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Landmark trial suggests aggressive fluid therapy in pancreatitis may cause more harm than good

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Randomized controlled trials that investigate the optimal parameters of fluid resuscitation in acute pancreatitis—such as the rate of infusion or the total volume of fluid to be infused—remain scarce. However, the newly published WATERFALL trial, published on September 15, 2022, in the New England Journal of Medicine, sought to answer if current guidance is too aggressive.

The study found no statistical clinical benefit in patients with acute pancreatitis treated with early aggressive fluid resuscitation versus patients treated with moderate resuscitation. Additionally, patients given early aggressive resuscitation had a much higher frequency of developed fluid overload compared to the moderate resuscitation group.

Study design

The WATERFALL trial included 249 patients from India, Italy, Mexico, and Spain. They were part of the randomized trial if they presented to the ED within 24 hours of pain onset and had been diagnosed with acute pancreatitis within 8 hours of arrival. Patients were excluded if they met criteria for moderately severe or severe pancreatic disease.

The patients were randomized in a 1:1 ratio to receive either aggressive fluid resuscitation or moderate fluid resuscitation. Aggressive resuscitation—representing the current standard of care—was defined as a bolus of lactated Ringer's solution (LR) at a dose of 20 mL/kg of body weight administered over a period of 2 hours, followed by infusion at a rate of 3 mL/kg per hour. Moderate fluid resuscitation was defined as LR at a dose of 1.5 mL/kg per hour. The protocol allowed the moderate resuscitation group to receive a 10 mL/kg bolus if the patient was also diagnosed with hypovolemia.

The trial's primary efficacy outcome was the development of moderately severe or severe acute pancreatitis during hospitalization. This was defined as meeting at least one of the Revised Atlanta Classification criteria of local complications, exacerbation of a pre-existing coexisting condition, a creatinine level of at least 1.9 mg/dL, a systolic blood pressure of > 90 mm Hg despite fluid resuscitation, or a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of no more than 300.

The main safety outcome was the occurrence of fluid overload, defined as the incidence of symptoms, physical signs, and imaging evidence of hypervolemia during hospitalization.


The researchers found no significant difference between the two groups. However, roughly 17% of the patients receiving moderate fluid resuscitation progressed to moderately severe and severe pancreatitis, compared to roughly 22% in the aggressive resuscitation arm—an adjusted relative risk increase of 30%.

The trial also found a stark statistically significant difference in the rates of fluid overload between the two groups. Patients receiving the aggressive fluid treatment had a fluid overload of roughly 20%, versus roughly 6% in the moderate resuscitation arm. In fact, due to the lack of significance in the efficacy outcomes and the pronounced significance in the safety outcome, the trial was halted early

Practice implications

Acute pancreatitis is not the most pervasive disease in the acute care setting. However, it is rising globally and challenging the health care system. Nearly one-third of acute pancreatitis patients progress to severe disease, often resulting in significant morbidity and mortality.

Targeted pharmacological treatment options for acute pancreatitis are practically nonexistent currently. Consequently, most treatment strategies are derived from observational studies that have shown that aggressive fluid crystalloid resuscitation, principally with LR, reduces pancreatic necrosis and mortality by mitigating pancreatic hypoperfusion. However, this recommendation is controversial in light of recent randomized trials, some with questionable quality, that suggest overaggressive fluid resuscitation may increase the risk of sepsis and mortality.

“These findings do not support current management guidelines, which recommend early aggressive resuscitation for the treatment of acute pancreatitis,” the authors stated. They went on to detail that patients with acute pancreatitis treated with aggressive fluid resuscitation experienced a higher intensity of symptoms, a longer duration of hospital stay, and a higher incidence of necrotizing pancreatitis than those who had received moderate fluid resuscitation.

“The absence of an efficacy signal for aggressive hydration is of practical importance given that it challenges a strong predilection in many clinicians for the use of early high-volume hydration,” the authors wrote.



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