Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial. Lancet. 2024 Feb 3;403(10425):450-458. doi: 10.1016/S0140-6736(23)02356-5 [MEDLINE]
Background: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention
Methods: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete
Findings: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups
Interpretation
For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement
These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines
In an Older Series of Patients Who Underwent ERCP with Sphincterotomy, Retroduodenal Perforation Occurred in 0.5-2.1% of Cases (Gastrointest Endosc, 1991) [MEDLINE]
Complication Rates Have Decreased with Increasing Skills of ERCP Endoscopists
In Series of Patients Who Underwent Endoscopic Sphincterotomy, Complications Occurred in 7.9% of Cases (with the Complication Rate Decreasing Significantly from 10.5% in Earlier Periods to 6.3% in Later Periods) (Endoscopy, 1998) [MEDLINE]: n = 3,498
However, Severe and Fatal Complications or ERCP Still Occur (Gastrointest Endosc, 2002) [MEDLINE]
In a Systematic Survey of Post-ERCP Complications (Including 21 Prospective Studies), Procedure-Related Perforation Occurred in 0.60% of Cases (with 0.06% of the Cases Resulting in Death) (Am J Gastroenterol, 2007) [MEDLINE]
In a Study of ERCP-Associated Complications (in Almost 210,000 ERCP’s), the ERCP-Associated Perforation Rate was 0.39% (95% CI: 0.34-0.69) with an Associated Mortality Rate of 7.8% (95% CI: 3.80-13.07) (World J Gastrointest Endosc, 2015) [MEDLINE]
Risk Factors for Perforation (Either Free Abdominal or Retroperitoneal) (Gastrointest Endosc, 2017) [MEDLINE] (Endoscopy, 2020) [MEDLINE]
General Comments
In Older Studies, Sphincter of Oddi Dysfunction was a Risk Factor for Perforation, But ERCP is Not Typically Performed for This Indication
Patient-Related Risk Factors
Dilated Common Bile Duct
Female Sex
Older Age
Presence of a Papillary Lesion
Surgically Altered Anatomy
Procedure-Related Risk Factors
Biliary Stricture Dilation
Difficult Cannulation
Endoscopic Papillary Large-Balloon Dilatation
Intramural Injection of Contrast Material
Less Experienced Endoscopist
Longer Procedure Duration
Sphincterotomy
Use of Precut Needle-Knife Methods for Bile Duct Access
Case Series of Post-ERCP Perforations (J Gastrointest Surg, 2011) [MEDLINE]: n = 44
In Series, 68% of Perforations were Retroperitoneal Duodenal Perforations, Which Usually Occurred as a Result of a Sphincterotomy or Large Balloon Dilation Which Extended Beyond the Intramural Portion of the Bile Duct
Study of ERCP-Related Perforations (World J Gastrointest Endosc, 2015) [MEDLINE]
Type I: accounted for 25% of perforations
Type II: accounted for 46% of perforations
Type III: accounted for 22% of perforations
Type IV: accounted for 3% of perforations
Single-Center Case Series of Post-ERCP Perforations (Gastrointest Endosc, 2016) [MEDLINE]: n = 79
Type 1: 7 perforations
Type II: 54 perforations
While Most Patients with Type II Perforations were Medically Managed, But 7% of These Cases Required Surgical Intervention
Liver and Pancreatic Parenchymal Perforation by the ERCP Guidewire Can Result in Subcapsular Liver Hematoma and/or Subcapsular Biloma (Case Rep Surg, 2015) [MEDLINE] (Can J Gastroenterol Hepatol, 2016) [MEDLINE]
Pancreas
Liver and Pancreatic Parenchymal Perforation by the ERCP Guidewire Can Result in Subcapsular Liver Hematoma and/or Subcapsular Biloma (Case Rep Surg, 2015) [MEDLINE] (Can J Gastroenterol Hepatol, 2016) [MEDLINE]
Method of Diagnostic Confirmation of ERCP-Associated Perforation
General Comments
Type I Perforations are Almost Always Recognized Immediately During the ERCP, Due to the Presence of Clinical Symptoms/Signs and Fluoroscopic Findings
Type II (Retroduodenal) Perforations are May Be Diagnosed Based on Radiographic Evidence of Air During the ERCP, by Presence of Contrast in the Retroperitoneal Space During the ERCP, or by Presence of Pneumoretroperitoneum on a Post-ERCP Abdominal/Pelvic CT Scan (Which is Typically Performed in the Setting of Post-ERCP Pain)
In Some Cases, Type II (Retroduodenal) Perforations are Diagnosed Endoscopically
Abdominal/Pelvic CT Scan is the Most Sensitive Diagnostic Method for Detecting and Localizing the Site of Perforation (Radiol, 1989) [MEDLINE] (Gastrointest Endosc, 1997) [MEDLINE]
The Clinical/Radiographic Amount of Air Does Not Always Reflect the Size of the Perforation Itself or Correlate with the Severity of the Complication
Clinical/Radiographic Amount of Air Reflects the Degree of Manipulation After the Perforation Occurred (Gastrointest Radiol, 1989) [MEDLINE] (Gastrointest Endosc, 1993) [MEDLINE]
Type I Free Perforation of Lateral/Medial Duodenal Wall (Remote from the Ampulla) or the Jejunum is Rare, is Caused by the Endoscope, and Usually Occurs in Patients with a Stricture or Altered Anatomy (Prior Billroth II Gastrectomy, etc) (Gastrointest Endosc, 1994) [MEDLINE] (Am J Gastroenterol, 1999) [MEDLINE] (Gastrointest Endosc, 2001) [MEDLINE] (Gastrointest Endosc, 2016) [MEDLINE]
Type II: retroperitoneal duodenal perforation secondary to periampullary injury
Most Common Type
Type III: perforation of the pancreatic or bile duct
While Perforation is Typically Associated with the Presence of Pneumoretroperitoneum (Detected by Chest X-Ray/KUB or CT), Pneumoretroperitoneum May Also Develop Following Sphincterotomy in Patients Who are Clinically Asymptomatic (Gastrointest Endosc, 1997) [MEDLINE] (Am J Gastroenterol, 1999) [MEDLINE]
In a Series of 21 Patients Studied Prospectively Who Underwent an Abdominal CT Scan Following sphincterotomy, Pneumoretroperitoneum was Observed in 6 (29%) of Cases, All of Whom were Asymptomatic and Had an Uneventful Post-ERCP Course (Am J Gastroenterol, 1999) [MEDLINE]
Mechanisms of Pneumoretroperitoneum
Dissection Through an Injured or Macroscopically Intact Bowel, a Phenomenon Which Has Been Described Following Colonoscopy (Gastrointest Radiol, 1977) [MEDLINE] (Endoscopy, 1983) [MEDLINE]
Sealed Microperforation
Time to Diagnostic Recognition of ERCP-Associated Perforation
In a Retrospective Series of ERCP-Associated Type I/II Perforations, 10% of Perforations were Diagnosed Endoscopically During the ERCP (with 90% Detected After the ERCP) and the Mean Time to Diagnosis of ERCP-Associated Perforation was 24 (+/-13) hrs (Gastrointest Endosc, 2016) [MEDLINE]
In Other Studies, the Diagnosis Rate for Perforation During ERCP Have Been Reported to Be Higher, Being Made During the ERCP in as Many as 73% of Cases (World J Gastrointest Endosc, 2015) [MEDLINE] (Surg Endosc, 2018) [MEDLINE]
Diagnosis of Retroperitoneal Perforation in the Setting of Concomitant Acute Pancreatitis
The Interpretation of Pneumoretroperitoneum Can Be Challenging in a Symptomatic Patient Following Sphincterotomy in Whom a Distinction Needs to Made Between Perforation, Clinically Insignificant Pneumoretroperitoneum, and Acute Pancreatitis (Particularly Since Acute Pancreatitis and Perforation Can Have a Similar Clinical Presentation or Occur Simultaneously) (J Comput Assist Tomogr, 1989) [MEDLINE] (Gastrointest Radiol, 1989) [MEDLINE] (Gastrointest Endosc, 1994) [MEDLINE]
Study of Patients with Prolonged Abdominal Pain Following Sphincterotomy (Gastrointest Radiol, 1989) [MEDLINE]: n = 36
Complications Included Acute Pancreatitis in 64% of Cases, Duodenal Perforation in 31% of Cases, and Both Pancreatitis and Duodenal Perforation in 17% of Cases
Study of Safety of Endoscopic Papillary Balloon Dilation in Patients Who Had Prior Billroth II Gastrectomy (Clin Endosc, 2015) [MEDLINE]
Two of Three Perforations in Patients with Billroth II Anatomy were Associated with Acute Pancreatitis
Study of Patients with Type I or II Duodenal Perforations (Gastrointest Endosc, 2016) [MEDLINE]: n = 61
Concurrent Post-ERCP Acute Pancreatitis was Diagnosed in 43% of Cases and was Associated with an Increased Mean Length of Stay
Clinical Presentation of Undetected Post-ERCP Perforation
Unplanned Hospital Admission <4 Nights in Duration
Moderate Perforation
Any of the Following
Unplanned Hospital Admission for4-10 Nights
Admission Requiring Intensive Care for ≥1 Night
Need for Blood Transfusion
Need for Repeat Endoscopy or Interventional Radiology
Intervention for Integument Injuries
Severe Perforation
Any of the Following
Unplanned Hospital Admission >10 Nights
Admission Requiring Intensive Care for >1 Night
Need for Surgery
Permanent Disability
Management
Supportive Care is Recommended for All Patients (Except Possibly for Asymptomatic Patients with Small Type III Perforations of the Pancreatic Duct/Bile Duct)
NPO Status
Intravenous Fluid Hydration
Nasogastric/Nasoduodenal Suction
Intravenous Antibiotics
Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition): for patients who will be kept NPO for >1 wk
General Comments
Surgery is Required in Approximately 20-50% of All Post-ERCP Perforations
Surgery is Performed Mostly for Type I Perforations
At Laparotomy, the Location of the Perforation in Cases of ERCP-Associated Injury May Not Be Identified (Especially in Patients with Type II or III Perforations) (HPB-Oxford, 2006) [MEDLINE]
Overall, Surgical Repair is Associated with a Higher Mortality Rate than Medical Mangement
In a Review of 11 Studies, Surgery was Required in 21% of Cases (Mortality Rate: 38%), as Compared to an Overall Mortality Rate of 9% (World J Gastrointest Endosc, 2015) [MEDLINE]
Indications for Surgery (Am J Surg, 1993) [MEDLINE]
Cholangitis
Lack of Improvement of Symptoms After Brief Period of Nonoperative Management
Major Contrast Leak
Persistent Biliary Obstruction
Type I (Free Bowel Wall) Perforation
If Recognized Immediately, Closure May Be Achieved with Endoscopic Clips, an Over-the-Scope Clip, or an Endoscopic Suturing Device
However, Type I Perforations (with Esophageal, Free Abdominal Gastric/Jejunal/Duodenal Perforations Usually Require Surgery
Type II (Retroperitoneal) Perforation (Due to Sphincterotomy)
Medical Management or Placement of Fully-Covered Metal Stent to Seal the Perforation
Early Surgical Consultation and Close Observation is Required, Since the Outcome May Be Poor in Patients Who Do Not Receive Prompt Intervention if Their Clinical Condition Worsens
In a Retrospective Study of Post-ERCP Perforations (n = 380 Patients) in Which 87% were Managed Nonoperatively and 13% were Managed Operatively, for the 20/50 Surgical Patients Where Surgery was Performed >24 hrs After ERCP, Delayed Surgery was Associated with a Higher Mortality Rate and Postoperative Duodenal Leak, as Compared to Patients Managed with Early Surgery (Surg Endosc, 2020) [MEDLINE]
Surgical Options
Choledochotomy with Stone Extraction and T-Tube Drainage
A retroperitoneal abscess should be suspected in patients with post-ERCP pancreatitis who develop back pain and persistent fever (Gastrointest Endosc, 1998) [MEDLINE]
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