Post-endoscopic retrograde cholangiopancreatography pancreatitis: Mechanistic pathways, diagnostic benchmarks, and emerging and mitochondria-targeted therapies

Table 1 Classification of post-endoscopic retrograde cholangiopancreatography pancreatitis

Type	Severity			Advantages and disadvantages
	Mild	Moderate	Severe
Consensus classification[22]	Length of hospital stay as 2-3 days	Length of hospital stay as 4-10 days	A hospital stay of more than 10 days, or the occurrence of hemorrhagic pancreatitis or pancreatic pseudocysts requiring intervention (percutaneous drainage or surgery)	Advantages: (1) Operational simplicity; (2) Strong clinical relevance; and (3) Facilitates statistical analysis and comparison. Disadvantages: (1) Lack of specificity; (2) Lack of sensitivity; and (3) Not applicable to all patient groups
Revised Atlanta classification[27]	The absence of complications	Transient (≤ 48 hours) organ failure or local or systemic complications	Persistent (> 48 hours) organ failure	Advantages: (1) Clear severity grading; (2) Based on clinical symptoms and signs; and (3) Promote clinical research and comparison. Disadvantages: (1) Inadequate identification of mild PEP cases; (2) Lack of reflection on the dynamic changes of the condition; and (3) Incomplete consideration of prognostic factors

Table 2 Overview of relevant randomized controlled trials

Ref.	Study design	Participants	Intervention	Control	Results
Luo et al[54], 2016	Multicentre, single-blinded, randomised controlled trial	Patients with native papilla undergoing ERCP at six centres in China	All patients received 100 mg rectal indometacin within 30 min before ERCP	High-risk patients received rectal indometacin immediately after ERCP	4% pancreatitis in universal indometacin group vs 8% in risk-stratified group (relative risk = 0.47; 95%CI: 0.34-0.66; P < 0.0001)
Fogel et al[57], 2020	Randomised, double-blind, comparative effectiveness trial	High-risk patients from six tertiary medical centres in the United States	Standard-dose group received two 50 mg indometacin suppositories and a placebo suppository; high-dose group received three 50 mg indometacin suppositories and an additional 50 mg suppository 4 hours after procedure	-	15% pancreatitis in standard-dose group vs 12% in high-dose group (risk ratio = 1.19, 95%CI: 0.87-1.61; P = 0.32)
Mok et al[72], 2017	Randomised, double-blinded, placebo-controlled trial	High-risk patients	Four groups: Normal saline + placebo, normal saline + indometacin, lactated Ringer's + placebo, lactated Ringer's + indometacin	-	6% pancreatitis in lactated Ringer's + indometacin group vs 21% in normal saline + placebo group (P = 0.04)
Patel et al[67], 2022	Randomised controlled trial	High-risk patients	Aggressive infusion of lactated Ringer's or normal saline	-	4% pancreatitis in lactated Ringer's group vs 11% in normal saline group (relative risk = 0.38, 95%CI: 0.10-1.42; P = 0.19)
Concepción-Martín et al[76], 2014	Randomised, double-blind trial	Patients undergoing ERCP at a single centre	Intravenous bolus of somatostatin followed by a 4-hour continuous infusion	Similar placebo regimen	7.5% pancreatitis in somatostatin group vs 6.7% in placebo group (relative risk = 1.12, 95%CI: 0.59-2.1; P = 0.73)
Wang et al[77], 2013	Randomised, placebo-controlled pilot trial	Patients scheduled for ERCP	Pre-ERCP somatostatin (0.5 mg/hour for 24 hours, starting 1 hour before ERCP), post-ERCP somatostatin (0.5 mg/hour for 24 hours, starting 1 hour after ERCP), or placebo (saline for 24 hours, starting 1 hour before ERCP)	-	16.7% pancreatitis in pre-ERCP somatostatin group, 10.6% in post-ERCP somatostatin group, 14.6% in placebo group (P = 0.715)
Norouzi et al[101], 2023	Double-blind randomised placebo-controlled clinical trial	High-risk patients	100 mg rectal indometacin + 250 g somatostatin bolus followed by 500 g infusion for 2 hours	100 mg rectal indometacin + placebo	11.4% pancreatitis in intervention group vs 15.2% in control group (P = 0.666)
Yoo et al[102], 2011	Prospective, randomised, double-blind, controlled trial	Patients undergoing ERCP	Intravenous nafamostat mesilate 60 min before and for 6 hours after ERCP	Placebo	2.8% pancreatitis in nafamostat group vs 9.1% in placebo group (P = 0.03)

ERCP: Endoscopic retrograde cholangiopancreatography.

Table 3 The risk stratification model for post-endoscopic retrograde cholangiopancreatography pancreatitis

Risk factors included	Predictive value	Advantages and disadvantages	Ref.
Pain; pancreatic duct cannulation; previous PEP; and the number of cannulation attempts	Low-risk: 1.9%; medium-risk: 6.9% and high-risk: 28%	Applicable to patients suspected of having SOD and those at high risk for PEP; not validated; a pioneer in the risk stratification model for PEP	Friedland et al[92], 2002
History of gastrectomy; high DBIL; high ALB; CBD stones; papillary opening with villous type; papillary opening with nodular type; pancreatic guidewire passage; pre-cut sphincterotomy; and high procedural experience	Low-risk: 6.1%; medium-risk, 17%; high-risk: 37.5%. AUC was 0.718–0.793; sensitivity was 0.705–0.727; and specificity was 0.676–0.797	Applicable to patients suspected of having SOD and those at high risk for PEP; not validated; a pioneer in the risk stratification model for PEP	Zheng et al[95], 2020
Complete papilla; PGW-assisted biliary cannulation; difficult cannulation; pancreatic injection; absence of a pancreatic stent	Extremely high-risk: 28.79%; the predicted incidence of severe pancreatitis was 9.09%. AUC was 0.86, while the AUC for internal validation was 0.81	Applicable to patients suspected of having SOD and those at high risk for PEP; not validated; a pioneer in the risk stratification model for PEP	Chiba et al[97], 2021
A history of PEP; complete papilla; difficult cannulation; pancreatic guidewire-assisted biliary cannulation; pancreatic injection; IDUS/sampling of the pancreas; biliary IDUS/sampling	The AUC in both the training and validation sets were 0.799 and 0.791, respectively; In the high-risk, the incidence of PEP was 13.4%	Applicable to patients suspected of having SOD and those at high risk for PEP; not validated; a pioneer in the risk stratification model for PEP	Fujita et al[4], 2022
Age ≤ 65 years; female sex; history of acute pancreatitis; malignant biliary obstruction	Low risk: 2.2%; medium risk: 3.8%; high risk: 6.9%	Pre-ERCP risk prediction model	Kim et al[81], 2022
Age ≤ 65 years; female sex; history of acute pancreatitis; malignant biliary obstruction; pancreatic sphincterotomy	Low risk: 2.0%; medium risk: 3.4%; high risk: 18.4%	Post-ERCP risk prediction model; the model based on retrospective data, its reliability in practical application remains uncertain	Kim et al[81], 2022
Extended total operation time; unexpected pancreatic duct cannulation; pancreatic imaging total operation time; unexpected pancreatic duct cannulation; and pancreatic imaging	Low-risk, medium-risk, and high-risk were 2.6%, 7.1%, and 12.6%, respectively	Using prospective cohort data; indicated that most patients without PEP had an operation time of less than 14 minutes	Kim et al[81], 2022
Female gender; pancreatic duct cannulation; papillary condition; pre-cut sphincterotomy; prolonged cannulation time; bile duct stenosis; patient age; pancreatic duct stent placement	An ROC curve statistic of 0.79; a predicted-to-observed risk ratio of 1.003	Has good discriminative ability and good calibration	Meng et al[98], 2024

SOD: Sphincter of Oddi dysfunction; PEP: Post-endoscopic retrograde cholangiopancreatography pancreatitis; DBIL: Direct bilirubin; ALB: Albumin; CBD: Common bile duct; AUC: Area under the curve; PGW: Pancreatic guide-wire; IDUS: Intraductal ultrasound; ROC: Receiver operating characteristic.