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

Study Overview
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Brief Summary
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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

Official Title
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Effect of Early Weight-based Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: an Open-label Multicenter Randomized-controlled Trial

Conditions
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Acute Pancreatitis

Intervention / Treatment
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* Drug: Lactated Ringer Solution


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aggressive fluid resuscitation<br>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 | Drug: Lactated Ringer Solution<br>* Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation<br>* Other names: Restrictive fluid resuscitation;|
| Experimental: Moderate fluid resuscitation<br>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 | Drug: Lactated Ringer Solution<br>* Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation<br>* Other names: Restrictive fluid resuscitation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Moderate-to-severe acute pancreatitis | Moderate or severe category of the Revised Atlanta Classification (Banks et al, Gut 2013) | From admission to discharge, up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death and/or persistent organ failure and/or infection of pancreatic necrosis | Analyzed as a composite endpoint and each of its components, includes in-hospital mortality, persistent organ failure (according to the revised Atlanta classification, Banks et al, Gut 2013) or infection of pancreatic necrosis | From admission to discharge, up to 24 weeks | 
| Fluid overload | Fluid overload is defined by the absence of Acute Respiratory Distress Syndrome and at least 2 of the following 3 criteria (based on Sharma et al, Lancet Diabetes Endocrinol 2016, with modifications): Criteria 1. Hemodynamic-imaging evidence (≥1): Non-invasive diagnostic evidence of heart failure (i.e., echocardiographic, cardiac MRI) Radiographic evidence of pulmonary congestion Invasive cardiac catheterization suggesting evidence of heart failure (i.e., pulmonary capillary wedge pressure [or left ventricular end-diastolic pressure] >18 mm Hg, right arterial pressure [or central venous pressure] >12 mm Hg, or cardiac index < 2·2 L/min per m2) Criteria 2. Heart failure symptoms (1): - Dyspnea Criteria 3. Heart failure signs (≥1): Peripheral edema Pulmonary rales or crackles, or crepitation Increased jugular venous pressure, hepatojugular reflux, or both | From admission to discharge, up to 24 weeks | 
| Shock | Systolic blood pressure <90 mmHg after fluid resuscitation | From admission to discharge, up to 24 weeks | 
| Respiratory failure | PaO2/FIO2<300 | From admission to discharge, up to 24 weeks | 
| Kidney failure | Creatinine >1.9 mg/dL | From admission to discharge, up to 24 weeks | 
| Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis) | As described on the revised Atlanta classification, Banks et al, Gut 2013 | From admission to discharge, up to 24 weeks | 
| Length of hospital stay |  | From admission to discharge, up to 24 weeks | 
| Intensive care unit stay | Need for intensive care unit (ICU) admission, and days admitted in the ICU | From admission to discharge, up to 24 weeks | 
| Need for invasive treatment | Endoscopic, percutaneous or surgical treatment of acute pancreatitis complications | From admission to discharge, up to 24 weeks | 
| Need for nutritional support | Need for enteral/parenteral feeding | From admission to discharge, up to 24 weeks | 
| PAN-PROMISE scale | Score on an acute pancreatitis Patient-Reported Outcome Measurement | At 12, 24, 48 and 72 hours | 
| C-reactive protein | Blood levels of C-reactive protein | 48 and 72 hours | 
| Systemic inflammatory response syndrome (SIRS) | SIRS at the different checkpoints. Presence of persistent (>48h) SIRS | Baseline, 12, 24, 48 and 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution