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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05781243

Acronym

WATERLAND

Enrollment

792

Registered

2023-03-23

Start date

2023-06-19

Completion date

2024-09-30

Last updated

2025-01-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Acute Pancreatitis

Keywords

Normal saline, Lactated Ringer solution, Acute pancreatitis, Fluid Therapy, Fluid resuscitation

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

Interventions

DRUGLactated 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.

DRUGNormal 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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)

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants with moderately severe or severe acute pancreatitis	From date of randomization until 30 days after randomization	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

Measure	Time frame	Description
Number of participants with necrotizing pancreatitis	From date of randomization until 30 days after randomization	Presence of acute necrotic collections according to the revised Atlanta Classification (https://doi.org/10.1136/gutjnl-2012-302779).
Number of participants with infection of pancreatic collections or necrosis	From date of randomization until 30 days after randomization	Extraluminal gas in the pancreatic and/or peripancreatic tissues on CT scan or when a sample from the collection/necrosis contains pus or is positive for bacteria and/or fungi on Gram stain or culture.
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 (final value and 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 date of randomization until 30 days after randomization	Days from baseline to oral refeeding
Number of participants with invasive treatment	From date of randomization until 30 days after randomization	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 30 days after randomization	Use of enteral (nasogastric or nasojejunal) or parenteral feeding
Number of participants with hyperchloremic acidosis	At 24 and 48 hours from randomization	Patients with venous chloride\>106mEq/L and venous blood pH \<7.35
Number of participants with intensive care unit admission	From date of randomization until 30 days after randomization	Admission in the intensive care unit
Number of participants with exacerbation of coexisting condition	From date of randomization until 30 days after randomization	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 30 days after randomization	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 30 days after randomization	Organ failure lasting more than 48h (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)
Number of participants with local complications	From date of randomization until 30 days after randomization	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 respiratory failure	From date of randomization until 30 days after randomization	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 30 days after randomization	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 30 days after randomization	Death
Number of participants with composite safety outcome (primary safety outcome)	At 24 and 48 hours from randomization	Fluid overload or acute kidney injury or hyperkalemia or hypercalcemia or hyperchloremia or acidosis
Hospital stay	From date of randomization until 30 days after randomization	Days from recruitment to discharge from index admission
C-reactive protein	At 48 hours from randomization	C-reactive protein blood levels
Number of participants with hypovolemia	At 24 and 48 hours from randomization	WATERFALL trial criteria for hypovolemia (see https://www.nejm.org/doi/10.1056/NEJMoa2202884)
Number of participants with fluid overload	From randomization to 72 h thereafter	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 randomization	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 randomization	Venous potassium\>5mEq/L
Number of participants with hypercalcemia	At 24 and 48 hours from randomization	Venous calcium corrected by proteins\>10.5mg/dL or 2.62 mmol/L
Number of participants with hyperchloremia	At 24 and 48 hours from randomization	Venous chloride\>106mEq/L
Number of participants with acidosis	At 24 and 48 hours from randomization	Venous blood pH \<7.35
Number of participants with shock	From date of randomization until 30 days after randomization	Systolic blood pressure \<90 mmHg despite fluid resuscitation (revised Atlanta classification: https://doi.org/10.1136/gutjnl-2012-302779)

Countries

Spain

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Feb 5, 2026