Keywords
preoperative biliary drainage - postoperative pancreatic fistula - pancreaticoduodenectomy
The effect of preoperative biliary drainage (PBD) prior to pancreaticoduodenectomy
(PD) on postoperative pancreatic fistula (POPF) is variably reported in literature.
Initial studies on PBD included both benign and malignant pathologies, employed the
percutaneous means of biliary drainage, and did not specifically address POPF after
PD.[1]
[2]
[3]
[4]
[5]
[6]
[7] Subsequently, some centers reported increased POPF rates after PD with PBD.[8]
[9]
[10]
[11] However, large series spoke of no such increase.[12]
[13]
[14] Although several meta-analyses and other retrospective studies have examined stented
versus nonstented patients, they have not specifically addressed POPF rates.[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23] Preoperative pancreatic drainage is rarely performed for very selected indications
such as preoperative pancreatitis, after initial endoscopic ampullectomy, and its
effects on POPF are largely unknown.
Why should biliary or pancreatic stenting affect the incidence of POPF? Stent placement
can not only induce pancreatic and bile duct wall inflammation but also introduce
infection into the biliopancreatic system, and this may be responsible.[24]
[25] Does the addition of pancreatic stenting contribute to a higher morbidity after
PD than biliary stenting alone? However, the increase in POPF rates after stenting
may well be as a result of other confounding factors such as disease stage, pancreatic
texture, and ductal diameter.[8]
[26] To address this issue, a retrospective cohort analysis of data over a 10-year period
was performed.
Aims
-
To analyze the incidence of POPF in patients who underwent biliary stenting versus
those who were not stented prior to PD and whether it affected the duration of hospital
stay.
-
To analyze whether the addition of pancreatic stenting adds to the incidence of POPF.
-
To determine whether demographic, preoperative, and intraoperative parameters have
significantly affected the incidence of pancreatic fistula in these groups.
Methods
Patient Eligibility Criteria
A retrospective observational longitudinal cohort study was performed after extracting
the data of patients who underwent PD over the past 10 years from the prospectively
maintained database in this center. Approval from the institutional reviewer board
and ethics committee was obtained for conducting this study and the approval number
is LEC/DMS/T/001–17.
Inclusion Criteria
Patients with carcinoma causing obstruction to the lower end of bile duct without
chronic pancreatitis who underwent PD.
Exclusion Criteria
Patients who had undergone prior surgical bypass: The patients who underwent biliary
stenting alone represented group 1, those who underwent biliary and pancreatic stenting
were put in group 2, and those not stented were assigned in group 3. Sequential consecutive
sampling was used. Pancreatic fistula in the postoperative period was defined according
to the ISGPF criteria as persistent drainage of fluid on or after postoperative day
3 with an amylase content greater than three times the upper normal serum value. The
indication for stenting in these patients was determined by examining the medical
records. The demographics, preoperative, intraoperative parameters, and postoperative
outcome were recorded.
Data Collection
The variables are shown in [Table 1]. These were recorded and compared for group 1, group 2, and group 3. For bilirubin
values, prestenting bilirubin in group 1 and 2 and preoperative bilirubin in group
3 were recorded and compared by dividing them further into three subgroups based on
the levels of bilirubin (0–10, 10–20, and ≥ 20 mgs%).
Table 1
Variables analyzed in the study
|
Preoperative
|
Intraoperative
|
Postoperative
|
|
Age
|
Pancreatic duct diameter (millimeters)
|
Pancreatic fistula
|
|
Sex
|
Pancreatic texture (soft, firm, or hard)
|
Postpancreatectomy hemorrhage
|
|
Co-morbidities
|
Requirement for portal vein resection
|
Duration of hospital stay
|
|
Serum albumin
|
|
|
|
Serum preoperative/prestenting bilirubin
|
|
|
Hospital stay was taken as the duration from the date of operation till the day of
discharge. All these details were recorded and tabulated in Microsoft Excel for each
of the patients.
Prior to operation, patients underwent a routine preoperative workup to assess fitness
and a CECT abdomen to assess resectability. Endoscopic biopsy was performed in all
periampullary tumors. Endoscopic stenting was universally done with a plastic stent
in resectable lesions. At operation, a standard pylorus-resecting PD was performed
in all the cases with a duct to mucosa pancreaticojejunostomy.
Primary Outcome
Primary outcome is the incidence of POPF and duration of hospital stay in the stented
versus the nonstented patients who underwent PD in the past 10 years at our institution.
Secondary Outcome
Secondary outcome is the association of demographic, preoperative, and intraoperative
variables with the incidence of pancreatic fistula.
Statistical Analysis
Statistical analysis was performed using Microsoft Excel and Graph Pad Prism with
the help of a statistician. Categorical variables were expressed as frequencies and
analyzed using Fishers exact test, while continuous variables were expressed as median
(interquartile range [IQR]) and analyzed using Mann–Whitney U test. Univariate and
multivariate analysis (Firth logistic regression) for predictive factors of pancreatic
fistula was performed using SPSS Version 24. Firth logistic regression was used to
reduce the bias of binary logistic regression in the analysis of rare events (biliary
and pancreatic stent) by using a penalized maximum likelihood estimation.[27]
[28]
[29] Factors with p value < 0.20 on univariate analyses were included in the multivariate analyses. Patients
with missing values were excluded from the analysis.
Patients
Three-hundred and ten patients with carcinoma obstructing the lower end of common
bile duct (CBD) were identified who underwent PD. Six were excluded because they underwent
surgical biliary bypass prior to PD. One-hundred and seventy-nine patients had periampullary,
96 had tumor located in the head of the pancreas, 18 and 11 had cholangiocarcinomas
and duodenal adenocarcinomas respectively. There were 62 patients who underwent biliary
stenting alone, 5 who underwent both biliary and pancreatic stenting, and 237 patients
who were not stented, but underwent direct surgery. The groups were comparable for
all parameters including subtype of carcinoma, except for albumin levels which were
marginally lower in the stented group ([Table 2]).
Table 2
Comparison of preoperative and intraoperative parameters in stented versus not stented
patients
|
Parameter[a]
|
Not stented(237)
|
Stented (67)
|
p Value
|
|
Age
|
60(53–65)
|
60(49–69)
|
0.501
|
|
Males
|
143
|
44
|
0.479
|
|
Comorbidities
|
105
|
27
|
0.580
|
|
Preoperative albumin
|
3.8(3.5–4.1)
|
3.5(3.2–3.9)
|
0.008
|
|
Firm/hard pancreas
|
44
|
14
|
0.725
|
|
Pancreatic duct diameter(mm)
|
5(3–5.5)
|
4(3–6.75)
|
0.495
|
|
Distribution of type of adenocarcinoma(periampullary/other types)
|
133/104
|
34/33
|
0.219
|
a Median with interquartile range for continuous variable.
Results
POPF developed in 24 out of 62 (38.7%) patients in the group1, 5 out of 5 (100%) patients
in group 2, and in 67 out of 237 (28.3%) patients in the nonstented group. There was
no statistically significant difference in pancreatic fistula rates in group 1 versus
group 3 (odds ratio [OR] =0.619, confidence interval [CI] =0.345–1.112, p = 0.121). However, there was a statistically significant increase in the pancreatic
fistula rates in the patients who underwent biliary and pancreatic stenting (group
2) compared with the nonstented (group 3) (p = 0.003) ([Fig. 1]).
Fig. 1 Postoperative pancreatic fistula in stented versus nonstented bilpancstent—biliary
and pancreatic stent.
There was no significant difference in the duration of hospital stay in stented (median
[IQR] = 15 days [13–21]) versus nonstented (median [IQR] = 14 days [11–19]) patients.
(p = 0.09).
From the medical records, the reason for stenting was probed and it showed that documented
cholangitis was seen in only six patients. The small number of patients who underwent
both biliary and pancreatic stenting had it done after endoscopic ampullectomy and
one for presentation of pancreatitis with periampullary malignancy.
Biliary stenting was not associated with any significant difference in the pancreatic
fistula rates across all the bilirubin subgroups ([Table 3]). Univariate analysis also pointed out that serum bilirubin level does not affect
the pancreatic fistula rate. Stenting did not affect the rate of postpancreatectomy
hemorrhage either in all the bilirubin subgroups ([Table 3]).
Table 3
Subgroup analysis of the effect of preoperative and prestenting serum bilirubin on
POPF and PPH
|
Preoperative/prestenting bilirubin[a]
|
Not stented
|
Stented
|
p Value
|
|
POPF
|
No POPF
|
PPH
|
No PPH
|
POPF
|
No POPF
|
PPH
|
No PPH
|
POPF stented versus not stented
|
PPH stented versus not stented
|
|
< 10
|
45
|
122
|
13
|
154
|
5
|
10
|
2
|
13
|
0.560
|
0.356
|
|
10–20
|
9
|
37
|
5
|
41
|
5
|
6
|
1
|
10
|
0.116
|
1.000
|
|
≥ 20
|
4
|
6
|
0
|
10
|
2
|
7
|
0
|
9
|
0.629
|
1.000
|
Abbreviations: POPF, postoperative pancreatic fistula rates; PPH, postpancreatectomy
hemorrhage.
a 41 bilirubin values missing, hence only 263 analyzed.
On univariate analysis of the predictive factors, there was a significant association
of six factors, namely age, serum albumin, biliary and pancreatic stenting, portal
vein infiltration, pancreatic duct diameter, and pancreatic texture, with POPF. However,
on multivariate analysis (Firth logistic regression after selecting those variables
with p value < 0.20 on univariate analysis), pancreatic texture and the presence of a biliary
and pancreatic stent were the only two factors that were significantly affecting the
pancreatic fistula rate ([Table 4]).
Table 4
Univariate and multivariate analysis of predictive factors for occurrence of POPF
|
Factor
|
Total (304)
|
Univariate analysis
|
Multivariate analysis
|
|
p Value
|
OR
|
p Value
|
OR
|
|
Age
|
|
0.011
|
1.033(1.008–1.06)
|
0.45
|
1.016(0.974–1.061)
|
|
Sex
|
Male
|
187
|
0.151
|
1.495(0.900–2.517)
|
0.470
|
1.412(0.557–3.721)
|
|
Female
|
117
|
|
Comorbidities
|
Yes
|
132
|
0.874
|
1.060(0.649–1.726)
|
NA
|
|
No
|
172
|
|
Preoperative bilirubin
|
0.802
|
1.003 (0.967–1.043)
|
NA
|
|
Preoperative serum albumin
|
0.041
|
1.833(1.036–3.418)
|
0.496
|
1.335(0.598–3.360)
|
|
Biliary and pancreatic stenting
|
0.002
|
25.33(2.826–3340.915)
|
0.027
|
14.806(1.314–2032.46)
|
|
Biliary Stent
|
Yes
|
62
|
0.108
|
1.642(0.910- 2.930)
|
0.118
|
2.291(0.808–6.666)
|
|
No
|
237
|
|
Portal vein infiltration
|
Yes
|
17
|
0.011
|
5.700(1.404–52.100)
|
0.831
|
1.237(0.771-.1.851)
|
|
No
|
287
|
|
Pancreatic duct diameter
|
0.002
|
1.266(1.081–1.511)
|
0.508
|
1.077(0.870–1.365)
|
|
Pancreatic texture
|
Firm/Hard
|
83
|
0.001
|
2.956(1.484–6.311)
|
0.032
|
3.334(1.108–11.89)
|
|
Soft
|
221
|
Abbreviation: NA, not available; OR, odds ratio; POPF, postoperative pancreatic fistula.
Discussion
There is a division of opinion in relevant literature as regards the effect of preoperative
stenting on POPF. In 1998, Povoski et al from MSKCC retrospectively analyzed 240 PD
and clearly showed that PBD is associated with an increased incidence of postoperative
complications, infectious complications, intra-abdominal abscesses, and death.[12] However, surgical, endoscopic, and percutaneous biliary drainage procedures were
included in this analysis unlike ours where we have excluded surgical PBD.
In 2000, Sohn et al reported from an analysis of 567 patients that preoperative biliary
stenting prior to PD does increase the rate of pancreatic fistula formation and wound
infection; however, it does not affect the overall morbidity or mortality.[8] However, 64% of the patients were stented via a percutaneous approach. A recent
retrospective analysis from Nagoya University also confirmed that endoscopic stenting
of the CBD is an independent predictor of POPF after PD.[11]
Pisters et al from MD Anderson Cancer Center concluded on the contrary from an analysis
of 300 patients that preoperative biliary stenting prior to PD does not increase the
rate of major postoperative complications or mortality except for wound infection.[13] Recent retrospective evidence from large volume centers also concludes that PBD
does not affect overall morbidity and mortality of PD except for wound infection[14] The recommendation was, therefore, that patients can be initially treated with endoscopic
biliary drainage and need not go for immediate laparotomy.
A well-conducted retrospective study from a single center showed that even in severely
jaundiced patients with a bilirubin more than 15 mg/dL, PBD contributed to increased
operative time, blood loss, and wound complications without affecting the POPF rate.[30] This is in contrast to some earlier studies that concluded that in severely jaundiced
patients, stenting reduces bleeding complications.[9] Thus, we have conflicting results from retrospective studies from different centers.
A very few randomized controlled trials have been done in this topic since it has
been proven that PBD definitely increases wound complications. van der Gaag et al
conducted a randomized controlled trial comparing plastic stenting versus direct surgery
for cancers of the head of pancreas with a maximum bilirubin value of 14.6, which
were not locally advanced and not in cholangitis.[31] This is the only randomized controlled trial which has specifically addressed PBD
by endoscopic stenting prior to PD. The occurrence of stent-related complications
in significant numbers led to the conclusion that routine PBD is not advisable. One
drawback of this study is that it does not analyze pathologies other than carcinoma
head of pancreas where the pancreatic fistula rates are known to be different. Also,
patients with a bilirubin of 15 or more and those with significant portal vein invasion
are excluded from this study.
Due to the paucity of randomized controlled trials, we can rely only on retrospective
data and meta-analyses. However, recent review articles and meta-analyses on this
topic have also come out with conflicting results. Moole et al concluded that PBD
reduces morbidity after PD,[32] while Lai et al advocated that it does not have any beneficial effect on periampullary
tumors.[33] A very few such as Chen et al have specifically addressed POPF rate which is a significant
factor affecting the postoperative course.[34] Most of the other meta-analyses have not been able to shed light on this subject.[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23] The probable reason for such conflicting results in these meta-analyses is the inclusion
of heterogeneous studies, such as including randomized controlled trials which studied
proximal as well as distal bile duct malignancies, endoscopic as well as percutaneous
biliary drainage, bypass and palliative resections.[33]
Thus, the importance and clarity of single center retrospective studies emerge where
patients are operated by a single surgical team with a standardized procedure, thereby
eliminating bias that creeps into clubbing heterogeneous studies.[30] In addition to being a single center study, we have selectively chosen only adenocarcinomas
obstructing the lower CBD, thereby eliminating bias that can be brought in by different
pathologies that are known to affect POPF such as underlying chronic pancreatitis,
intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumors, and cystic
neoplasms.
A limitation of this study seems to be the fact that there are earlier randomised
trials and meta-analyses published on PBD. Another limitation is that there can be
several confounding factors influencing the primary outcome of this study which is
POPF such as pancreatic texture, pancreatic duct diameter, comorbidities, age, sex,
serum albumin, serum bilirubin, and portal vein infiltration. However, we have negated
this bias by a multivariate analysis which included all these confounding factors.
The other limitation is that the sample size in the stented group is much less. Again
there is a definite reason for lower size of the stented group, since evidence is
already established that PBD increases septic wound complications, leading us away
from routine to selective PBD. Many patients who have been referred to us with a stent
already placed have contributed to this number of 67. On the whole, the number of
304 patients was adequate sample size for this cohort study. This is proven by the
fact that the confidence intervals of the significant results are not crossing one.
Also we have selected only adenocarcinomas obstructing the lower CBD, thereby eliminating
bias that could be brought out by heterogeneous pathologies such as underlying chronic
pancreatitis, IPMN, neuroendocrine tumors, and cystic neoplasms.
Simultaneous biliary and pancreatic stenting is rarely done and so the sample will
always be small. Prospective studies cannot also be done in this topic for the same
reason. So, a retrospective multivariate analysis adjusting for rare events using
established statistical methods such as Firth logistic regression seems appropriate.
Analysis of our data showed that biliary stenting alone does not significantly affect
the incidence of pancreatic fistula across all the bilirubin subgroups except when
combined with pancreatic stenting. This is probably because of pancreatic duct wall
inflammation at the site of the future anastomosis and bacterial infection of the
bile and pancreatic fluid induced by stenting as has been reported before.[24]
[25] The result we obtained adds evidence to the hypothesis that pancreatic ductal wall
inflammation induced by the pancreatic stent at the site of the future pancreaticoenteral
anastomosis may be responsible for POPF and that biliary stent per se does not have
any adverse effect at this site. In other words, careful biliary cannulation avoiding
repeated inadvertent pancreatic duct cannulation is of utmost importance. This would
reduce the need for prophylactic pancreatic duct stenting to prevent pancreatitis.
Pancreatic stenting may reduce the incidence of postendoscopic retrograde cholangiopancreatography
(ERCP) pancreatitis in difficult biliary cannulation and after endoscopic ampullectomy.[35] However, it has its limitations such as unsuccessful stent placement due to the
inability to advance a wire into the PD or the inability to place a stent after wire
placement. This results in an increased risk of post-ERCP pancreatitis.[36] There can also be inadvertent duct injury during stent placement and long-term stent-related
duct or gland injury. Variable expertise and familiarity with their placement in less
experienced hands are indeed a point against prophylactic pancreatic stenting.[36] We have found in our study that the addition of pancreatic to biliary stenting may
increase the rate of POPF significantly in the postoperative period. So, our recommendation
is to endorse PBD in selected patients prior to PD, however, with utmost care and
technique to avoid repeated pancreatic cannulation and the need for a pancreatic stent.
More studies from other centers are required to confirm the same as combined biliary
and pancreatic stenting is rarely done. Yet it assumes significance if it has a harmful
effect on healing of the pancreatic anastomosis as has been proven in our study.
Conclusion
PBD alone has no significant effect on POPF except when combined with pancreatic stenting.
