Normal Saline Versus Lactated Ringer's Solution for Acute Pancreatitis Resuscitation (WATERLAND)

Normal Saline Versus Lactated Ringer's Solution for Acute Pancreatitis Resuscitation, an Open-label Multicenter Randomized Controlled Trial: the WATERLAND Trial

Background: Acute pancreatitis (AP) is an acute inflammatory disease of variable severity. Mild cases have an uncomplicated clinical course, but local and systemic complications occur in one-third of patients and are associated with a longer hospital stay, increased morbidity, increased hospital costs, and increased risk of death. Some evidence suggests that fluid resuscitation with lactated Ringer's solution (LR) may have an anti-inflammatory effect on AP when compared to normal saline (NS), and may be associated with a decrease in severity, but randomized controlled trials showed conflicting results. The WATERLAND trial has been designed to investigate the efficacy and safety of fluid resuscitation using LR as compared with NS in patients with AP.

Methods: The WATERLAND trial is an international multicenter, open-label, parallel-group, randomized, controlled, superiority trial. Patients will be randomly assigned in a 1:1 ratio to receive LR versus NS-based moderate fluid resuscitation. The primary outcome will be moderately severe to severe AP, according to the revision of the Atlanta classification. The primary safety outcome will be a composite variable involving any of the following: fluid overload, acute kidney injury, hyperkalemia, hypercalcemia, or acidosis. A total sample of 720 patients, 360 in the LR group and 360 in the NS group will achieve 90% power to detect a difference between the group proportions of 10%, assuming that the frequency of moderately severe to severe AP in LR group will be 17%. The frequency in the NS group is assumed to be 27% under the null hypothesis and 17% under the alternative hypothesis. The test statistic used is the two-sided Z test with pooled variance set at a 0.05 significance level.

Study Overview

• Status: Recruiting
• Conditions: Acute Pancreatitis
• Intervention / Treatment: Drug: Lactated Ringer Solution; Drug: Normal saline

• Study Type: Interventional
• Enrollment (Estimated): 720
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alicia Vaillo-Rocamora, BPHARM; Phone Number: 0034 965913975; Email: vailloalicia@gmail.com

Study Locations

• Spain
  • Alicante, Spain, 03010
    • Recruiting
    • Dr. Balmis General University Hospital
    • Contact: Alicia Vaillo-Rocamora, BPHARM; Phone Number: 0034 965913975; Email: vailloalicia@gmail.com
    • Principal Investigator: Enrique de Madaria, MD PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patient is 18 years or older
• Diagnosis of acute pancreatitis according to the revision of the Atlanta classification (Banks et al, Gut 2013), which requires at least two of the following three criteria: A) typical abdominal pain, B) increase in serum amylase or lipase levels higher than three times the upper limit of normality, and C) signs of acute pancreatitis in imaging
• Signature of informed consent

Exclusion Criteria:

• New York Heart Association class II heart 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 or 2.62 mmol/L)
• Criteria for moderately severe or severe acute pancreatitis (revision of the Atlanta classification, Banks et al, Gut 2013) at recruitment: any of the following: A) presence of creatinine ≥1.9 mg/dL or ≥170 mmol/l, B) PaO2/FiO2≤300, C) systolic blood pressure <90 mmHg despite initial fluid resuscitation, D) presence of local complications (acute peripancreatic fluid collections, acute necrotic collection, pseudocyst, walled-off necrosis, gastric outlet dysfunction, splenic or portal vein thrombosis, or colonic necrosis), E) exacerbation of previous comorbidity such as coronary artery disease or chronic lung disease, precipitated by the acute pancreatitis
• Signs of volume overload or heart failure at recruitment (peripheral edema, pulmonary rales, or increased jugular ingurgitation at 45º)
• Time from pain onset to arrival to emergency room >12 h
• Time from confirmation of pancreatitis to randomization >8 h
• Chronic pancreatitis defined by a Wirsung duct ≥4mm and/or pancreatic calcifications
• More than 1 previous episode of acute pancreatitis (only 2 episodes of acute pancreatitis are allowed, one of them the present episode)

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: Lactated Ringer solution (LR); LR: Lactated Ringer solution. Patients in the LR treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours.	Drug: Lactated Ringer Solution; Patients in the LR (Lactated Ringer solution) treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours.
Active Comparator: Normal saline (NS); NS: Normal Saline. Patients in the NS treatment arm will receive fluid therapy based on normal saline for a minimum of 48 hours.	Drug: Normal saline; Patients in the NS (Normal Saline) treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with moderately severe or severe acute pancreatitis	Presence of local complications, exacerbation of previous comorbidity or organ failure, according to the definitions of these complications provided by the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779)	From date of randomization until 30 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with systemic inflammatory response syndrome	At least 2 criteria: A) pulse >90 beats/min, B) respirations >20/min or arterial blood PaCO2 <32 mm Hg, C) temperature <36°C or >38°C, D) white blood cell count <4,000 cells/mm3 or >12,000 cells/mm3 or >10% bands	At 24 and 48 hours
Number of systemic inflammatory response syndrome criteria	The criteria are: A) pulse >90 beats/min, B) respirations >20/min or arterial blood PaCO2 <32 mm Hg, C) temperature <36°C or >38°C, D) white blood cell count <4,000 cells/mm3 or >12,000 cells/mm3 or >10% bands	At 24 and 48 hours
PAN-PROMISE symptom scale	PAN-PROMISE scale: a 7-symptom scale patient-reported outcome (range, 0 to 10 for each symptom; overall range, 0 to 70, with higher scores indicating higher symptom intensity). Details: https://doi.org/10.1136/gutjnl-2020-320729	At 24 and 48 hours (change from baseline)
Number of participants with local complications	Presence of acute peripancreatic fluid collections, acute necrotic collection, pseudocyst, walled-off necrosis, gastric outlet dysfunction, splenic or portal vein thrombosis, and colonic necrosis according to the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779).	From date of randomization until 30 days after randomization
Number of participants with necrotizing pancreatitis	Presence of acute necrotic collections according to the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779).	From date of randomization until 30 days after randomization
Time to oral refeeding	Days from baseline to oral refeeding	From date of randomization until 30 days after randomization
Number of participants with invasive treatment	Any of the following: thoracocentesis due to pancreatitis-induced pleural effusion, percutaneous and/or endoscopic drainage of pancreatic or peripancreatic fluid collections or necrosis, endoscopic or surgical necrosectomy, endoscopic retrograde cholangiopancreatography due to A) ruptured common bile duct, B) jaundice caused by compression of the common bile duct, C) main pancreatic duct leakage	From date of randomization until 30 days after randomization
Number of participants with nutritional support	Use of enteral (nasogastric or nasojejunal) or parenteral feeding	From date of randomization until 30 days after randomization
Number of participants with intensive care unit admission	Admission in the intensive care unit	From date of randomization until 30 days after randomization
Number of participants with exacerbation of coexisting condition	Exacerbation of pre-existing co-morbidity. The definition provided by the Revised Atlanta Classification is " Exacerbation of pre-existing co-morbidity, such as coronary artery disease or chronic lung disease, precipitated by the acute pancreatitis is defined as a systemic complication. In this document, we distinguish between persistent organ failure (the defining feature of severe acute pancreatitis) and other systemic complications, which are an exacerbation of pre-existing co-morbid disease." (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779) For the WATERLAND trial we define exacerbation of pre-existing co-morbidity as	From date of randomization until 30 days after randomization
Number of participants with any organ failure	Definition according to the revised Atlanta classification (https://doi.org/10.1136/gutjnl-2012-302779): organ failure is defined by the presence of any of the following criteria: A) kidney failure as a creatinine ≥1.9 mg/dL or >170 micromol/L, B) cardiovascular failure as a systolic blood pressure <90 mmHg despite fluid resuscitation, and C) respiratory failure as a PaO2/FIO2≤300	From date of randomization until 30 days after randomization
Number of participants with persistent organ failure	Organ failure lasting more than 48h (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)	From date of randomization until 30 days after randomization
Number of participants with shock	Systolic blood pressure <90 mmHg despite fluid resuscitation (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)	From date of randomization until 30 days after randomization
Number of participants with respiratory failure	PaO2/FIO2≤300 (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)	From date of randomization until 30 days after randomization
Number of participants with kidney failure	Creatinine ≥1.9 mg/dL or >170 micromol/L (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)	From date of randomization until 30 days after randomization
Mortality (number of participants)	Death	From date of randomization until 30 days after randomization
Hospital stay	Days from recruitment to discharge from index admission	From date of randomization until 30 days after randomization
C-reactive protein	C-reactive protein blood levels	At 48 hours from randomization
Number of participants with hypovolemia	WATERFALL trial criteria for hypovolemia (see https://www.nejm.org/doi/10.1056/NEJMoa2202884)	At 24 and 48 hours from randomization
Number of participants with fluid overload	WATERFALL trial criteria for fluid overload (see https://www.nejm.org/doi/10.1056/NEJMoa2202884)	At 24 and 48 hours from randomization
Number of participants with acute kidney injury	KDIGO criteria: increase in serum creatinine of ≥0.3 mg/dL within 48 hr or ≥50% within 7 days or urine output of <0.5 mL/kg/hr for >6 hr (https://doi.org/10.1159/000339789)	At 24 and 48 hours from randomization
Number of participants with hyperkalemia	Venous potassium>5mEq/L	At 24 and 48 hours from randomization
Number of participants with hypercalcemia	Venous calcium corrected by proteins>10.5mg/dL or 2.62 mmol/L	At 24 and 48 hours from randomization
Number of participants with hyperchloremia	Venous chloride>106mEq/L	At 24 and 48 hours from randomization
Number of participants with acidosis	Venous blood pH <7.35	At 24 and 48 hours from randomization
Number of participants with composite safety outcome (primary safety outcome)	Fluid overload or acute kidney injury or hyperkalemia or hypercalcemia or hyperchloremia or acidosis	At 24 and 48 hours from randomization

Collaborators and Investigators

• Sponsor: Enrique de-Madaria
• Collaborators: Hospital General Universitario Gregorio Marañon; Zagazig University; Hospital Universitario Ramon y Cajal; Corporacion Parc Tauli; Hospital del Mar; University Hospital Olomouc; Instituto de Salud Carlos III; Hospital Universitario La Fe; Universidad Miguel Hernandez de Elche; University Hospital "Sestre Milosrdnice"; Hospital Miguel Servet; Hospital Costa del Sol; Hospital Universitario Marqués de Valdecilla; Instituto de Investigación Sanitaria Hospital Universitario de la Princesa; Attikon Hospital; University Hospital Bratislava; Dr. Negrin University Hospital; Hospital Clinico Universitario de Santiago; Hospital Regional de Alta Especialidad del Bajio; Hospital Universitario Puerta del Mar; Hospital Universitario de Burgos; Hospital Universitario Lucus Augusti; Hospital Clínico Universitario Lozano Blesa; Hospital Nacional Rosales; University Hospital Virgen de las Nieves; Hospital Clínico Universitario de Valencia; Hospital Universitario Insular Gran Canaria; Asian Institute Of Medical Sciences; Hayatabad Medical Complex; Hospital Dr. Jaime Mendoza Sucre Bolivia; SIDS Hospital & Research Centre Gujarat India; Sanatorio Allende; Nuevo Hospital Iturraspe Santa Fe Argentina
• Investigators: Principal Investigator: Enrique de-Madaria, MD PhD, Dr. Balmis General University Hospital

Publications and helpful links

General Publications

• de-Madaria E, Sanchez-Marin C, Carrillo I, Vege SS, Chooklin S, Bilyak A, Mejuto R, Mauriz V, Hegyi P, Marta K, Kamal A, Lauret-Brana E, Barbu ST, Nunes V, Ruiz-Rebollo ML, Garcia-Rayado G, Lozada-Hernandez EE, Pereira J, Negoi I, Espina S, Hollenbach M, Litvin A, Bolado-Concejo F, Vargas RD, Pascual-Moreno I, Singh VK, Mira JJ. Design and validation of a patient-reported outcome measure scale in acute pancreatitis: the PAN-PROMISE study. Gut. 2021 Jan;70(1):139-147. doi: 10.1136/gutjnl-2020-320729. Epub 2020 Apr 3.
• 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): June 19, 2023
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: February 25, 2023
• First Submitted That Met QC Criteria: March 10, 2023
• First Posted (Actual): March 23, 2023

Study Record Updates

• Last Update Posted (Actual): September 25, 2023
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Fluid resuscitation; Normal saline; Fluid Therapy; Acute pancreatitis; Lactated Ringer solution
• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis
• Other Study ID Numbers: Eudract 2023-000010-18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Members of the ERICA consortium that recruited patients in the WATERLAND trial may claim access to the final dataset to perform post-hoc studies; these proposals will be studied by the steering committee.
• IPD Sharing Time Frame: Data will be available upon publication of the main study.
• IPD Sharing Access Criteria: Have enrolled patients in the WATERLAND study.; The Steering Committee will evaluate the project and decide whether it is of sufficient scientific quality.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

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