Indomethacin Decreases Post-ERCP Pancreatitis
Indomethacin Decreases Post-ERCP Pancreatitis
Endoscopic retrograde cholangiopancreatography (ERCP) is now a widely accepted therapy for
 treating benign and malignant diseases of the pancreatobiliary tree. Acute pancreatitis
 represents the most common and feared complication following ERCP. The reported incidence of
 this complication is from 1% to 40% according to the presence of high-risk factors for this
 complication or the presence dysfunction in the sphincter of Oddi (SOD). In most prospective
 series, the incidence has ranged between 3.5% and 20% for nonselected and high-risk patients,
 respectively. Independent risk factors for post-ERCP pancreatitis are either patient- or
 procedure-related.
Design This is a randomized clinical trial carried out in patients scheduled for ERCP at the
 Department of Gastrointestinal Endoscopy and Department of Gastroenterology of the
 Specialties Hospital of the Western Medical Center, in Guadalajara, Jalisco, Mexico. The
 investigators include patients with an elevated baseline risk of post-ERCP pancreatitis based
 on prospectively validated patient- and procedure-related independent risk factors.

 The ERCP procedures are performed with the patient under topical pharyngeal anesthesia with
 2% lidocaine and after administration of sedation (midazolam) and analgesia (fentanyl)
 intravenously, with dosages at the discretion of the endoscopist. Patients receive
 complementary oxygen through an external nasal device at 3 to 5 L/min and infusion of 200 to
 500 mL of 0.9% sterile saline solution.

 The equipment and protocol that are being used to perform ERCP consist of a video
 duodenoscope (Olympus, Tokyo, Japan), sphincterotome traction for selective cannulation of
 the bile duct, a needle scalpel to perform precut sphincterotomy, a hydrophilic guide wire
 via the bile duct, a Dormia basket and/or balloon catheter for stone extraction, and nonionic
 water-soluble contrast medium at 300 mg/mL (Optira 300™; ioversol injection 64%; Mallinckrodt
 Pharmaceuticals, Dublin, Ireland) for opacification of the biliary and pancreatic ducts.

 Pancreatic stents are being used only to treat pancreatic fistulas and to prevent
 pancreatitis. All patients are monitored continuously during the procedure, with
 determinations of blood pressure, heart rate, respiratory rate, and arterial blood oxygen
 saturation.

 Eligible patients who provide written informed consent undergo the randomization at
 conclusion of the ERCP procedure because patients without risk factors could be included in
 the study based on procedure-related factors alone. If patients met the inclusion criteria,
 they are randomly assigned to receive a 100 mg suppository of indomethacin or 2.4 g of
 glycerin suppository immediately afterwards while still under sedation. All patients are
 observed to prevent spontaneous expulsion of the suppository until they became completely
 awake. All patients, staff endoscopists, residents, and researchers are blinded to the
 treatment assigned to each of them.

 The following data that is being collected.

 1. A clinical history, particularly patient-related risk factors for post-ERCP
 pancreatitis; blood test results for the determination of basal amylase, liver enzymes,
 and bilirubin levels; as well as results of ultrasonography of the liver and biliary
 tract.

 2. All data generated during the ERCP is being recorded, particularly those related to
 procedure-related risk factors for developing acute pancreatitis. In addition, other
 nonpancreas-related complications are being recorded as perforation or bleeding.

 3. Any adverse events related to the rectally applied indomethacin or glycerin
 suppositories are being recorded as expulsion, irritation, or bleeding.

 Post-ERCP pancreatitis is considered the main outcome variable and is defined as the
 development of new or increased abdominal pain consistent with pancreatitis, and elevated
 blood amylase or lipase >3 times the upper limit of normal until 24 h after the procedure,
 and hospitalization (or prolongation of existing hospitalization) for at least 2 nights. The
 severity is determined according to consensus guidelines, with mild post-ERCP pancreatitis
 resulting in hospitalization of less than 3 days, and moderate post-ERCP pancreatitis
 resulting in hospitalization of 4-10 days. Severe post-ERCP pancreatitis is qualified as
 resulting in a hospitalization of >10 days, or leading to the development of pancreatic
 necrosis or pseudocysts, or requiring percutaneous or surgical intervention. Patients with
 acute pancreatitis are being followed up for 30 days after hospital discharge. Asymptomatic
 hyperamylasemia is defined as any amylase level at least three times above the normal serum
 level in the absence of abdominal pain.

 Follow up The patients are kept under surveillance in the endoscopy recovery area for 3 h
 after ERCP. Measurement of serum amylase is determined at 2 h post-ERCP in all included
 patients. Asymptomatic outpatients are discharged after 6 h of surveillance with monitoring
 for signs and symptoms of acute post-ERCP pancreatitis by telephone contact for 24 hours.

 Hospitalized asymptomatic patients are being discharged to their assigned bed after 4 hours
 of surveillance, where clinical surveillance is continued for up to 24 h. If new abdominal
 pain suggestive of pancreatic origin appeares at any time, the 2-h amylase level is checked
 and confirmed with serum lipase determination.

 All routine laboratory examinations are being performed when acute pancreatitis of any
 etiology is established. All patients diagnosed with post-ERCP pancreatitis are being managed
 under the medical care of the Department of Gastroenterology.

 Patients are being submitted to computed tomography scanning to determine the severity of the
 episode of pancreatitis. Severity was established according to Cotton's criteria.

 Statistical analysis Statistical software, SPSS for IBM (version 20 for Windows; IBM Corp.,
 Armonk, NY, USA) is beign used for data analysis.

 The data obtained will be expressed as frequencies and percentages, means and standard
 deviations. For comparing results, Student's t test will be used for continuous variables and
 Chi2 or Fisher's exact tests will be used for qualitative data when appropriate.

 Relative risk (RR) and 95% confidence intervals (95% CI) will be determined as well as the
 absolute risk reduction (ARR), relative risk reduction (RRR), and number needed to treat
 (NNT).

 Statistical significance from two-tailed tests was assumed when p < 0.05
Inclusion Criteria:

 -  If they met one or more of the following criteria:

 -  a clinical suspicion of SOD dysfunction;

 -  or a history of post-ERCP pancreatitis, pancreatic

 -  or precut sphincterotomy,

 -  more than eight cannulation attempts,

 -  pneumatic dilatation of an intact biliary sphincter,

 -  or ampullectomy

 -  Patients were also eligible for inclusion if they met two of the following criteria:

 -  aged 50 years or younger and female gender

 -  or a history of recurrent pancreatitis (>2 episodes),

 -  three or more injections of contrast agent into the pancreatic duct with at least
 one injection to the tail of the pancreas,

 -  excessive injection of contrast agent into the pancreatic duct resulting in
 opacification of pancreatic acini,

 -  or the need for acquisition of a cytology specimen from the pancreatic duct with
 the use of a tissue-sampling brush.

 Exclusion Criteria:

 -  unwillingness or inability to consent for the study

 -  pregnancy

 -  breast feeding

 -  standard contraindications for ERCP

 -  hypersensitivity to aspirin or NSAIDs

 -  previous use of NSAIDs within 1 week

 -  renal failure (creatinine clearance rate >1.4 mg/dL)

 -  active or recent (< 4 weeks) gastrointestinal hemorrhage

 -  chronic calcified pancreatitis

 -  pancreatic head malignancy

 -  any procedure performed on the major papilla/ventral pancreatic duct in patients with
 a pancreatic divisum

 -  previous ERCP for biliary stent removal or exchange without an anticipated
 pancreatogram

 -  subjects with prior biliary sphincterotomy and scheduled for repeat biliary therapy
 without an anticipated pancreatogram

 -  or anticipated inability to follow our protocol