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Aggressive Hydration for the Prevention of Post-ERCP Pancreatitis: Effective When Combined With Rectal NSAIDs?

To the Editor: With great interest, we read the meta-analysis by Zhang et al,1 concerning aggressive hydration as a prophylactic measure for pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). We applaud the thorough methodology used in the study. The meta-analysis showed a significantly reduced incidence of post-ERCP pancreatitis (PEP) in patients receiving aggressive hydration [P=0.0006; odds ratio (OR), 0.47 (0.30-0.72)]. Sensitivity analyses did not change this outcome. These preliminary results suggest that its effectiveness is comparable to rectal nonsteroidal anti-inflammatory drugs (NSAIDs) [OR, 0.44 (0.34-0.57)] and pancreatic duct (PD) stents [OR, 0.35 (0.25-0.49)].2,3 Furthermore, the adverse event rate was similar between studied groups [P=0.23; OR, 0.48 (0.15-1.57)]. The GRADE assessment in this meta-analysis (low-moderate) can be ascribed in part to the small sample sizes of the studies. Six out of 7 randomized controlled trials in this meta-analysis had a sample size <171 patients, which is inadequate for investigating a rare complication such as PEP. Assuming a similar effectiveness of rectal NSAIDs, 878 patients would have been needed to reach adequate statistical power. In addition, 5 out of 7 studies did not use the Cotton criteria for PEP. The studies use abdominal pain and hyperamylasemia to score PEP, both of which are common after ERCP.4 For a proper PEP diagnosis, both conditions should still be present 24 hours after ERCP and hospitalization should be prolonged for at least 2 nights.5 The use of a less stringent PEP definition leads to an overestimation of PEP incidence. On the basis of these results, the authors conclude that aggressive hydration is “very promising in clinical practice” and add that the low cost and wide availability of lactated Ringer’s solution will enhance acceptance. We feel that this conclusion is premature, because the authors excluded studies that used other prophylactic measures such as rectal NSAIDs and PD-stents. The evidence for their effectiveness in high-risk patients is irrefutable, prompting both the European and American Society for Gastrointestinal Endoscopy (ESGE and ASGE) to recommend their use.6,7 Furthermore, the evidence for routine use of rectal NSAIDs in all patients is accumulating,8 especially following a large clinical trial in 2600 patients.9 In the era of prophylactic rectal NSAIDs, an important debate is concerned with combining rectal NSAIDs and other prophylactics: “Do PD-stents (or other prophylactic treatment modalities such as periprocedural hydration) give PEP prevention in addition to rectal NSAIDs/ standard of care?” To that end, Elmunzer et al10 are currently investigating the combination of rectal NSAIDs and PDstents. Periprocedural hydration should be approached similarly. Because of the burden of 9-hour hydration schedules, it is unlikely that periprocedural hydration will replace rectal NSAIDs as (costeffective) measure to prevent PEP, but it could serve as an adjunctive therapy, or as an alternative for those with contraindications against NSAIDs. To our knowledge, only 2 RCTs have investigated prophylactic lactated Ringer’s solution in addition to rectal NSAIDs.11,12 The first trial,11 in 192 patients, found a significant lower PEP rate in patients receiving both lactated Ringer’s solution (1L/30min before ERCP) and 100mg indomethacin compared with controls (1 L/30min normal saline with placebo). The second study12 in 406 patients found that the combination of hydration and indomethacin significantly reduced the incidence of PEP compared with either treatment alone or placebo. These results suggest a role for periprocedural hydration in PEP prevention, but the small sample sizes and design of intervention groups (whether 1L/30min before ERCP qualifies as aggressive hydration is debatable) preclude firm conclusions. The 3 issues above (an adequate sample size, use of the Cotton criteria, and combination with rectal NSAIDs) are addressed in a nationwide randomized controlled trial currently recruiting patients in the Netherlands (ISRCTN 13659155). A sample of 826 patients receiving rectal NSAIDs is randomized to either aggressive hydration with Ringer’s (20mL/kg within 60 minutes at the start of ERCP, followed by 3mL/kg/h for eight hours) or no hydration. We believe this trial will answer the question whether periprocedural hydration can prevent PEP in patients already receiving rectal NSAIDs.