Recent Advances in Pancreatic Cancer
Chapter 4
Perioperative Care and Management of
Complications in Pancreatic Surgery
Gokhan Cipe and Fatma Umit Malya*
Department of General Surgery, Bezmialem Vakıf
University, Turkey
*
Corresponding Author: Fatma Umit Malya, Depart-
ment of General Surgery, Bezmialem Vakıf University,
Turkey, Email: fumitm@gmail.com
First Published July 10, 2016
Copyright: © 2016 Gokhan Cipe and Fatma Umit Malya.
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
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Recent Advances in Pancreatic Cancer
Abstract
Pancreatic surgeries, including pancreaticoduodenec-
tomy, are complex surgical procedures. There is increas-
ing interest in implementing comprehensive perioperative
protocols to improve the success of surgery. Patients are
often elderly and may have significant comorbidities and
malnutrition. Careful patient selection, appropriate preop-
erative evaluation and optimization can greatly contribute
to a favorable outcome after major pancreatic resections.
In recent years, along with advances in anesthesia and
intensive care practice, the mortality rates have reduced
significantly. On the other hand, the morbidity rates are
still as high. Therefore it is important to understand that a
multidisciplinary professional system is crucial to reduce
mortality and morbidity in pancreatic surgery.
Introduction
Pancreatic surgery is performed as a result of benign
or malignant causes. Cystic pancreatic tumors, pancreatic
complications, and trauma are among the benign reasons
for pancreatic surgery.
Presently, the most common reason for pancreatic
surgery is pancreatic cancer. Pancreatic cancer can be lo-
cated in the head, body, or tail of the pancreas,. The pan-
creatic head cancer is the most common location. For this
reason, the most common surgical procedure in pancre-
atic cancer is the pancreaticoduodenectomy [1]. On the
other hand, total pancreatectomy or distal pancreatecto-
my can be applied for tumors located in the body and tail
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Recent Advances in Pancreatic Cancer
of the pancreas. The pancreaticoduodenectomy is also the
preferred surgery for other tumors in the periampullary
regions.
Pancreatic cancer is the ninth most common cancer in
the world and is the fourth leading cause of cancer-associ-
ated deaths. Every year, 138,100 men and 127,900 women
are expected to die from pancreatic cancer. Furthermore,
the life expectancy of patients diagnosed with pancreatic
cancer is less than 5%. It is 1.3 times more common in
males and its incidence increases with age [2,3]. The most
important and the most effective treatment of pancreatic
cancer is surgery. However, only 15-20% of diagnosed pa-
tients are eligible for surgery. After successful surgery, the
average 5-year survival is 25-30% [4].
Pancreatic surgeries, including pancreaticoduodenec-
tomy, are complex surgical procedures that might disrupt
the function and integrity of the gastrointestinal tract.
Pancreatic surgeries were always associated with high
mortality and morbidity rates due to either technical diffi-
culty during the operation or the effects of surgery on me-
tabolism. However, in recent years, along with advances in
anesthesia and intensive care practice, the mortality rates
have reduced significantly. Some centers have reported
that their pancreatic surgery associated mortality rates
were 2-5%, while some high-volume centers reported rates
lower than 2%. On the other hand, the morbidity rates are
still as high as 30-65% [2]. Therefore, a multidisciplinary
approach is needed for implementation of a surgical pro-
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Recent Advances in Pancreatic Cancer
cedure with such a high morbidity rate. Lower mortality
and morbidity rates have been reported when the pan-
creatic surgery is performed in high-volume centers [1].
Lieberman et al. evaluated a total of 1971 pancreatectomy
procedures conducted in 184 centers, including a center
in New York. According to this study, the mortality rate
was 4% in centers that performed more than 40 pancrea-
tectomy procedures per year, while it was 12.3% in centers
that performed less than 40 [l]. Several other studies have
also reported lower mortality, length of hospital stay, and
cost in high volume centers [13-15]. The most important
reason for that is that the management of perioperative
care and postoperative complications are standardized in
such centers.
Preoperative Evaluation, Preparation
and Risk Scores
Following the diagnosis of pancreatic cancer, patients
should be evaluated in terms of conformity for surgery,
which begins by determining the extent of the tumor. Pa-
tients are divided into three groups: patients that are not
candidates for surgery due to disseminated disease, pa-
tients with locally advanced disease, and patients that are
eligible for surgery. The patients that eligible for surgery
are further evaluated in terms of absence of celiac trunk,
superior mesenteric artery and hepatic artery involve-
ment, and no evidence of superior mesenteric vein and
portal vein invasion [5]. Patients that have a borderline
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Recent Advances in Pancreatic Cancer Recent Advances in Pancreatic Cancer

resectable tumor can be directed to the neoadjuvant treat-
ment. However, patients that have borderline resectable
tumors, also have long segment, and don’t have more than
180-degree artery involvement can also be recommended
for surgery [6-9].
After evaluating patients’ technical eligibility for sur-
gery, it is important to assess the surgical risk. Pancreatic
cancer peaks in the seventh and eighth decades, therefore
most of the patients undergoing surgery are geriatric pa-
tients. The physiological changes and comorbidities ac-
companying old age may not allow for complex abdominal
surgery. Many studies have indicated that old age alone is
not contraindication for surgery. However, it is important
to correctly evaluate specific changes and comorbidities
related to this patient group and provide optimal surgical
conditions as well as post-operative care [10-12].
Correct and adequate assessment of patients in the
morbidity risks. These systems are generally based on the
data obtained from patients during pre-hospitalization
and hospitalization periods. Moreover, they can provide
a relationship between the patient data and the extent of
the surgical procedure. Along with physiological scoring
systems that determine the risk based on the preopera-
tive state of organ systems, there are preoperative systems
that assess the overall preoperative health state of patients
[16,18,21]. In order to evaluate patients using these sys-
tems, detailed assessment of cardiological, respiratory,
neurological, gastrointestinal, and nephrological systems
should be performed. These scoring systems are summa-
rized in Table 1.
Table 1: Perioperative scoring systems.
Physiological scoring systems Preoperative scoring systems
APACHE(I,II) ASA

preoperative stage allows for comfortable and easy intra- E-PASS Goldman cardiac risk index
operative and postoperative care. Specific evaluations per- ISS/TRISS Hospital prognostic index
taining to individual characteristics of each patient must POSSUM Prognostic nutritional index
be done in order to achieve the aforementioned kind of
P-POSSUM Risk of pulmonary complications
care. Moreover, the combination of many factors should
SAPS
be considered when assessing the risk of surgical inter-
vention. Patient related risks are comorbid diseases, the Sepsis score

duration of disease, and the ability to tolerate the physi- Disease score
ological stress due to surgical procedure. Treatment-related intervention score

Several scoring systems have been created to evalu-

ate possible surgery and anesthesia related mortality and

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Recent Advances in Pancreatic Cancer Recent Advances in Pancreatic Cancer

Goldman Cardiac Risk Index [22] is probably one of perioperative variables, such as perioperative morbidity
the best models that evaluate cardiac risk with regards to and mortality, as well as blood loss during surgery, post-
surgery. Scoring is done by nine different clinical factors operative ventilation time, and length of stay in intensive
and patients are divided into four risk groups based on care. It has been shown that postoperative morbidity in-
their total score (Table 2). creases proportionally with the size of surgical interven-
Table 2: Goldman cardiac risk index. tion, ASA class, respiratory disease symptoms, and the
Causes of cardiac risk Points presence of tumor [17].
Myocardial infarction within the last 6 months 10
Table 3: ASA Classification.
Age>70 5
I Normal Healthy patient
Severe stenosis of aortic valve 11
II Patient with mild systemic disease
Non-sinus rhythmin the preoperative ECG 3
III Patient with non-incapacitating systemic disease
or atrial premature beats with sinus rhythm
IV Patient with an incapacitating systemic disease that is a constant threat to life
More than five premature ventricular contractions 7
V Moribund patient that is not expected to survive for 24 hours
per minute in the preoperative period
E Urgent
Worsening of general condition 3

Abdominal, thoracic or aortic surgery 3

Emergency surgery 4 Nutritional assessment is important in terms of

evaluating patients’ physiological state, immunological
Group Point Risk of life-threatening complications Risk of cardiac death (%) function, and fluid balance as well as regulating patients’
I 0-5 0,7 0,2
metabolic responses to trauma and surgery. Loss of 10%
II 6-12 5 2
of body weight in the last 6 months and albumin values
III 3-25 11 2
lower than 3g/dL allow for patients to be diagnosed with
IV ≥26 22 56
malnutrition. The frequency of postoperative complica-
The American Society of Anesthesiologists (ASA) tions in patients with malnutrition is higher, therefore
scoring system (Table 3) was initially developed to inform these patients should be provided with nutritional support
the anesthetist about patients’ comorbid diseases. Due to for at least 2 weeks prior to surgery [23]. The prognostic
its ease of use and lack of need for additional testing, ASA nutritional index (PNI) has been developed for the pre-
continues to be used in order to assess surgery related diction of mortality-related risk of complications and is
risks. The ASA scoring system is directly associated with directly proportional with postoperative sepsis and death

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Recent Advances in Pancreatic Cancer
[24]. The following four factors are used in PNI: serum
albumin levels, serum transferrin levels, delayed skin hy-
persensitivity, and triceps muscle skinfold thickness. The
first three of these factors are definitively associated with
postoperative morbidity and mortality. Furthermore, PNI
can also be used for the prediction of the need for nutri-
tion support in the perioperative period.
Acute Physiology and Chronic Health Evaluation
(APACHE) scoring system was first defined in 1981 and
amended in 1985 as APACHE II system. Although this
scoring system was first developed for patients in the in-
tensive care unit, later it has been used for the evaluation
of clinical conditions in severe trauma, abdominal sepsis,
postoperative enterocutaneous fistula, and acute pancrea-
titis along with the prediction of postoperative outcome.
The disadvantages of APACHE II system are its relative
complexity and failure to consider cardiac symptoms that
can increase the patient’s nutritional status and surgical
risk. In addition, the size of the surgical intervention is
not considered to be a factor in the APACHE II system.
Recently, APACHE III system has also been developed but
is considered to be too complicated for routine use [19].
The Physiological and Operative Severity Score for
the enumeration of Mortality and Morbidity (POSSUM)
was developed with the aim of grading predicted mortali-
ty and morbidity. The POSSUM provides multivariate dis-
integration analysis of retrospective and prospective data
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in order to evaluate the quality of surgical follow-up care.
The POSSUM calculates predicted mortality and morbid-
ity rates based on 6 surgical and 12 physiological variables
that are scored as 1, 2, 4, or 8 (Table 4). The biggest advan-
tage of this system is the ability to predict both the mor-
tality and morbidity. Moreover, it allows for successful
comparison of performance between surgery centers, hos-
pitals, and countries. On the other hand, the disadvantage
of the POSSUM scoring system is not taking into account
factors that may affect the results of surgery, such as op-
erating time and differences between surgeons and anes-
thetists. Therefore, other additional factors should also be
considered when POSSUM is used in patients undergoing
surgery. Another disadvantage is that primary diagnosis is
not used as a factor in the POSSUM scoring system. Nev-
ertheless, when POSSUM and APACHE II systems were
compared, the POSSUM has been shown to be superior
in terms of identifying mortality risks in patients in the
intensive care unit following a general surgery. A prob-
lem with the POSSUM system is that it has a minimum
mortality of 1.1% and is six times more likely to predict
mortality and morbidity, which may lead to a greater
number of false positives. In order to overcome these dis-
advantages, P-Portsmouth POSSUM (P-POSSUM) sys-
tem was developed by using different mathematical for-
mulas. P-POSSUM’s minimum mortality rate was reduced
to 0.2%. Furthermore, Chen et al. compared P-POSSUM
and POSSUM systems in terms of predicting the mortal-
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ity and morbidity in hepatopancreatobiliary surgery. They
concluded that these scores were insufficient in making a
proper assessment and suggested that more studies with
additional parameters are needed [25].
Table 4: Parameters used to calculate the POSSUM score.
Physiological Parameters
Age (year) Size of the operation
Cardiac symptoms/Posteroanterior lung x-ray Multiple procedures
Respiratory symptoms/Posteroanterior lung x-ray Blood loss (ml)
Pulse Peritoneal damage
Malignancy
Systolic blood pressure (mmHg)
Type of surgery
Glasgow coma score
Hemoglobin
Leukocyte count (x1012)
Urine (mmol/l)
Na+ and K+ levels (mmol/l)
ECG
The most common complications following pancreat-
ic surgery are delayed gastric emptying, pancreatic fistula,
wound site infection, and cardiopulmonary incidents. The
rate of these complications remains high even in high-vol-
ume centers; therefore various, different special scoring
systems are being developed for predicting complications
and planning appropriate treatment approaches. There are
scoring systems that can evaluate preoperative evaluation
findings, intraoperative, and postoperative findings either
separately or by combining all of these parameters.
In 2007, Assifi Mura et al. evaluated the value of Sur-
gical Apgar Score (SAS), which was recommended by
Gavende et al. and is used in many surgical procedures
to predict mortality and morbidity, in pancreatic surgery
[26,27]. The postoperative complications were calculated
by SAS based on intraoperative bleeding, mean blood
Surgical Parameters pressure, and pulse rate values; furthermore, they were
classified and compared based on the morbidity score
proposed by Clavien et al [28]. The grade 1-2 of this clas-
sification comprises of complications that do not lead
to any changes in normal postoperative course, and the
ones that do not require either reoperation or endoscopic
and radiological procedures. Wound site infections that
can be treated at bedside also fall into this group. Grade
3 complications include complications that require surgi-
cal, endoscopic, or radiological intervention; while grade
4 includes complications that require intensive care and
may lead to organ failure; lastly, grade 5 complications are
the ones that result in death. In this study, low SAS scores
were shown to be effective in predicting morbidity and the
development of pancreatic fistula; however, it was not ef-
fective in predicting mortality.
The most common pancreatic surgery specific com-
plication is pancreatico-digestive anastomosis, which
includes bleeding due to the development of pancreatic
fistula, bilioenteric anastomosis complications, and intra-
abdominal collections. Soft pancreas, pancreatic duct that
is not expanded, and extensive intraoperative bleeding

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Recent Advances in Pancreatic Cancer
were identified as independent risk factors for develop-
ment of pancreatic fistula [29]. Moreover, elevated serum
amylase levels on day zero of the surgery have been shown
to indicate the development of pancreatic fistula [30].
Palani Velu et al. investigated the effectiveness of serum
amylase and C-reactive protein in predicting pancreas
specific complications. They reported that serum amyl-
ase levels below 130 units/l on postoperative day zero and
C-reactive protein levels below 180mg/l on postoperative
day 2 were associated with low morbidity and that patients
with these parameters were suitable for early discharge
[31].
Callery et al. have worked on a clinical risk scoring
system that predicts development of severe pancreatic fis-
tula. Soft pancreas, pancreatic duct that is not expanded,
pathologies other than pancreatic adenocarcinoma, and
chronic pancreatitis as well as extensive intraoperative
blood loss have been identified as risk factors and assigned
scores. The scoring is done from 1 to 10 and the authors
showed that their scoring was effective in predicting de-
velopment of fistula [32].
During the preoperative preparation it is important to
evaluate patients’ cardiovascular system, nutritional sta-
tus, and scoring systems along with blood tests. Patients
with anemia can tolerate the surgery well unless they have
other diseases; therefore, there is no need for preopera-
tive blood transfusion when excessive blood loss is not ex-
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Recent Advances in Pancreatic Cancer
pected during the surgery. The importance of determining
blood groups and doing cross-comparison is obvious for
patients scheduled for major surgery, where significant
blood loss may develop. Prior to major surgery, medical
files of even the patients that are not expected to require
transfusion or cross-comparison should contain infor-
mation regarding their blood type. This way, a two-level
security system is created, where an emergency blood
transfusion can be performed speedily in the event of the
development of intraoperative bleeding and the risk of
transfusion reactions is eliminated. When extensive blood
loss is not expected during the surgery, anemia rarely re-
sults in changes in treatment strategies. Allogenic transfu-
sion can be applied to anemic patients undergoing elective
surgery in the preoperative period [33].
Antibiotic prophylaxis prior to pancreatic surgery and
continuation of postoperative antibiotic use is another
controversial issue. Antibiotic prophylaxis is implemented
in abdominal surgeries according to the infectious diseas-
es guidelines and the Surgical Care Improvement Project
(SCIP) recommendations. However, prophylaxis applied
based on these protocols has been shown to be inadequate
in preventing wound infections in pancreaticoduodenec-
tomy [34]. The most important reasons for this are the bil-
iary stents that are applied prior to the surgery and biliary
bacterial contamination. Therefore, a bile culture should
be taken from each patient during the surgery, which will
help determine the patient’s antibiogram protocol. Proph-
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Recent Advances in Pancreatic Cancer
ylaxis will be administered according to this protocol and
based on the culture results, it will be determined whether
or not to continue the antibiotic treatment and which an-
tibiotic to use in the post-operative period [35,36].
According to the venous thromboembolism prophy-
laxis guideline criteria, pancreatic surgery falls into the
middle-high group [37] (Table 5). However, in prophylax-
is with low molecular weight, heparin is usually avoided
due to the concern that it might increase postoperative
bleeding complications. Hayashi et al. have investigated
the effects of thromboembolism prophylaxis on bleed-
ing complications [38]. They concluded that although
prophylaxis increased the risk of minor bleeding com-
plications, there was no significant increase in the risk of
major complications. Moreover, the prophylaxis resulted
in a decrease in thromboembolic complications. Based on
these results, thromboembolism prophylaxis is beneficial
in pancreatic surgery and can be safely administered. The
duration of prophylaxis is another issue for discussion.
In a Cochrane analysis performed by Rasmussen et al., it
indicated that prolonged prophylaxis in major abdominal
surgeries decreased thromboembolic complications. They
therefore recommended this type of prophylaxis [39]. In
addition, there are also studies in literature that report the
benefits of prophylaxis throughout treatment in cancer
patients receiving chemotherapy [40]. Another important
issue is how to approach patients that use acetylsalicylic
acid for reasons such as coronary artery disease, where
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discontinuation might pose a risk to patients. While the
general approach has been to discontinue acetylsalicylic
acid 7-10 days before surgery, more recently surgeries are
performed while patients are still on acetylsalicylic acid
in order to avoid the risk of cardiac failure. Andrea et al.
have shown that there was no increase in postoperative
complications in patients that underwent surgeries with-
out discontinuation of acetylsalicylic acid. Currently, the
recommended approach in pancreatic surgery is the use
of acetylsalicylic acid throughout the perioperative period
without any interruption [41].
One of the most controversial issues that impacts
morbidity in pancreatic surgery is whether the bilayer
drainage should be performed in patients with high pre-
operative bilirubin levels; and if it needs to be done, then
what method of bilayer drainage should be chosen. The
purpose of drainage is to reduce potential mortality and
morbidity as well as to relieve patients’ rash symptoms
and treat cholangitis. However, there are several studies
indicating that hyperbilirubinemia may increase the risk
of surgery-related mortality and morbidity. Sugiyama et
al. have conducted an extensive review of literature on this
subject [42]. Based on the results of many studies, they
suggested that given the possibility that preoperative bil-
iary drainage can increase the risk of postoperative com-
plications, it should only be performed in selected cases
that have severe cholangitis or malnutrition. When the
surgery is scheduled in the early stages the drainage is
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Recent Advances in Pancreatic Cancer Recent Advances in Pancreatic Cancer

not recommended. On the other hand, many studies have Intraoperative Stage
reached a consensus about which method of drainage to
use when necessary. Since percutaneous biliary drainage The importance of intraoperative period and early
poses a risk of spreading the tumor, the method of choice postoperative period in the evaluation of perioperative
is stenting with metal or plastic stents by using the endo- period has been raised in recent years.
scopic method. There are several studies comparing differences in
Table 5: Venous thromboembolism prophylaxis based on perioperative care at both low and high mortality hospi-
risk classification. tals. In these studies using intraoperative hemodynamic
monitoring, perioperative sequential compression devic-
Risk type Low Medium High Very high
Example Minor surgery, Major abdominal Major abdominal Major abdominal es, postoperative venous thromboembolism chemopro-
no additional risk surgery surgery surgery
factors phylaxis and epidural catheters for effective pain control
Age>40 Age>60 History of major

No additional risk Additional risk

venous thromboem- are found the factors to be important for reducing mortal-
bolism
factor factors ity and morbidity rates. Epidural catheters provide superi-
Hypercoagulopty
disorders or pain control and reduce the incidence of cardiopulmo-
Deep vein 2% 10-20% 20-40% 40-80%
thrombosis risk nary complications, compared to systemic opioid [47-50].
(without pro-
phylaxis)
Pulmonary O,2% 1-2% 2-4% 4-10%
Recently there are studies which evaluate the rela-
emboli risk tionship between perioperative fluid resuscitation and
Primary pro- No need IPC LDUH(5000U 3 LDUH(5000U 3
phylaxis times a day) times a day) postoperative complications in patients undergoing pan-
Or Or creaticoduodenectomy. It is well known that patients fre-
LMWH(Deltaparin
5000U/day or
LMWH(Deltaparin
5000U/day or Enaxi-
quently receive large volumes of intravenous fluid during
Enaxiparin 4000U/
day or Tinzaparin
parin 4000U/day or
Tinzaparin 4500U/
and following major intraabdominal operations with the
4500U/day) day) intension of replacing operative fluid losses. However the
Alternative No need LDUH(5000U 2 IPC Heparin and IPC
propylaxis times a day) impact of fluid resuscitation on the development of post-
Or operative complications is examined. Liberal fluid admin-
LMWH(Deltaparin
2500U/day or
istration is correlated with bowel edema and anastomotic
Enaxiparin 2000U/
day or Tinzaparin
compromise. It is well documented that increased perio-
3500U/day) perative fluid especially in the early postoperative period
IPC: Intermittent Pneumatic Compression; LDUH: Low Dose Un-
is associated with increased major adverse events. Finally
fractioned Heparin; LMWH: Low Molecular Weight Heparin.

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Recent Advances in Pancreatic Cancer
restrictive fluid protocols especially in patients at high risk
of anastomotic compromise are recommended [43-46,51].
Enhanced Recovery after Surgery (ERAS) protocols
are comprehensive multimodal perioperative care path-
ways designed to optimize patient outcomes after major
surgery.
ERAS protocols are multidisciplinary, include preop-
erative, intraoperative, and postoperative elements, and
are designed to optimize outcomes by reducing surgical
stress and supporting organ function [52]. There are two
essential and relatively novel components of ERAS. These
fundamental components are; restriction of IV fluid ad-
ministration and preoperative carbohydrate loading in or-
der to avoid insulin resistance. However, the effectiveness
and outcomes of ERAS protocols after pancreas surgery
is controversial. In their study, Morgan et al. have shown
that “Enhanced Recovery after Surgery” is safely applica-
ble procedure. Furthermore, they have suggested that this
procedure decreases postoperative morbidity, especially
delayed gastric emptying [53]. Overall, this approach is
valuable in terms of demonstrating all-important factor is
the system, not the surgeon himself in major abdominal
operations.
Postoperative Period
Postoperative care includes; close monitoring of pa-
tient’s vital signs and fluid balance, wound care, follow-
ing-up of drains, evaluating possible risk factors and ad-
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Recent Advances in Pancreatic Cancer
ministrating appropriate medications. This period starts
immediately after the operation and continues until the
30th postoperative day.
Initially, controlling the patient’s pain is vital in order
to improve quality of life and to reduce cardiac and respir-
atory complications [54]. During the early postoperative
period, to prevent respiratory complications, early mobili-
zation and standard respiratory physiotherapy are two key
elements. Additionally, early mobilization accelerates the
recovery time of gastrointestinal motility.
As it is defined in ERAS protocol; nasogastric tubes
are avoided or removed early. In the same way, Foley cath-
eters are also recommended to be removed early. In this
protocol, prolonged postoperative fasting is avoided. Be-
sides, early enteral nutrition is essential.
A moderate to severe risk of malnutrition was iden-
tified in 52-88% of patients who underwent pancreatic
resection for cancer. This malnourished state, either it is
evident or not, is associated with increased morbidity and
mortality [55].
Therefore, nutrition plays an integral role in pan-
creatic cancer surgery, not only preoperatively, but also
in the postoperative period. According to observational
studies and available randomized control trials in pancre-
atic surgery, and additional literature from other surgi-
cal disciplines, oral feeding at will, recognized as the best
approach. On the other hand, if preoperative nutritional
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support was initiated due to insufficient nutrition it would Postoperative Pancreatic Fistula (POPF)
be appropriate to continue after surgery according to cur-
Pancreatic fistula is the Achilles heel of the Whipple
rent guidelines [56]. As generally recognized, parenteral
operation. A pancreatic fistula increases the morbidity of
nutrition is associated with an increased risk of compli-
the operation by leading to other infectious complications
cations. However, this is beneficial during postoperative
(such as wound infection, abscess), delaying resumption
period of undernourished patients, in whom enteral nu-
of oral diet, prolonging hospital stay, and sometimes re-
trition is not feasible or tolerated within 7-10 days of their
quiring reoperation. In large series, pancreatic fistula rate
procedure [57].
following Whipple is reported as 2-12%. In patients with
Complications soft-textured glands or with a pancreatic duct smaller than
3 mm leakage, pancreatic fistula is observed in 20-30% of
In spite of its low associated mortality, significant cases. The definition of pancreatic fistula is controversial.
morbidity is still observed after pancreatic surgery espe- With the aim of creating possible comparisons between
cially in Whipple procedures. A large number of compli- published results and arrive at a definition of pancreatic
cations are possible, and many are not directly related to fistula, an international group of pancreatic surgeons met
the pancreatic operation. These possible complications are [58]. As a result they came to an agreement and defined a
shown on Table 6. postoperative pancreatic fistula as; a failure of healing of a
Table 6: Complications after the Whipple operation. pancreatic-enteric anastomosis or a parenchymal leak not
Some possible complications after the whipple operation directly related to an anastomosis. In order to achieve a
Pancreatic fistula Cardiopulmonary complications standardized quantitation, they included a value in their
Delayed gastric emptying Gastrointestinal bleeding
definition; any drain fluid output after postoperative day
Biliary fistula Deep venous thrombosis/pulmonary embolism
3 with an amylase content, three times greater than the
Wound infection Cerebrovascular accident
serum value constitutes a pancreatic fistula. Furthermore
Intraabdominal abcess Urinary tract infection
with the aim of categorizing the severity of a pancreatic
Cholangitis Line infection
fistula, they created 3 different grades and predefined ten
Pancreatitis
main criteria are utilized to differentiate each grade. These
Reoperation
ten criteria are; elevated drain amylase, persistent drain-
age, signs of infection, diagnostic imaging, specific treat-
ments, readmission, critical condition, re-operation, sep-

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Recent Advances in Pancreatic Cancer
sis and death. These 3 grades of Postoperative Pancreatic
Fistula are explained below in details.
Grades of Postoperative Pancreatic Fistula
(POPF)
POPF grade A
• Requires little change in management or devia-
tion from the normal clinical pathway
• Computed tomographic (CT) scan might not be
required and if it is required this often shows no
peripancreatic fluid collections
• Oral feeding is not interrupted and general condi-
tion of the patients remain well
• The initiation of total parenteral nutrition, antibi-
otics, or somatostatin analogues are not indicated
• Is not associated with a delay in hospital discharge
and is managed frequently by slow removal of the
operatively placed drains
POPF grade B
• Requires a change in management or adjustment
in the clinical pathway
• The peripancreatic drains are usually maintained
in place
• Antibiotics are usually required; somatostatin an-
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Recent Advances in Pancreatic Cancer
alogues may also be used
• A CT scan is often required and usually shows
peripancreatic collection(s) requiring reposition-
ing of the drains
• Often oral feeding is interrupted and the patient
is supported with partial or total parenteral or en-
teral nutrition
• Usually leads to a delay in discharge, or readmis-
sion after a previous discharge may be required
• Mostly patients can be discharged with drains in
situ and observed in the outpatient setting
POPF grade C
• A major change in clinical management
• Clinical intervention should be aggressive
• A CT scan usually shows worrisome, peripancre-
atic fluid collection(s) that require percutaneous
drainage
• There are often associated complications
• The risk of mortality is considered to be high
• Total parenteral nutrition or enteral nutrition, in-
travenous antibiotics, and somatostatin analogues
are required
• The patient’s hospital stay is markedly prolonged.
A deteriorating clinical status, together with sep-
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Recent Advances in Pancreatic Cancer
sis and organ dysfunction, may require re-explo-
ration for 1 of 3 options:
1. Repairing the site of leakage with wide peri-
pancreatic drainage
2. Conversion to alternative means of pancreatic-
enteric anastomosis (eg, conversion of pancre-
aticojejunostomy to pancreaticogastrostomy)
3. Completion pancreatectomy
Most surgeons agree that not all pancreatic glands are
at the same risk for postoperative fistula formation. Where
the texture of the parenchyma is soft or normal to palpa-
tion and when pancreatic duct is small or normal sized,
the risk of formation of the fistula considered to be high
[59]. There are several measures to apply at the time of
surgery to prevent fistula formation, or decrease morbid-
ity if a fistula develops. For example in recent years, fi-
brin glue sealants have been introduced into the surgical
practice. These are marketed as tissue adhesives to use in
hemostasis, wound closure, and sealing of anastomosis.
Initial reports on the use of fibrin glue in pancreatic resec-
tions suggested that this method is effective in reducing
fistula rates. Multiple randomized controlled trials (RCTs)
followed and a significant difference could not be demon-
strated [60].
The use of octreotide in the prevention and treatment
of postoperative pancreatic fistulas have been extensively
studied in multiple RCTs. Octreotide is a synthetic analog
26 www.avidscience.com
Recent Advances in Pancreatic Cancer
of somatostatin that has inhibitory effects on the secre-
tory functions of the pancreas. A metaanalysis of all RCT-
son octreotide in the setting of pancreatic surgery shows
that current data support octreotide as an effective tool in
reducing total morbidity and pancreas-related complica-
tions. On the other hand, these effects have not translated
into improved postoperative mortality rates [61]. For that
reason, the use of prophylactic somatostatin and its ana-
logs in pancreatic resections is controversial.
Recent RCTs showed that somatostatin and its analogs
did not reduce the mortality, POPF or other postoperative
complication rates after pancreatic resection [62]. Accord-
ing to the latest consensus meetings, initiation of somato-
statin is indicated before the development of POPF.
For years, surgical drains have been regularly used in
pancreatic surgery. In recent randomized controlled tri-
als, the need for routine drain placement after pancreatec-
tomy has been questioned [63]. However, most pancreatic
surgeons today continue to use surgical drains, and find
them effective in the management of fistulas without fur-
ther necessity for reoperation or percutaneous drainage.
Based on concerns that the pancreatic juice can digest
the pancreaticodigestive anastomosis and/or surrounding
tissue, external or internal drainage of the pancreatic duct
has been considered to decrease the incidence of POPF
formation. Nevertheless, the use of an external drainage
tube leads to difficulties in the daily activities of the pa-
tient and this may delay the discharge process. In order to
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Recent Advances in Pancreatic Cancer
successfully prevented POPF formation and avoid these
problems, internal stenting was designed. On the contra-
ry, one RCT and four observational studies showed that
internal trans-anastomotic pancreatic duct stenting does
not decrease the frequency or severity of POPF, the total
morbidity, the length of hospital stay or the hospital mor-
tality even in patients with a soft pancreatic texture [64].
Instead, one meta-analysis and three RCTs revealed that
external stenting significantly decreased the incidence of
POPF formation, independent of the pancreatic texture
[65]. As a result in the high risk cases of POPF such as
with soft pancreatic texture, using external or internal
stenting may be the right approach.
As an alternative, wrapping the anastomosis with
omentum/falciform ligament is one of the procedures
used to protect the surrounding organs against the pan-
creatic juice.
This surgical technique is simple and easy for surgeons
to perform. However, several reports claim this method
does not serve its purpose and it is useless to prevent the
POPF related complications [66].
Management of the great majority of pancreatic fis-
tulas is nonoperative. Drains placed at the time of sur-
gery are usually sufficient, but interventional radiology
catheters are also an option if undrained collections are
identified. Antibiotics may be added if active infection is
demonstrated.
28 www.avidscience.com
Recent Advances in Pancreatic Cancer
Some patients can fail to improve or actually deterio-
rate clinically during conservative management. Major
hemorrhage can be observed in association with a pancre-
atic fistula. This event usually indicates either ruptures of
a pseudoaneurysm of the gastroduodenal artery, or major
disruption of the pancreaticojejunal anastomosis. In some
cases, embolization by interventional radiology methods
can help control this hemorrhage without re-exploration.
However, when all conservative measures have failed, re-
operation is indicated. Reoperation usually involves peri-
toneal irrigation, repair, or revision of the pancreatic anas-
tomosis, and wide drainage. Other alternatives, depending
on the clinical situation, include conversion to Roux-en-Y
pancreaticojejunostomy and total pancreatectomy. In the
presence of massive hemorrhage or severe sepsis, total
pancreatectomy can be a life-saving procedure.
Delayed Gastric Emptying
Delayed gastric emptying (DGE) without mechanical
obstruction can occur in the postoperative period follow-
ing upper gastrointestinal tract surgery. During postop-
erative period following pancreatic surgery DGE is espe-
cially common therefore this can delay discharge of the
patient. In addition to pancreatic fistulaand postoperative
hemorrhage, DGE is one of themost common postopera-
tive complications after pancreatic surgery, occurring in
19%-57% of patients [67]. DGE occurs after both classic
and pylorus-preserving pancreatoduodenectomy. Con-
sensus definition of delayed gastric emptying after pan-
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Recent Advances in Pancreatic Cancer
creatic surgery consists of 3 different grades. According to
this definition DGE is classified as; Grade A (mild), Grade
B (moderate), Grade C (severe). These 3 grades of DGE
are listed below in details.
Grade A (mild) DGE
• The nasogastric tube (NGT) is requiredbetween
the POD 4 and 7
• Reinsertion of NGT may be necessary owing to
nausea and vomiting after removal by POD 3
• The patient is unable to tolerate a solid diet on
POD 7, but resumes a solid diet before POD 14.
Grade B (moderate) DGE
• The NGT is required from POD 8-14
• Reinsertion of the NGT was necessary after POD
7 week.
• The patient cannot tolerate unlimited oral intake
by POD 14, but is able to resume a solid oral diet
before POD 21.
Grade C (severe) DGE
• Nasogastric intubation cannot be discontinued.
• NGT has to be reinserted after POD 14
• The patient is unable to maintain unlimited oral
intake by POD 21.
30 www.avidscience.com
Recent Advances in Pancreatic Cancer
DGE directly impacts thepatient’s postoperative nu-
tritional status. Poor nutrition can lead to other complica-
tions, particularly with relation to healing and immunity.
Therefore, maintenance of caloric intake becomes
a priority whenever the diagnosis is DGE. For the most
part, DGE is expected to resolve with conservative meas-
ures. During this process the surgeon must be very pa-
tient, as this condition can take several weeks to improve.
Reoperation is rarely necessary.
Hepaticojejunostomy Leakage
Hepaticojejunostomy (HJ) leakage occurs with an es-
timated frequency between 3 and 8 % [68]. The most com-
mon clinical signs associated with an HJ leak included;
bilious drainage in the drains placed at surgery, leukocy-
tosis, a change in the abdominal examination and fever.
Typically, patients presented during the first postoperative
Richard et al proposed a grading system of HJ leak-
age, using the International Study Group on Pancreatic
Fistula (ISGPF) system as a sample model.
According to the grading system of Richard et al, there
are 3 grades of HJ leakage; Grade A HJ leaks, Grade B HJ
leaks and Grade C HJ leaks. These 3 grades of HJ leaks are
listed in details below.
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Recent Advances in Pancreatic Cancer
Grade A HJ Leaks
• Are evident based on the presence of bile in surgi-
cally placed drains
• Are not associated with any change in clinical
condition
• There is no additional infection
• May be evaluated by sinogram to define the leak
and managed with continued abdominal drainage
• The patients typically do not require any addition-
al procedures
Grade B HJ Leaks
• Are associated with mild signs of infection, such
as a leukocytosis and fever
• A sinogram may be performed to define the leak,
and a CT scan is generally necessary to evaluate
for undrained collections
• Surgically placed drains can be manipulated or
exchanged by an interventional radiologist to op-
timize drainage in these patients
• Often, an additional abdominal drain is neces-
sary; rarely, a percutaneous transhepatic biliary
catheter (PTBD) is required to control a high-out-
put leak and facilitate healing of the anastomosis
32 www.avidscience.com
Recent Advances in Pancreatic Cancer
Grade C HJ Leaks
• Involve an infection that results in significant
physiologic derangements or sepsis requiring an
increased level of care
• A sinogram often demonstrates a substantial and
uncontrolled leak, and early drain outputs are
high
• In addition to optimization of abdominal drains,
the leaks virtually always require a PTBD
• In patients with severe sepsis reoperative inter-
vention to revise the HJ anastomosis or optimize
drainage may also be useful
Finally, all HJ leaks increase length of hospital stay
and require several months of abdominal drainage until
the leak is completely healed.
Postpancreatectomy Hemorrhage
Although uncommon, hemorrhage after pancreatic
resection is a potentially fatal complication that requires
timely diagnosis and treatment [69]. The pathogenesis
of postpancreatectomy hemorrhage (PPH) is multifacto-
rial. Early PPH within the first 24h after surgery is gener-
ally caused by technical failures of inadequate hemostasis
and perioperative coagulopathy and usually necessitates
immediate relaparotomy. Late PPH after the first postop-
erative day has a more complex pathogenesis. This may
be related to erosion of peripancreatic vessels secondary
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Recent Advances in Pancreatic Cancer
to pancreatic fistula formation or ulceration at the site of
an anastomosis [70]. Gastrointestinal or intraabdominal
hemorrhage occurs in somewhere between 1% to 8% of
all pancreatic resections and accounts for 11% to 38%
of overall mortality [71] PPH was defined according to
the International Group of Pancreatic Surgeons (ISGPS)
guidelines considering the following three parameters: (1)
time of onset, (2) location, and (3) severity. Early PPH re-
fer to bleeding occurring within 24h and late PPH refers
to the bleeding started after 24h postoperatively. The lo-
cation of bleeding was categorized as intraluminal or ex-
traluminal. Severe hemorrhage required more than 4U of
packed cells within 24h, a decrease in hemoglobin of more
than 4g/dL, or a need for relaparotomy or interventional
angiography to stop the bleeding.
Depending on the severity of hemorrhage, the post-
operative bleeding complications can be categorized in
three different grades. PPH Grade A, has little or no clini-
cal implication, while PPH Grades B and C lead to critical
worsening of the patient’s clinical condition necessitating
further treatment. PPH Grade C was defined as poten-
tially life-threatening bleeding [69].
Sentinel bleeding is a small amount of blood loss via
abdominal drains or NGT several hours before massive
hemorrhage and may be present in 30% to 100% of the
cases. Recognizing this event in a timely fashion may
prevent severe complications, even death. The manage-
ment of early PPH usually involves relaparotomy. How-
34 www.avidscience.com
Recent Advances in Pancreatic Cancer
ever, the management of late PPH is usually conservative
in hemodinamically stabile patients. Endoscopy was fre-
quently undertaken for patients presenting with intralu-
minal bleeding. However the success rate was not high.
Other treatments to achieve definite control of the bleed-
ing, such as surgery or angiographic intervention, may be
required. Finally angiographic intervention should be the
preferred treatment option in hemodynamically stabile
patients whereas relaparotomy remains a valid treatment
option for hemodynamically unstable patients.
Other Complications
Leakage of the gastroenteric or duodenoenteric anas-
tomosis, is the least common anastomotic complication
in pancreatic surgery. The incidence is reported around
1% [72]. Gastroenteric leakage usually led to several ad-
ditional complications, longer hospital stay, and higher
mortality. Its median postoperative day of diagnosis was
approximately 1 week after the index operation, and the
clinical presentation generally consisted of acute abdo-
men and the presence of high drain output suspicious of
gastric content. Although some patients can be managed
by percutaneous drainage alone, operative management
is indicated in most patients with gastroenteric leakage,
unlike leakage of the pancreaticojejunostomy or hepati-
cojejunostomy.
Postoperative chyle leak in the peritoneal cavity,
termed ‘chylous ascites’, is a rare complication following
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Recent Advances in Pancreatic Cancer
abdominal surgery. Chylous ascites following abdominal
surgery results from surgical damage to the cisterna chy-
li or its major tributaries [73]. The incidence is between
0.6-3% in different series. The traditional treatment for
chylous ascites is dietary control with a medium-chain
triglyceride (MCT) diet, intended to reduce the flow of
lymph. However, the effectiveness of MCT therapy as a
single-modality treatment is low. Therefore, total paren-
teral nutrition (TPN) combined with therapeutic para-
centesis has recently been recommended. Moreover, ad-
ministration of octreotide, has been advocated for the
treatment of chylous ascites, because octreotide reduces
fat absorption and decreases lymph fluid excretion. Surgi-
cal treatment is rarely required for postoperative chylous
leakage. It is generally considered that reoperation should
comprehensively depend on daily leakage volume, dura-
tion, decreasing tendency, and patient’s general condition.
If leakage volume is greater than 1500mL/d or drainage
volume remains at high levels (1000mL/d) after fasting,
and total parenteral nutrition is supplied for more than
one week, or lymphography show a large lymphatic vessel
broken parts, surgery should be adopted for chylous leak-
age treatment.
Conclusion
Pancreatic surgery is one of the most complicated
operations. Careful study in this field will increase un-
derstanding, which will lead to additional protocol im-
36 www.avidscience.com
Recent Advances in Pancreatic Cancer
provements to achieve optimal perioperative patient care
for the patient with pancreatic disease. Consequently, it is
important to understand that a multidisciplinary profes-
sional system is crucial to reduce mortality and morbidity
in pancreatic surgery.
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