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

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.

Post-ERCP Pancreatitis: Prevention, Diagnosis and Management

“…The aggressive arm received 20 mL/kg bolus-administered over 2 h, followed by 3 mL/kg/h for 12 h-vs. a moderate arm receiving a bolus 10 mL/kg-administered over 2 h in case of hypovolemia or no bolus in patients with normovolemia, followed by 1.5 mL/kg/h for 12 h; afterward, all patients with normovolemia received 1.5 mL/kg/h. The final results of this trial will be available in the following weeks (accepted, under press embargo) [85].…”

Aggressive versus controlled fluid resuscitation in acute pancreatitis: A systematic review and meta-analysis of randomized controlled trials

“…For example, acute kidney injury was suggested as an indicator of hypovolemia in the WATERFALL trial and was reported to be related to acute kidney injury in previous studies. [19,36] Central venous pressure (CVP) seemed to be a considerable indicator of hypovolemia in AP, especially SAP. [37][38][39] Finally, we did not discuss other factors of fluid resuscitation, such as different routes and types of fluids due to a lack of data.…”

“…The detailed criteria for fluid overload and hypovolemia were based on previous studies. [18,19] Secondary outcomes…”

The present and future of gastroenterology and hepatology: an international SWOT analysis (the GASTROSWOT project)

“…There is increasing research in the field of molecular diagnostics for pancreatobiliary diseases such as pancreatic cancer (addressed in the oncology section) and pancreatic cysts. National and international multicentre trials are being developed for Viewpoint the treatment of acute and chronic pancreatitis, 53,54 following a successful model of collaborative research designed by the Dutch Pancreatitis Study Group. 55…”