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

Study Overview
=================
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.

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

Conditions
-----------------
Acute Pancreatitis

Intervention / Treatment
-----------------
* Drug: Lactated Ringer Solution
* Drug: Normal saline


Participation Criteria
=================
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 >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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lactated Ringer solution (LR)<br>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<br>* 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.<br>|
| Active Comparator: Normal saline (NS)<br>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<br>* Patients in the NS (Normal Saline) treatment arm will receive fluid therapy based on lactated Ringer's solution for a minimum of 48 hours.<br>|

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 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 | 
| 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) | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Normal saline, Lactated Ringer solution, Acute pancreatitis, Fluid Therapy, Fluid resuscitation