'Stunning' Results Upend Fluid Resuscitation in Acute Pancreatitis

Early aggressive fluid resuscitation for acute pancreatitis, a widely recommended practice, failed to improve clinical outcomes and led to more fluid overload when compared with moderate fluid resuscitation, the randomized WATERFALL study showed.

In an interim analysis of the trial, which was halted early for safety reasons, incidence of moderately severe or severe pancreatitis was not significantly different between groups, though numerically higher in patients who received early aggressive fluid resuscitation (22.1% vs 17.3%; adjusted relative risk [aRR] 1.30, 95% CI 0.78-2.18), reported Enrique de-Madaria, MD, PhD, of the Hospital General Universitario in Alicante, Spain, and colleagues.

And 20.5% of those in the aggressive-resuscitation group experienced fluid overload versus only 6.3% in the moderate-resuscitation group (aRR 2.85, 95% CI 1.36-5.94), they wrote in the New England Journal of Medicine.

"Given the data showing increased harm without improvement with regard to the primary outcome, the data and safety monitoring board unanimously recommended that the trial be stopped," stated de-Madaria and coauthors. "These findings do not support current management guidelines, which recommend early aggressive resuscitation for the treatment of acute pancreatitis."

No significant differences were seen for other clinical outcomes, but patients receiving early aggressive fluid resuscitation tended to do worse, with numerically higher rates of local complications, necrotizing pancreatitis, organ or respiratory failure, admission to the intensive care unit (ICU), and need for nutritional support.

Approximately one-third of acute pancreatitis patients go on to develop moderately severe or severe pancreatitis. While recommendations have widely supported the use of early aggressive fluid resuscitation in acute pancreatitis, de-Madaria noted, the evidence behind this practice had been lacking.

Total fluid volume over the 72-hour trial period was higher for patients receiving aggressive fluid resuscitation (8.3 vs 6.6 liters for the moderate-resuscitation group), "a finding that indicates that not only should the rate of resuscitation be slower but the total infused volume should be lower," said Timothy Gardner, MD, of Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, writing in an accompanying editorial.

"These results are stunning and, given the carefully crafted trial methods, irrefutable," said Gardner.

In light of these findings, clinicians should first focus on a steady rate of initial resuscitation, the editorialist wrote, meaning no more than 1.5 mL/kg per hour and administering a bolus of 10 mL/kg "only if there are signs of initial hypovolemia."

"Second, careful clinical and hemodynamic monitoring are essential during the first 72 hours after admission to make sure that patients remain euvolemic and to avoid fluid overload," he said. "Third, diuresis in patients with fluid overload in the first 72 hours is most likely beneficial and certainly not detrimental to important clinical outcomes."

WATERFALL's interim analysis included 249 adults presenting with acute pancreatitis at 18 centers in Italy, India, Mexico, and Spain. From May 2020 to September 2021, participants were randomized to moderate or aggressive fluid resuscitation with lactated Ringer's solution.

Moderate fluid resuscitation required a 10 mL/kg bolus for those with hypovolemia or no bolus for normovolemia, followed by 1.5 mL/kg per hour. Aggressive fluid resuscitation required a 20 mL/kg bolus, followed by a 3 mL/kg per hour infusion. Patients were assessed at multiple time points thereafter (up to 72 hours), with fluid resuscitation adjusted according to their clinical status.

Higher risk of fluid overload was detected both in the overall population and in subgroups of patients with hypovolemia, as well as both those without and with systemic inflammatory response syndrome at baseline, a group at higher risk for severe pancreatitis.

As noted, multiple secondary outcomes also trended worse for the aggressive-resuscitation approach, including local complication rates (20.5% vs 16.5%), necrotizing pancreatitis (13.9% vs 7.1%), organ failure (7.4% vs 3.9%) and persistent organ failure (6.6% vs 1.6%), respiratory failure (7.4% vs 2.4%), ICU admission (6.6% vs 1.6%), and use of nutritional support (5.7% vs 3.9%).

Mean age was 56-57, and patients were evenly divided between men and women. Over half had hypovolemia, and 56-66% had gallstone-related pancreatitis. Comorbid conditions included diabetes in 15-19% of patients, as well as cancer within the past 5 years in 4-7%.

Study limitations included the small sample size and open-label design, which introduced bias. The planned study was expected to enroll 744 patients, so the interim analysis was underpowered to definitively assess efficacy outcomes, the authors stated.

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