Acute Pancreatitis: Need IV Fluid Resuscitation But Avoid a WATERFALL!
Shria Kumar, MD, MSCE1 and Timothy B. Gardner, MD MS2
1Assistant Professor, Division of Digestive and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL
2Professor of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH
This summary reviews: de-Madaria E, Buxbaum JL, Maisonneuve P, et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med 2022;387(11):989-1000. http://www.doi.org/10.1056/NEJMoa2202884.
Correspondence to Shria Kumar, MD, MSCE, Associate Editor. Email: EBGI@gi.org
Question: What degree of intravenous (IV) fluid hydration leads to optimal outcomes in acute pancreatitis?
Design: Multi-center, prospective randomized control trial (RCT), entitled the WATERFALL study (the Early Weight-Based Aggressive vs Nonaggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis).
Setting: Eighteen centers across 4 countries: India, Italy, Mexico, and Spain.
Patients: Adults at least 18 years of age who met clinical criteria of acute pancreatitis (Revised Atlanta Classification: meeting 2 of the following 3: classical abdominal pain, serum amylase or lipase level higher than 3 times the upper limit of the normal, or signs of acute pancreatitis on imaging) were screened for enrollment. The trial only included patients who received a diagnosis of acute pancreatitis within 8 hours prior to screening and had presented to the emergency room within 24 hours of pain onset. Those with severe disease at baseline, including respiratory, heart, or kidney failure, chronic pancreatitis, or other severe comorbidities including uncontrolled arterial hypertension, hypernatremia, hyponatremia, hyperkalemia, hypercalcemia, decompensated cirrhosis, or low life expectancy were excluded. Patients provided informed consent to participate in the trial.
Interventions: Patients were randomly assigned (in a 1:1 ratio) to receive aggressive fluid resuscitation or moderate fluid resuscitation with lactated Ringer’s solution. The groups are depicted in Table 1. In both groups, investigators performed an initial physical assessment at 0 hours to evaluate for fluid overload, and additional assessments at 3, 12, 24, 48, and 72 hours. As such, hydration was decreased or stopped if there was suspicion of fluid overload in both groups. Oral feeding was started at 12 hours if there was a lower degree of abdominal pain. Fluid resuscitation was stopped once a patient was tolerating oral feeding for 4 hours.
Outcomes: Primary outcome was the development of moderately severe or severe acute pancreatitis during hospitalization, defined as meeting at least 1 of the following criteria: local complications, exacerbation of a pre-existing coexisting condition, a creatinine level of at least 1.9 mg per deciliter (170 μmol per liter), a systolic blood pressure of less than 90 mm Hg despite fluid resuscitation, and a ratio of the partial pressure of arterial oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of no more than 300. Multiple secondary outcomes were assessed, including organ failure, intensive care unit admission, infected necrotizing pancreatitis, persistent symptoms, and need for nutritional support, among others. The main safety outcome was fluid overload and required meeting at least 2 of the following 3 criteria: symptoms, physical signs, and imaging evidence of hypervolemia.
Data Analysis: The primary outcome, development of moderately severe or severe acute pancreatitis, was evaluated for superiority with an intention-to-treat analysis. There were 3 a priori stopping rules: (1) a between-group difference in the primary outcome with a 2-sided P value of less than 0.0002 at interim analysis or of less than 0.012 at the second interim analysis; (2) clear evidence of harm in 1 trial group over the other (safety) by the data and safety monitoring board; and (3) a slow recruitment rate.
Results: Two hundred forty-nine patients were randomized: 122 patients to the aggressive resuscitation group and 117 patients to the moderate resuscitation group. There were no significant differences between the groups regarding age, sex, gallstones as ideology of the pancreatitis, body mass index, comorbidities and severity, baseline abdominal pain severity, pancreatitis severity, lab markers, respiratory status, or hypovolemic status.
There was no significant difference in the development of the primary outcome, moderately severe or severe acute pancreatitis, which occurred in 22.1% of the aggressive resuscitation group and 17.3% of those in a moderate resuscitation group. Most importantly, aggressive fluid resuscitation was associated with a significantly higher incidence of fluid overload: 20.5% vs 6.3% (adjusted relative risk, 2.85; 95% confidence interval [CI], 1.36 to 5.94). Accordingly, the data and safety monitoring board halted the trial owing to significantly worse results with respect to safety outcomes, and the lack of trend toward improved outcomes. The notable findings are summarized in Table 2. Given that the trial was halted, subgroup analyses were limited but fluid overload was also noted in the subgroups of patients with or without systemic inflammatory response syndrome and those with hypovolemia.
Funding: Grants from the Instituto de Salud Carlos III, the Spanish Association of Gastroenterology, ISABIAL (Instituto de Investigación Sanitaria y Biomédica de Alicante), the Italian Ministry of Health, Ricerca Corrente, and 5×1000.
Why Is This Important?
Acute pancreatitis is a vexing problem – there is no clear pharmacologic therapy that has been shown to be of benefit. A standard guideline-recommended intervention is “early aggressive hydration” during the first 12–24 hours.1 However, the basis of this is theoretical, and the goal is to avoid the intravascular depletion that occurs in pancreatitis, secondary to vomiting, reduced oral intake, third-spacing of fluids, increased respiratory losses, and diaphoresis, with researchers hypothesizing that the third-spacing contributes to pancreatic necrosis and death.2,3 In fact, studies are conflicting regarding early aggressive hydration in acute pancreatitis, with some showing benefit4-6 while others show harm.7,8 Furthermore, not only is it unclear if it is beneficial, but the term “early aggressive hydration” is vague – there is limited clear guidance about how much fluid, when to start, or when to stop. The WATERFALL study is a well-designed and clinically relevant randomized control trial that overcomes methodological issues of prior studies.
Key Study Findings
This well-designed RCT compares moderate and aggressive fluid resuscitation strategies in acute pancreatitis.
Therefore, per a priori stopping rules, the trial was halted by the data safety and monitoring board.
Given the nature of this RCT, there are some methodologic limitations that could not be overcome. First, it is underpowered due to being halted by the data and safety monitoring board. As such, outcomes were unable to be assessed in a statistically sound manner. It was unblinded, which would have been impractical. Lastly, patients in this trial tended to be younger than most acute pancreatitis patients, likely due to the exclusion of patients with heart or kidney failure. Nevertheless, this heightens our caution to avoid overly aggressive fluid resuscitation in patients with acute pancreatitis.
This study has made us more cautious about fluid management in acute pancreatitis. Previously, we would monitor volume status. Now, we are even more vigilant, given the clear harm that aggressive fluid resuscitation can entail. Currently, we follow the authors’ strategy: an initial fluid rate of 1.5 mL/kg of body weight/hour with boluses only for signs of hypovolemia. We frequently and carefully reassess to avoid volume overload in the first 72 hours with consideration given to diuresis as needed.
A point of interest for us is how this study developed. The first-author, Dr. Enrique de-Madaria, has commented on how a clinical question inspired this paradigm-shifting WATERFALL study – and we are inspired by how a clinical observation regarding a gap in the literature led to such a monumental effort and this multi-center international trial with striking results (https://twitter.com/demadaria/status/1570165278587207680?s=42&t=Wpl242NtG5NaC-1i618fsA).
For Future Research
Since routine aggressive fluid resuscitation can be harmful, we need to identify what moderate resuscitation strategy improves outcomes. This trial only tested 1 moderate-resuscitation strategy. We also need to optimize outcomes for those patients who were excluded from this trial, including those with respiratory, kidney or heart failure at baseline. Lastly, we need pharmacologic therapy: a 17.3% incidence of moderately severe or severe pancreatitis in the moderate-resuscitation group–the arm with “better” outcomes–speaks to how much room for improvement there is.
Conflicts of Interest
Dr. Kumar and Dr. Gardner report no conflicts of interest.
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