EVIDENCE BASED CASE REPORT

EFFICACY OF SOMATOSTATIN TO PREVENT

PANCREATITIS IN POST ENDOSCOPIC RETROGRADE
CHOLANGIOPANCREATOGRAPHY PATIENTS

Steven Sutanto Sihombing

1306490724

Department of Internal Medicine

Faculty of Medicine University of Indonesia
Cipto Mangunkusumo Hospital
Jakarta, June 2015
CHAPTER 1
1

INTRODUCTION
1.1 Objective
To assess somatostatin efficacy in preventing post-endoscopic retrograde
cholangiopancreatography (post-ERCP) pancreatitis.
1.2 Introduction
ERCP is a procedure that combines the use of endoscopy and fluoroscopy
to diagnose and treat biliary and pancreatic disorders. However, it has been
associated with higher risk of severe complications.
The most common complication encountered after ERCP is pancreatitis,
known as post-ERCP pancreatitis (PEP).1-3 A systematic survey from 21 selected
studies involving 16,855 patients showed pancreatitis occured in 3.47% of all
patients with 11.4% developed severe pancreatitis and 3.08% estimated
pancreatitis-related mortality.3
According to international consensus, PEP is defined as new or worsened
abdominal pain and tenderness persisting for >24 h following ERCP, with an
elevated serum amylase level >3 times the normal upper limit. The severity of
pancreatitis is classified into mild when the length of hospital stays was 3 nights,
moderate when the hospital stay was 4-10 nights, and severe if >10 days of
hospitalization, intensive care unit admission, or surgery were required for
pancreatitis.4
Many pharmacological agents have been studied to prevent and reduce the
incidence of PEP such as nonsteroidal anti-inflammatory drugs (NSAIDs),
protease inhibitors, glyceryl trinitrate (GTN), ocreotide, somatostatin and also
antibiotics. However, many of these drugs failed to show a benefit or had
conflicting results in large scale, randomized studies and meta-analyses.
Somatostatin is potent inhibitors of pancreas secretion but available data
currently are inconclusive and it remain unclear whether somatostatin should be
administated before ERCP to prevent pancreatitis. Prophylaxis of post-ERCP
pancreatitis guideline by European Society of Gastrointestinal Endoscopy (ESGE)
in 2014 does not recommend universal administration of prophylactic
somatostatin in average-risk patient undergoing ERCP but new data from recent
randomized control trials (RCT) had shown the efficacy of somatostatin in
preventing PEP.5-6

This inconclusive data might be the reason why only a few endoscopist
use prophylactic measures against PEP. In an Austrian nationwide ERCP survey,
PEP prophylaxis was administered in only 4.0% of patients and in 7.0% patients
in 2011.7
None of these trials regarding using pharmacological agents to prevent
PEP, specifically somatostatin was done in Indonesia and there is also no local
data available about the efficacy of somatostatin to prevent PEP. Is somatostatin
really effective in preventing PEP? To answer this question, we used new trials
and publications and applied directly on patient in this case, as an evidence-based
case report (EBCR).

CHAPTER 2
CASE RESUME
2.1 Case Resume
Female 44 years old with chief complain right upper quadrant pain of the
abdomen since five months ago. The pain was intermittent and accompanied with
nausea, vomitus and scleral icterus. Three months later, the pain became more
often and the skin also became icteric. She went to Persahabatan Hospital and
was diagnosed as cholelithiasis and cholecystitis and referred to Cipto
Mangunkusumo Hospital for endoscopic retrograde cholangiopancreatography.
She did not have smoking nor alcohol drinking habit.
Her vital sign was stable with scleral icterus and feeling discomfort when
we palpate right upper quadrant of her abdomen. Laboratory examination showed
3

her total bilirubin was 4.73 mg/dL with direct bilirubin 4.45 mg/dL and indirect
bilirubin 0.28 mg/dL. Amilase level was normal (36 U/L), with increasing
transaminase (AST 70 U/L and ALT 39 U/L) and CA 19-9 level (66,4 U/L). Her
abdominal ultrasonography interpretation was common bile duct obstruction with
dilated both intrahepatic bile duct and cholelithiasis with cholecystitis. She was
scheduled for endoscopic retrograde cholangiopancreatography procedure.
Endoscopic retrograde cholangiopancreatography procedure showed
dilatation of both intrahepatic bile duct until below the bifurcation due to stenosis,
without dilatation of common bile duct. Pancreatic duct and gall bladder was not
visualized. Sphincterotomy was done and pus came through. We did brushing
cytology and inserted billiary stent 10 fr 11 cm into left hepatic duct and 7fr 11 cm
into the right one. Bile flew out smoothly after that.
After the procedure, she was given somatostatin 3000 g intravenous drip
continuously every 12 hours. Antibiotics were also given in the form of
Cefoperazone sulbactam 1 gram intravenous, two times daily. Other medication
was OMZ 1x40 mg i.v, Vitamin K 3x10 mg i.v, Transamin 3x500 mg i.v, and
Pethidine 150 mg i.v drip continuously for 24 hours.
The next day after the procedure, she complained pain and tenderness in
the abdomen. The pain getting intense when we palpate the abdomen but no sign
of peritonitis. Her amilase and lipase level was increased up to 819 U/L and 840
U/L. White blood cell level also increased up to 17,430/L and hs-CRP 220.18
mg/L. She was diagnosed with post-endoscopic retrograde cholangiopancreatography pancreatitis.
Somatostatin was given to her with the same dose as before, 3000g i.v
drip continuously every 12 hours for seven days. Amilase and lipase level became
normal on the fifth day after the procedure and the pain became minimal after a
week. She was discharged and diagnosed with obstructive jaundice suspected due
to Klatskin tumor and post-endoscopic retrograde cholangio-pancreatography
pancreatitis.
2.2 Clinical Question
Is prophylactic somatostatin effective to prevent post-endoscopic retrograde
cholangiopancreatography pancreatitis?

CHAPTER 3
METHODS
3.1 Search The Evidence
P : adult, post ERCP patient
I : somatostatin
C : placebo (no somatostatin)
O : prevention OR prophylaxis AND pancreatitis
We searched PubMed and Cochrane library database on March 16 th, 2015
using the terms : ((((((Somatostatin) AND Prophylaxis) AND Pancreatitis) AND
ERCP)) OR ((((Somatostatin) AND Prevention) AND Pancreatitis) AND ERCP))
OR ((((Somatostatin) AND Prevent) AND Pancreatitis) AND ERCP). Our search
produced 60 results from PubMed and 32 results from Cochrane. After that, in
order to attain the newest evidence, we limit our search only articles that was
published within five years back from now (2010-2015). We found 9 articles from
PubMed and 5 articles from Cochrane. Next, we screened the abstract for trials
that only used somatostatin as a single agent as a prophylactic measure to prevent
PEP compared to placebo and got 5 articles from PubMed and 3 articles from
Cochrane. From those articles, we only included randomized control trials (RCTs)
and systematic review using RCTs from 2010 until 2015. We found 3 articles from
PubMed and 2 articles from Cochrane. All articles from Cochrane were included
in the PubMed result. From 3 articles that we had, one article did not have full text
so 2 articles remain. We read the full text of these articles and decided it can be
used in the next process.

((((((Somatostatin) AND Prophylaxis) AND Pancreatitis) AND ERCP)) OR

((((Somatostatin) AND Prevention) AND Pancreatitis) AND ERCP)) OR
((((Somatostatin) AND Prevent) AND Pancreatitis) AND ERCP)
PubMed

Cochrane

60 articles

32 articles

Limit
Publication dates from
2010-2015

9 articles

5 articles

Screening the abstract

Trials that using
somatostatin as a single
agent vs placebo

5 articles

3 articles

3 articles

2 articles

Limit
RCTs and systemic review
using RCTs from 2010
until 2015

Articles from Cochrane were

included in the PubMed results
1 article did not have full text
2 articles

Figure 3.1 Flowchart of Conducted Search

3.2 Appraise The Evidence
The best and highest level of evidence of therapeutic type clinical question
is systematic review of randomized controlled trials (RCTs) [Level 1a]. The
second best level of evidence is individual RCT with narrow confidence interval
[Level 1b], followed by a systematic review of cohort studies [Level 2a],
individual cohort study [Level 2b], systematic review of case-control studies
[Level 3a], individual case-control study [Level 3b], case series [Level 4] and

expert opninion [Level 5].8 After searching the PubMed and Cochrane to answer
the clinical questions, we found only 2 articles and both of them are RCTs. There
is one article with systematic review of RCTs, but it did not match our criteria for
using trials from 2010 until 2015.
We appraised the scientific evidence of this 2 articles using guidance from
Centre for Evidence-Based Medicine : Critical Appraisal for Therapy Articles. 9
The result was shown below.
Table 3.2 Critical Appraisal of Randomized Controlled Trials

Appraisal questions

Bai Y et al Concepcion-Martin
(2015)6

M et al (2014)10

Validity
1.Was the assignment of patients to treatment

Yes

Yes

randomised?
2.Were the groups similar at the start of the

No

Yes

trial?
3.Aside from the allocated treatment, were

Yes

Yes

groups teated equally?

4.Were all patients who entered the trial

Yes

Yes

No

Yes

Yes
Precise enough
Yes

Yes
Not precise enough
Yes

No

No

Yes
Yes

Yes
Yes

1b

1b

accounted for?-and were they analysed in the

groups to which they were randomised?
5.Were measures objective or were the
patients and clinicians kept blind to which
treatment was being received?
Importancy
6.Is the size effect practically relevant?
7.How precise is the estimate of the effect?
Were confidence intervals given?
Applicability
8.Is my patient so different to those in the
study that the results canot apply?
9.Is the treatment feasible in my setting?
10.Will the potential benefits of treatment
outweigh the potential harms of treatment for
my patient?
Level of Evidence*

*Level of Evidence obtained from Centre for Evidence Based Medicine, University of
Oxford (available at : http://www.cebm.net/oxford-centre-evidence-based-medicinelevels-evidence-march-2009/)

After appraising both articles, we found that RCT done by ConcepcionMartin M et al in 2014 has more similar demographic and baseline characteristics
of study patients than those in Bai Y et al. Both of the endoscopist and the patient
were blinded to the treatment allocation in Concepcion-Martin M et al while the
patient was not blinded in Bai Y et al. Therefore, we conclude that ConcepcionMartin M et al study results is more valid and applicable than Bai Y et al.

CHAPTER 4
RESULTS
In this evidence based case report, we try to answer if prophylactic
somatostatin

is

effective

to

prevent

post-endoscopic

retrograde

cholangiopancreatography pancreatitis. We found two new RCTs that were

focused on answering this question. Results of these studies have been
summarized in table shown below.
Table 4.1 Summary of the Studies Results

Bai Y et al
(2015)6

Methods

Concepcion-Martin M et al

(2014)10
Intravenous bolus of 250g of Intravenous bolus of 250g of
somatostatin before ERCP

somatostatin slowly infused

and 250 g/h continous

over 3 minutes prior to the

infusion for 11 hours after

attempt at cannulation of the

ERCP. The total dose of

papilla of Vateri. This was

somatostatin was 3000g.

followed by 4-hour continous

infusion of the drug at 250g/h.
The total dose of somatostatin
was 1250g.

RR
ARR
NNT

0.54
(P=0.026)
3.5%
(95%CI 2.0%-6.2%)
29
(95%CI 16-636)

1.12
(P=0.73, 95%CI 0.59-2.1)
-

In the Bai Y et al study, PEP developed in 52 patients : 34 of 455 occured

in the control group (7.5%; 95%CI 5,4%-10,3%) and 18 of 445 occured in the
somatostatin group (4.0%; 95%CI 2.6%-6.3%) with P value 0.0276. This indicate
an absolute risk reduction of 3.5% (95%CI 2.0%-6.2%) and number needed to
treat to prevent one episode of PEP is 29 (95% CI 16-636). Based on this result,
somatostatin 250g intravenous bolus before ERCP plus 250g/hour continous
infusions for 11 hours after ERCP significantly reduced the incidence of PEP.6
Concepcion-Martin M et al used a shorter duration of continous
somatostatin infusion with total dose less than half of the total dose used in Bai Y
et al. PEP occured in 36 patients : 19 of 255 (7.5%) occured in the somatostatin
group and 17 of 255 (6.7%) occured in the placebo group with relative risk (RR)
1.12; P=0.73; 95%CI 0.59-2.1.10 This means there is no significant difference
between somatostatin group and placebo and the result is not conclusive whether
somatostatin can prevent pancreatitis or not.

CHAPTER 5
DISCUSSION
Somatostatin is a potent inhibitor of exocrine secretion of pancreas and it
also has direct anti-inflammatory and cytoprotective effects. Therefore, it has been
used in the treatment of acute pancreatitis. 11,12
Not only act as a pharmacologic agent to treat acute pancreatitis,
somatostatin has also been proposed to prevent pancreatitis after ERCP procedure.
Many trials using somatostatin and its analogue have been done to show the
efficacy of these agents and yet the results are controversial.
European Society of Gastrointestinal Endoscopy (ESGE) has published an
updated guideline about prophylaxis of post-ERCP pancreatitis in 2014. It does
not recommend universal administration of somatostatin in average-risk patients
undergoing ERCP. Despite this statement, up to now there are still many clinical
trials are done regarding somatostatin efficacy in preventing PEP. The possible
reason is because most of the prior studies included small sample size and some
had methodological drawbacks which may caused non statistically significant
decrease in the incidence of PEP in somatostatin phrophylactic group.1,6,13
Bai Y et al gave somatostatin 250g intravenous bolus before ERCP and
250g/hour continous infusion for 11 hours after ERCP in the somatostatin group.
This method shown the efficacy of somatostatin in reducing the incidence of PEP
(P=0.026) but the study has limitations as it was not a placebo-controlled study
and was not double blinded. There was also a statistically significant differences in
age and sex between the control and study group (P=0.02).6
Concepcion-Martin M et al shown different results from Bai Y et al. They
gave intravenous bolus of 250g of somatostatin slowly infused over 3 minutes
prior to the attempt at cannulation of the papilla of Vater followed by a 4-hour
continuous infusion of the drug at 250g/hour and shown that somatostatin did
not influence the incidence of PEP.10
Both of Bai Y et al and Concepcion-Martin M et al studies have large
sample size, which differentiates them from most of the prior. Total dosage of
somatostatin given to the study group was different in both studies and this might
10

cause the different results. The relatively low dose of somatostatin administered is
a limitation of Concepcion-Martin M et al study. Meta-analysis about
somatostatin which compared its treatment regimen and duration of therapy to
prevent PEP hypothesized that a minimum of 3000g of somatostatin is needed
when a 12-hour infusion is administered.14
In our case, we decided to use somatostatin as a prophylactic agent to
prevent PEP. Our patient was given somatostatin 3000g intravenous drip
continuously every 12 hours after the ERCP procedure but not the intravenous
bolus of 250g somatostatin before the procedure like both of the study groups.
She developed PEP afterwards.
From our case, it might seems that somatostatin was not effective in
preventing PEP but then again no intravenous bolus of somatostatin was given to
the patient. The importance of giving intavenous bolus of somatostatin before the
procedure is observed by Concepcion-Martin M et al. They found that acute
pancreatitis decreased from 11.3% to 3% after administration of a single bolus of
somatostatin. This could be consistent with the pathogenic hypothesis which
argues that the inflammatory response appears immediately after the endoscopic
procedure.10
Timing to start the somatostatin infusion beside the duration of continuous
infusion might also play an important role in somatostatin efficacy to prevent PEP.
Lee KT et al showed that the incidence of PEP was significantly lower in the
group in which somatostatin administration was continued for 12 hours starting 30
minutes before ERCP (P=0.02).15
Our patient didnt get the intravenous bolus of somatostatin and also the
timing to start the somatostatin was much longer than 30 minutes after the ERCP
procedure which might reduced the efficacy of somatostatin in preventing PEP.

CHAPTER 6
CONCLUSION
Based on both studies and our experience in using somatostatin as a
prophylactic agent to prevent PEP, we do think that somatostatin is effective in

11

preventing PEP if it is given by intravenous bolus before the ERCP followed by

continuous infusion for 12 hours starting 30 minutes after the procedure, just like
how it is done in Bai Y et al study.

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