By Betty Tran, MD, MSc
Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago
SYNOPSIS: In this multicenter randomized clinical trial, an early aggressive fluid resuscitation strategy led to an increased incidence of fluid overload without reducing the risk of developing moderately severe or severe acute pancreatitis.
SOURCE: de-Madaria E, Buxbaum JL, Maisonneuve P, et al. Aggressive or moderate fluid resuscitation in acute pancreatitis. N Engl J Med 2022;387:989-1000.
The Early Weight-Based Aggressive vs. Nonaggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: An Open-Label Multicenter Randomized Controlled (WATERFALL) Trial enrolled consecutive adults with a diagnosis of acute pancreatitis at 18 centers in four countries (India, Italy, Mexico, and Spain) with the goal of determining the safety and efficacy of aggressive fluid resuscitation in patients with acute pancreatitis. Notably, patients with moderately severe or severe disease at baseline and those with comorbid conditions, such as heart failure, uncontrolled hypertension, electrolyte derangements (e.g., hyper-/hyponatremia, hyperkalemia, hypercalcemia), chronic pancreatitis, chronic renal failure, or decompensated cirrhosis, were excluded. The primary outcome was development of moderately severe or severe acute pancreatitis. There were several secondary outcomes, including organ failure, local complications, duration of hospital stay, intensive care unit (ICU) admission and number of days, use of nutritional support, need for invasive treatment, presence of systemic inflammatory response syndrome (SIRS), and C-reactive protein levels.
Patients were randomized 1:1 to receive an aggressive vs. moderate fluid resuscitation strategy, with randomization stratified by trial center, the presence of SIRS, and the presence of baseline hypovolemia. The aggressive resuscitation group received a bolus of 20 mL/kg of lactated Ringer’s (LR) solution, followed by an infusion at 3 mL/kg/hour; in the moderate resuscitation group, patients received an LR infusion at 1.5 mL/kg/hour and only received a bolus of 10 mL/kg if they were hypovolemic. A safety checkpoint for both groups was performed at three hours where the infusion was decreased or stopped if there was concern for fluid overload. Subsequent goal-directed therapy checkpoints occurred at 12, 24, 48, and 72 hours, with a protocol defining next steps if patients were hypovolemic (aggressive: bolus LR at 20 mL/kg, then infuse at 3 mL/kg/hour; moderate: bolus LR at 10 mL/kg, then infuse at 1.5 mL/kg/hour), euvolemic (for both groups: continue infusion at 1.5 mL/kg/hour; aggressive: stop at 48 hours if oral feeding tolerated; moderate: stop at 20 hours if oral feeding tolerated), or hypervolemic (for both groups: decrease or stop infusion).
Overall, 249 patients were randomized and included in the first planned interim analysis. In terms of amount of LR received in the first 48 hours, patients in the aggressive resuscitation group received a median of 7.8 L (interquartile range [IQR], 6.5 L to 9.8 L) vs. 5.5 L (IQR, 4.0 L to 6.8 L) in the moderate resuscitation group. There was no significant difference in the development of moderately severe or severe acute pancreatitis in the aggressive vs. moderate resuscitation groups (22.1% vs. 17.3%, respectively; adjusted relative risk [RR], 1.30; 95% CI, 0.78-2.18; P = 0.32). There were trends toward worse outcomes in the aggressive resuscitation group, with an increased percentage of patients with organ failure, local complications, respiratory failure, necrotizing pancreatitis, and need for ICU care. The median duration of hospitalization was six days (IQR, 4-8) in the aggressive resuscitation group compared to five days (IQR, 3-7) in the moderate resuscitation group. Aggressive fluid resuscitation was associated with a significant increase in fluid overload compared to moderate fluid resuscitation (20.5% vs. 6.3%; RR, 2.85; 95% CI, 1.36-5.94), with most patients being managed with diuretics. The trial was halted by the data and safety monitoring board given these safety outcome results.
COMMENTARY
The theoretical basis for intravenous fluid (IVF) resuscitation in acute pancreatitis centers on correcting microcirculatory disturbances resulting from endothelial injury and increased capillary permeability in the inflamed pancreas.1 However, few randomized trials prior to the one presented here were able to provide a definitive recommendation. Although this trial specifically excluded patients with acute pancreatitis who generally would be admitted initially to the ICU (i.e., those with severe disease at baseline), the results reported still are clinically relevant given that some patients with acute pancreatitis who receive initial treatment on a general medical floor may later transfer to an ICU setting or may have acute pancreatitis as a secondary (non-admitting) diagnosis in the ICU.
Not only did this trial report no significant difference between groups in its primary outcome, there was a trend toward worse clinical outcomes in patients randomized to the aggressive fluid resuscitation strategy. Notably, the enrolled patients were relatively young (mean age, 56-57 years) and had no apparent contraindications to receiving aggressive IVF, as those with conditions such as heart failure, cirrhosis, and chronic kidney disease were excluded. Furthermore, this trial had several built-in “safety” checkpoints at 3, 12, 24, 48, and 72 hours to assess for volume overload, a protocol that is not standard in real-world practice. As such, the actual harms related to aggressive fluid resuscitation may be underestimated compared to less monitored settings outside a trial design.
In keeping with the general trend of recent literature, this trial’s main lesson is that volume resuscitation with IVF should not be considered completely harmless, and a judicious use of IVF in specific scenarios, such as acute pancreatitis and sepsis, should be employed.2 Similar to sepsis, a one-size-fits-all approach in managing resuscitation in acute pancreatitis is not only ineffective but may be harmful, and future studies should focus on defining important dynamic biomarkers or parameters that could guide targeted resuscitation efforts.
REFERENCES
- Aggarwal A, Manrai M, Kochhar R. Fluid resuscitation in acute pancreatitis. World J Gastroenterol 2014;20:18092-18103.
- Radigan K. Intravenous fluids in ICU patients with septic shock: Is restriction the answer? Critical Care Alert 2022;30:60-62.
