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Original Article

The impact of a postoperative pancreatic fistula on clinical andeconomic outcomes following pancreaticoduodenectomy

Manish Srivastava*, Vinay Kumaran, Naimish Mehta

Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India

Keywords:

Postoperative pancreatic fistula

Pancreaticoduodenectomy

Cost analysis

* Corresponding author. Tel.: þ91 9910276749E-mail address: manishsrivastava_dr@ya

2352-0817/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.cmrp.2014.01.010

a b s t r a c t

Introduction: A postoperative pancreatic fistula is the most serious complication after

pancreaticoduodenectomy (PD). We studied its impact on the patients’ clinical and eco-

nomic outcomes in a tertiary care teaching hospital in India.

Methods: We performed a prospective analysis of 95 patients who underwent PD in our

hospital for various periampullary and pancreatic lesions between January 2009 and

December 2012. The effect of the pancreatic fistula on the postoperative clinical and eco-

nomic outcomes including the length of hospital stay and treatment cost was analyzed.

Results: Thirty-five (36.8%) patients developed a fistula according to the International Study

Group on Pancreatic Fistula (ISGPF) definition. There were 12 grade A fistulas (12.6%), 17

grade B (17.9%) and 6 grade C (6.6%). The median length of hospital stay for the no fistula,

grades A, B, and C fistula groups was 11, 11, 15, and 17.5 days, respectively. The hospital

stay of the patients significantly increased with the increasing severity of the fistula

(p ¼ 0.002). The median total cost of the treatment was Indian Rupees 297605, 327768,

501374, and 671617 in the no fistula, grades A, B, and C fistula groups, respectively.

Conclusions: The standardized definitions of PF as put forth by the ISGPF allow for more

equitable comparison among institutions. Increasing PF grades had a negative clinical and

economic impact on patients and their healthcare resources.

Copyright ª 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All

rights reserved.

1. Introduction

Pancreaticoduodenectomy (PD) is the recommended treat-

ment of choice for various benign andmalignant lesions in the

periampullary and pancreatic head region.1 Along with being

a technically demanding procedure, it is also accompanied by

morbidity and mortality and also causes a substantial strain

on the patient’s health and economic resources. Previous re-

ports2 on PD reported a postoperative morbidity rate of 60%

.hoo.co.in (M. Srivastava).2014, Sir Ganga Ram Hosp

and mortality rate reaching 33%, with a dismal long term

outcome. Disheartened with the risk accompanying this pro-

cedure, Crile et al3 and van Heerden et al4 even advocated the

alternative bypass procedures rather than proceeding for PD.

However in the last few decades, there has been a dramatic

decline in the surgical morbidity and mortality rates. Many of

the high volume pancreatic surgical centers, mainly from the

west, have reported a mortality rate of less than 5% and

morbidity between 35% and 50%.5,6 The factors stated as

ital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved.

c u r r e n t m e d i c i n e r e s e a r c h and p r a c t i c e 4 ( 2 0 1 4 ) 1e62

contributing to this transformation are continued improve-

ment in the surgical techniques, better understanding of

pancreatic diseases, advances in the diagnostic accuracy with

computed tomography (CT) angiography, better patient se-

lection, and improvements in the peri-operative care espe-

cially better management of the postoperative

complications.7

The most common postoperative complications after PD

are delayed gastric emptying (DGE), wound infections and

postoperative pancreatic fistula (POPF).8 Of these, POPF is

considered as the most ominous. The reported incidence of

POPF varies from 10% to 30% depending on the definition

used.9e12 This variability is mainly due to the different defi-

nitions of POPF based on drain fluid amylase, volume and

duration of the drainage.13 When various definitions of POPF

are applied to the same group of patients, the incidence of

POPF can range from 10% to 29%.13 In an effort to address this

problem, an international consortium of 37 leading pancreatic

surgeons from 15 countries, the International Study Group on

Pancreatic Fistula (ISGPF) recommended a universally appli-

cable definition of POPF and a grading system for fistula, based

on severity and clinical impact on the patient.14

Studies15,16 have reported that POPF adversely affects

postoperative outcome after PD including prolonging the

length of hospital stay and increasing the cost of treatment.

Furthermore, POPF often requires imaging-guided percuta-

neous drainage, prolonged parenteral antibiotic therapy, im-

aging surveillance and, sometimes, reoperations. The goal of

our study was to quantify the consequences of adverse out-

comes after PD especially POPF using the ISGPF criteria in

terms of the length of hospital stay, the cost of treatment and

medical resources utilization in a high volume surgical

gastroenterology unit in a tertiary care teaching hospital in

India. We hypothesized that POPF increases the length of

hospital stay and the cost of the treatment, with increasing

severity of the fistula.

2. Methods

2.1. Patients

This study was conducted in surgical gastroenterology unit 1

at Sir Ganga Ram Hospital, a tertiary care teaching hospital in

New Delhi, India. A prospective analysis was carried out in 95

patients who underwent classic PD (91) or pylorus-preserving

PD (4) for periampullary and pancreatic lesions between

January 2009 and December 2012. Imaging revealed that the

majority of patients had periampullary lesions (64). The others

had pancreatic head lesions (23), CBD lesions (3), duodenal

lesions (3) and combined stomach and duodenal lesions (2).

All patients were taken to the operating room with intent for

curative or palliative resection of suspected periampullary/

pancreatic head neoplasms, pancreatitis, intraductal papillary

mucinous neoplasm, or cystic neoplasms. There were 77 pa-

tients with adenocarcinoma proven in final biopsy, neuroen-

docrine carcinoma (7), cystic neoplasms of the pancreas (3),

gastrointestinal stromal tumor (1), leiomyosarcoma (1),

pancreatitis (1), arteriovenous malformation (1), and miscel-

laneous (4).

2.2. Surgical technique

Following resection of the pancreaticoduodenectomy spec-

imen, a pancreatico-jejunal anastomosis was constructed in

dunking (77) or binding (3) techniques, end-to-end; and duct-

to-mucosa technique (15), end-to-side; with a two layer

interrupted anastomosis. External ductal stents were used in

76 cases and exteriorized through the lateral abdominal wall.

No pancreaticogastrostomies were performed. Reconstruc-

tion was done using an isolated Roux loop in 67 and a single

loop in 28 cases. Hepatico-jejunal anastomosis was done in an

end-to-side fashion, with a single layer interrupted or

continuous anastomosis. A T tube was used to stent the

hepatico-jejunal anastomosis in 42 cases and exteriorized

through the lateral abdominal wall. A single drain was

routinely placed anterior to the pancreatico-jejunal anasto-

mosis and exteriorized through the lateral abdominal wall. A

feeding jejunostomy by the Witzel technique, using a No. 12

soft Ryle’s tube, was fashioned in all the patients.

2.3. Postoperative management

All patients were treated by a standardized postoperative

protocol for pancreaticoduodenectomy used in our unit. The

amylase levels were estimated from the intra-operatively

placed drain fluid on postoperative day (POD) 3 and every

alternate day, usually till the drain was removed. Post-

operative Octreotide was given subcutaneously (dose 150 mcg

every 8 hours) for 5 days in 58 cases and continued in patients

who developed POPF. All patients had drains removed at the

operating surgeon’s discretion. Drains were maintained

longer if the patient had high amylase levels, generous fluid

output, or a sinister appearance of the effluent. Computed

tomography was used to assess for fluid collections whenever

indicated based on clinical suspicion (37). Additional man-

agement methods for POPF with intra-abdominal collection

included percutaneous computed tomography (CT)-guided

drainage, administration of antibiotics, and supplemental

(i.e., parenteral or enteral) nutritional support.

2.4. Definitions of POPF and other morbidity

A POPF was defined, according to the ISGPF criteria, as output

via intra-operatively placed drain of any measurable volume

of drain fluid on or after POD 3, with amylase content greater

than three times of the upper normal serum value (>300 IU).14

All patients below this threshold were considered to have no

fistula. Three grades of POPF were determined according to

the clinical severity. The grades were determined only after

complete postoperative follow-up was accomplished.

Grade A fistula, is also called a “transient fistula” which has

no clinical impact. The patients require little or no change in

the clinical management. A grade A fistula is not associated

with a delay in hospital discharge; however, the patient may

be discharged with the drain. The drain is usually removed

within three weeks. Imaging studies do not reveal worrisome

or suspicious peri-pancreatic collections.

Grade B fistula is symptomatic and clinically apparent, and

patients require changes in clinical management or adjust-

ment of the clinical pathway. Theymay experience abdominal

c u r r e n t m e d i c i n e r e s e a r c h and p r a c t i c e 4 ( 2 0 1 4 ) 1e6 3

pain, fever, nausea, intolerance to oral intake, or other bowel

related symptoms. The patients with grade B fistulae usually

require antibiotic therapy and enteral or parenteral nutrition.

The peri-pancreatic drain or percutaneously inserted drains

may usually be needed to be in place for more than three

weeks.

A grade C fistula is severe and clinically significant, and

requires major clinical adjustments and aggressive interven-

tion is needed for these patients. They are treatedwith enteral

or parenteral nutrition, antibiotics, and somatostatin analogs

often in the intensive care unit (ICU). A CT scan usually shows

a worrisome peri-pancreatic fluid collection that needs

percutaneous drainage. Patients with these fistulae, in

contrast to grade B fistulae, appear ill and unstable, present in

critical condition, and are susceptible to sepsis, organ

dysfunction and even death. Surgical re-exploration may be

indicated in some cases.

Delayed gastric emptying (DGE) was defined as the inability

to take a regular solid diet after POD 10 and/or nasogastric

tube reinsertion after POD 5.

Postoperative hemorrhage was defined as blood loss via

the abdominal drain, gastrointestinal tract or abdominal

cavity, with a drop in serum hemoglobin levels after surgery.

Overall postoperative complications were assessed ac-

cording to the ClavieneDindo classification i.e., grade I: any

deviation from the normal postoperative course; grade II:

pharmacological treatment; grade III: surgical, endoscopic, or

radiologic intervention; grade IV: single-organ or multiorgan

dysfunction; and grade V: death of patient.17

2.5. Data collection

All aspects of care were directed by the operating surgeon.

Data on preoperative, intraoperative, and postoperative care

were retrospectively collected from a prospectively main-

tained database. Preoperative parameters include patient de-

mographics (i.e., age, gender and medical/surgical history),

presenting symptoms (i.e., jaundice, weight loss, pain), labo-

ratory tests, prior imaging studies, and preoperative therapies

(i.e., endoscopic ductal stenting or sphincterotomy). Intra-

operative parameters include total blood loss, operative time,

blood transfusions, use of drains and stents. Postoperative

events and clinical outcomeswere recorded, that included: in-

hospital mortality, overall complications (as per the Clav-

ieneDindo classification), incidence and type of specific

complications (such as POPF, DGE, cardiopulmonary compli-

cations, sepsis, wound infection, intra-abdominal collection/

abscess and hemorrhage), reoperation, hospital length of stay

as well as ICU stay.

2.6. Cost calculations

The economic consequences of POPF were determined by the

cost of the treatment during the hospital stay. The hospital

costs covered operating room, pharmacy (medication, fluid

management, and nutritional support), radiology (imaging

studies and interventional radiology), transfusion (blood

products), laboratory examination, ICU, and room costs. The

costs are expressed in Indian rupees. Results are expressed as

median and interquartile range (IQR).

2.7. Statistical analysis

Statistical analysis was performed by the Statistical Product

and Service Solutions (SPSS) program for Windows,

version 17.0. Continuous variables were presented as

mean � standard deviation (SD) or median (IQR), if data was

skewed, and categorical variables were presented as absolute

numbers and percentage. Data were checked for normality

before statistical analysis. Normally distributed continuous

variables were compared using the unpaired t test, whereas

the ManneWhitney U test was used for those variables that

were not normally distributed. Categorical variables were

analyzed using either the Chi-square test or Fisher’s exact

test. One-way analysis of variance (ANOVA) was used to

evaluate the significance of the differences among the three

groups. For all statistical tests, a p value less than 0.05 was

taken to indicate a significant difference.

3. Results

All the patients met criteria for evaluation by the ISGPF clas-

sification scheme. Of the 95 patients who were evaluated, 67

(70.5%) were males and 28 (29.5%) were females with a mean

age of 57 � 12 (range 16e77) years. Thirty-five patients

developed fistulae according to ISGPF definition with an

overall incidence of 36.8%. There were 12 grade A fistulas

(12.6% overall), 17 grade B (17.9% overall) and 6 grade C (6.6%

overall). As per the ClavieneDindo classification, overall

complications were: grade 1e8 (8.4%), grade 2e35 (36.8%),

grade 3e9 (9.5%), grade 4e10 (10.5%) and grade 5e11 (11.6%).

The other specific complications, apart from POPF were: DGE

e 18 (18.9%), cardiopulmonary complications e 22 (23.3%),

sepsis e 19 (20%), wound infection e 10 (10.5%), intra-

abdominal collections e 36 (37.9%), hemorrhage e 12 (12.6%)

and reoperation e 1 (1.1%). The overall in-hospital mortality

was 11 (11.6%) patients. Three patients died as a result of grade

C fistulae and eight died from other causes. The median

postoperative length of hospital stay was 11 (IQR 9e15) days

and median postoperative length of ICU stay was 3 (IQR 1e4)

days. The median treatment cost, in Indian rupees, was Rs.

327112 (IQR Rs. 232894eRs. 521723).

3.1. Clinical and economic consequences of pancreaticfistula

On comparison of clinical outcomes between two groups

based on the POPF, there was no statistically significant dif-

ference found in the in-hospital mortality, overall complica-

tions, and specific complications including DGE,

cardiopulmonary complications, sepsis, wound infection,

hemorrhage and reoperation; and postoperative length of ICU

stay. However, there was a statistically significant difference

found in the intra-abdominal collection rate (57.1% vs. 26.7%,

p ¼ 0.003), postoperative length of hospital stay [median e 13

(IQR 11e18) days vs. 11 (IQR 9e13) days, p ¼ 0.004] and total

treatment cost [median e Rs. 501374 (IQR Rs. 287353eRs.

584396) vs. Rs. 297605 (IQR Rs. 215284eRs. 426358) days,

p ¼ 0.011, between the two groups (see Table 1). The

Table 1 e Comparison of clinical outcomes between two groups based on POPF.

POPF group (n ¼ 35) No POPF group (n ¼ 60) p value

Overall in-hospital mortality 3 (8.6%) 8 (13.3%) 0.741

Overall complications (as per ClavieneDindo classification)

Grade 1 3 (8.6%) 5 (8.3%) 1.000

Grade 2 13 (37.1%) 22 (36.7%) 0.963

Grade 3 5 (14.3%) 4 (6.7%) 0.282

Grade 4 4 (11.4%) 6 (10%) 1.000

Grade 5 3 (8.6%) 8 (13.3%) 0.741

Specific complications

Cardiopulmonary complications 8 (22.9%) 14 (23.3%) 0.958

Delayed gastric emptying 7 (20%) 11 (18.3%) 0.842

Sepsis 8 (22.9%) 11 (18.3%) 0.595

Wound infection 6 (17.1%) 4 (6.7%) 0.164

Intra-abdominal collections/abscesses 20 (57.1%) 16 (26.7%) 0.003

Hemorrhage 6 (17.1%) 6 (10%) 0.348

Reoperation 0 (0%) 1 (1.7%) 1.000

Postoperative hospital stay, days 13 (11e18) 11 (9e13) 0.004

Postoperative ICU stay, days 3 (1e4) 2 (0e3.7) 0.311

Treatment cost, in Indian rupees 501374 (287353e584396) 297605 (215284e426358) 0.011

Data are presented as n (%) or mean � S.D (range) or median (IQR).

Bold values are statistically significant.

c u r r e n t m e d i c i n e r e s e a r c h and p r a c t i c e 4 ( 2 0 1 4 ) 1e64

postoperative length of hospital stay and total treatment cost

significantly increased in the patients who developed POPF.

On comparison of clinical outcomes between three groups

based on POPF grades, there was a statistically significant

difference found in the postoperative length of hospital stay

(p ¼ 0.002), postoperative length of ICU stay (p ¼ 0.005), and

total treatment cost (p ¼ 0.014), with increasing severity of the

fistula grades (see Table 2). The postoperative length of hos-

pital stay, postoperative length of ICU stay and total treatment

cost, all three, progressively increased with increasing

severity of the fistula grades. Our study did not include indi-

rect costs such as lost work time.

4. Discussion

Following pancreaticoduodenectomy, a pancreatic fistula has

been mainly implicated in increased rates of postoperative

complications leading to adverse clinical and economic out-

comes in the patients. There has been a wide variation in the

reported incidence of POPF in the past because of different

definitions used in various series. This variance makes the

accurate comparisons of techniques and outcomes reported

in these series, difficult. In July 2005, the ISGPF developed and

published a universal definition and classification scheme for

pancreatic fistula, based on the clinical impact of pancreatic

fistulae.14 But, the ISGPF definition includesmany leaks which

Table 2 e Comparison of clinical outcomes between three grou

POPF grade A group (n ¼ 12) POP

Postoperative hospital stay, days 11 (9.2e11)

Postoperative ICU stay, days 2 (1.2e4)

Treatment cost, in Indian Rupees 327768 (213058e514529) 5

Data are presented as n (%) or mean � S.D (range) or median (IQR).

Bold values are statistically significant.

are of no clinical significance and would not be detected

without routine measurement of drain amylase levels. It is

hopeful that the standardized definitions of POPF as put forth

by the ISGPF will likely allow for more equitable comparison

among institutions.

In our study, we critically and objectively examined the

ISGPF POPF classification scheme and studied its relevance

in the clinical and economic outcomes of the patients un-

dergoing PD. Grade A fistulae present with an elevated drain

amylase only and lack any clinical consequences. Their

duration of stay, rates of complications, and ICU stay, are

not significantly increased, and hospital costs are equiva-

lent to those patients without pancreatic fistulae. Grade B

fistulae require therapeutic interventions and behave in an

intermediate fashion. Duration of stay, rates of complica-

tions, and ICU stay are marginally increased, and hospital

treatment costs are higher than costs for grade A fistulae.

Grade C fistulas are the most severe and have a major

impact. Hospital stays are substantially longer, and patients

require longer ICU stay for sepsis management. Aggressive

interventions are indicated and often include surgical re-

exploration. These three fistula grades, as described by the

ISGPF classification scheme, are distinct and validated

based on varying clinical and economic outcomes for each.

In one study, Pratt et al,15 sought to validate the ISGPF

classification scheme in their series of 176 patients who un-

derwent PD. There were 30.1% patients with POPF. Grade A, B

ps based on POPF grades.

F grade B group (n ¼ 17) POPF grade C group (n ¼ 6) p value

15 (12.5e18) 17.5 (10.5e23.5) 0.002

3 (0e3.5) 6.5 (4e10.5) 0.005

01374 (301348e552319) 671617 (535843e951208) 0.014

c u r r e n t m e d i c i n e r e s e a r c h and p r a c t i c e 4 ( 2 0 1 4 ) 1e6 5

and C fistulas occurred 15%, 12%, and 3% (overall), respec-

tively. All measurable outcomes were equivalent between the

no fistula and grade A classes. Conversely, costs, duration of

stay, ICU duration and resource utilization progressively

increased from grade A to C. Biochemical evidence alone of a

pancreatic fistula had no clinical consequence and did not

result in increased resource utilization.

In another study, Daskalaki et al,16 in their series of 755

patients who underwent PD found that 19.5% developed a

POPF according to the ISGPF definition. Out of these, grade A, B

and C fistula occurred in 19%, 70.7% and 8.8%, respectively.

Increasing fistula grades had higher hospital costs (V11,654,

V25,698, and V59,492 for grades A, B, and C, respectively;

p < 0.001). The development of a POPF does not always

determine a substantial change of the postoperative man-

agement. Clinically relevant fistulae can be treated conser-

vatively in most cases. The grading system proposed by the

ISGPF allows a correct stratification of the complicated pa-

tients based on the real clinical and economic impact of the

POPF.

In our experience, the incidence of PF was 36.8% according

to ISGPF definition. Grade A, B and C fistulae occurred in 12.6%,

17.9% and 6.3%, respectively. The PF rate is our series may be

higher than other reported series because of the fact thatmost

of the PD in our series was done for periampullary and

pancreatic head neoplasms which are more likely to result in

pancreatic fistulae due a softer pancreas and smaller caliber

pancreatic duct as compared to chronic pancreatitis that has a

firmer pancreas and larger caliber pancreatic duct.

There were 8.6% in-hospital mortalities in the patients

who developed POPF. Nonetheless, POPFs continues to

cause significant morbidity, prolonged hospital stay, and

increased hospital cost. Patients with PF in our study had an

increased treatment cost and longer hospital stay without

significant difference in overall in-hospital mortality rate

and postoperative complication rate when compared with

patients with no fistula. Postoperative length of hospital

stay, postoperative length of ICU stay and treatment cost

also progressively increased with increasing severity of

pancreatic fistula from grade A to C, leading to negative

clinical and economic impact on patients and their health-

care resources.

The incidence of pancreatic cancer is low (0.5e2.4 per

100,000 men and 0.2e1.8 per 100,000 women) in most parts of

India.18 Therefore, there were not many large series on out-

comes of PD reported from India. But recently Shrikhande

et al,19 in their series from1992 to 2011, of 500 PDs published in

2013, have reported a morbidity and mortality rate of 33% and

5.4%, respectively. The overall incidence of POPF, DGE, hem-

orrhage and bile leak was 11%, 3.4%, 6%, and 3.2%,

respectively.

Our center is a tertiary level teaching hospital in NewDelhi,

India, where major GI surgical procedures including liver

transplantation are been routinely performed. We perform on

average 45 PDs per year. Therefore, we can be considered a

high volume center as per the American20 or European21

definition and medium volume center as per the Asian22

definition. In our experience with PF in this series of 95 PDs

performed over a 4-year period, the yearly rate of pancreatic

fistula has not changed much over the years. But the deaths

due to pancreatic fistula have significantly declined over the

years. Only 3 deaths can be attributed to pancreatic fistula.

There has been no death due to pancreatic fistulas in the last

67 cases in our series. This success has been achieved mainly

due to experience gained by the doctors and staff, from similar

complex GI surgical procedures been routinely performed.

Eight deaths that occurred due to reasons other than

pancreatic fistula were mainly due to severe peri-operative

cholangitis in patients who had undergone preoperative

biliary stenting and patients with a not-so-good preoperative

performance status.

It has to be emphasized that the infrastructure to support

the postoperative period is equally important as are surgeon’s

experience and volume in determining the favorable outcome.

This protective effect of having surgery in a large volume

center is believed to be due to early recognition and effective

management of complications.23 The continued high

morbidity of PD is compensated by the ability to treat com-

plications non-operatively. The standardization of the peri-

operative care pathway and surgical technique allows to

limit the surgical complications such as POPF and impor-

tantly, minimizes the mortality due POPF. The skills required

to undertakemajor GI surgical procedures are not exclusive to

PD. Surgeons at our center are also routinely performing all

the major GI surgical procedures including liver trans-

plantation. It has resulted in a crossover of skills and that is

probably very important inmaintaining the expertise required

to achieve good results, as is the presence of supporting skills

in radiology, gastroenterology, anesthetics and intensive care.

A recent study24hasdemonstrated improvedoutcomesafter

PD undertaken in training centers. It has found that the degree

of effect onoutcome isgreater than that of surgeon frequencyor

hospital volume. The belief that trainees (residents) may

adversely affect patient care or detract from the highest level of

care in the operating room or on the ward is not supported in

literature. Conversely, that study suggested that thepresence of

both trainersand traineesworking incollaborationmayactually

achieve superior care of patients following PD.

Thus, our study validated the clinical and economic impact

on outcomes of the ISGPF pancreatic fistula classification in

patients undergoing PD in a high volume tertiary care teach-

ing hospital.

5. Conclusions

The standardized definition of POPF as put forth by the ISGPF

is likely to allow for a more equitable comparison among in-

stitutions. POPF remarkably affected the clinical and eco-

nomic outcomes in these patients with POPF with an

increased treatment cost and longer length of hospital stay

without significant difference in overall in-hospital mortality

rate and postoperative complication rate. Increasing PF grades

had a negative clinical and economic impact on patients and

their healthcare resources.

Conflicts of interest

All authors have none to declare.

c u r r e n t m e d i c i n e r e s e a r c h and p r a c t i c e 4 ( 2 0 1 4 ) 1e66

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