Clinical trial NCT05781243: Normal Saline Versus Lactated Ringer's Solution for Acute Pancreatitis Resuscitation
Official title: Normal Saline Versus Lactated Ringer's Solution for Acute Pancreatitis Resuscitation, an Open-label Multicenter Randomized Controlled Trial: the WATERLAND Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Acute Pancreatitis
Keywords: Normal saline
Lactated Ringer solution
Acute pancreatitis
Fluid Therapy
Fluid resuscitation
Lead sponsor: Hospital General Universitario de Alicante
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
name: Universidad Miguel Hernandez de Elche
name: Hospital del Mar
name: Hospital Clinico Universitario de Santiago
name: Hospital Clínico Universitario de Valencia
name: Hospital Costa del Sol
name: Corporacion Parc Tauli
name: Hospital Clínico Universitario Lozano Blesa
name: Hospital General Universitario Gregorio Marañon
name: Hospital Universitario La Fe
name: Hospital Miguel Servet
name: Hospital Universitario Ramon y Cajal
name: Hospital Universitario Insular Gran Canaria
name: University Hospital Virgen de las Nieves
name: Hospital Universitario de Burgos
name: Hospital Universitario Lucus Augusti
name: Hospital Universitario Marqués de Valdecilla
name: Hospital Universitario Puerta del Mar
name: Instituto de Investigación Sanitaria Hospital Universitario de la Princesa
name: Dr. Negrin University Hospital
name: Hospital Regional de Alta Especialidad del Bajio
name: Asian Institute Of Medical Sciences
name: Hospital Dr. Jaime Mendoza Sucre Bolivia
name: Hayatabad Medical Complex
name: University Hospital Olomouc
name: SIDS Hospital & Research Centre Gujarat India
name: Sanatorio Allende
name: University Hospital Bratislava
name: University Hospital Sestre Milosrdnice
name: Attikon Hospital
name: Nuevo Hospital Iturraspe Santa Fe Argentina
name: Hospital Nacional Rosales
name: Zagazig University
name: University of Utah
name: Hospitales Universitarios Virgen del Rocío
name: Hospital Universitari Dr Josep Trueta
name: Hospital of Navarra
name: Hospital Clínico Universitario de Valladolid
name: Hospital Universitario Central de Asturias
name: Kalinga Hospital, Bhubaneswar
name: Ohio State University
name: Zhengzhou University
name: Jinling Hospital, China
name: Hospital Privado de Cordoba, Argentina
name: Prince of Wales Hospital, Shatin, Hong Kong
name: Postgraduate Institute of Medical Education and Research in Chandigarh
name: RML Specialty Hospital
name: Wannan Medical College Yijishan Hospital
name: Bucharest Emergency Hospital
name: The First Affiliated Hospital of Henan University of Science and Technology
name: Emergency County Hospital Pius Brinzeu; Timisoara, Romania
name: King Hamad University Hospital, Bahrain
First posted: 2023-03-23
Enrollment: 792
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background: Some evidence suggests that fluid resuscitation with lactated Ringer's solution (LR) may have an anti-inflammatory effect on acute pancreatitis (AP) when compared to normal saline (NS), and may be associated with a decrease in severity, but existing single center randomized controlled trials showed conflicting results. The WATERLAND trial aims to investigate the efficacy and safety of fluid resuscitation using LR compared to 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 fluid resuscitation for at least 48 hours. The primary outcome will be moderately severe or severe AP, according to the revision of the Atlanta classification. The secondary objectives of the WATERLAND trial are to determine the effect of LR versus NS fluid resuscitation on several efficacy and safety outcomes in patients with AP.

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 or severe AP in the LR group will be 17%. A loss to follow-up of 10% of patients is expected, so the total sample size will be 396 patients in each treatment arm (792 patients overall). The test statistic used is the two-sided Z test with pooled variance set at a 0.05 significance level.

Discussion: The WATERLAND study aims to improve the early management of AP. Fluid resuscitation is an inexpensive treatment available in any hospital center worldwide. If a better evolution of pancreatitis is demonstrated in one of the treatment arms, it would have important repercussions in the management of this frequent disease.

Detailed description: The entire protocol is published in open-access format, including the Statistical Analysis plan, in the journal Trials: https://doi.org/10.1186/s13063-024-08539-2

Eligibility criteria: 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 \>24 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)

Primary outcomes:
measure: Number of Participants with moderately severe or severe acute pancreatitis
timeFrame: From date of randomization until 30 days after randomization
Secondary outcomes:
measure: Number of participants with local complications
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with necrotizing pancreatitis
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with infection of pancreatic collections or necrosis
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with systemic inflammatory response syndrome
timeFrame: At 24 and 48 hours
measure: Number of systemic inflammatory response syndrome criteria
timeFrame: At 24 and 48 hours
measure: PAN-PROMISE symptom scale
timeFrame: At 24 and 48 hours (final value and change from baseline)
measure: Time to oral refeeding
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with invasive treatment
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with nutritional support
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with intensive care unit admission
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with exacerbation of coexisting condition
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with any organ failure
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with persistent organ failure
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with shock
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with respiratory failure
timeFrame: From date of randomization until 30 days after randomization
measure: Number of participants with kidney failure
timeFrame: From date of randomization until 30 days after randomization
measure: Mortality (number of participants)
timeFrame: From date of randomization until 30 days after randomization
measure: Hospital stay
timeFrame: From date of randomization until 30 days after randomization
measure: C-reactive protein
timeFrame: At 48 hours from randomization
measure: Number of participants with hypovolemia
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with fluid overload
timeFrame: From randomization to 72 h thereafter
measure: Number of participants with acute kidney injury
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with hyperkalemia
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with hypercalcemia
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with hyperchloremia
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with acidosis
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with hyperchloremic acidosis
timeFrame: At 24 and 48 hours from randomization
measure: Number of participants with composite safety outcome (primary safety outcome)
timeFrame: At 24 and 48 hours from randomization
Other outcomes:
Locations:
city: Alicante
country: Spain
facility: Dr. Balmis General University Hospital
Study officials:
affiliation: Dr. Balmis General University Hospital
name: Enrique de-Madaria, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.
citation: Guilabert L, Cardenas-Jaen K, Vaillo-Rocamora A, Garcia Garcia de Paredes A, Chhoda A, Sheth SG, Lopez-Valero C, Zapater P, Navarrete-Munoz EM, Maisonneuve P, Hernandez-Barco YG, Capurso G, Buxbaum JL, de-Madaria E; ERICA consortium. Normal saline versus lactated Ringer's solution for acute pancreatitis resuscitation, an open-label multicenter randomized controlled trial: the WATERLAND trial study protocol. Trials. 2024 Oct 21;25(1):699. doi: 10.1186/s13063-024-08539-2.