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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE3

Total Enrollment

249 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-05-28

Study Completion Date

2021-09-25

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

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Detailed Description

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Conditions

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Acute Pancreatitis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Aggressive fluid resuscitation

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

Group Type EXPERIMENTAL

Lactated Ringer Solution

Intervention Type DRUG

Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation

Moderate fluid resuscitation

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

Group Type EXPERIMENTAL

Lactated Ringer Solution

Intervention Type DRUG

Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation

Interventions

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Lactated Ringer Solution

Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation

Intervention Type DRUG

Other Intervention Names

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Aggressive fluid resuscitation Moderate fluid resuscitation Restrictive fluid resuscitation

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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No