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

Acute Pancreatitis Clinical Trial

— WATERLAND  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05781243
• Other study ID #: Eudract 2023-000010-18
• Status: Recruiting
• Phase: Phase 4
• Start date: June 19, 2023
• Est. completion date: April 1, 2026

Study information

• Verified date: September 2023
• Source: Hospital General Universitario de Alicante
• Contact: Alicia Vaillo-Rocamora, BPHARM
• Phone: 0034 965913975
• Email: vailloalicia[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 720
• Est. completion date: April 1, 2026
• Est. primary completion date: April 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Acute Pancreatitis
• Pancreatitis

Intervention

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.
• 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.

Locations

Country	Name	City	State
Spain	Dr. Balmis General University Hospital	Alicante

Sponsors (34)

Lead Sponsor

Collaborator

Enrique de-Madaria

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

Country where clinical trial is conducted

Spain, 

References & Publications (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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	Time to oral refeeding	Days from baseline to oral refeeding	From date of randomization until 30 days after randomization
Secondary	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
Secondary	Number of participants with nutritional support	Use of enteral (nasogastric or nasojejunal) or parenteral feeding	From date of randomization until 30 days after randomization
Secondary	Number of participants with intensive care unit admission	Admission in the intensive care unit	From date of randomization until 30 days after randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Mortality (number of participants)	Death	From date of randomization until 30 days after randomization
Secondary	Hospital stay	Days from recruitment to discharge from index admission	From date of randomization until 30 days after randomization
Secondary	C-reactive protein	C-reactive protein blood levels	At 48 hours from randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of participants with hyperkalemia	Venous potassium>5mEq/L	At 24 and 48 hours from randomization
Secondary	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
Secondary	Number of participants with hyperchloremia	Venous chloride>106mEq/L	At 24 and 48 hours from randomization
Secondary	Number of participants with acidosis	Venous blood pH <7.35	At 24 and 48 hours from randomization
Secondary	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