Aggressive or moderate fluid resuscitation in acute pancreatitis
de-Madaria E, Buxbaum JL, Maisonneuve P, et al. N Engl J Med. 2022;387(11):989-1000.
Patients with acute pancreatitis have high rates of morbidity, associated multiorgan dysfunction, and mortality. As many as 25% require ICU-level care.
The traditional ED procedure has been to treat these patients with an aggressive fluid resuscitation strategy based on findings from animal models and early observational data indicating an association of hypovolemia and hemoconcentration with pancreatic necrosis.
However, a recent (2020) meta-analysis on the topic has not found any benefit from aggressive rehydration and has suggested that the practice may actually be associated with harm. The studies included were small, and significant heterogeneity was observed between trials.
This study, Early Weight-Based Aggressive vs Nonaggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis (the WATERFALL study), was a multicenter, open-label, parallel-group, randomized, controlled superiority trial from 18 centers across 4 countries (India, Italy, Mexico, and Spain).
The authors approached a consecutive sample of adult patients with <24 hours of pain and acute pancreatitis according to the revised Atlanta classification, which requires patients to meet 2 of the following 3 criteria: typical abdominal pain; serum amylase or lipase levels 3 times higher than the upper limit of the normal range; or signs of acute pancreatitis on imaging.
The study excluded patients with congestive heart failure and moderate/severe pancreatitis (shock or respiratory failure), among other conditions.
Patients were randomized to aggressive fluids (20 mL/kg bolus of lactated Ringer solution [LR], then 3 ml/kg/hour infusion for 48 hours) or moderate fluids (10 mL/kg bolus of LR only if the patient was hypovolemic, followed by 1.5 mL/kg/hour infusion for 20 hours).
The primary outcome was the development of moderate or severe acute pancreatitis. Many secondary and safety outcomes were also assessed. The calculated sample size was 744 to detect a between-group difference of 10%.
The trial was stopped early at the first planned interim analysis, after 249 patients had been enrolled, because of massive differences in safety outcomes between groups, which were not balanced with any trend toward improved outcomes with fluid resuscitation.
The median fluid volume received was 7.8 L in the aggressive group and 5.5 L in the moderate group.
The primary outcome of progression to moderate/severe pancreatitis occurred in 22.1% of the aggressive group vs 17.3% of the moderate group (RR 1.3).
Although not statistically significant, trends in almost all secondary outcomes favored moderate fluids (severe pancreatitis, 6.6% vs 1.6%; necrotizing pancreatitis, 20.5% vs 16.5%; ICU admission, 6.6% vs 1.6%; respiratory failure, 7.4% vs 2.4%; and death, 3.3% vs 0.8%).
The difference in fluid overload was statistically and clinically significant (20.5% vs 6.3%, RR 2.85).
This is an exceptionally well-done trial with excellent methods, no patients lost to follow-up, a focus on objective outcome assessments, and explicit protocols for fluid administration.
Some study limitations include the open-label design, which might have introduced bias; the exclusion of all ill patients, because of the focus on mild acute pancreatitis; the use of only LR; and the lack of clarity regarding whether fluids given before randomization were accounted for.
Because the trial was stopped early as a result of safety concerns, the desired sample size was not reached; however, no indication suggests that enrolling more patients would have changed the efficacy findings to favor aggressive therapy, whereas clear evidence of harm with more fluids was shown.
EDITOR’S COMMENTARY: Several recent studies have suggested that an aggressive fluid strategy in the ED for sick patients, including those with systemic inflammatory response syndrome/sepsis, may do more harm than good. Although it was stopped early because of safety concerns, the WATERFALL study was exceptionally well done, and suggests that the traditional teaching of aggressive fluid resuscitation for patients with mild acute pancreatitis may also be wrong. I think we can use their findings to change practice and start treating patients with acute mild pancreatitis with a more moderate amount of maintenance fluids, use small boluses when necessary (10 cc/kg), and avoid the bolus all together when clinical hypovolemia is not present.