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

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

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 Overview

• Status: Terminated
• Conditions: Acute Pancreatitis
• Intervention / Treatment: Drug: Lactated Ringer Solution

• Study Type: Interventional
• Enrollment (Actual): 249
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Alicante, Spain, 03010
    • Alicante
  • Alicante, Spain, 03550
    • Hospital General Universitario de Alicante

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Lactated Ringer Solution; Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation; Other Names: Aggressive fluid resuscitation; Moderate fluid resuscitation; Restrictive fluid resuscitation
Experimental: 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	Drug: Lactated Ringer Solution; Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation; Other Names: Aggressive fluid resuscitation; Moderate fluid resuscitation; Restrictive fluid resuscitation

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Enrique de-Madaria
• Collaborators: Instituto de Salud Carlos III; Asociación Española de Gastroenterología; Asociación Española de Pancreatología

Publications and helpful links

General Publications

• Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25.
• de-Madaria E, Buxbaum JL, Maisonneuve P, Garcia Garcia de Paredes A, Zapater P, Guilabert L, Vaillo-Rocamora A, Rodriguez-Gandia MA, Donate-Ortega J, Lozada-Hernandez EE, Collazo Moreno AJR, Lira-Aguilar A, Llovet LP, Mehta R, Tandel R, Navarro P, Sanchez-Pardo AM, Sanchez-Marin C, Cobreros M, Fernandez-Cabrera I, Casals-Seoane F, Casas Deza D, Lauret-Brana E, Marti-Marques E, Camacho-Montano LM, Ubieto V, Ganuza M, Bolado F; ERICA Consortium. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. doi: 10.1056/NEJMoa2202884.

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2020
• Primary Completion (Actual): September 25, 2021
• Study Completion (Actual): September 25, 2021

Study Registration Dates

• First Submitted: May 2, 2020
• First Submitted That Met QC Criteria: May 5, 2020
• First Posted (Actual): May 8, 2020

Study Record Updates

• Last Update Posted (Actual): March 21, 2022
• Last Update Submitted That Met QC Criteria: March 4, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution
• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis
• Other Study ID Numbers: CEIM HGUA 2019/003; PI19/01628 (Other Grant/Funding Number: Instituto de Salud Carlos III); 2019-000788-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No