WATERFALL Trial – Fluid Resuscitation in Acute Pancreatitis

Written by – Dr Jose Chacko

Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis

Hypoperfusion and hemoconcentration in acute pancreatitis may lead to necrosis, and adverse clinical outcomes.

Population

The WATERFALL multicenter, open-label, parallel-group, randomized, controlled, superiority trial, enrolled patients at 18 centres from India, Italy, Mexico, and Spain. Acute pancreatitis was diagnosed according to the revised Atlanta Classification. For inclusion in the study, patients were within 24 hours after pain onset and 8 hours or less since confirmation of diagnosis.

Excluded

• Patients who met the criteria for moderately severe or severe disease at baseline (shock, respiratory failure, and renal failure)
• Heart failure (New York Heart Association functional class II, III, or IV),
• Uncontrolled arterial hypertension; electrolyte abnormalities including hypernatremia, hyponatremia, hyperkalemia, hypercalcemia
• A life expectancy of less than 1 year
• Chronic pancreatitis
• Chronic renal failure
• Decompensated cirrhosis

Aggressive resuscitation

Bolus of lactated Ringer’s solution at 20 ml per kilogram of body over a period of 2 hours, followed by infusion at a rate of 3 ml per kilogram per hour.

Moderate resuscitation

Bolus of 10 ml/kg as bolus over 2 hours if hypovolemic; by 1.5 ml/kg/h as maintenance.

Both groups

Evaluation at 3 hours for fluid overload. Biochemical and physical assessments at 12, 24, 48, and 72 h; adjustments made to the rate of fluid administration; stopped if suspicion of fluid overload. Oral feeds at 12 h if pain intensity is less than 5 on the PAN-PROMISE scale. Fluid resuscitation stopped if oral intake was tolerated for more than 8 h, earliest at 20 h and 48 h after randomization in the moderate vs. aggressive groups, respectively.

Sample size

Based on an anticipated incidence of moderately severe or severe acute pancreatitis of 35%. A sample size of 744, with 372 patients in each group, for 80% power to detect a between-group difference of 10 percentage points at a two-sided significance level (alpha) of 0.05.

Two planned interim analysis after 248 and 496 patients. The study was terminated early due to safety concerns of fluid overload with the aggressive strategy.

Results

Aggressive: 122 patients; moderate: 127 patients. Baseline characteristics were well-matched.

Fluid administered during the first 48 h: Aggressive: 7.8 liters (interquartile range, 6.5 to 9.8) vs.  Moderate: 5.5 liters (interquartile range, 4.0 to 6.8)

(Diagnosis of fluid overload: at least two of the following three criteria: symptoms, physical signs, and imaging evidence of hypervolemia; ARDS had to be ruled out

• 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 JVP or hepatojugular reflex

Mild fluid overload: if it was responsive to medical therapy or decreased hydration and if the ratio of PaO2 to FiO2 never decreased to less than 300

Moderate fluid overload: if it was responsive to medical therapy or decreased hydration but the ratio of PaO2 to FiO2 was less than 300 at least once

Severe fluid overload: if mechanical ventilation or hemofiltration was required

Outcomes: Primary outcome, green; secondary outcomes, blue; safety outcomes, yellow

Strengths

• No loss to follow up
• Balanced baseline characteristics, except gall stone pancreatitis higher in the aggressive group
• Protocol-based fluid administration; assessment at regular time intervals at 3, 12, 24, 48, and 72 h
• Poorly reliable clinical signs were not followed in the assessment of fluid overload
• Focus on safety outcomes

Limitations

• Included only patients with mild pancreatitis
• Less co-morbidities
• Unblinded
• Sample size not achieved
• Assumed progression to moderately severe or severe pancreatitis of 35%; actual progression was only 20%