Perioperative Care and Management of Complications in Pancreatic

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Recent Advances in Pancreatic Cancer Recent Advances in Pancreatic Cancer

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AbstractPancreatic 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.

IntroductionPancreatic 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

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: [email protected]

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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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-

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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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 preoperative stage allows for comfortable and easy intra-operative and postoperative care. Specific evaluations per-taining to individual characteristics of each patient must be done in order to achieve the aforementioned kind of care. Moreover, the combination of many factors should be considered when assessing the risk of surgical inter-vention. Patient related risks are comorbid diseases, the duration of disease, and the ability to tolerate the physi-ological stress due to surgical procedure.

Several scoring systems have been created to evalu-ate possible surgery and anesthesia related mortality and

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)

E-PASS

ISS/TRISS

POSSUM

P-POSSUM

SAPS

Sepsis score

Disease score

Treatment-related intervention score

ASA

Goldman cardiac risk index

Hospital prognostic index

Prognostic nutritional index

Risk of pulmonary complications



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Goldman Cardiac Risk Index [22] is probably one of the best models that evaluate cardiac risk with regards to surgery. Scoring is done by nine different clinical factors and patients are divided into four risk groups based on their total score (Table 2).

Table 2: Goldman cardiac risk index.

The American Society of Anesthesiologists (ASA) scoring system (Table 3) was initially developed to inform the anesthetist about patients’ comorbid diseases. Due to its ease of use and lack of need for additional testing, ASA continues to be used in order to assess surgery related risks. The ASA scoring system is directly associated with

perioperative variables, such as perioperative morbidity and mortality, as well as blood loss during surgery, post-operative ventilation time, and length of stay in intensive care. It has been shown that postoperative morbidity in-creases proportionally with the size of surgical interven-tion, ASA class, respiratory disease symptoms, and the presence of tumor [17].

Table 3: ASA Classification.

Nutritional assessment is important in terms of evaluating patients’ physiological state, immunological function, and fluid balance as well as regulating patients’ metabolic responses to trauma and surgery. Loss of 10% of body weight in the last 6 months and albumin values lower than 3g/dL allow for patients to be diagnosed with malnutrition. The frequency of postoperative complica-tions in patients with malnutrition is higher, therefore these patients should be provided with nutritional support for at least 2 weeks prior to surgery [23]. The prognostic nutritional index (PNI) has been developed for the pre-diction of mortality-related risk of complications and is directly proportional with postoperative sepsis and death

Causes of cardiac risk Points

Myocardial infarction within the last 6 months 10

Age>70 5

Severe stenosis of aortic valve 11

Non-sinus rhythmin the preoperative ECG 3

or atrial premature beats with sinus rhythm

More than five premature ventricular contractions 7

per minute in the preoperative period

Worsening of general condition 3

Abdominal, thoracic or aortic surgery 3

Emergency surgery 4

Group Point Risk of life-threatening complications Risk of cardiac death (%)

I 0-5 0,7 0,2

II 6-12 5 2

III 3-25 11 2

IV ≥26 22 56

I Normal Healthy patient

II Patient with mild systemic disease

III Patient with non-incapacitating systemic disease

IV Patient with an incapacitating systemic disease that is a constant threat to life

V Moribund patient that is not expected to survive for 24 hours

E Urgent



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[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

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.

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 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

Physiological Parameters Surgical Parameters

Age (year)

Cardiac symptoms/Posteroanterior lung x-ray

Respiratory symptoms/Posteroanterior lung x-ray

Pulse

Systolic blood pressure (mmHg)

Glasgow coma score

Hemoglobin

Leukocyte count (x1012)

Urine (mmol/l)

Na+ and K+ levels (mmol/l)

ECG

Size of the operation

Multiple procedures

Blood loss (ml)

Peritoneal damage

Malignancy

Type of surgery



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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-

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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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

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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not recommended. On the other hand, many studies have reached a consensus about which method of drainage to use when necessary. Since percutaneous biliary drainage poses a risk of spreading the tumor, the method of choice is stenting with metal or plastic stents by using the endo-scopic method.

Table 5: Venous thromboembolism prophylaxis based on risk classification.

IPC: Intermittent Pneumatic Compression; LDUH: Low Dose Un-fractioned Heparin; LMWH: Low Molecular Weight Heparin.

Intraoperative StageThe importance of intraoperative period and early

postoperative period in the evaluation of perioperative period has been raised in recent years.

There are several studies comparing differences in perioperative care at both low and high mortality hospi-tals. In these studies using intraoperative hemodynamic monitoring, perioperative sequential compression devic-es, postoperative venous thromboembolism chemopro-phylaxis and epidural catheters for effective pain control are found the factors to be important for reducing mortal-ity and morbidity rates. Epidural catheters provide superi-or pain control and reduce the incidence of cardiopulmo-nary complications, compared to systemic opioid [47-50].

Recently there are studies which evaluate the rela-tionship between perioperative fluid resuscitation and postoperative complications in patients undergoing pan-creaticoduodenectomy. It is well known that patients fre-quently receive large volumes of intravenous fluid during and following major intraabdominal operations with the intension of replacing operative fluid losses. However the impact of fluid resuscitation on the development of post-operative complications is examined. Liberal fluid admin-istration is correlated with bowel edema and anastomotic compromise. It is well documented that increased perio-perative fluid especially in the early postoperative period is associated with increased major adverse events. Finally

Risk type Low Medium High Very highExample Minor surgery,

no additional risk factors

Major abdominal surgery

Age>40

No additional risk factor


Age>60

Additional risk factors


History of major venous thromboem-bolism

Hypercoagulopty disorders

Deep vein thrombosis risk (without pro-phylaxis)

2% 10-20% 20-40% 40-80%

Pulmonary emboli risk

O,2% 1-2% 2-4% 4-10%

Primary pro-phylaxis

No need IPC LDUH(5000U 3 times a day)

Or

LMWH(Deltaparin 5000U/day or Enaxiparin 4000U/day or Tinzaparin 4500U/day)

LDUH(5000U 3 times a day)

Or

LMWH(Deltaparin 5000U/day or Enaxi-parin 4000U/day or Tinzaparin 4500U/day)

Alternative propylaxis

No need LDUH(5000U 2 times a day)

Or

LMWH(Deltaparin 2500U/day or Enaxiparin 2000U/day or Tinzaparin 3500U/day)

IPC Heparin and IPC



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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 PeriodPostoperative 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-

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 be appropriate to continue after surgery according to cur-rent guidelines [56]. As generally recognized, parenteral nutrition is associated with an increased risk of compli-cations. However, this is beneficial during postoperative period of undernourished patients, in whom enteral nu-trition is not feasible or tolerated within 7-10 days of their procedure [57].

ComplicationsIn spite of its low associated mortality, significant

morbidity is still observed after pancreatic surgery espe-cially in Whipple procedures. A large number of compli-cations are possible, and many are not directly related to the pancreatic operation. These possible complications are shown on Table 6.

Table 6: Complications after the Whipple operation.

Postoperative Pancreatic Fistula (POPF)Pancreatic fistula is the Achilles heel of the Whipple

operation. A pancreatic fistula increases the morbidity of the operation by leading to other infectious complications (such as wound infection, abscess), delaying resumption of oral diet, prolonging hospital stay, and sometimes re-quiring reoperation. In large series, pancreatic fistula rate following Whipple is reported as 2-12%. In patients with soft-textured glands or with a pancreatic duct smaller than 3 mm leakage, pancreatic fistula is observed in 20-30% of cases. The definition of pancreatic fistula is controversial. With the aim of creating possible comparisons between published results and arrive at a definition of pancreatic fistula, an international group of pancreatic surgeons met [58]. As a result they came to an agreement and defined a postoperative pancreatic fistula as; a failure of healing of a pancreatic-enteric anastomosis or a parenchymal leak not directly related to an anastomosis. In order to achieve a standardized quantitation, they included a value in their definition; any drain fluid output after postoperative day 3 with an amylase content, three times greater than the serum value constitutes a pancreatic fistula. Furthermore with the aim of categorizing the severity of a pancreatic fistula, they created 3 different grades and predefined ten main criteria are utilized to differentiate each grade. These ten criteria are; elevated drain amylase, persistent drain-age, signs of infection, diagnostic imaging, specific treat-ments, readmission, critical condition, re-operation, sep-

Some possible complications after the whipple operationPancreatic fistula

Delayed gastric emptying

Biliary fistula

Wound infection

Intraabdominal abcess

Cholangitis

Pancreatitis

Reoperation

Cardiopulmonary complications

Gastrointestinal bleeding

Deep venous thrombosis/pulmonary embolism

Cerebrovascular accident

Urinary tract infection

Line infection



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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-

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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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

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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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.

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 EmptyingDelayed 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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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

• 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.

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 LeakageHepaticojejunostomy (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 week.

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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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

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 HemorrhageAlthough 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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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-

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 ComplicationsLeakage 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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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.

ConclusionPancreatic surgery is one of the most complicated

operations. Careful study in this field will increase un-derstanding, which will lead to additional protocol im-

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.

References1. Revels SL, Wong SL, Banerjee M, Yin H, Birkmey-

er JD. Differences in perioperative care at low- and high-mortality hospitals with cancer surgery. Ann Surg Oncol. 2014; 21: 2129-2135.

2. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001; 37: S4-66.

3. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2011; 61-69

4. Jimenez RE, Fernandez-del Castillo C, Rattner DW, Chang Y, Warshaw AL. Outcome of pancrea-ticoduodenectomy with pylorus preservation or with antrectomy in the treatment of chronic pan-creatitis. Ann Surg. 2000; 231: 293-300.

5. Edge SB, Fritz AG, Byrd DR. AJCC Cancer staging Manual Handbook. 7th edn. New York: Springer. 2010.

6. Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, et al. Borderline resectable pancreatic cancer: the



www.avidscience.com

importance of this emerging stage of disease. J Am Coll Surg. 2008; 206: 833-846.

7. Vauthey JN, Dixon E. AHPBA/SSO/SSAT Con-sensus Conference on Resectable and Borderline Resectable Pancreatic Cancer: rationale and over-view of the conference. Ann Surg Oncol. 2009; 16: 1725-1726.

8. Tempero MA, Arnoletti JP, Behrman SW, Ben-Josef E, Benson AB 3rd. Pancreatic Adenocar-cinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2012; 10: 703-713.

9. Mollberg N, Rahbari NN, Koch M, Hartwig W, Hoeger Y, et al. Arterial resection during pancrea-tectomy for pancreatic cancer: a systematic review and meta-analysis. Ann Surg. 2011; 254: 882-893.

10. Cameron JL, Pitt HA, Yeo CJ, Lillemoe KD, Kauf-man HS, et al. One hundred and forty-five con-secutive pancreaticoduodenectomies without mortality. Ann Surg. 1993; 217: 430-435.

11. Fernández-del Castillo C, Rattner DW, Warshaw AL. Standards for pancreatic resection in the 1990s. Arch Surg. 1995; 130: 295-299.

12. Katlic MR. Principles of Geriatric Surgery. InR.A. Rosenthal et al (eds). Principles and Practice of Geriatric Surgery. Springer Science +Business

Media. LLC. 2011; 235-251.

13. Lieberman MD, Kilburn H, Lindsey M, Brennan MF. Relation of perioperative deaths to hospital volume among patients undergoing pancreatic resection for malignancy. Ann Surg. 1995; 222: 638-645.

14. Gordon TA, Burleyson GP, Tielsch JM, Cameron JL. The effects of regionalization on cost and out-come for one general high-risk surgical proce-dure. Ann Surg. 1995; 221: 43-49.

15. Imperato PJ, Nenner RP, Starr HA, Will TO, Rosenberg CR, et al. The effects of regionalization on clinical outcomes for a high risk surgical pro-cedure: a study of the Whipple procedure in New York State. Am J Med Qual. 1996; 11: 193-197.

16. Arvidsson S, Ouchterlony J, Sjöstedt L, Svărdsudd K. Predicting postoperative adverse events. Clini-cal efficiency of four general classification systems. The project perioperative risk. Acta Anaesthesiol Scand. 1996; 40: 783-791.

17. Menke H, Klein A, John KD, Junginger T. Predic-tive value of ASA classification for the assessment of the perioperative risk. Int Surg. 1993; 78: 266-270.

18. Klotz HP, Candinas D, Platz A, Horvàth A, Dindo D, et al. Preoperative risk assessment in elective



www.avidscience.com

general surgery. Br J Surg. 1996; 83: 1788-1791.

19. Goffi L, Saba V, Ghiselli R, Necozione S, Mattei A, et al. Preoperative APACHE II and ASA scores in patients having major general surgical operations: prognostic value and potential clinical applica-tions. Eur J Surg. 1999; 165: 730-735

20. Prytherch DR, Whiteley MS, Higgins B, Weaver PC, Prout WG, et al. POSSUM and Portsmouth POSSUM for predicting mortality. Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity. Br J Surg. 1998; 85: 1217-1220.

21. Kiran RP, Delaney CP, Senagore AJ, Preoperative evaluation and risk assessment scoring. ClinColo-rectSurg. 2003; 16: 75-84.

22. Goldman L, Caldera DL, Nussbaum SR, South-wick FS, Krogstad D, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977; 297: 845-850.

23. Probst P, Haller S, Dörr-Harim C, Bruckner T, Ul-rich A, et al. Nutritional Risk in Major Abdominal Surgery: Protocol of a Prospective Observational Trial to Evaluate the Prognostic Value of Differ-ent Nutritional Scores in Pancreatic Surgery JMIR Res Protoc. 2015; 4: e132.

24. Mullen JL, Gertner MH, Buzby GP, Goodhart GL, Rosato EF. Implications of malnutrition in the

surgical patient. Arch Surg. 1979; 114: 121-125.

25. Chen T, Wang H, Wang H, Song Y, Li X, et al. POSSUM and P-POSSUM as predictors of post-operative morbidity and mortality in patients un-dergoing hepato-biliary-pancreatic surgery: a me-ta-analysis.Ann SurgOncol. 2013; 20: 2501-2510.

26. Gawande AA, Kwaan MR, Regenbogen SE, Lipsitz SA, Zinner MJ. An Apgar score for surgery. J Am Coll Surg. 2007; 204: 201-208.

27. Assifi M, Lindenmeyer J, Leiby B, Grunwald Z, Rosato E, et al. Surgical Apgar Score Predicts Peri-operative Morbidity in Patients Undergoing Pan-creaticoduodenectomy at a High-Volume Center. J GastrointestSurg. 2012; 16: 275-281.

28. Dindo D, Demartines N, Clavien PA. Classifica-tion of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240: 205-213.

29. Miller BC, Christein JD, Behrman SW, Drebin JA, Pratt WB, et al. A multi-institutional external vali-dation of the fistula risk score for pancreatoduo-denectomy. J Gastrointest Surg. 2014; 18: 172-179.

30. Palani Velu LK, Chandrabalan VV, Jabbar S, Mc-Millan DC, McKay CJ, et al. Serum amylase on the night of surgery predicts clinically significant pancreatic fistula after pancreaticoduodenectomy. HPB (Oxford). 2014; 16: 610-619.



www.avidscience.com

31. Velu LK, McKay CJ, Carter CR, McMillan DC, Jamieson NB, et al. Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy. Br J Surg. 2016.

32. Callery MP, Pratt WB, Kent TS, Chaikof EL, Vollmer CM Jr. A Prospectively Validated Clini-cal Risk Score Accurately Predicts Pancreatic Fis-tula after Pancreatoduodenectomy. Journal of the American College of Surgeons. 2013; 216: 1-14.

33. Brecher ME, Goodnough LT. The rise and fall of preoperative autologous blood donation. Transfu-sion. 2001; 41: 1459-1462.

34. Donald GW, Sunjaya D, Lu X, Chen F, Clerkin B, et al. Perioperative antibiotics for surgical site infection in pancreaticoduodenectomy: does the SCIP-approved regimen provide adequate cover-age? Surgery. 2013; 154: 190-196.

35. Fong ZV, McMillan MT, Marcegian G, SahoraK, Malleo G, et al. Discordance Between Periopera-tive Antibiotic Prophylaxis and Wound Infection Cultures in Patients Undergoing Pancreaticoduo-denectomy. JAMA Surg. Published online. 2015.

36. Mohammed S, Evans C, VanBuren G, Hodges S, Silberfein E, et al. Treatment of bacteriobilia decreases wound infection rates after pancreati-coduodenectomy. HPB (Oxford). 2014; 16: 592-

598.

37. JCS Joint Working Group. Guidelines for the di-agnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2009). Circ J. 2011; 75: 1258-1281.

38. Hayashi H, Morikawa, Yoshida H, Motoi F, Okada T, et al. Safety of postoperative thromboprophy-laxis after major hepatobiliary-pancreatic surgery in Japanese patients. Surg Today. 2014; 44: 1660-1668.

39. Rasmussen MS, Jørgensen LN, Wille-Jørgensen P. Prolonged thromboprophylaxis with low molecu-lar weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2009; 1: CD004318.

40. Di Nisio M, Porreca E, Otten HM, Rutjes AW. Pri-mary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemo-therapy. Cochrane Database Syst Rev. 2014; 8: CD008500.

41. Wolf A, Pucci M, Gabale S, McIntyre C, Irizarry A, et al. Safety of perioperative aspirin therapy in pancreatic operations. Surgery Volume 155, Issue. 2014; 39-46.

42. Sugiyama H, Tsuyuguchi T, Sakai Y, Mikata R, Yasui S, et al. Current status of preoperative drain-age for distal biliary obstruction.World J Hepatol. 2015; 7: 2171-2176.



www.avidscience.com

43. Fischer M, Matsuo K, Gonen M, Grant F, Demat-teo RP, et al. Relationship between intraoperative fluid administration and perioperative outcome after pancreaticoduodenectomy: results of a pro-spective randomized trial of acute normovolemic hemodilution compared with standard intraoper-ative management. Ann Surg. 2010; 252: 952-958.

44. de Aguilar-Nascimento JE, Diniz BN, do Carmo AV, Silveira EA, Silva RM. Clinical benefits after the implementation of a protocol of restricted perioperative intravenous crystalloid fluids in ma-jor abdominal operations. World J Surg. 2009; 33: 925-930.

45. Grocott MP, Mythen MG, Gan TJ. Perioperative fluid management and clinical outcomes in adults. Anesth Analg. 2005; 100: 1093-1106.

46. Brandstrup B, Tønnesen H, Beier-Holgersen R, Hjortsø E, Ørding H, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg. 2003; 238: 641-648.

47. Behman R, Hanna S, Coburn N, Law C, Cyr DP, et al. Impact of fluid resuscitation on major adverse events following pancreaticoduodenectomy. Am J Surg. 2015; 210: 896-903.

48. Amin AN, Lin J, Johnson BH, Schulman KL. Clin-ical and economic outcomes with appropriate or

partial prophylaxis. Thromb Res. 2010; 125: 513-517.

49. Hamilton MA, Cecconi M, Rhodes A. A systemat-ic review and meta-analysis on the use of preemp-tive hemodynamic intervention to improve post-operative outcomes in moderate and high-risk surgical patients. Anesthesia and analgesia. 2011; 112: 1392-1402.

50. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, et al. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002; 359: 1276-1282.

51. Melis M, Marcon F, Masi A, Sarpel U, Miller G, et al. Effect of intra-operative fluid volume on peri-operative outcomes after pancreaticoduodenecto-my for pancreatic adenocarcinoma. J Surg Oncol. 2012; 105: 81-84.

52. Gustaffson UO, Hausel J, Thorell A. Adherence to the Enhanced Recovery after Surgery proto-col and outcomes after colorectal cancer surgery. Arch Surg. 2011; 146: 571-e577.

53. Katherine A Morgan, William P Lancaster, Megan L Walters, Stefanie M Owczarski, Carlee A Clark, et al. Enhanced Recovery After Surgery Protocols Are Valuable in Pancreas Surgery Patients. J Am Coll Surg. 2016; 222: 658-664.

54. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Post-



www.avidscience.com

operative pain experience: results from a national survey suggest postoperative pain continues to be unmanaged. AnesthAnalg. 2003; 97: 534-540

55. La Torre M, Ziparo V, Nigri G, Cavallini M, Bal-ducci G, et al. Malnutrition and pancreatic sur-gery: prevalence and outcomes. J Surg Oncol. 2013; 107: 702-708.

56. Weimann A, Braga M, Harsanyi L. ESPEN Guide-lines on Enteral Nutrition: Surgery including or-gan transplantation. ClinNutr. 2006; 25: 224-244.

57. Lassen K, Coolsen MM, Slim K, Carli F, de Agui-lar-Nascimento JE, et al. ERAS® Society; European Society for Clinical Nutrition and Metabolism; In-ternational Association for Surgical Metabolism and Nutrition. Guidelines for perioperative care for pancreaticoduodenectomy: Enhanced Recov-ery after Surgery (ERASÂ®) Society recommenda-tions. Clin Nutr. 2012; 31: 817-830.

58. Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, et al. Postoperative pancreatic fistula: an inter-national study group (ISGPF) definition. Surgery. 2005; 138: 8-13.

59. Lin JW, Cameron JL, Yeo CJ, Riall TS, Lillemoe KD. Risk factors and outcomes in postpancreati-coduodenectomy pancreaticocutaneous fistula. J Gastrointest Surg. 2004; 8: 951-959.

60. Lillemoe KD, Cameron JL, Kim MP. Does fibrin glue sealant decrease the rate of pancreatic fis-tula after pancreaticoduodenectomy? Results of a prospective randomized trial. J GastrointestSurg. 2004; 8: 766-772.

61. Connor S, Alexakis N, Garden OJ, Leandros E, Bramis J, et al. Meta-analysis of the value of soma-tostatin and its analogues in reducing complica-tions associated with pancreatic surgery. Br J Surg. 2005; 92: 1059-1067.

62. Wang W, Tian B, Babu SR, Zhang Y, Yang M. Ran-domized, Placebocontrolled study of the efficacy of preoperative somatostatin administration in the prevention of postoperative complications fol-lowing pancreaticoduodenectomy. Hepatogastro-enterology. 2013; 60.

63. Conlon KC, Labow D, Leung D. Prospective rand-omized clinical trial of the value of intraperitoneal drainage after pancreatic resection. Ann Surg. 2001; 234: 487-493.

64. Lai EC, Chung NT, Yang GP, Li MK. Internal pancreatic ductal stenting to reduce leakage rate of pancreaticojejunostomy after pancreaticoduo-denectomy: a comparative study. Hepatogastro-enterology. 2011; 58: 163-167.

65. Motoi F, Egawa S, Rikiyama T, Katayose Y, Unno M. Randomized clinical trial of external stent



www.avidscience.com

drainage of the pancreatic duct to reduce postop-erative pancreatic fistula after pancreaticojejunos-tomy. Br J Surg. 2012; 99: 524-531.

66. Tani M, Kawai M, Hirono S, Hatori T, Imaizumi T, et al. Use of omentum or falciform ligament does not decrease complications after pancreaticoduo-denectomy: nationwide survey of the Japanese Society of Pancreatic Surgery. Surgery. 2012; 151: 183-191.

67. Moritz N Wente, Claudio Bassi, Christos Der-venis, Abe Fingerhut, Dirk J et al. Delayed gastric emptying (DGE) afterpancreatic surgery: A sug-gesteddefinition by the International Study Group of Pancreatic Surgery (ISGPS) Surgery. 2007; 142: 761-768.

68. Suzuki Y, Fujino Y, Tanioka Y, Ajiki T, Hiraoka K, et al. Factors influencing hepaticojejunostomy leak following pancreaticoduodenal resection; importance of anastomotic leak test. Hepatogas-troenterology. 2003; 50: 254-257.

69. Moritz N Wente, Johannes A Veit, Claudio Bassi, Christos Dervenis, Abe Fingerhut, et al. Postpan-createctomy hemorrhage (PPH) An International Study Groupof Pancreatic Surgery (ISGPS) defini-tion. Surgery. 2007; 142: 20-25.

70. Darnis B, Lebeau R, Chopin-Laly X, Adham M. Postpancreatectomy hemorrhage (PPH): predic-

tors and management from a prospective data-base. Langenbecks Arch Surg. 2013; 398: 441-448.

71. Tien YW, Lee PH, Yang CY, Ho MC, Chiu YF. Risk factors of massive bleeding related to pancreatic leak after pancreaticoduodenectomy. J Am Coll Surg. 2005; 201: 554-559.

72. Winter JM, Cameron JL, Yeo CJ, Lillemoe KD, Campbell KA, et al. Duodenojejunostomy leaks after pancreaticoduodenectomy. J Gastrointest Surg. 2008; 12: 263-269.

73. Malik HZ, Crozier J, Murray L, Carter R. Chyle leakage and early enteral feeding following pan-creatico-duodenectomy: management options. Dig Surg. 2007; 24: 418-422.

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Perioperative Care and Management of Complications in Pancreatic