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

Enrique de-Madaria

Status and phase: Terminated; Phase 3

Conditions: Acute Pancreatitis

Treatments: Drug: Lactated Ringer Solution

Study type: Interventional

Funder types: Other

Identifiers

NCT04381169

2019-000788-26 (EudraCT Number)

PI19/01628 (Other Grant/Funding Number)

CEIM HGUA 2019/003

Details and patient eligibility

About

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

Enrollment: 249 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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249 participants in 2 patient groups

Aggressive fluid resuscitation

Experimental group

Description:

Lactated Ringer Solution 20 ml/kg bolus (administered over 2 hours) followed by an infusion of 3 ml/kg/h. At 12(±4) hours: A) Hypovolemia: same bolus and infusion B) No hypovolemia: infusion of lactated Ringer Solution 1.5 ml/kg/h C) Fluid overload: infusion rate of lactated Ringer Solution will be decreased or stopped Similar adjustments are repeated at 24(±4), 48(±4) and 72(±4) hours Fluid resuscitation is maintained at least 48h, and then it can be stopped in case of tolerating oral feeding for at least 8 hours

Treatment:

Drug: Lactated Ringer Solution

Moderate fluid resuscitation

Experimental group

Description:

At recruitment: A) Hypovolemia: Lactated Ringer Solution 10 ml/kg bolus (administered over 2 hours) followed by an infusion of 1.5 ml/kg/h. B) No hypovolemia: infusion of lactated Ringer Solution of 1.5 ml/kg/h (no bolus). At 12(±4) hours: A) Hypovolemia: same bolus and infusion B) No hypovolemia: infusion of lactated Ringer Solution 1.5 ml/kg/h C) Fluid overload: infusion rate of lactated Ringer Solution will be decreased or stopped Similar adjustments are repeated at 24(±4), 48(±4) and 72(±4) hours Fluid resuscitation can be stopped before the first 48h in case of tolerating oral feeding for at least 8 hours

Treatment:

Drug: Lactated Ringer Solution