SGEM#382: Don’t Go Chasing Waterfalls to Treat Pancreatitis

Podcast: Play in new window | Download

Subscribe: RSS

Date: November 10th, 2022

Reference: de-Madaria E et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis (WATERFALL). NEJM 2022.

Guest Skeptic: Dr. Salim R. Rezaie completed his medical school training at Texas A&M Health Science Center and continued his medical education with a combined Emergency Medicine/Internal Medicine residency at East Carolina University. Currently, Salim works as a community emergency physician at Greater San Antonio Emergency Physicians (GSEP), where he is the director of clinical education. Salim is also the creator and founder of REBEL EM and REBEL Cast, a free, critical appraisal blog and podcast that try to cut down knowledge translation gaps of research to bedside clinical practice.

Case: A 38-year-old male presents to the emergency department (ED) with acute mid epigastric abdominal pain with nausea and vomiting.  As part of the patient’s workup, he has an elevated lipase, and a CT abdomen and pelvis ultimately shows the patient to have acute pancreatitis. You remember a new trial was just published on whether to use aggressive versus nonaggressive goal-directed fluid resuscitation in the early phase of acute pancreatitis and wonder which would be better for this patient.

Background: It’s interesting to see how fluid resuscitation has been debated over the years. This includes fluid type and rate for things like renal colic (SGEM#32), pediatric diabetic ketoacidosis  (SGEM#255), hyponatremia (SGEM#326), trauma (SGEM#369), and critically ill adults (SGEM#347 and SGEM#368).

Standard management of acute pancreatitis has focused mainly on hydration, analgesia, and investigation for an underlying cause.  Recent evidence has challenged the routine use of aggressive large volume fluid resuscitation with the potential to increase the severity of pancreatitis as well as fluid overload.  High-quality evidence demonstrating harms of aggressive fluid resuscitation in acute pancreatitis have been lacking.

Clinical Question: Does the use of a moderate fluid resuscitation strategy in acute pancreatitis decrease the rate of progression to moderate/severe pancreatitis in comparison to aggressive fluid resuscitation?

Reference: de-Madaria E et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis (WATERFALL). NEJM 2022.

• Population: Adult patients (≥18 years of age) diagnosed with acute pancreatitis based on the Revised Atlanta Classification (Requires 2 of 3: Typical abdominal pain, serum amylase or lipase level higher than three times the upper limit of normal, or signs of acute pancreatitis on imaging) that presented within 24 hours of pain onset
  • Exclusions: Patients who met the criteria for moderately severe or severe disease at baseline (shock, respiratory failure, and renal failure) or who had baseline heart failure (NYHA II, III, or IV), uncontrolled arterial hypertension, electrolyte disturbances (hypernatremia, hyponatremia, hyperkalemia, hypercalcemia), an estimated life expectancy of <1 year, chronic pancreatitis, chronic renal failure, or decompensated cirrhosis
• Intervention: Moderate fluid resuscitation (bolus of 10 cc/kg lactated Ringer’s [LR] over two hours in patients with hypovolemia or no bolus in those with normovolemia followed by 1.5 cc/kg/hour of LR)
• Comparison: Aggressive fluid resuscitation (bolus of 20 cc/kg LR over two hours regardless of fluid status followed by 3.0 cc/kg/hour of LR)
• Outcome:
  • Primary Outcome: Progression to moderately severe or severe acute pancreatitis (according to the Revised Atlanta Classification).
  • Secondary Outcomes: Organ failure, local complications, persistent organ failure, respiratory Failure, hospital length of stay (LOS), ICU admission, and ICU LOS
  • Safety Endpoint: Fluid Overload defined by 2 of the following 3:
    • Criterion 1: Non-invasive evidence of heart failure (ie echo), radiographic evidence of pulmonary congestion, invasive cardiac Cath suggesting heart failure.
    • Criterion 2: Dyspnea
    • Criterion 3: Heart failure signs: peripheral edema, pulmonary rales, increased jugular venous pressure (JVP) or hepatojugular reflex
• Type of Study: Multicenter, multinational, open-label, parallel-group, randomized, controlled, superiority trial at 18 centers across four countries (India, Italy, Mexico, and Spain)

Authors’ Conclusions: “In this randomized trial involving patients with acute pancreatitis, early aggressive fluid resuscitation resulted in a higher incidence of fluid overload without improvement in clinical outcomes.”

Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the emergency department. Yes
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. Yes
4. The patients were analyzed in the groups to which they were randomized. Yes
5. The study patients were recruited consecutively (i.e. no selection bias). Yes
6. The patients in both groups were similar with respect to prognostic factors. No
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
8. All groups were treated equally except for the intervention. Unsure
9. Follow-up was complete (i.e. at least 80% for both groups). Yes
10. All patient-important outcomes were considered. Yes
11. The treatment effect was large enough and precise enough to be clinically significant. No
12. Financial conflicts of interest. No

Results: They screened 676 patients with acute pancreatitis for inclusion. The final cohort consisted of 249 patients randomly assigned (127 moderate and 122 aggressive). Mean age was 57 years. It was about a 50/50 male female split but 9.2% more females were in the aggressive group. There was also about a 10% difference in gallstone causes of pancreatitis (65.6% aggressive vs 55.9% moderate). The aggressive group got more fluid in the first 48 hours (7.8L vs 5.5L).

Key Result: In adult patients with non-severe acute pancreatitis, there was a lack of benefit with aggressive fluid resuscitation but there was an increase in harm.

• Primary Outcome: Progression to moderate/severe pancreatitis
  • Moderate 17.3% vs Aggressive 22.1%
  • Absolute Difference 4.8%; aRR 1.30 (95% CI, 0.78 to 2.18)
• Secondary Outcomes: 
  • No statistical difference in organ failure, local complications, persistent organ failure or respiratory failure between groups
• Primary Safety Outcome: Fluid overload
  • Moderate 6.3% vs Aggressive 20.5%
  • Absolute Difference: 14.2%; aRR 2.85 (95% CI, 1.36 to 5.94) NNH 7

1. Trial Stopped Early: This trial was stopped early due to an interim analysis demonstrating a significantly higher rate of fluid overload in the aggressive hydration group. We have discussed the issues around stopping trials early before on the SGEM. Guyatt et al published an article in the BMJ 2012 describing the dangers of stopping trials early for benefit and Veile et al covered the issue in JAMA 2016.

This trial was stopped early for harm after about 1/3 of the power calculation to include 744 participants. The investigators a priori specified what conditions would trigger the trial to be stopped in a publication by Bolando et al Front Med 2020.

• a between-group difference in the primary outcome with a two-sided P value of less than 0.0002 at the first interim analysis
• less than 0.012 at the second interim analysis
• clear evidence of harm in one trial group over the other (safety) as adjudicated by the data and safety monitoring board,
• slow recruitment rate

At the time the trial was stopped, there was a 4.8% non-statistically significant difference in the primary outcome (favoring moderate fluid resuscitation), which was smaller than the pre-set criteria of 5% difference.  However, given the statistically significant difference in the primary safety outcome, a larger study shouldn’t be necessary to change practice.

2. Open-Label Trial: Patients and investigators were aware of group allocation while the outcome assessors were blinded. Blinding to group allocation is an important method to mitigate potential bias. A good primer on the importance of blinding can be found on the Cochrane website Students 4 Best Evidence..

Sometimes it is not possible to blind trials, and this can introduce a potential risk of bias.  This is particularly important as the safety outcome (fluid overload) in the Waterfall trial has some subjectivity to it and means we should be more skeptical of this result.

3. Statistically Significant vs Clinically Significant: We have often mentioned the difference between statistical and clinical significance. Although none of the secondary outcomes reached statistical significance, all of them had numeric trends toward harm in the aggressive fluid group. Normally secondary outcomes are hypothesis generating, however given the worsened primary safety outcome of fluid overload, we need to consider this clinical information carefully.

4. Volume of Fluids: The authors did achieve separation between groups when looking at median fluids received in the first 48 hours. It was 7.8L in the aggressive group (range 6.5 to 9.8L) and 5.5L in the moderate group (range 4.09 to 6.8L) Not sure what point you are making??

5. Exclusion Criteria: There was a fairly extensive list of exclusion criteria which excluded most patients that were approached for enrollment. Of the 676 patients assessed only 249 met inclusion/exclusion criteria (39%). Some of the exclusion criteria seemed questionable (i.e. HTN, electrolyte abnormalities) which resulted in 96 patients (14%) being excluded.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion that an aggressive fluid resuscitation strategy led to more fluid overload without improvement in other clinical outcomes.

SGEM Bottom Line: We cannot recommend aggressive fluid resuscitation in patients with moderate acute pancreatitis.

Case Resolution: Based on this new high-quality level of evidence you decide to treat your patient with a moderate fluid strategy.

Dr. Salim Rezaie

Clinical Application: This high-quality randomized clinical trial should change clinical practice with the administration of smaller fluid boluses (10cc/kg) in patients with hypovolemia (and no bolus in those with normovolemia) with the addition of 1.5cc/kg/hr of maintenance fluids.

What Do I Tell My Patient?

Keener Kontest: There was no winner last week. Justin relocated his  dislocated shoulder using the Whistler technique.

Listen to the show this week to hear the keener question. The first person to email the correct answer to TheSGEM@gmail.com with “keener” in the subject line will receive a cool skeptical prize.

Other FOAMed:

• Rebel EM: Less is More Again – Speed of IV fluid Administration in Pancreatitis
• EMCrit: Ep333 – The State of Fluids Show with the EMCrit Core Team
• The Bottom Line: Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.