Risk stratification, rationale for thromboprophylaxis,
and recommendations
In patients undergoing general and abdominal-pelvic
tify risk of malnutrition has been recommended by many surgery, the risk of venous thromboembolism (VTE)
national, international, and specialist organisations[44,45]. varies depending on both patient- and procedure-specific
The malnutrition universal screening tool (MUST) for factors[57]. Pancreatic cancer is among the most common
adults was recently validated by several studies, which malignancies associated with thrombosis, as it occurs in
have demonstrated that as a screening procedure, MUST 50% of total patients[58]. Prophylaxis against postopera-
is rapid and easy to use[46,47]. tive venous thromboembolism should be tailored to the
The MUST appears to be a valid and easy screening patient’s level of risk. A model (the Caprini score) that
tool for pancreatic surgery[20], which can identify patients can potentially be used for such purposes estimates VTE
at high risk for major complications and death. Further- risk by adding points for various VTE risk factors[59].
more, the MUST can prompt the implementation of ef- Pharmacological prophylaxis reduces the risk of pul-
fective nutritional interventions to reduce poor outcomes monary embolism by 75% in general surgical patients and
and thereby optimise the use of postoperative critical by 57% in medical patients[60]. The use of low-molecular-
care beds and hospital resources. weight heparins (LMWHs) to prevent thrombotic events in
As soon as malnutrition is recognised, preoperative these patients is a common and well-documented practice.
nutritional supplements should be provided when possi- Current recommendations strongly advise effective
ble. This supplementation can include high-energy foods, and preventive strategies for all hospitalised patients who
vitamins, enteral feedings, or, if necessary, total parenteral are defined as moderate to high risk for VTE and are
nutrition. awaiting pancreatic surgery.
LMWHs appear to be effective and are potentially
Mechanical bowel preparation associated with a lower risk of bleeding when the first
“Enhanced recovery” or “fast-track” (FT) programmes, dose is administered 12 h preoperatively[57,61]. We recom-
which were first developed by Kehlet[48], are structured mend the administration of LMWH from the day prior
interdisciplinary strategies that have been introduced to surgery to all patients scheduled for pancreatic cancer
to optimise peri-operative care and to accelerate post- surgery.
operative recovery[49]. A major intervention principle of In the case of patients who are receiving anticoagu-
this approach is the avoidance of preoperative mechani- lants or antiplatelet therapy and require an elective sur-
cal bowel preparation (MBP), which has been employed gery or procedure, the actual guidelines addressing their
as a preventative measure in gastrointestinal surgery for management are underlined in Table 3 and are modified
more than a century as an essential factor for avoiding from Douketis et al[62].
infectious complications and anastomotic dehiscence. FT
programmes, which exclude MBP, have been proposed
more often in other surgical fields (elective colorectal, INTRAOPERATIVE MANAGEMENT
gastro-oesophageal and aortic surgery) and rarely have Combined general and epidural anaesthesia
been applied to liver and pancreatic surgery[50]. The appli- The use of thoracic epidurals is widespread for intraop-
cation of MBP in this type of surgery has been evaluated erative and postoperative analgesia. Thoracic epidural
by limited studies (a retrospective case-control study by anaesthesia (TEA) reduces sympathetic activity, thereby
the Jefferson University[51] and a review by Salvia et al[52]), influencing the perioperative function of vital organ sys-
which have shown that it did not improve perioperative tems. Thoracic epidural anaesthesia has been used widely
outcomes. At our institution, MBP has been excluded to provide excellent pain relief, to attenuate the catabolic

Table 3 Guidelines on the prophylaxis of venous thromboembolism and antiplatelet and anticoagulant management adjusted
according to recent guidelines
In patients receiving bridging anticoagulation with a therapeutic-dose Ⅳ of unfractionated heparin, treatment is recommended to be stopped no later
than at 4 to 6 h prior to surgery
In patients receiving bridging anticoagulation with a therapeutic-dose of LMWH, the last preoperative dose of LMWH is recommended to be
administered at approximately 24 h prior to surgery instead of at 12 h prior to surgery
In patients receiving bridging anticoagulation with a therapeutic-dose of LMWH and are undergoing high-bleeding-risk surgery, resumption of the
therapeutic dose of LMWH is recommended at 48 to 72 h after surgery instead of within 24 h following surgery
In moderate-to-high-risk patients receiving acetylsalicylic acid who require non-cardiac surgery, treatment with acetylsalicylic acid is recommended to be
continued around the time of surgery instead of discontinued at 7 to 10 d prior to surgery
In patients with a coronary stent who require surgery, deferment of surgery is recommended at 6 wk or 6 mo after the placement of a bare-metal or drug-
eluting stent, respectively, instead of initiating surgery during these time periods
In patients requiring surgery within 6 wk or 6 mo of the placement of a bare-metal or drug-eluting stent, respectively, continuing perioperative
antiplatelet therapy is recommended instead of stopping therapy at 7 to 10 d prior to surgery
Modified from Douketis et al[62]. LMWHs: Low-molecular-weight heparins.
response to abdominal surgery, to lower the incidence of role in the prevention of surgical site infections by en-
pulmonary morbidity, to decrease the cardiac metabolic suring the administration of appropriate antimicrobial
demand, to reduce the risk of thromboembolic compli- prophylaxis[73,74].
cations, to promote the recovery of intestinal function Current recommendations state that the infusion of
and to minimise motor blockade[63,64]. Moreover, epidural the first dose of drug should begin within 30-60 min of
anaesthesia and mild hypercapnia have been shown to incision. This period can be lengthened to 120 min for
increase subcutaneous tissue oxygenation[65]. drugs such as vancomycin, where high infusion rates
The combination of general anaesthesia and thoracic have been associated with complications[75]. The drugs
epidural anaesthesia has become the technique of choice used should be defined in advance for each interven-
at many institutions for major abdominal surgery[66,67]. tion, including alternatives in the event that the patient
Recent studies have suggested that for some types of presents with any contraindication for the frontline anti-
cancer, TEA might also reduce the rate of recurrence af- biotics. The determination of the ideal preoperative an-
ter surgical resection. The possibility of reducing tumour tibiotic therapy for a patient who is awaiting pancreatic
recurrence makes the combination of general anaesthesia surgery requires efforts by a multidisciplinary team (an-
and TEA even more appealing, despite the existence of aesthesiologist, surgeon and microbiologist). A proper
certain contraindications[68,69]. and effective antimicrobial prophylaxis should be based
TEA represents a powerful tool that is available to upon the application of a standard protocol and quality
anaesthesiologists for perioperative intervention in pan- management[76].
creatic surgery. At our University Medical Centre, we Concerning the duration and dosage of prophylaxis,
strongly address its use in the context of multimodal the guidelines generally recommended a single standard
intervention. intravenous therapeutic dose of antibiotic in the majority
of procedures. Repeated doses have only been indicated
Prevention of surgical site infection in special circumstances such as prolonged surgery with a
Surgical site infections continue to represent a substantial duration longer than the half-life of the antibiotic used or
source of morbidity and mortality in the surgical patient cases of major blood loss. This recommendation is based
population. They are the second most common cause of on published evidence, which suggested that the admin-
nosocomial infection after urinary tract infections and istration of short-duration prophylaxis is equally effective
account for approximately 17% of all hospital-acquired as longer-duration prophylaxis in the prevention of surgi-
infections[70]. cal site infections[77,78]. It is advisable to administer at least
Increasing evidence indicates that anaesthesiologists two antibiotic doses during pancreatic surgery.
play a prominent role in the prevention of surgical site
infections. Anaesthesiologists are involved in the adminis- Avoid hypothermia
tration of antibiotics, in the use of supplemental oxygen, Mild perioperative hypothermia (core body temperature
in the maintenance of normothermia and normoglycae- 34-36 ℃) is commonly observed in surgical patients. The
mia, in the perioperative fluid management and in the complications of mild perioperative hypothermia have
administration of blood transfusions[71,72]. Therefore, been studied extensively and include increased duration
decreasing surgical site infections depends on the optimi- of hospitalisation, increased intraoperative blood loss
sation of some perioperative conditions, which are gener- and transfusion requirements, increased adverse cardiac
ally controlled by anaesthesiologists. events, and an increase in patient thermal discomfort in
the recovery room[79,80]. The effects of mild hypothermia
Antimicrobial prophylaxis on surgical site infections have also been studied. The
The anaesthesiologist can play a simple but effective major relation between hypothermia and increased surgi-

cal site infections is thought to be a decrease in subcuta- concentrations are greater than 100 g/L, they confer
neous tissue perfusion mediated by vasoconstriction[81,82]. benefit when the haemoglobin concentrations are less
The reduced oxygenation of the wound is responsible than 60-70 g/L. Studies that have described transfusion
for reduced oxidative killing elicited by neutrophils and management in Jehovah’s witnesses have shown that
for the reduced production of superoxide radicals for any morbidity and mortality only increase postoperatively for
given oxygen tension[80]. each gram of decrement when the haemoglobin concen-
Intraoperative core temperature monitoring (oe- tration is less than 70 g/L[93]. Patients with cardiovascular
sophageal temperature probe) and adequate control of diseases exhibit a significantly increased rate of post-
body temperature are essential during pancreatic cancer operative mortality, and for this reason, the transfusion
surgery[83]. Heat loss during the first hour of anaesthesia trigger should be different for patients with or without
is generally a result of the redistribution of core-to-pe- cardiovascular disease[94,95]. Although multiple trials have
ripheral temperature gradients caused by an anaesthetic- assessed the effects of transfusion thresholds on pa-
induced decrease in vasoconstriction. The exposure of tient outcome, the literature is insufficient for defining
the large bowel, significant amounts of fluids adminis- a transfusion trigger in surgical patients with substantial
tered, and long surgical procedures represent other causes blood loss. In the light of recent findings, the transfu-
of intraoperative hypothermia. Actively pre-warming sion management of surgical patients should be patient
patients for 2 h prior to the induction of either general or specific and should not be based on arbitrary laboratory
regional anaesthesia[80] using forced-air warming blankets values but guided by patient covariables[96-99]. As under-
together with fluid-warming systems represents an im- lined by the recent guidelines on perioperative bleeding
portant way to keep patients normothermic[84]. management of the European Society of Anaesthesiolo-
gy, we suggest a target haemoglobin concentration of 7-9
Glucose control g/dL and the guidance of transfusions based on levels
Hyperglycaemia is associated with an increased risk of of serum lactate, base deficit, and central venous oxygen
morbidity and mortality[85]. Several studies have shown saturation[100].
the negative effects of hyperglycaemic phases during
hospitalisation on the rate of nosocomial infections, Intraoperative fluid management
length of hospital stay and mortality[71,86]. In a recent trial, Optimal perioperative fluid management remains highly
the use of insulin infusions to maintain serum glucose at challenging, particularly in patients undergoing major ab-
less than 110 mg/dL in critically ill patients decreased the dominal surgery[101-103]. Perioperative physicians generally
mortality rate from 8.0% to 4.6%, regardless of diabetic administer intravenous fluids to replace fasting deficits,
status[87]. In subsequent studies, the concept of intensive third space losses, and blood loss to maintain adequate
glucose control was modified towards less-extreme blood cardiac output, blood pressure, and urine output.
glucose levels because of dangerous hypoglycaemic epi- Fluid excess can have a negative impact on cardiac,
sodes that were attributable for worse patients outcomes pulmonary, bowel function and wound healing, predis-
than that originally reported[88,89]. Intraoperative glucose posing the patient to tissue oedema and anastomotic
control should be a standard practice during long and breakdown[104,105]. In contrast, excessive fluid restriction
complex surgical procedures to reduce perioperative can expose the patient to hypovolaemia and hypoperfu-
complications. sion[106]. Surgery causes inflammation and a correspond-
The optimal glucose level during the periopera- ing release of mediators that can induce local tissue oede-
tive period has not been prospectively investigated, and ma[107]. Anaesthetists generally manage perioperative fluid
the available data from recent reports do not indicate a administration by using unmonitored fixed fluid regimens
specific threshold for the treatment of hyperglycaemia. and estimating fluid loss.
There is some evidence that keeping glucose levels within In recent years, restrictive fluid management has re-
a range of 110-180 mg/dL and not limiting the treatment placed this approach, and the concept of fast-track sur-
to values higher than 200 mg/dL is safe and appropriate. gery has challenged the traditional administration of large
It is important not only to limit glucose control dur- amounts of fluids during surgery[108,109].
ing the intraoperative period but also to continue insulin These findings have prompted fervent discussion on
infusion during the postoperative period. The frequent how liberal or restrictive perioperative fluid management
and precise measurement of glycaemia must become a should be applied, and several randomised controlled trial
standard of pancreatic cancer patient management both have attempted to settle this issue[104,108,110,111].
during surgical procedures as well as during the postop- Due to the lack of consensus on the optimal imple-
erative period[90]. mentation of fluid management, a new and more precise
approach based on goal-directed fluid therapy and indi-
Blood transfusion management vidualised fluid administration has been developed[103].
Several published studies have demonstrated how blood Goal-directed fluid optimisation has markedly increased
product transfusions increase the postoperative risk of tissue oxygen tension and microcirculatory perfusion in
infection[91,92]. both healthy and perianastomotic tissues compared to
Published guidelines generally concur that although the restricted fluid strategy[106,112,113].
transfusions are not beneficial when the haemoglobin Central venous pressure (CVP) remains the most

widely used clinical marker of volume status, despite nu-

merous studies indicating no association between CVP Optimisation of intraoperative ventilation
and circulating blood volume[114]. Because of this limi- Postoperative pulmonary complications following major
tation, central venous and pulmonary artery occlusion upper abdominal surgery increase morbidity, mortality,
pressures, which are the only variables for guided fluid the length of hospital stay and costs[33]. Reduced lung in-
therapy and optimised preload, are not recommended. flation represents one of the basic mechanisms of post-
Dynamic parameters such as stroke volume variation operative pulmonary complications. The adjustment of
or pulse pressure variation provide a more favourable the body positioning from upright to supine itself can re-
prediction of fluid responsiveness. Individualised goal- duce the resting lung volume by approximately 0.8-1.0[126].
directed fluid therapy, particularly oesophageal Doppler- The additive effect of supine positioning, general anaes-
guided fluid optimisation, has been shown to improve thesia, and abdominal incisions significantly reduces func-
patient outcomes and to reduce the length of hospital tional residual capacity and increases airway resistance.
stays compared with conventional fluid replacement[115]. In addition, during the induction of anaesthesia, most of
Doppler-guided fluid boluses appear to improve clinical the general anaesthetics further reduce functional residual
outcomes, particularly in elderly and frail patients[116,117]. capacity. The combination of these effects predisposes
This method, however, cannot be universally performed patients to atelectasis with the risks of hypoxemia and
for practical and financial reasons[118]. infection. Additionally, postoperative pain and the use of
Using a “goal-directed” approach, it is generally pos- analgesics can contribute to a reduced tidal volume and
sible to replace lost plasma, whereas the extracellular impaired clearing of secretions, depending on adequate
compartment cannot currently be monitored. Therefore, coughing and deep breathing[126,127].
losses from the latter should be replaced based on the Mechanical ventilation is mandatory in patients un-
protocol suggested by Chappell et al[101], which involves dergoing general anaesthesia. High tidal volumes can
the substitution of insensible perspiration with 1 mL/kg overdistend non-injured lungs, particularly in non-de-
per hour during abdominal surgery and does not include pendent lung tissues. The non-aerated atelectatic lung re-
the possibility of primary fluid consumption by the third gions are prone to repeated collapse and re-expansion of
space, the existence of which is denied[119]. the alveoli, causing shear stress and diffuse mechanical
The optimal solution for volume replacement and damage of the alveoli. During surgical procedures, both
optimisation remains an ongoing issue of heated debate. phenomena can induce stress in non-injured lung tissues,
The goal of perioperative fluid management is to main- triggering local inflammation[128,129]. Retrospective and
tain fluid balance and to minimise the possible risks by prospective studies have shown the potential beneficial
choosing the right fluid at the right time. effects of reduced tidal volumes in patients who are on
Colloids are criticised because of their ability to dif- short-term mechanical ventilation following surgery[130].
fuse into the interstitium, making further extravasation Protective mechanical ventilation using reduced tidal
more likely[120], because of the cumulative and persistent volumes can accordingly reduce ventilator-associated
effects related to their infusion[121] and, finally, because of lung injury. The application of positive end expiratory
safety concerns. Recent studies of the potential increase pressure (PEEP) can prevent alveolar collapse and atel-
in the risk of bleeding and acute kidney injury following ectasis formation, and recruitment manoeuvres can sup-
the application of various colloids have shown that the port the beneficial effects of PEEP during short-term
use of hydroxyethyl starch appears to be associated with ventilation[131]. Effective anaesthesiological management
an increased need for dialysis[122] and might even increase during pancreatic surgery should involve the application
mortality in patients with sepsis[123]. of a protective ventilation strategy (lower tidal volumes
Current evidence suggests that beyond fluid compo- < 8 mL/kg, PEEP = 6-12 mmHg and recruitment ma-
sition, the timing and volume of the administered fluid noeuvres) to improve respiratory function during the
represent two additional factors that are likely to influ- postoperative period following abdominal surgery and to
ence perioperative patient outcome. For patients with reduce the clinical signs of pulmonary infection during
mild-to-moderate volume deficits, crystalloids are still the the postoperative period[132].
first choice. In the case of severe volume depletion, we
recommend starting fluid resuscitation with a colloid to Intraoperative thromboprophylaxis
rapidly reverse volume deficits and ensure oxygenation The use of LMWHs to prevent thrombotic events in
and then to switch to crystalloids once the patient ap- these patients represents a common and well-document-
proaches euvolaemia. ed practice. Effective pharmacological thromboprophy-
Goal-directed fluid management enables appropriate laxis includes the administration of LMWH from the day
use of fluids, vasopressors, and inotropes, and results in prior to the surgery. In addition to this useful approach
improved outcomes. The vasodilatatory effect of anaes- mechanical prophylaxis including graduated compres-
thetic cannot be ignored and must be expected to termi- sion stockings and intermittent pneumatic compression
nate at the end of surgery. Treating vasodilatation with is highly recommended during the surgical operation and
crystalloids or colloids can be a mistake in all euvolaemic during the postoperative period until the risk of bleeding
patient, whereas vasopressor infusion during surgical op- has diminished and the application of new pharmaco-
eration can help in avoiding excessive fluid overload[124,125]. logical prophylaxis might be initiated[57,60].

Thromboelastography can play a potential role, de- of delayed gastric emptying and earlier bowel activity.
spite its limitations, as a valuable tool for the evaluation Given the risk of pulmonary complications, significant
of the entire perioperative coagulation process and hy- patient discomfort and lack of benefit associated with
percoagulability changes, as well as for increasing patient prophylactic nasogastric tube aspiration, this practice
safety through more effective management of antithrom- should not be routinely used[139,140].
botic therapy[133,134]. Consistent with a recent study, in our daily practice,
we remove nasogastric tubes on postoperative day 1 only
if the tube drainage amount is less than 300 mL or at the
POSTOPERATIVE MANAGEMENT end of surgery in cases of distal pancreatectomy which
Over the past 20 years, surgery and anaesthesia for pa- makes delayed gastric emptying less frequent[52].
tients undergoing abdominal surgery have undergone
immense development. A novel concept of periopera- Abdominal drains: The presence of an abdominal drain
tive patient care following surgical abdominal procedures represents a significant impediment to achieving early and
has emerged. Fast track programmes, a new concept of appropriate levels of mobilisation. Several randomised
enhanced recovery after surgery and the implementation trials have not found any benefit of prophylactic drains
of multimodal rehabilitation, have heavily influenced this after surgical operations, such as cholecystectomy[141],
modern change, optimising perioperative care, accelerat- colorectal surgery[142] or hepatectomy[143]. Rather, these
ing recovery and reducing hospital stays and costs. The prospective randomised studies found that routine drain-
objective of this integrated approach between surgeon, age resulted in an increased frequency of complications
anaesthetist, nurses and physiotherapist is to reduce the and no difference in outcome.
impact of surgery on patient homeostasis. The main pil- Because pancreatic surgery is associated with high
lars of this new management are those shared by fast rates of morbidity, the purpose of prophylactic drainage
track surgery and can be summarised as follows: (1) re- is to prevent fluid collection and to aid in the early de-
duction of surgical invasiveness (early removal of drains, tection of anastomotic leak and associated haemorrhage.
nasogastric tube, small incisions, pharmacological stimu- Following pancreatectomy, the use of a prophylactic
lation of the gut); (2) pain relief/non-opioid oral anal- drain is supported by the belief that the early detection
gesia; (3) early oral nutrition/goal-directed fluid therapy; of pancreatic fistulae through the measurement of amy-
(4) intensive postoperative ambulation and prevention of lase in the draining fluid will allow for the efficient man-
venous thromboembolism; and (5) intensive respiratory agement and the avoidance of major complications[144].
rehabilitation. Despite reports of randomised, control trials and cohort
All of these basic points, combined with the preven- studies that do not support the use of drains, most sur-
tion of intraoperative hypothermia, neural blockades[135], geons routinely place prophylactic intraperitoneal drains
maintenance of euglycaemia, and the development of at the time of pancreatic resections[145,146]. Evidence-
goal-directed fluid therapy contribute to the reduction of based practice guidelines for drain management during
surgical stress. pancreatectomy remain to be established despite the
A systematic review of the literature regarding peri- remarkable number of studies that are available to help
operative care in pancreatic cancer surgery has revealed guide practice.
a limited number of studies providing low levels of evi- At our University Hospital, abandoning drainage dur-
dence[50,54,136]. Despite their potential weaknesses, the stud- ing pancreatic surgery is believed to be unsafe, and ac-
ies detailed above have demonstrated that implementa- cording to Kaminsky et al[146], it is reasonable to suggest
tion of fast-track peri-operative care pathways is feasible a practice of selective drainage based on the presence
in pancreatic surgery and can be associated with reduced of risk factors. The presence of soft pancreas texture, a
length of stay, reduced relevant hospital costs and no in- small pancreatic duct diameter, increased intraoperative
crease in morbidity, 30-d mortality or re-admission rates. blood loss (> 200 mL) and prolonged operative time
are risk factors that reflect abdominal drains. In the case
Early nasogastric tube, catheter and drain removal that patient is doing well and the drain amylase levels are
Nasogastric tube: Nasogastric tubes have been rou- below 5000 U/L, drains [on postoperative day 1 (POD
tinely used following abdominal surgery until normal 1)] can be safely removed on POD 3 in patients with low
bowel function is restored, following the notion that gas- risk of pancreatic fistulae.
tric decompression resulting from decreased air and fluid
accumulation can prevent abdominal distension, nausea Early oral nutrition
and vomiting. Many studies have subsequently ques- The restoration of normal gastrointestinal function to al-
tioned this practice, advising against its routine use. In low adequate food intake and rapid recovery is one of the
fact, prophylactic nasogastric tube aspiration is associated primary objectives of postoperative care. A meta-analysis
with pulmonary complications[137] and significant patient of controlled trials of early enteral or oral versus ‘nil by
discomfort. A recent study on the implementation of mouth’ feeding after gastrointestinal surgery indicated no
fast-track recovery pathways in pancreatic surgery[138] has clear advantage to continued patient fasting after the elec-
underlined the advantages of the early removal of naso- tive gastrointestinal resection[147].
gastric tubes and early oral feeding in terms of incidence Concerning nutrition, studies have clearly found that

allowing eating/drinking until late the day prior to sur- method[158], whereas the perioperative use of an artificial
gery and commencement of eating/drinking soon after endocrine pancreas enables strict glycaemic control of
surgery has many advantages[148,149]. Through the earlier euglycaemia without severe hypoglycaemia[159,160].
intake of fluids and solids, the gastrointestinal system is Modern pancreatic enzyme formulations have im-
less affected with an earlier initiation of normal intestinal proved exocrine insufficiency, facilitating glycaemic con-
activity. trol due to the avoidance of malabsorption[155].
An interesting review analysing which feeding routine The enhanced patient understanding of the conse-
was more favourable following pancreatoduodenectomy quences of total pancreatectomy, early education on dia-
revealed no consensus in terms of postoperative nutri- betes (all patients should consult an endocrinologist im-
tion of patients who had undergone pancreatic surgery. mediately following their operation), advances in medical
Current European guidelines recommend routine en- therapies, and blood glucose monitoring might all have
teral feeding after pancreatoduodenectomy, whereas the contributed to enhanced glycaemic control[161].
American guidelines do not. Gerritsen et al[150] concluded
that there is no evidence to support routine enteral or Goal-directed fluid therapy
parenteral feeding after pancreatoduodenectomy, whereas Early oral nutrition has to be associated to the individu-
the oral diet appears to be the best feeding strategy. alised postoperative fluid therapy that is administered in
At our University Hospital, it is common to allow accordance to the optimisation of stroke volume. Dy-
the patient to take clear liquids from POD 1 but not be- namic parameters such as stroke volume or pulse pres-
fore 6 h postoperatively and a light diet from POD 2, in sure variation can provide a more favourable prediction
the absence of any complications. In patients at risk of of fluid responsiveness. Oesophageal Doppler-guided
postoperative complications such as pancreatic fistulae or fluid optimisation has been shown to improve patient
abdominal collections, we advocate the use of combined outcomes, although this method cannot be performed
parenteral and enteral nutrition[52]. on conscious patients[116,117]. Fluid challenges and the leg-
raising test can represent simple and valid alternatives[118].
Total pancreatectomy and postoperative glycaemic Thus, oral nutrition has clearly be associated with a pro-
control gressive decrease of intravenous fluids.
Total pancreatectomy, usually performed for the treat-
ment of multifocal disease or in case of atrophic, soft, Pain relief/non opioid oral analgesia
friable remnant pancreatic tissue is responsible of en- One aim of fast track surgery is to obtain favourable pain
docrine and exocrine insufficiency. In addition to the control, which is intended to enable patient mobilisation,
absence of insulin, the endocrine abnormalities accom- coughing and early nutrition. One of the modern princi-
panying total pancreatectomy include both glucagon and ples for analgesia is the concept of opioid-sparing, which
pancreatic polypeptide deficiencies, which appears to enhances recovery by avoiding the opioid-related side ef-
play a key role in the increased hepatic insulin resistance fects. In major abdominal procedures, the administration
observed in pancreatogenic diabetes[151]. Moreover, fol- of continuous thoracic epidural analgesia with local an-
lowing pancreatectomy, insulin receptors are upregulated aesthetics has been demonstrated to be the most efficient
peripherally, rendering patients uniquely sensitive to hor- technique to obtain optimal analgesia, allowing for early
mone replacement[152]. mobilisation, reducing postoperative ileus and pulmonary
This type of diabetic condition is defined “pancrea- morbidity[162], and therefore acting as an important com-
togenetic” diabetes and is often considered to be dif- ponent of multimodal recovery strategies[163,164]. A mid-
ferent from type 1 and 2 diabetes. This diabetic state is thoracic epidural activated prior to the initiation of sur-
commonly described as “brittle”, as a result of enhanced gery also blocks stress hormone release[165] and attenuates
peripheral insulin sensitivity, decreased hepatic insulin postoperative insulin resistance[166,167].
sensitivity and reduction of glucagon secretion. The Fast-track clinical pathways in the peri-operative care
resulting labile glycaemic control is characterized by peri- of patients undergoing pancreatic resection provide for
odic episodes of both hyper and hypoglycaemia[153,154]. a catheter placed in the midthoracic level at T8/9 to
In recent years, studies have shown that diabetes fol- achieve both analgesic and sympathetic blocks[168].
lowing total pancreatectomy is not necessarily associated Small doses of epidural opioids have been shown
with poor glycaemic control, and the majority of cases to act in synergy with epidural local anaesthetics in
exhibit equivalent biochemical controls compared to the providing analgesia, allowing reduced dosages of both
normal type 1 diabetic population[155,156]. agents[169].
Recently, the development of accurate, continuous For break-through pain, non-steroidal anti-inflam-
blood glucose monitoring devices, particularly closed- matory drugs and bolus epidural bupivacaine should be
loop systems, for computer-assisted blood glucose con- administered whilst the epidural is running. Non-steroidal
trol in the intensive care unit have been reported to assist anti-inflammatory drugs should be administered just
in obtaining favourable glycaemic control in patients with prior to the removal of the epidural and continued until
pancreatogenic diabetes following pancreatic resection[157]. and/or after discharge.
The hyperglycaemia induced by surgical stress can- As the optimal duration of continuous postoperative
not be controlled using the conventional sliding scale mid-thoracic epidural analgesia has not been established

in well-designed randomised trials, we suggest that two- A systematic review showed that postoperative non-
to-three days might be a sufficient period for pancreatic invasive ventilation, specifically continuous positive air-
surgery. way pressure (CPAP), improves hypoxaemia and reduces
Patient-controlled analgesia using intravenous opioids both postoperative complications and the requirement
does not provide the same efficient analgesia and elicits for intubation in patients undergoing abdominal sur-
less beneficial physiological effects on surgical stress gery[170]. Furthermore, there is no specific study focusing
responses compared to local epidural anaesthetic tech- on the role of chest physiotherapy after pancreatic re-
niques. However, it is performed whenever contraindica- section; it is nonetheless included in the care plan at our
tions prevent the execution of peridural analgesia. institution. Every patient who has undergone pancreatic
surgery is instructed to use a blow bottle (5 min/h) and
Intensive postoperative ambulation and prevention of undergoes an individualised exercise schedule that is de-
venous thromboembolism signed by physiotherapists. Further, certain short courses
Among the standardised clinical pathways, which repre- of non-invasive mechanical ventilation (CPAP) can be
sent the basis of the fast-track programme, early mobili- performed as needed.
sation is a cornerstone. It has been shown to play a major
role in postoperative functional recovery. Improved early Intensive postoperative management
ambulation can elicit beneficial effects in the resolution Despite continuous improvements in operative tech-
of postoperative ileus and can reduce the risk of lower nique and perioperative management, the increasing age
extremity deep venous thrombosis. Furthermore, mobili- of patients undergoing major abdominal surgery ex-
sation might reduce pulmonary complications[170]. The poses patients to an increasing number of postoperative
risk for VTE, which is particularly high in this patient complications, leading to increased morbidity, mortality,
population, must be managed from the beginning of the length of hospital stay, and hospital costs. Although the
preoperative period and continue during the entire surgi- concept of fast-track surgery has questioned the tra-
cal operation until the postoperative period as a result of ditional use of intensive care units, there is increasing
early mobilisation and proper pharmacological throm- evidence indicating that access to ICUs results in a more
boprophylaxis. At our University Hospital, we generally favourable impact on the outcomes of major abdominal
mobilise patients out of their beds for more than one surgeries.
hour from POD 1 and progressively increase the hours In the case of pancreaticoduodenectomy, even high-
of mobilisation from POD 2. Patients who had under- volume centres report a major postoperative complica-
gone major abdominal surgery for gastrointestinal ma- tion rate of approximately 20%[175]. Because of these
lignancies should be considered for post-discharge VTE observations, patients who undergo pancreatic cancer
prophylaxis for up to 4 wk following surgery during the surgeries might benefit from admission to the ICU.
following situations: residual or metastatic disease, obe- An ideal ICU model should involve the cooperation
sity or previous history of VTE. of the intensivists who primarily care for the patients
with the primary physician and surgeon[176].
Intensive respiratory rehabilitation Current general concepts of fast track surgery have
Pulmonary complications following pancreatic resection been implemented in intensive care units. Early mobilisa-
occur in approximately one quarter of all patients[171]. tion, early enteral feeding, and restrictive perioperative
Many pathophysiological modifications that occur under fluid management are generally performed at the ICUs
anaesthesia and/or following surgery can interact with of our institution. In addition to these programmes, ICU
each other, resulting in respiratory complications. stays can offer extended haemodynamic monitoring,
Reduced lung inflation is one of the basic causes of which is useful in goal-directed fluid therapy, the possibil-
postoperative pulmonary dysfunction[172]. ity of invasive and non-invasive ventilation, the continu-
After upper abdominal and thoracic surgery, postop- ous application of intravenous drugs or subsequently
erative diaphragmatic dysfunction[173], which is the most required extracorporeal procedures.
important determinant of respiratory complications and In summary, most patients who undergo elective
atelectasis, is commonly observed and is caused by the pancreatic surgery for cancer do not necessary require
mechanical compression of alveoli and the resorption of intensive care admission, whereas high-risk patients
alveolar gases, which are the factors most commonly im- might benefit from postoperative care in the ICUs. We
plicated in respiratory complications[174]. suggest that surgical intensive care units play a pivotal
In recent years, breathing (deep breathing and di- role in the perioperative care of patients undergoing ma-
rected cough) and chest wall physiotherapy have been jor abdominal surgeries, and patients with co-morbidities
introduced into clinical practice to prevent pulmonary or elderly patients should be scheduled for intensive care
complications. Physiotherapy includes a variety of man- treatment[177,178].
ual treatments (postural drainage, percussion, clapping,
vibration, or shaking) as well as the use of mechanical
breathing devices (incentive spirometry, blow bottles, CONCLUSION
intermittent positive pressure breathing, and continuous In recent decades, diagnostic modalities and the surgi-
positive airway pressure). cal treatments of PC have significantly progressed, de-

spite the fact that overall prognosis has only marginally 541-545 [PMID: 16525584]
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P- Reviewers: Hartwig W, Tang Y S- Editor: Wen LL

L- Editor: A E- Editor: Wu HL

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com/esps/ World J Gastroenterol 2014 March 7; 20(9): 2304-2320

WJG 20th Anniversary Special Issues (14): Pancreatic cancer

Lesley De Pietri, Roberto Montalti, Bruno Begliomini

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Preoperative Intraoperative Postoperative

Modified from Grade et al[10].

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Table 2 Perioperative clinical predictors of postoperative

Modified from Canet et al[36]. ASA: American Society of Anesthesiologists.

WJG|www.wjgnet.com 2307 March 7, 2014|Volume 20|Issue 9|

Modified from Douketis et al[62]. LMWHs: Low-molecular-weight heparins.

WJG|www.wjgnet.com 2308 March 7, 2014|Volume 20|Issue 9|

WJG|www.wjgnet.com 2309 March 7, 2014|Volume 20|Issue 9|

widely used clinical marker of volume status, despite nu-

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WJG|www.wjgnet.com 1314 March 7, 2014|Volume 20|Issue 9|

15670540 DOI: 10.1016/j.amjcard.2004.09.029] 38 Squadrone V, Coha M, Cerutti E, Schellino MM, Biolino P,

WJG|www.wjgnet.com 2315 March 7, 2014|Volume 20|Issue 9|

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P- Reviewers: Hartwig W, Tang Y S- Editor: Wen LL

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© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

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