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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 18  |  Issue : 1  |  Page : 66-69

Role of rectal NSAID administration time in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis


1 Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission04-Feb-2019
Date of Decision13-Jun-2019
Date of Acceptance10-Jul-2019
Date of Web Publication26-Mar-2020

Correspondence Address:
Zakarya M Zakarya
Internal Medicine Department, Faculty of Medicine, Al-Azhar University, Cairo, 11884
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_22_19

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  Abstract 


Objectives Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Many NSAIDs have been used to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). We aimed to evaluate the appropriate time to start rectal indomethacin in patients undergoing ERCP for treatment of calcular obstructive jaundice for prevention of PEP.
Patients and methods Over 10 months, 80 consecutive patients with calcular obstructive jaundice underwent ERCP. Patients were assigned to receive indomethacin suppository 100 mg either just before the procedure (group A=30 patients), directly after the end of the procedure (group B=30 patients), or just before and 5 h after the procedure (group C=20 patients). Serum amylase levels and clinically pertinent evaluations were measured in all patients after ERCP.
Results Of 80, 18 (22.5%) patients developed PEP. The rate of PEP was lower in group C patients (15.0%) when compared with groups A and B (30.0 and 20.0%, respectively). No patients in group C had severe PEP in comparison with 11% in group A and 17% in group B.
Conclusion This study shows that rectal indomethacin given immediately before and 5 h after ERCP can reduce the incidence and severity of PEP.

Keywords: endoscopic retrograde cholangiopancreatography, post-endoscopic retrograde cholangiopancreatography pancreatitis, rectal indomethacin


How to cite this article:
Zakarya ZM, Hussein MS, Gaafar AM. Role of rectal NSAID administration time in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. Al-Azhar Assiut Med J 2020;18:66-9

How to cite this URL:
Zakarya ZM, Hussein MS, Gaafar AM. Role of rectal NSAID administration time in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. Al-Azhar Assiut Med J [serial online] 2020 [cited 2020 Jul 10];18:66-9. Available from: http://www.azmj.eg.net/text.asp?2020/18/1/66/281354




  Introduction Top


Acute pancreatitis is the most common complication of post-endoscopic retrograde cholangiopancreatography (ERCP). The incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) varies from 1 to 10% but may reach 30% in high-risk cases [1]. Most cases of PEP are mild or moderate, but severe pancreatitis occurs in 0.4–0.6% of patients [2],[3]. Approximately 10% of those who develop PEP will follow a complicated clinical course that results in prolonged hospitalization and/or additional interventions [4]. Mechanisms involved in PEP pathogenesis are transient obstruction of the outflow of pancreatic juice owing to mechanical trauma and increased hydrostatic pressure within the pancreatic duct. Eventually, there is activation of proteolytic enzymes and autodigestion of pancreas and impaired acinar secretion. Concomitantly, there is activation of inflammatory cascade causing both local inflammation and systemic effects [5],[6].

NSAIDs are potent inhibitors of phospholipase A2 activity [7]. They are used to prevent PEP. Being administered via the mouth or rectum [8], inexpensive, and having a favorable risk profile when given as a single dose make them an attractive option in the prevention of PEP [9]. However, it was reported that oral prophylactic NSAIDs do not affect PEP in high-risk patients [10]. In contrast, several studies have shown that prophylactic rectal NSAIDs had significant effect on PEP prevention [11]. The rectal route has the advantages of rapid and complete absorption and faster attainment of peak plasma levels [12]. The aim of this study was to evaluate the appropriate time to start rectal indomethacin in patients undergoing ERCP for treatment of calculary obstructive jaundice.


  Patients and methods Top


This interventional, prospective study was performed on 80 consecutive patients with calcular obstructive jaundice subjected to endoscopic retrograde cholangiopancreatography (ECRP) at Endoscopy Unit, Department of Internal Medicine, Al-Hussein University Hospital, during the period from September 2017 to April 2018.

Exclusion criteria were acute and chronic calcified pancreatitis, age less than 18 years, pregnancy, breastfeeding, hypersensitivity or contraindication to or being on NSAIDs, recent gastrointestinal bleeding, or pancreatic head malignancy. The Local Ethical Research and Review Committee approved the study protocol, and informed consent was obtained from all participants.

All patients were subjected to clinical history taking, thorough clinical examination, and laboratory investigations. Blood samples were obtained from the antecubital vein into vacuum plain tubes for determination of basal amylase (2-chloro-pNpG3), liver enzymes Alanine amiontransferase (ALT) and Aspartate aminotransferase (AST) (Tris buffer with pyridoxal-5-phosphate), and bilirubin level (Didzo with sulphanilic acid) using Cobas chemistry auto analyzer (COBAS INTEGRA® 400 plus, Roche Diagnostics Ltd., CH-6343 Rotkreuz, Switzerland). Ultrasound examination of the liver and biliary tract was performed. Patients were randomized to receive one 100-mg indomethacin suppository either just before the procedure (group A, n=30), directly after the end of the procedure (group B, n=30) or just before and 5 h after the procedure (group C, n=20) as the mean half-life of rectal indomethacin is estimated to be ∼4.5 h. All participants were subjected to standard ERCP procedure under general anesthesia.

Development of PEP was considered the main outcome. It was defined as having new or increased abdominal pain consistent with pancreatitis and elevated amylase or lipase greater than three times the normal upper limit within 24 h after the procedure, and hospitalization (prolongation of existing hospitalization) for at least two nights. The severity of pancreatitis was determined according to consensus guidelines, with mild PEP resulting in hospitalization of less than 3 days, moderate PEP resulting in a hospitalization of 4–10 days, and severe PEP resulting in hospitalization more than 10 days and/or the development of pancreatic necrosis or pseudocyst, or requiring percutaneous or surgical intervention. Asymptomatic hyperamylasemia was defined as any amylase level at least three times above the normal serum level in the absence of abdominal pain.

Patients were kept under observation in the endoscopy recovery area for 3 h after ERCP. Measurement of serum amylase was performed every 2 h within the first 24 h after ERCP in all study patients. All patients were moved to ward and remained in their assigned bed for 24 h where they were thoroughly monitored, and laboratory investigations were repeated. If new abdominal pain suggestive of pancreatic origin appeared at any moment during the observation period, serum lipase (colorimetric method) was measured, and patients diagnosed with PEP were managed accordingly.

Statistical analysis was performed using the statistical package SPSS (IBM-SPSS, Armonk, New York, USA) version 23. The data were expressed as mean±SD or number and percentage. Comparisons including numerical variables were achieved by one-way analysis of variance with post-hoc analysis using Bonferroni method, whereas categorical variables were compared using Fisher exact test. P value less than 0.05 was considered statistically significant.


  Results Top


Comparison between the studied groups regarding the clinical and operative data revealed no statistically significant differences ([Table 1]). Regarding the postoperative data, it was found that group C patients had significantly lower rate of severe PEP and significantly shorter hospital stay when compared with the other two groups ([Table 2]).
Table 1 Comparison between the studied groups regarding basic and operative and postoperative data

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Table 2 Comparison between the studied groups regarding postoperative data

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  Discussion Top


Pancreatic stents are of proven benefit in preventing PEP [13],[14] but difficult to use in routine practice because of difficulty in pancreatic duct cannulation and requirement of operator expertise. Drugs used to prevent PEP are commonly divided as sphincter relaxants, antisecretory agents, protease inhibitors, anti-inflammatory agents, antioxidants, etc. The rationale of NSAIDs for PEP is based on their ability to inhibit inflammatory substances in the early phase of pancreatitis, such as prostaglandins, phospholipase A2, and a neutrophil–endothelial interaction [15].

Our study has shown that dual-dose administration of rectal indomethacin just before and 5 h after ECRP is superior to a single dose of rectal indomethacin just before or after the procedure, and this dual regimen has reduced the incidence of PEP. Moreover, it has profound effect on reducing the severity of PEP.

In line with our conclusions, Shi et al. [16] noted significant reduction in prevalence and severity of PEP with prophylactic rectal indomethacin use. Likewise, Elmunzer et al. [11] concluded that rectal indomethacin given immediately after ERCP significantly reduced the rate and severity of PEP. Moreover, our findings coincide with previously published meta-analysis [11],[17],[18],[19].

However, one study argued against the value of rectal indomethacin in reduction of PEP rate [20]. Of note, patients included in this study were heterogenous population with low and high-risk of PEP. This may indicate that indomethacin administration can have most benefit in high-risk patients.

The therapeutic approach followed by this study may serve to solve the controversy involving the timing of indomethacin administration, with many studies and meta-analyses favoring the pre-procedural administration [21],[22].


  Conclusion Top


We recommend the use of this simple, cheap, and safe medication for the prevention of PEP and reducing the severity of PEP, before and 5 h after the ERCP in patients with calcular obstructive jaundice. Other studies with more cases are needed for evaluation of the degree of influence of this medication for the prevention of PEP in this subgroup of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
ASGE Standards of Practice Committee, Anderson MA, Fisher L, Jain R, Evans JA, Appalaneni V et al. Complications of ERCP. Gastrointest Endosc 2012; 75:467–473.  Back to cited text no. 1
    
2.
Rabenstein T, Hahn EG. Post-ERCP pancreatitis: new momentum. Endoscopy 2002; 34:325–329.  Back to cited text no. 2
    
3.
Vandervoort J, Soetikno RM, Tham TC, Wong RC, Ferrari AP Jr, Montes H et al. Risk factors for complications after performance of ERCP. Gastrointest Endosc 2002; 56:652–656.  Back to cited text no. 3
    
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Kochar B, Akshintala VS, Afghani E, Elmunzer BJ, Kim KJ, Lennon AM et al. Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials. Gastrointest Endosc 2015; 81:143–149 e9.  Back to cited text no. 4
    
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Messmann H, Vogt W, Holstege A, Lock G, Heinisch A, von Fürstenberg A et al. Post-ERP pancreatitis as a model for cytokine induced acute phase response in acute pancreatitis. Gut 1997; 40:80–85.  Back to cited text no. 5
    
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Karne S, Gorelick FS. Etiopathogenesis of acute pancreatitis. Surg Clin North Am 1999; 79:699–710.  Back to cited text no. 6
    
7.
Makela A, Kuusi T, Schroder T. Inhibition of serum phospholipase-A2 in acute pancreatitis by pharmacological agents in vitro. Scand J Clin Lab Invest 1997; 57:401–407.  Back to cited text no. 7
    
8.
Patil S, Pandey V, Pandav N, Ingle M, Phadke A, Sawant P. Role of rectal diclofenac suppository for prevention and its impact on severity of post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients. Gastroenterology Res 2016; 9:47–52.  Back to cited text no. 8
    
9.
Wildenhain PM, Melhem MF, Birsic WI, Sell HW, Rao KN. Acute hemorrhagic pancreatitis in mice: improved survival after indomethacin administration. Digestion 1989; 44:41–51.  Back to cited text no. 9
    
10.
Cheon YK, Cho KB, Watkins JL, McHenry L, Fogel EL, Sherman S et al. Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial. Gastrointest Endosc 2007; 66:1126–1132.  Back to cited text no. 10
    
11.
Elmunzer BJ, Waljee AK, Elta GH, Taylor JR, Fehmi SM, Higgins PD. A meta-analysis of rectal NSAIDs in the prevention of post-ERCP pancreatitis. Gut 2008; 57:1262–1267.  Back to cited text no. 11
    
12.
Van Der Marel CD, Anderson BJ, Romsing J, Jacqz-Aigrain E, Tibboel D. Diclofenac and metabolite pharmacokinetics in children. Paediatr Anaesth 2004; 14:443–451.  Back to cited text no. 12
    
13.
Fazel A, Quadri A, Catalano MF, Meyerson SM, Geenen JE. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study. Gastrointest Endosc 2003; 57: 291–294.  Back to cited text no. 13
    
14.
Freeman ML. Pancreatic stents for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. Clin Gastroenterol Hepatol 2007; 5:1354–1365.  Back to cited text no. 14
    
15.
Andriulli A, Clemente R, Solmi L, Terruzzi V, Suriani R, Sigillito A et al. Gabexate or somatostatin administration before ERCP in patients at high risk for post-ERCP pancreatitis: a multicenter, placebo-controlled, randomized clinical trial. Gastrointest Endosc 2002; 56:488–495.  Back to cited text no. 15
    
16.
Shi N, Deng L, Altaf K, Huang W, Xue P, Xia Q. Rectal indomethacin for the prevention of post-ERCP pancreatitis: a meta-analysis of randomized controlled trials. Turk J Gastroenterol 2015; 26:236–240.  Back to cited text no. 16
    
17.
Badalov N, Tenner S, Baillie J. The prevention, recognition and treatment of post-ERCP pancreatitis. JOP 2009; 10:88–97.  Back to cited text no. 17
    
18.
Zheng MH, Xia HH, Chen YP. Rectal administration of NSAIDs in the prevention of post-ERCP pancreatitis: a complementary meta-analysis. Gut 2008; 57:1632–1633.  Back to cited text no. 18
    
19.
Dai HF, Wang XW, Zhao K. Role of nonsteroidal anti-inflammatory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int 2009; 8:11–16.  Back to cited text no. 19
    
20.
Levenick JM, Gordon SR, Fadden LL, Levy LC, Rockacy MJ, Hyder SM. Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients. Gastroenterology 2016; 150:911–917. [quiz e19].  Back to cited text no. 20
    
21.
Rustagi T, Njei B. Factors affecting the efficacy of nonsteroidal anti-inflammatory drugs in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and meta-analysis. Pancreas 2015; 44:859–867.  Back to cited text no. 21
    
22.
Wan J, Ren Y, Zhu Z, Xia L, Lu N. How to select patients and timing for rectal indomethacin to prevent post-ERCP pancreatitis: a systematic review and meta-analysis. BMC Gastroenterol 2017; 17:43.  Back to cited text no. 22
    



 
 
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