aggressive versus non-aggressive goal-directed fluid resuscitation in acute pancreatitis

Conditions: Acute Pancreatitis

Summary: 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


Eligibility criteria:
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 (\ 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

Keywords: acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; ringer lactate; lactated ringer's solution