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De-Madaria et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis: The WATERFALL Trial. NEJM 2022

Question: Does aggressive fluid resuscitation compared to moderate fluid resuscitation improve clinical outcomes in patients with acute pancreatitis?

Why ask it: How to administer intravenous fluids (IVF) for patients with acute pancreatitis remains a source of debate. Early IVF may improve pancreatic microcirculatory hypoperfusion and help prevent pancreatic necrosis. However, excessive IVF can contribute to complications including respiratory failure and abdominal compartment syndrome.

Intervention: 249 patients in 8 countries presenting to the emergency department with mild acute pancreatitis randomized to aggressive or moderate fluid resuscitation protocols (see comment for important exclusion criteria and details of intervention).

Results (all written as aggressive IVF group vs moderate IVF group):

• Development of moderately severe or severe acute pancreatitis (primary outcome)
  • 1% vs 17.3% (adjusted RR 1.3; [95% CI, 0.78 – 2.18], p=0.32)
• Fluid overload during hospitalization (primary safety outcome)
  • 5% vs 6.3% (adjusted RR 2.85; [95% CI, 1.36 – 5.94])
• No signal of benefit with aggressive IVF across a range of secondary outcomes (select secondary outcomes listed below)
  • Necrotizing pancreatitis
    • 9% vs 7.1% (adjusted RR 1.95; [95% CI, 0.87 – 4.38])
  • Local complications
    • 5% vs 16.5% (adjusted RR 1.28; [95% CI, 0.74 – 2.22])
  • Any organ failure
    • 4% vs 3.9% (adjusted RR 1.23; [95% CI, 0.47 – 3.23])
  • Respiratory failure
    • 4% vs 2.4% (adjusted RR 2.19; [0.63 – 7.64])
  • ICU admission
    • 6% vs 1.6% (adjusted RR 2.71; [95% CI, 0.64 – 11.51])
  • Death
    • 3% vs 0.8% (adjusted RR 3.05; [95% CI, 0.32 – 28.76]

• The trial was halted by the DSMB at the first interim analysis due to worse safety outcomes in the aggressive IVF group
• Similar results in prespecified subgroup analyses of patients with SIRS at baseline and those with baseline hypovolemia

Conclusion: In patients with mild acute pancreatitis, aggressive IVF did not improve clinical outcomes and was associated with more fluid overload compared to moderate IVF.

Comments:

• Acute pancreatitis pathobiology
  • Intra-acinar activation of trypsin causes autodigestive injury to the vascular endothelium, interstitium, and acinar cells with a resulting inflammatory response
  • Acute pancreatitis and sepsis share similar pathobiology including microcirculatory dysfunction, dysregulated inflammatory and coagulation cascades, and the potential for systemic and end-organ complications
• Central goals of IVF in acute pancreatitis are the correction of hypovolemia and restoration of perfusion to the pancreatic microcirculation
• WATERFALL was a multi-center, open-label, parallel-group, controlled superiority trial conducted at 18 centers in 4 countries (India, Italy, Mexico, Spain)
• Many exclusion criteria
  • Moderately severe or severe disease per the Revised Atlanta Classification
  • NYHA CHF II – IV
  • Uncontrolled HTN
  • Hyper or hyponatremia
  • Hyperkalemia
  • Hypercalcemia
  • Life expectancy < 1 year
  • Chronic pancreatitis
  • Chronic renal failure
  • Decompensated cirrhosis
• Details of interventions (Lactated Ringers used for all)
  • Aggressive-resuscitation group
    • Enrollment
      • Bolus 20 mL/kg, then infusion 3 mL/kg/hr
    • Hour 3 (“safety checkpoint”)
      • Physical assessment to evaluate for signs of volume overload
      • If present, decrease or stop infusion
    • Hours 12, 24, 48, and 72 (“goal-directed therapy checkpoints”)
      • Hypovolemia
        • Bolus 20 mL/kg, then infusion 3mL/kg/hr
        • Additional boluses of 20 mL/kg if low UOP or SBP
      • Normovolemia
        • Infusion 1.5 mL/kg/hr
        • Stop after 48 hrs if oral feeding tolerated for > 8 hrs
      • Suspicion of fluid overload
        • Decrease or stop infusion
        • Infusion stopped after 48 hrs if oral feeding tolerated for > 8hr
  • Moderate-resuscitation group
    • Enrollment
      • 1.5 mL/kg/hr without bolus in pts without hypovolemia
      • If hypovolemia present, bolus 10 ml/kg over 2 hrs then start infusion
    • Hour 3
      • Physical assessment to evaluate for signs of volume overload
      • If present, decrease or stop infusion
    • Hours 12, 24, 48, and 72
      • Hypovolemia
        • Bolus 10 mL/kg, then infusion 1.5 mL/kg/hr
        • Additional boluses of 10 ml/kg if low UOP or SBP
      • Normovolemia
        • Infusion 1.5 mL/kg/hr
        • Stop after 20 hrs if oral feeding tolerated for > 8 hrs
      • Suspicion of fluid overload
        • Decrease or stop infusion
        • Infusion stopped after 20 hrs if oral feeding tolerated for > 8hr
  • Oral feeding started at 12 hrs in both groups if minimal abd pain per the PAN-PROMISE SCORE
  • Fluid overload identified by at least 2 of the following: symptoms, physical signs, and imaging evidence of hypervolemia
• Notable patient characteristics
  • Age: ~57
  • Gallstone pancreatitis: 61%
  • CAD: 1%
  • Median BiSPAP score: 1
  • 2 or more SIRS: 26%
• Results of intervention (all written as aggressive IVF group vs moderate IVF group)
  • Median cumulative IVF
    • 12 hrs: 3.4 L vs 1.5 L
    • 24 hrs: 5.4 L vs 3.3 L
    • 48 hours: 7.8 L vs 5.5 L
    • 72 hours: 8.3 L vs 6.6L

My take

• The trial asks an important and clinically relevant question. As noted in the 2018 American Gastroenterological Association Guidelines on Initial Management of Acute Pancreatitis, there is a paucity of high-quality evidence to inform how and when to administer IVF for patients with acute pancreatitis
• The intensity of bedside reassessment in the trial (structured safety and goal-directed therapy checks at hours 3, 12, 24, 48, and 72) exceeds what is provided for many hospitalized patients in a real-world setting. The trial therefore likely underestimates the harm associated with aggressive IVF in less monitored settings.
• By design, the patients in this trial were not that sick. They had minimal co-morbidities and they could not have any organ failures or local/systemic complications related to their acute pancreatitis at the time of enrollment. The results are therefore not generalizable to the care of critically ill patients with acute pancreatitis. Patients who present with severe disease (who may have more pronounced hypovolemia and be at higher risk of progression to necrotizing pancreatitis) may uniquely benefit from IVF. Conversely, those with chronic pulmonary, cardiac, and renal disease are at higher risk of developing clinically significant complications from aggressive IVF. A tough balance.
• The trial aimed to enroll 744 patients to detect a 10% difference between groups in the development of moderately severe or severe acute pancreatitis assuming an incidence of 35%. Given the lower-than-expected incidence of moderately severe or severe acute pancreatitis during the trial (20% overall) and the early trial termination at an enrollment of 249 patients, the study is underpowered to detect differences in the primary outcome
• This trial does not inform a safe lower limit for IVF in acute pancreatitis. Do patients really need an infusion of 1.5 mL/kg/hr at days 2 and 3? My guess is no but this trial doesn’t answer that.
• My simplified view is that we should approach IVF resuscitation in acute pancreatitis much like we do with sepsis (they share many similarities as noted above). IVF in both settings is probably of most benefit when given early and in patients with more severe disease. For the floor patients we evaluate for MICU transfer (worsening disease or organ dysfunction several days into their hospital stay), ongoing high-volume maintenance fluids are likely of little benefit.
• As in sepsis care, there is not one perfect marker to guide resuscitation in acute pancreatitis. IVF should be guided by serial reassessment of intravascular volume, perfusion pressure, and tissue oxygenation using all of the imperfect tools at our disposal rather than a one-size-fits-all protocol.