Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in Acute Pancreatitis

Phase 3TerminatedNCT04381169

Enrique de-Madaria249 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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