This editorial refers to “Lactated Ringer’s solution in combination with indomethacin for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A prospective, randomized trial” by Amalou et al, 2026; https://dx.doi.org/10.4253/wjge.v18.i1.113788.
INTRODUCTION
In the field of biliary endoscopy, post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography, occurring in 1%-40% of cases, and is associated with specific risk factors[1-3]. Pathogenesis is multifactorial, stemming from mechanical trauma to the papillary orifice, hydrostatic injury from elevated intraductal pressure, enzymatic activation, chemical factors, and thermal mechanisms[4]. Experimental studies have shown that both contrast agents and hydrostatic pressure can promote inflammatory responses, cellular apoptosis, and tight junction disruption through nuclear factor kappa B and STAT3 pathway activation[5]. Among the proposed mechanisms, elevated intraductal hydrostatic pressure appears to be the primary underlying cause[6]. Endoscopic sphincterotomy reduces pancreatic intraductal pressure, potentially mitigating the severity of PEP[7]. The current strategies with the strongest evidence for prevention of PEP include pancreatic duct stenting and rectal non-steroidal anti-inflammatory drugs (NSAIDs)[8]. In the recent issue of World Journal of Gastrointestinal Endoscopy, Amalou et al[9] showed in their randomized, double-blind, controlled study that lactated Ringer’s (LR) solution combined with rectal administration of indomethacin (IND) may decrease the occurrence of PEP and post-procedure readmission in high-risk patients, compared with either LR solution or IND administered separately. The high cost and lack of experience with endoscopic procedures to prevent PEP could pose obstacles, whereas increasing awareness of this potential complication among biliary endoscopists would promote the adoption of preventative strategies. This editorial discusses non-endoscopic measures for the prevention of PEP.
MEDICATIONS FOR PEP PREVENTION
Several medications with various routes of administration are currently available for the prevention of PEP. Depending on patient circumstances, these include topical rectal administration of NSAIDs, parenteral medications such as somatostatin analogues, protease inhibitors (gabexate mesylate, ulinastatin, and nafamostat mesylate), and anti-inflammatory corticosteroids, as well as a variety of miscellaneous agents such as nitroglycerin and antibiotics.
NSAIDs
Rectal administration of IND or diclofenac at a dose of 100 mg before or immediately after ERCP as a monotherapy resulted in a 50% reduction in PEP (4% vs 8%, P < 0.0001)[10] and is recommended by the American Society of Gastrointestinal Endoscopy guidelines[11,12] for all patients undergoing ERCP. IND and diclofenac are considered equally effective. Rectal IND has been found to be superior to risk-stratified post-procedural use, reducing PEP compared with controls in both high-risk (6% vs 12%) and average-risk (3% vs 6%) patients[10]. Rectal NSAIDs are now considered standard prophylaxis, with guidelines recommending their use in high-risk patients[13]. Rectal NSAIDs may be superior to pancreatic stents, but combination therapy with aggressive hydration is not necessarily better than NSAIDs alone[14,15].
Somatostatin analogues
Administered intravenously (IV), despite varied efficacy[16], somatostatin analogues are still a proven modality and are listed as “possibly effective”[17].
Protease inhibitors
IV gabexate mesylate[18], ulinastatin, and nafamostat mesylate, have shown conflicting results in meta-analyses[16] with limited evidence of efficacy.
Corticosteroids
Promising early results were observed, which have not been replicated in larger clinical trials[19].
Miscellaneous agents
A systematic review reported that sublingual nitroglycerin and antibiotics are ineffective or impractical[14].
Current clinical recommendations
Evidence suggests that rectal NSAIDs provide the most effective standard prophylaxis[11].
USE OF IV FLUIDS FOR PREVENTION OF PEP
A systematic review[19] and a randomized clinical trial by Shaygan-Nejad et al[20] have confirmed that an aggressive hydration regimen with LR solution is superior to standard hydration for prevention of PEP. This beneficial effect is explained by the prevention of intravascular volume depletion during the procedure, immediate correction of fluid shifts post-procedure, and maintenance of pancreatic microcirculation[21].
Several dosing protocols have been proposed that differ in the timing of administration of LR solution with respect to the ERCP procedure: A dose of 3 mL/kg/hour during ERCP; 20 mL/kg as a bolus immediately following ERCP, or 3 mL/kg/hour eight hours after completion of ERCP[22,23].
A high volume of IV fluids can be administered as a continuous drip or as a bolus. Patients receiving continuous IV hydration (high-volume group) received significantly more fluid volume than those in the control group (3600 mL vs 2413 mL, P < 0.001). PEP incidence was not different between the high-volume and control groups (14% vs 15%; relative risk 0.93: 95%CI: 0.48-1.83, P = 0.84). No differences were observed between patients with moderate and severe PEP (3% vs 4%; relative risk, 0.75: 95%CI: 0.17-3.27, P = 1.00)[24]. Patients presenting ERCP were provided with preemptive hydration of 2000 mL preoperatively followed by an additional 1000 mL/10 hours of LR solution postoperatively (hydration group) and showed a lower incidence of PEP (12.4%) compared with patients given no intervention (control group) (24.3%) [odds ratio (OR): 0.44; 95%CI: 0.26-0.75, P = 0.003]. The incidence of severe PEP was 2.0% and 6.9% in the hydration and control groups (OR: 0.27; 95%CI: 0.09-0.84, P = 0.027), respectively. The incidence of fatal PEP in the hydration and control groups was 0% and 2.0% (OR: Not identified; P = 0.123), respectively[25].
Aggressive hydration was effective in reducing the incidence of PEP to 5.3% vs 22.7% in patients who received standard hydration (P = 0.002)[22]. Furthermore, the incidence of PEP was reduced (OR: 0.29; 95%CI: 0.16-0.53)[21], and moderate-to-severe PEP was reduced with an OR of 0.16[21]. Nonetheless, a large multicenter trial found that aggressive periprocedural hydration (starting within 60 minutes of ERCP, followed by 3 mL/kg/hour for 8 hours) had limited additional benefit when combined with rectal administration of NSAIDs[26]. Most recently a significant reduction of PEP has been reported following aggressive hydration using LR solution alone (OR: 0.23; 95%CI: 0.13-0.40, P < 0.001), following a combination of LR hydration with stents, and that NSAIDs was superior to LR alone (OR: 0.63; 95%CI: 0.41-0.98, P < 0.04)[27].
COMBINED USE OF IV FLUIDS AND MEDICATIONS FOR PREVENTION OF PEP
Rectal NSAIDs combined with aggressive intravenous hydration is the most studied combination, primarily IND or diclofenac (100 mg) combined with aggressive LR hydration (3 mL/kg/hour during ERCP, 20 mL/kg bolus post-procedure, 3 mL/kg/hour for 8 hours). This combination resulted in a reduction in PEP risk (OR: 0.21; 95%CI: 0.05-0.83) compared with placebo, as reported in a network meta-analysis[28]. In contrast, in a large multicenter trial (813 patients) comparing aggressive hydration plus NSAIDs with NSAIDs alone, Sperna Weiland et al[24] found no significant difference in the PEP rate (8% vs 9%, P = 0.53). Other combinations, including somatostatin or gabexate with hydration, have shown limited benefit[17]. Normal saline and LR solutions were studied in combination with NSAIDs in a recent network meta-analysis by Arabpour et al[27]: IND and normal saline were ranked as the best preventive method for overall and mild PEP in the average-risk group. However, IND and LR solution were the most effective methods for preventing moderate-to-severe PEP. When pancreatic stents were considered for the prevention of PEP in high-risk groups, IND combined with a pancreatic stent was the best preventive method for overall and mild PEP. However, diclofenac alone was most effective for preventing moderate-to-severe PEP[29].
A recent network meta-analysis by Oh et al[28] revealed that the most efficacious combinations of pharmacological agents for the overall prevention of PEP are rectally administered IND with IV LR solution, diclofenac and sublingual nitrate, or IND with IV normal saline.
The controversy that has been raised based on the findings of the network meta-analyses that were partially opposed by the FLUYT trial may be explained by the fact that the FLUYT trial is a large trial (813 Dutch patients in multiple centers) that was conducted in moderate-to-high risk patients who are randomized to NSAID and aggressive hydration (intervention) or NSAID alone (control), which would eventually be expected to produce a remarkable outcome in both arms. Meanwhile, the network meta-analysis by Arabpour et al[27] presented findings of a total cohort of 11493 patients according to risk of PEP assigned as high-risk and average-risk for PEP and severity categorized as mild and moderate-to-severe. Furthermore, another network Meta-analysis by Oh et al[28] concluded that combined aggressive hydration with NSAID, among which IND and normal saline for individuals with average-risk and diclofenac for those with high-risk, can minimize the incidence of PEP. These findings for average-risk individuals were thus similar to the Arabpour et al[27] analysis and differed from the high-risk group due to the exclusion of pancreatic stents from the analysis by Oh et al[28].
Technical issues pertinent to the network meta-analysis that may have affected the findings are a type 1 error due to sample size comparisons of small vs large studies, lack of blinding leading to potential detection bias, and low to moderate confidence ratings in pairwise comparisons.
CLINICAL OUTCOMES OF COMBINED USE OF IV FLUIDS AND MEDICATIONS TO PREVENT PEP
Mixed results have been observed with combination therapy, with some studies demonstrating benefits and others suggesting limited additional advantages over monotherapy. The clinical outcomes are presented as primary outcomes that denote the incidence of PEP post-ERCP, and secondary outcomes that refer to a reduction in the severity of acute PEP and hospital admissions.
Primary outcome - pancreatitis incidence
Positive combination results: A network meta-analysis by Njei et al[26] showed that LR, along with rectal NSAIDs, significantly reduced PEP risk compared with placebo [beta coefficient (B) = -1.58; 95%CI: -3.0 to 0.17][28]. Additionally, a randomized trial with a combination of rectal IND and a bolus of LR solution reduced the PEP rate to 6% vs 21% with a placebo (P = 0.04)[30].
Limited additional benefit: A large study of 813 patients examining monotherapy vs combined therapy demonstrated no significant difference in PEP rates between aggressive hydration plus NSAIDs (8%) and NSAIDs alone (9%, P = 0.53)[26].
Secondary clinical outcomes
Reduction of PEP severity: A meta-analysis by Wu et al[19] reported that aggressive hydration reduces moderate-to-severe PEP (OR: 0.16; 95%CI: 0.03-0.96).
Hospital outcomes: The length of hospital stay is decreased significantly by combination therapy compared with NSAID monotherapy (2% vs 13%, P = 0.03)[31].
Safety outcomes
No significant differences were observed in serious adverse events between combination and monotherapy, including hydration-related complications (relative risk, 0.99), ERCP-related complications (relative risk, 0.90), intensive care unit admission rates, and 30-day mortality[26].
PATIENT SELECTION FOR PROPHYLAXIS
The available evidence favors universal prophylaxis with rectal NSAIDs for most patients[10], whereas aggressive hydration is selectively recommended for specific populations of patients. High-risk patients who benefit most from prophylaxis are categorized according to the following patient factors: Female sex, younger age, suspected sphincter of Oddi dysfunction, normal bilirubin levels, previous PEP, and procedural factors: Difficult cannulation, pancreatic duct manipulation, and repeated cannulations[31], precut sphincterotomy, and pancreatic sphincterotomy[19]. These patients can benefit from non-endoscopic prophylaxis, such as aggressive hydration, a combination of IV hydration and rectal NSAIDs, and endoscopic prophylaxis consisting of placement a pancreatic stent[32]. Contraindications to prophylaxis by aggressive hydration and/or NSAID use include renal impairment, volume overload risk, and age > 85 years[26]. Nevertheless, there are situations where aggressive hydration protocols are not indicated, including frail older patients above the age of 75 years, those with significant comorbidities, and outpatient procedures where prolonged monitoring is not feasible[23]. Machine learning models have been employed as methods to predict the occurrence of PEP. LR was used initially with the area under the curve (AUC) initially reported to be 0.5. Furthermore, to improve machine learning ability for prediction, Gradient Boosting, a validated predictive model that incorporates bilirubin, age, body mass index, procedure time, previous sphincterotomy, alcohol units/day, cannulation attempts, sex, gallstones, use of LR solution, and periprocedural NSAIDs. This model was studied in a point-of-care proof-of-concept. This model proved superior to LR with an AUC in cross-validation of 0.7 vs 0.585, P = 0.012[33,34]. This modest value has been reported in several studies as the most robust value reported for this method[35].
When factoring cost effectiveness, rectal IND was the most cost-effective strategy for preventing PEP in both average-risk and high-risk patients undergoing ERCP. For high-risk patients, all strategies were cost-effective compared with no prophylaxis, whereas in average-risk patients, all strategies except aggressive hydration with LR solution were cost-effective[36].
PRACTICAL BARRIERS TO THE PROPHYLAXIS OF PEP
Several barriers are recognized stemming from the patient, the physician, and the facility that hinder the implementation of PEP prophylaxis. Patients may show no acceptance for rectal treatment route and prefer alternative administration methods[16]. Patient comorbidity is an important underlying patient factor, and includes morbidities such as cardiac insufficiency limited volume infusion and rendering the patient into a status of volume overload, renal insufficiency, liver dysfunction, respiratory insufficiency, pregnant women, and patients individuals aged > 70 years old, who are not candidates for NSAID use[12]. Nonspecific clinical presentation of PEP and elevation of pancreatic enzymes may hurdle appropriate recognition of PEP[19]. Second, physician related barriers include their own reluctance to use a rectally administered medication, time consuming procedures[31], and local expertise. Finally, facility related barriers include logistical challenges and cost, and extended IVF regimens that are not feasible or cost-effective in outpatient settings[31].
Suggested approach for PEP prophylaxis
Preprocedural administration of rectal NSAIDs alone are recommended for patients with average-risk for PEP prophylaxis. For high-risk patients, additional prophylaxis is recommended using pancreatic stents based on the underlying comorbidity or risk of the patient, or the combination of aggressive hydration and NSAIDs based on the best available evidence presented above. Our suggested approach for patients with no contraindication for IV fluids and NSAID use is diclofenac (100 mg) or IND (100 mg) combined with aggressive LR hydration administered at a rate of 3 mL per kg per hour during the performance of ERCP procedure followed by 20 mL per kg of IV fluids bolus and eventually 3 mL per kg per hour for 8 hours after the end of the ERCP procedure. A careful assessment of the volume status and urine output in conjunction with the process is important. Patients with contraindications to NSAID use and/or IVF administration need an alternative preventive strategy that starts with early recognition, patient discussion, and consideration of the available options using pancreatic duct stents to lower the risk and severity of PEP as well as wire-guided cannulation to avoid contrast injection into the pancreas[37].
FUTURE RESEARCH
In future, studies should investigate the administration of other types of IV fluids in combination or without other preventive measures for PEP, as well as the long-term effects of vigorous IV fluids on patients undergoing ERCP by conducting multi-center, prospective studies to better understand the impact of fluid resuscitation on clinical outcomes[38]. Future research directions are needed to identify new pharmacological treatments to address the early pathogenetic mechanisms of a systemic inflammatory response and the onset of pancreatic necrosis[38] associated with PEP.
CONCLUSION
The prevention of PEP has evolved significantly, with robust evidence supporting non-endoscopic pharmacological and hydration strategies. Despite proven benefits, the implementation of prophylactic measures remains suboptimal in clinical practice, suggesting a need for broader adoption of evidence-based recommendations[13]. Thus, rectal NSAIDs, specifically IND and diclofenac, have emerged as the cornerstone of prophylaxis and are universally recommended for all patients undergoing ERCP due to their proven efficacy, favorable safety profile, and cost-effectiveness. Therefore, a multimodal approach is recommended for high-risk patients. The addition of aggressive periprocedural hydration with LR solution provides additional benefits, particularly in reducing the incidence and severity of moderate-to-severe PEP, although some studies have shown mixed results regarding its incremental value over NSAIDs alone. Prophylactic stenting of the pancreatic duct remains a critical endoscopic adjunct in selecting high-risk patients.
Ultimately, a stratified risk-adaptive strategy is essential. Clinicians should implement universal rectal NSAID administration while reserving combination therapy with aggressive hydration and/or pancreatic stents for high-risk patients, considering patient- and procedure-related factors. Contraindications such as renal impairment or volume overload risk must be carefully measured. Future efforts should focus on refining risk prediction models to personalize prophylaxis and clarify optimal protocols for combination therapy to maximize benefits while ensuring patient safety and resource efficiency.
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: American College of Gastroenterology.
Specialty type: Gastroenterology and hepatology
Country of origin: Saudi Arabia
Peer-review report’s classification
Scientific quality: Grade C
Novelty: Grade C
Creativity or innovation: Grade D
Scientific significance: Grade B
P-Reviewer: Vicardi M, Italy S-Editor: Liu JH L-Editor: A P-Editor: Xu J
