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 Table of Contents  
Year : 2022  |  Volume : 28  |  Issue : 1  |  Page : 62-66

Factors associated with development of post-operative pancreatic fistula: A record-based observational study

1 Department of General Surgery, Aster Malabar Institute of Medical Sciences, Kozhikode, Kerala, India
2 Department of GI Surgery and Liver Transplantation, Aster Malabar Institute of Medical Sciences, Kozhikode, Kerala, India

Date of Submission24-Jun-2022
Date of Decision10-May-2022
Date of Acceptance11-May-2022
Date of Web Publication14-Jul-2022

Correspondence Address:
Dr. Amal George
Department of General Surgery, Aster Malabar Institute of Medical Sciences, Govindapuram P. O, Kozhikode - 673 016, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ksj.ksj_3_22

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Introduction: Post-operative pancreatic fistula (POPF) is one of the major complications of pancreaticoduodenectomy (PD), which is the procedure of choice for many peripancreatic diseases. POPF may lead to or be combined with post-pancreatectomy haemorrhage and delayed gastric emptying or abscesses and sepsis, possibly leading to subsequent shock, multiorgan failure and mortality. The study was conducted with the objective to identify the factors associated with the development of POPF following PD. Methodology: This was a record-based cross-sectional study done in Kerala which recorded the details of 125 patients who underwent surgery between January 2018 and January 2020. Inclusion criteria were patients admitted with pathology in and around the head of the pancreas and requiring PD. Patient characteristics, disease-related details, pre-operative morbidities, details of surgery, and post-operative details were accessed from the patient record. Results: The mean standard deviation age of the participants was 60 (11.2) years. There was a higher proportion of males compared to females. The underlying lesion was malignant for the majority. Nearly 90% of the participants underwent classical PD. Nearly half of the patients developed POPF of which one-third were clinically relevant. Lack of history of chronic pancreatitis and post-operative drain fluid amylase was found to be significantly associated with POPF occurrence. Conclusion: Lack of history of chronic pancreatitis, amount of drainage fluid and amylase level was found to be significantly associated with the presence of post-operative fistula.

Keywords: Computed tomography, diagnosis, pancreas, pancreaticoduodenectomy

How to cite this article:
George A, Sajan P, Kuruvilla R, Akshay Viswanath U V, Augustine JT, Rajan A, Nambiar R, Sahadevan S, Noushif M. Factors associated with development of post-operative pancreatic fistula: A record-based observational study. Kerala Surg J 2022;28:62-6

How to cite this URL:
George A, Sajan P, Kuruvilla R, Akshay Viswanath U V, Augustine JT, Rajan A, Nambiar R, Sahadevan S, Noushif M. Factors associated with development of post-operative pancreatic fistula: A record-based observational study. Kerala Surg J [serial online] 2022 [cited 2023 Feb 5];28:62-6. Available from: http://www.keralasurgj.com/text.asp?2022/28/1/62/350901

  Introduction Top

Pancreatic cancer is the seventh-most common cause of death due to cancer worldwide and is expected to reach the third position in the future.[1] Significant advances in surgical techniques have brought down perioperative morbidity compared to historic rates.[2] Pancreaticoduodenectomy (PD) involves the removal of the pancreatic head, duodenum, gall bladder and bile duct with or without the removal of the gastric antrum.[2] It is a challenging surgical operation with high post-operative morbidity and mortality.[3] The operation is in most cases performed due to suspected neoplasms in the head of the pancreas, distal common bile duct (CBD) or in the periampullary region.

The post-operative complications of PD operation include post-operative pancreatic fistula (POPF), post-pancreatectomy haemorrhage (PPH) and delayed gastric emptying (DGE). Of these, POPF is often considered to be the clinically most challenging complication.[4] The incidence varies widely across the literature, partly due to different definitions of complications. Today, international definitions of the most common complications of PD make it easier to compare studies. According to the definition provided by the International Study Group of Pancreatic Fistula (ISGPF), POPF manifests as a drain (obtained from operatively or postoperatively placed drain) output with amylase content greater than three times the upper limit of the normal level of serum amylase on or after the 3rd post-operative day (POD)[5] POPF may lead to or be combined with PPH and DGE or abscesses and sepsis, possibly leading to subsequent shock, multiorgan failure and mortality. The previously reported risk factors for POPF include soft pancreatic texture and normal exocrine function, narrow pancreatic duct, and operational details, but the exact pathophysiology for POPF has remained obscure.[6],[7],[8],[9],[10],[11],[12],[13]

Furthermore, ISGPF also divided POPF into three grades, Grade A, B, and C. Grade A pancreatic fistula is an asymptomatic fistula, whereas Grade B and C pancreatic fistula are symptomatic fistulae which need therapeutic intervention such as antibiotics and/or percutaneous drainage for Grade B and resuscitation and/or exploratory laparotomy for Grade C.[5] Once post-operative patients suffer from Grade B or C pancreatic fistula, a series of other severe complications might develop, including intra-abdominal infection, bleeding and even shock.[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] Therefore, it is necessary to minutely understand the pathophysiology of POPF as well as make an early diagnosis and perform corrective measures. The current study was done with the objective of looking at various factors affecting the development of POPF.

  Methodology Top

This was a hospital-based retrospective observational study conducted in a private tertiary care centre located in northern Kerala, India among patients attending the outpatient department of the gastroenterology department. Data collection was record-based and conducted between July 2018 and July 2020. Any patients admitted with pathology in and around the head of the pancreas and requiring PD between January 2018 and January 2020 served as the study population. Patients undergoing emergency PD, patients in infected state, patients with anatomical variations of pancreases and related structures and patients for whom pre-operative computed tomography (CT) findings were unavailable were excluded from the study. The sample size calculation was 125 based on the primary study objective of looking at the predictive value of pre-operative CT in POPF that is published elsewhere. Consecutive sampling of all eligible cases in the study period was done.

Operational definitions

Post-operative pancreatic fistula

POPF was defined as per the 2016 update on ISGPF and was considered to have occurred if there was a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant (CR) development/condition related directly to the POPF. The grades of fistula were categorised as follows:

  • Grade A/BL – A simple 'biochemical leak' that has no clinical importance
  • Grade B – One that requires a change in the post-operative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures
  • Grade C ‒ Fistula that requires reoperation or leads to single or multiple organ failure and/or mortality attributable to the pancreatic fistula.

Chylous drainage

Chyle leak was defined as the output of milky coloured fluid from a drain, drain site or wound on or after POD 3, with a triglyceride (TG) content ≥110 mg/dL (≥1.2 mmol/L).

High drain fluid amount

Persistent drain output of 400–500 mL/day.

High drain fluid amylase

An amylase level that is three times the normal serum amylase level (<100 U/L) was considered high drain fluid amylase. Drain amylase was assessed on the 4th POD.

High drain fluid triglyceride/cholesterol

TG level of >110 mg/dL and cholesterol level varies depends on TG level.

Study procedure

It was a retrospective record-based study. After ethical clearance, records of all patients who underwent surgery in the department of surgical gastroenterology from January 2018 were accessed from the electronic database of the hospital system. Patient characteristics, disease-related details, pre-operative morbidities, details of surgery and post-operative details were accessed from the patient record. No added cost or investigations or treatment procedures happened as part of the study. Ethical clearance was obtained from the Institutional Ethics Committee of Malabar Institute of Medical Sciences Limited before beginning the study.

Data entry and analysis

Data were entered using Microsoft Excel 2016 and analysed using Stata 12 software (manufactured by StataCorp LP, College Station, Texas, USA) and OpenEpi software.

Age was expressed as mean and standard deviation (SD) as the data were normally distributed and also categorised by 10-year intervals. Other continuous variables such as post-operative hospitalisation and intensive care unit (ICU) stay which were non-normally distributed were summarised as median with interquartile range. Categorical variables such as gender, presence of chronic pancreatitis, type of lesion, site of tumour, stage of tumour, type of surgery and drain fluid characteristics were reported as percentages with a 95% confidence interval (CI). Association of development of pancreatic fistula with pre-operative and post-operative factors was also studied using Chi-square test and Fisher's exact test. P < 0.05 was considered statistically significant.

  Results Top

[Table 1] shows the baseline characteristics of the study participants. The age of study participants ranged from 14 to 83 years. The mean (SD) age was 60 (11.2) years, with the highest number of participants falling in the 60–69 group, followed by 50–59 group. There was a higher proportion of males compared to females. Out of 125 participants, 79 (63.2%) were male, whereas the remaining were female.
Table 1: Baseline characteristics of the study participants (n=125)

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Table 2: Post-operative drain fluid characteristics among study participants (n=125)

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Of all the participants who underwent surgery, 114 (91.2%; 95% CI 84.9–95.0) had a malignant lesion and the remaining 11 (8.8%; 95% CI 5.0–15.1) had benign lesions. The most common diagnosis among malignant lesions was periampullary cancer (57.9%). Out of them, 7 (10.6%) were cholangiocarcinoma and 5 (7.6%) were duodenal cancers. Of those with cholangiocarcinoma, four were of distal CBD, two of mid-CBD and one of ampulla. The second-most common was cancer of the head of the pancreas (35.1%), followed by cancer of the uncinate process (5.3%). Majority of the participants had a stage of T2 or higher. However, around 66% of the participants did not have nodal involvement. None of the patients had metastatic lesions. The number of participants who underwent regular PD was 112 (89.6%; 95% CI 83.0–93.8), whereas the remaining 13 underwent pylorus-preserving PD (10.4%; 95% CI 6.2–17.0). The mean (SD) number of days spent in the hospital after surgery was 10.8 (4.1). ICU stay was limited to 1 day for all post-operative patients except two, who stayed for 12 and 14 days, respectively.

Sixty-seven (54%) of patients did not have pancreatic fistula, whereas the rest 58 (46%) had pancreatic fistula. Drain fluid characteristics were normal in the majority of participants. The most common abnormality detected was a high level of amylase in the drain fluid, found in 59 (47.2%), followed by a higher amount of drainage seen in 54 (43.2%). Very few had chylous drainage with high-fat content. POPF of some grade developed in 58 (46.4%; 95% CI 37.9–55.1) participants. The remaining 67 (53.6%; 95% CI 44.8–62.1) did not develop POPF.

[Table 3] and [Table 4] look at the association of various factors with the development of fistula. There was no significant association between sociodemographic details and the development of POPF. Those with no history of chronic pancreatitis as part of their disease profile were found to have a higher risk of developing POPF (P = 0.004). However, there was no significant association between CR-POPF and chronic pancreatitis even though a higher proportion of CR-POPF reported a lack of history of chronic pancreatitis. The amount of drain fluid collected and level of drain fluid amylase were found to be associated with the presence of POPF, with excellent statistical significance (P < 0.001) [Table 2]. However, the nature of the fluid and TG/cholesterol (CH) levels were not found to be associated with it.
Table 3: Association of post-operative fistula with sociodemographic and disease-related characteristics (n=125)

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Table 4: Association of post-operative fistula with drain fluid characteristics (n=125)

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  Discussion Top

The current study found that there was a significant inverse relation of POPF with a history of chronic pancreatitis. There was a negative correlation between the two events. This is supported by the previous literature. In a review published in 2018, Nahm et al. reported how rates of POPF are lowest for patients who have a histopathological diagnosis of either pancreatic ductal adenocarcinoma or chronic pancreatitis, as both are associated with atrophy of the remnant gland due to chronic ductal obstruction. This results in a fibrotic pancreas with a widened pancreatic duct, in which pancreatoenteric anastomosis may be technically easier to achieve.[15] This is directly reported in two studies by Wen et al. and McMillan and Vollmer who report a significant association of chronic pancreatitis with POPF occurrence.[11],[16]

This has also been expressed in terms of fibrosis by many other studies. Jutric et al. found that higher CT density values correlated with a higher level of pancreatic fibrosis, which in turn, correlates negatively with POPF occurrence.[17] Kim et al. found that fibrosis of the remnant pancreatic stem was related to the probability of POPF development.[18] Similarly, Deng et al. reported that pancreatic CT value and the percentage fibrosis of pancreatic lobule in the pancreatic fistula group were both lower than those in non-pancreatic fistula group, indicating that there is a negative correlation between the severity of pancreatic fistula and the pancreatic CT value or the per cent of fibrosis of pancreatic lobule.[19]

The significance of amylase concentration in post-operative drainage fluid has been well recorded and is part of the ISGPF definition of POPF.[5] This has been corroborated by other studies even later. Hanaki et al. and Griffith et al. reported that increased amylase levels on the 1st POD correlated with CR-POPF.[20],[21] Serene et al. reported a negative predictive value of 98.7% if drain amylase values were low on POD 1 and POD 3.[22] Teixeira et al. quantified the relationship between POPF and amylase levels, by stratifying patients based on POD 1 levels. The incidence of fistula increased across the groups. Furthermore, people who died of POPF-related complications had drain fluid amylase values on POD 1 significantly higher than the others in the same fistula group. Hence, they concluded that early drain fluid amylase value is a useful test to stratify patients in relation to the risk of developing pancreatic fistula after pancreatoduodenectomies, in addition to correlate with the severity of this complication.[23] This could not be checked in the current study as amylase levels were recorded as dichotomous values.

Age was reported as associated factor in one study, but the current study did not find any statistical significance in the same.[24] Two studies reported male gender as a risk factor for POPF, but in the current study, there was no significant difference in POPF rates across males and females.[16],[25]

The study has several strengths. Since it was based on the hospital's routine electronic database, records were complete. We did not encounter any missing data. All patients who met the eligibility criteria were taken consecutively and hence there is no sampling bias. Even though it was a retrospective study, the hospital records served as a reliable data source with no recall bias. One limitation of the study was that absolute numerical values were not collected for many variables, which led to the inability in assessing the correlation of values of amylase, amount and TG/CH with POPF grade.

  Conclusion Top

There is a significant inverse association between POPF and chronic pancreatitis, and a positive relation between POPF and amylase levels and findings from this study will help in predicting the chances of developing POPF.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Fischer JE. Pancreaticoduodenectomy and total pancreatectomy for cancer. In: Fischer's Mastery of Surgery. 7th ed., Ch. 127. China: Wolters Kluver; 2019. p. 4459-504.  Back to cited text no. 2
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Lee CW, Pitt HA, Riall TS, Ronnekleiv-Kelly SS, Israel JS, Leverson GE, et al. Low drain fluid amylase predicts absence of pancreatic fistula following pancreatectomy. J Gastrointest Surg 2014;18:1902-10.  Back to cited text no. 7
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DI Martino M, Mora-Guzman I, Blanco-Traba YG, Díaz MC, Khurram MA, Martín-Pérez E. Predictive factors of pancreatic fistula after pancreaticoduodenectomy and external validation of predictive scores. Anticancer Res 2019;39:499-504.  Back to cited text no. 13
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Nahm CB, Connor SJ, Samra JS, Mittal A. Postoperative pancreatic fistula: A review of traditional and emerging concepts. Clin Exp Gastroenterol 2018;11:105-18.  Back to cited text no. 15
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Jutric Z, Johnston WC, Grendar J, Haykin L, Mathews C, Harmon LK, et al. Preoperative computed tomography scan to predict pancreatic fistula after distal pancreatectomy using gland and tumor characteristics. Am J Surg 2016;211:871-6.  Back to cited text no. 17
Kim Z, Kim MJ, Kim JH, Jin SY, Kim YB, Seo D, et al. Prediction of post-operative pancreatic fistula in pancreaticoduodenectomy patients using pre-operative MRI: A pilot study. HPB (Oxford) 2009;11:215-21.  Back to cited text no. 18
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Griffith D, Hanna T, Wong K, Reece-Smith A, Aroori S, Bowles M, et al. Comparison of lipase and amylase for diagnosing post-operative pancreatic fistulae. ANZ J Surg 2018. doi: 10.1111/ans.14266.  Back to cited text no. 21
Serene TEL, Vishalkumar SG, Padmakumar JS, Terence HC, Keem LJ, Bei W, et al. Predictive value of postoperative drain amylase levels for postoperative pancreatic fistula. Ann Hepato-Biliary-Pancreat Surg. 2018;22:397-404.  Back to cited text no. 22
Teixeira UF, Rodrigues PD, Goldoni MB, Sampaio JA, Fontes PR, Waechter FL. Early drain fluid amylase is useful to predict pancreatic fistula after pancreatoduodenectomy: Lessons learned from a southern brazilian center. Arq Gastroenterol 2018;55:160-3.  Back to cited text no. 23
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  [Table 1], [Table 2], [Table 3], [Table 4]


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