WATERLAND: Normal Saline Versus Lactated Ringer's Solution for Acute Pancreatitis Resuscitation
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Study Design
Arms and Interventions
| 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.
|
Outcome Measures
Primary Outcome Measures
- Number of Participants with moderately severe or severe acute pancreatitis [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
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)
Secondary Outcome Measures
- Number of participants with local complications [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
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).
- Number of participants with necrotizing pancreatitis [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Presence of acute necrotic collections or walled-off necrosis according to the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779).
- Number of participants with systemic inflammatory response syndrome [At 24 and 48 hours]
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
- Number of systemic inflammatory response syndrome criteria [At 24 and 48 hours]
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
- PAN-PROMISE symptom scale [At 24 and 48 hours (change from baseline)]
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
- Time to oral refeeding [From recruitment to oral refeeding within index admission]
Days from baseline to oral refeeding
- Number of participants with invasive treatment [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
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
- Number of participants with nutritional support [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Use of enteral (nasogastric or nasojejunal) or parenteral feeding
- Number of participants with intensive care unit admission [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Admission in the intensive care unit
- Number of participants with exacerbation of coexisting condition [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
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
- Number of participants with any organ failure [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
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
- Number of participants with persistent organ failure [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Organ failure lasting more than 48h (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)
- Number of participants with shock [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Systolic blood pressure <90 mmHg despite fluid resuscitation (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)
- Number of participants with respiratory failure [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
PaO2/FIO2≤300 (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)
- Number of participants with kidney failure [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Creatinine ≥1.9 mg/dL or >170 micromol/L (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)
- Mortality (number of participants) [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Death
- Hospital stay [From date of randomization until the date of discharge due to patient improvement or date of death from any cause, whichever came first, assessed up to 3 months]
Days from recruitment to discharge from index admission
- C-reactive protein [At 48 hours from recruitment]
C-reactive protein blood levels
- Number of participants with hypovolemia [At 24 and 48 hours from recruitment]
WATERFALL trial criteria for hypovolemia (see https://www.nejm.org/doi/10.1056/NEJMoa2202884)
- Number of participants with fluid overload [At 24 and 48 hours from recruitment]
WATERFALL trial criteria for fluid overload (see https://www.nejm.org/doi/10.1056/NEJMoa2202884)
- Number of participants with acute kidney injury [At 24 and 48 hours from recruitment]
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)
- Number of participants with hyperkalemia [At 24 and 48 hours from recruitment]
Venous potassium>5mEq/L
- Number of participants with hypercalcemia [At 24 and 48 hours from recruitment]
Venous calcium corrected by proteins>10.5mg/dL or 2.62 mmol/L
- Number of participants with hyperchloremia [At 24 and 48 hours from recruitment]
Venous chloride>106mEq/L
- Number of participants with acidosis [At 24 and 48 hours from recruitment]
Venous blood pH <7.35
- Number of participants with composite safety outcome (primary safety outcome) [At 24 and 48 hours from recruitment]
Fluid overload or acute kidney injury or hyperkalemia or hypercalcemia or hyperchloremia or acidosis
Eligibility Criteria
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
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Signature of informed consent
Exclusion Criteria:
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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
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Decompensated cirrhosis (Child's class B or C)
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Hyper or hyponatremia (<135 or >145 mEq/L)
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Hyperkalemia (>5 mEq/L)
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Hypercalcemia (albumin or protein-corrected calcium >10.5 mg/dL or 2.62 mmol/L)
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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
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Signs of volume overload or heart failure at recruitment (peripheral edema, pulmonary rales, or increased jugular ingurgitation at 45º)
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Time from pain onset to arrival to emergency room >12 h
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Time from confirmation of pancreatitis to randomization >8 h
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Chronic pancreatitis defined by a Wirsung duct ≥4mm and/or pancreatic calcifications
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More than 1 previous episode of acute pancreatitis (only 2 episodes of acute pancreatitis are allowed, one of them the present episode)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Dr. Balmis General University Hospital | Alicante | Spain | 03010 |
Sponsors and Collaborators
- Enrique de-Madaria
- Instituto de Salud Carlos III
- Universidad Miguel Hernandez de Elche
- Hospital del Mar
- Hospital Clinico Universitario de Santiago
- Hospital Clínico Universitario de Valencia
- Hospital Costa del Sol
- Corporacion Parc Tauli
- Hospital Clínico Universitario Lozano Blesa
- Hospital General Universitario Gregorio Marañon
- Hospital Universitario La Fe
- Hospital Miguel Servet
- Hospital Universitario Ramon y Cajal
- Hospital Universitario Insular Gran Canaria
- University Hospital Virgen de las Nieves
- Hospital Universitario de Burgos
- Hospital Universitario Lucus Augusti
- Hospital Universitario Marqués de Valdecilla
- Hospital Universitario Puerta del Mar
- Instituto de Investigación Sanitaria Hospital Universitario de la Princesa
- Dr. Negrin University Hospital
Investigators
- Principal Investigator: Enrique de-Madaria, MD PhD, Dr. Balmis General University Hospital
Study Documents (Full-Text)
None provided.More Information
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.
- 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.
- Eudract 2023-000010-18