Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in Acute Pancreatitis
Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in Acute Pancreatitis
WATERFALL is an investigator-initiated international multicenter open-label randomized
 clinical trial comparing aggressive versus moderate fluid resuscitation in acute
 pancreatitis. The main outcome variable will be the proportion of patients with
 moderate-to-severe AP. Aggressive fluid resuscitation will consist in Lactated Ringer
 Solution (LR) 20 ml/kg bolus (administered over 2 hours) followed by LR 3 ml/kg/h and
 moderate a LR bolus 10 ml/kg in case of hypovolemia or no bolus in patients with normal
 volemia, followed by LR 1.5 ml/kg/h. The patients will be assessed at 3 (±1), 12 (±4), 24
 (±4), 48 (±4) and 72 (±4) hours from recruitment, and fluid resuscitation will be adjusted to
 the patient´s clinical and analytical status according to a protocol. Subgroup analysis will
 include patients with systemic inflammatory response syndrome (SIRS) at admission, with
 persistent (>48h) SIRS and with hypovolemia at admission.

 Based on available data (Sternby et al, Ann Surg 2019) we expect a 35% incidence of moderate
 to severe AP in the moderate arm. Sample sizes of 372 per arm of treatment (744 patients)
 achieve 80% power to detect a difference of 10% between the treatment arms at a significance
 level (alpha) of 0.05 using a two-sided z-testNA, assuming a 10% dropout. These results
 assume that 3 sequential tests are made using the O'Brien-Fleming spending function to
 determine the test boundaries.

 All analyses will be performed on an intention-to-treat basis. The trial could be stop early
 for efficacy (primary end-point) if the observed two-sided P value is <0.0002 at the first
 interim analysis (after 1/3 of patients have been enrolled) or is <0.012 at second interim
 analysis (after 2/3 of patients have been enrolled), favoring aggressive fluid resuscitation.
 At final analysis, the hypothesis that the incidence of moderate-to-severe pancreatitis is
 similar in the two treatment arms will be rejected if p<0.046
Inclusion Criteria:

 -  Patients age greater or equal to 18 presenting to one of the collaborating centers

 -  Diagnosis of acute pancreatitis according to the revised Atlanta classification which
 requires 2 of the following 3 criteria: A) Typical abdominal pain; B) Increase in
 serum amylase or lipase levels higher than 3 times the upper limit of normality; and
 C) Signs of AP in imaging.

 Exclusion Criteria:

 -  Uncontrolled arterial hypertension (systolic blood pressure >180 and/or diastolic
 blood pressure 100 mmHg);

 -  New York Heart Association Class II hear failure (slight limitation of physical
 activity; fatigue, palpitations or dyspnea with ordinal physical activity) or worse,
 or ejection fraction<50% in the last echocardiography;

 -  Decompensated cirrhosis (Child's Class B or C);

 -  Hyper or hyponatremia (<135 or >145 mEq/l);

 -  Hyperkalemia (>5 mEq/l);

 -  Hypercalcemia (albumin or protein-corrected calcium>10.5 mg/dl);

 -  Chronic kidney failure (basal glomerular filtration rate <60 mL/min/1.73m2);

 -  Clinical signs or symptoms of volume overload or heart failure at recruitment
 (dyspnea, peripheral edema, pulmonary rales, or evident increased jugular
 ingurgitation at 45º);

 -  Shock or respiratory failure according to the revised Atlanta classification at
 recruitment (non-fluid responding systolic blood pressure< 90 mmHg, PaO2/FIO2≤300
 mmHg);

 -  Time from pain onset to arrival to emergency room >24h;

 -  Time from confirmation of pancreatitis to randomization >8h;

 -  Severe comorbidity associated with an estimated life expectancy <1 year;

 -  Confirmed chronic pancreatitis (in case of recurrent alcoholic pancreatitis a recent
 (<6 months) CT scan/MRI or endoscopic ultrasound is needed to rule out chronic
 pancreatitis