Washington University Emergency Medicine Journal Club– November 2022
Vignette
You are moonlighting in a large community hospital ED one afternoon when you
encounter Ms. Y, a pleasant 50-year-old woman with a history of hypertension,
hyperlipidemia, and alcohol use disorder. She is complaining of about 12 hours of
epigastric abdominal pain that does not radiate, with associated nausea and
nonbloody emesis. She endorses drinking heavily for the last 3 days due to her
recent birthday. Her abdomen is tender in the epigastrium with no rebound or
guarding, and the remainder of her exam is normal aside from mild tachycardia and
dry oral mucous membranes. She weighs 70 kg. Her vital signs are as follows:
T 37.1 HR 103 BP 137/75 RR 16 SpO2 99%
You order basic labs, including LFTs and a lipase. Her lipase is 2300 Units/L (normal
10-99) and her LFTs are unremarkable.
You order a liter of lactated ringers, IV analgesia, antiemetics, and place a call to the
hospitalist. The hospitalist calls back and suggests you given the patient an
additional liter of fluid and start her on aggressive hydration, at a rate of 3 mL/kg/
hr. However, you recently read a summary of an article which demonstrated worse
outcomes with such aggressive hydration. You stick to your guns and order a less
aggressive hydration regimen, but after your shift you decide to look at the evidence
yourself…
PICO Question
Population:
Adult patients with pancreatitis requiring admission to the hospital with IV hydration
Intervention: High rates of fluid administration
Comparison: Moderate or low rates of fluid administration
Outcome:
Mortality, kidney injury, need for renal replacement therapy, development of SIRS, clinical improvement, volume overload, length of stay
Search Strategy
PubMed was searched using the terms “pancreatitis AND aggressive AND fluid”
(https://tinyurl.com/2p292f9f). This resulted in 237 citations, from which 3
randomized controlled trials and 1 systematic review were chosen. The Cochrane
Database of Systematic Reviews was also searched, revealing no additional articles
for inclusion.
Article 1: Di Martino M, Van Laarhoven S, Ielpo et al. Systematic review and metaanalysis
of fluid therapy protocols in acute pancreatitis: type, rate and route. HPB
(Oxford). 2021 Nov;23(11):1629-1638. Answer Key.
Article 2: de-Madaria E, Buxbaum JL, Maisonneuve P, et al; ERICA Consortium.
Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022
Sep 15;387(11):989-1000. Answer Key.
Article 3: Buxbaum JL, Quezada M, Da B, Jani N, Lane C, Mwengela D, Kelly T, Jhun P,
Dhanireddy K, Laine L. Early Aggressive Hydration Hastens Clinical Improvement in
Mild Acute Pancreatitis. Am J Gastroenterol. 2017 May;112(5):797-803. Answer Key.
Article 4: Angsubhakorn A, Tipchaichatta K, Chirapongsathorn S. Comparison of
aggressive versus standard intravenous hydration for clinical improvement among
patients with mild acute pancreatitis: A randomized controlled trial. Pancreatology.
2021 Oct;21(7):1224-1230. Answer Key.
Bottom Line
Pancreatitis is a common gastrointestinal cause of hospitalization worldwide, with
an approximate annual incidence of 44 to 111 persons per 100,000 population in
the US (Gungabissoon 2021). This incidence has been increasing over the last
several decades (Iannuzzi 2021). Some guidelines for the initial management of
pancreatitis include aggressive hydration with as much as 250-500 mL per hour of
isotonic crystalloid (American College of Gastroenterology 2013), while other
recognize the limitations of the evidence and make no specific recommendations
regarding initial fluid management (American Gastroenterological Association
Institute 2018). Given this lack of consensus and the recent publication of a
randomized controlled trial addressing this issue, we sought to review the evidence
surrounding aggressive versus moderate hydration strategies for patients with acute
pancreatitis.
Three randomized controlled trials comparing standard (10 ml/kg bolus followed
by an infusion at 1.5 ml/kg/hr) and aggressive hydration (20 ml/kg bolus followed
by an infusion at 3 ml/kg/hr) were identified in our search. The earliest of these
studies was conducted at LA County/University of Southern California Medical
Center between April 2013 and November 2015 (Buxbaum 2017). After
randomization of 60 patients, patients in the aggressive hydration group were found
to be more likely to have clinical improvement within 36 hours compared to patients
in the standard resuscitation group (adjusted OR 7.0, 95% CI 1.8-27.8), improved
more quickly, and were less likely to develop SIRS. Clinical improvement in this
study was not entirely patient-centered as it was primarily laboratory-driven,
requiring a decrease in hematocrit, BUN, and creatinine, as well as a decrease in pain
level and tolerance of oral nutrition.
A similar study conducted at Phramongkutklao Hospital in Bangkok, Thailand
between August 2019 and October 2020 enrolled only 44 patients (Angsubhakorn
2021). The authors found that there was no statistically significant difference in the
3 proportion of patients in the aggressive and standard protocol groups who had
clinical improvement at 24 hours (RR 1.43, 95% CI 0.67 to 3.1) or at 36 hours (RR
0.86, 95% CI 0.52 to 1.4), and no difference in development of SIRS. Again, the
primary outcome was primarily reliant on laboratory findings and the study was
rather limited by a very small sample size.
The most recent study on this topic was the WATERFALL trial, a multicenter,
international, open label, randomized controlled trial conducted at 18 centers in
four countries (India, Italy, Mexico, and Spain), between May 2020 and September
2021 (de-Madaria 2022). The authors planned to enroll 744 patients per their
sample size calculation, but stopped early enrollment after 249 patients due to an
increased rate of the primary safety outcome of fluid overload in the aggressive
hydration group (adjusted RR 2.85, 95% CI 1.36-5.94). It should be noted that there
was no significant difference in the incidence of moderate-to-severe fluid overload
(aRR 3.62, 0.37-35.22), only one patient required intubation, and no patients
required hemodialysis. There was no significant difference in the development of the
primary outcome, development of moderately severe or severe acute pancreatitis:
22.1% in the aggressive resuscitation group vs. 17.3% in the moderate resuscitation
group, adjusted RR 1.30 (95% CI 0.78-2.18). The study was primarily limited by it’s
smaller-than-planned sample size, especially given the decision to stop early was
based on potentially subjective findings of unclear clinical significance.
A systematic review and meta-analysis, published prior to the WATERFALL and Thai
trials, identified 15 randomized controlled trials evaluating fluid therapy in
pancreatitis (Di Martino 2021). Regarding our specific question, in 12 studies
comprising 853 participant high-rate fluid infusion was associated with higher
mortality compared with moderate-rate infusion (OR 2.88, 98% CI 1.41-5.88) and
was associated with increased rates of serious adverse events compared to
moderate-rate infusion (RR 1.42, 95% CI 1.04-1.93). Among 231 patients in 3 trials,
high-rate fluid infusion was associated with decreased rates of sepsis compared to
moderate-rate infusion (RR 2.80, 95% CI 1.51-5.19).
While these data are somewhat inconsistent, there is at least some suggestion in
both the meta-analysis and the largest of the randomized controlled trials that high
rates of fluid resuscitation is associated with worse outcomes in patients with
pancreatitis. The evidence is limited by lack of blinding in all of the trials assessed
(and all of the trials included in the meta-analysis), small sample sizes, and a trial
that was stopped early with only a third of the planned enrollment. It is therefore
difficult to make definitive management recommendations based on this evidence,
and the rate of fluid administration should instead by dictated by the clinical picture
on a case-by-case basis.