Early Weight-Based Aggressive vs. Non-Aggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: An Open-Label Multicenter Randomized Controlled Trial (The WATERFALL Trial), Design, and Rationale

Federico Bolado; James L Buxbaum; Alicia Vaillo-Rocamora; Karina Cárdenas-Jaén; Patrick Maisonneuve; Enrique de-Madaria

doi:10.3389/fmed.2020.00440

Early Weight-Based Aggressive vs. Non-Aggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: An Open-Label Multicenter Randomized Controlled Trial (The WATERFALL Trial), Design, and Rationale

Front Med (Lausanne). 2020 Sep 2:7:440. doi: 10.3389/fmed.2020.00440. eCollection 2020.

Authors

Federico Bolado¹, James L Buxbaum², Alicia Vaillo-Rocamora³, Karina Cárdenas-Jaén³, Patrick Maisonneuve⁴, Enrique de-Madaria³

Affiliations

¹ Gastroenterology Department, Complejo Hospitalario de Navarra, Pamplona, Spain.
² Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States.
³ Gastroenterology Department, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.
⁴ Division of Epidemiology and Biostatistics, IEO-Istituto Europeo di Oncologia IRCCS, Milan, Italy.

Abstract

Treatment options are limited for acute pancreatitis (AP). Early aggressive fluid resuscitation (AFR) has been widely considered beneficial because of theoretical improvement in end-organ perfusion, including the pancreas and gut, with pancreatic necrosis and bacterial translocation as consequences of ischemia. There is scarce direct evidence for its association to improved outcomes. Furthermore, it has been described that AFR may be associated with poor outcomes in severe AP. WATERFALL is an investigator-initiated international multicenter open-label randomized controlled trial comparing AFR vs. moderate fluid resuscitation (MFR) in AP. The main outcome variable will be the incidence of moderate to severe AP (a clinically relevant outcome that has been validated). Aggressive fluid resuscitation will consist in lactated Ringer solution (LR) 20-mL/kg bolus (administered over 2 h) followed by LR 3 mL/kg per hour. Patients randomized to MFR will receive an LR bolus 10 mL/kg in case of hypovolemia or no bolus in patients with normal volemia, followed by LR 1.5 mL/kg per hour. The patients will be assessed at 3 (±1), 12 (±4), 24 (±4), 48 (±4), and 72 (±4) h from recruitment, and fluid resuscitation will be adjusted to the patient's clinical and analytical status according to a protocol. Based on a prospective multicenter study, the incidence of moderate to severe AP is 35%. Sample sizes of 372 patients per group (overall 744) achieve 80% power to detect a difference in the incidence of moderate to severe AP of 10%, at a significance level (α) of 0.05 using a two-sided z-test, assuming a 10% dropout rate. These results assume that three sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries.

Keywords: acute pancreatitis (AP); fluid resuscitation; fluid therapy; randomized controlled (clinical) trial; ringer lactate.