Acute Pancreatitis
Conditions
Keywords
Acute pancreatitis; fluid resuscitation; therapy; outcomes; randomized controlled trial; Ringer lactate; Lactated Ringer's solution
Brief summary
WATERFALL is an investigator-initiated international multicenter open-label randomized clinical trial comparing aggressive versus moderate fluid resuscitation in acute pancreatitis. The main outcome variable will be the proportion of patients with moderate-to-severe AP. Aggressive fluid resuscitation will consist in Lactated Ringer Solution (LR) 20 ml/kg bolus (administered over 2 hours) followed by LR 3 ml/kg/h and moderate a LR bolus 10 ml/kg in case of hypovolemia or no bolus in patients with normal volemia, followed by LR 1.5 ml/kg/h. The patients will be assessed at 3 (±1), 12 (±4), 24 (±4), 48 (±4) and 72 (±4) hours from recruitment, and fluid resuscitation will be adjusted to the patient´s clinical and analytical status according to a protocol. Subgroup analysis will include patients with systemic inflammatory response syndrome (SIRS) at admission, with persistent (\>48h) SIRS and with hypovolemia at admission. Based on available data (Sternby et al, Ann Surg 2019) we expect a 35% incidence of moderate to severe AP in the moderate arm. Sample sizes of 372 per arm of treatment (744 patients) achieve 80% power to detect a difference of 10% between the treatment arms at a significance level (alpha) of 0.05 using a two-sided z-testNA, assuming a 10% dropout. These results assume that 3 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries. All analyses will be performed on an intention-to-treat basis. The trial could be stop early for efficacy (primary end-point) if the observed two-sided P value is \<0.0002 at the first interim analysis (after 1/3 of patients have been enrolled) or is \<0.012 at second interim analysis (after 2/3 of patients have been enrolled), favoring aggressive fluid resuscitation. At final analysis, the hypothesis that the incidence of moderate-to-severe pancreatitis is similar in the two treatment arms will be rejected if p\<0.046
Interventions
Comparison of aggressive versus moderate Lactated Ringer-based fluid resuscitation
Sponsors
Instituto de Salud Carlos III
Asociación Española de Gastroenterología
Asociación Española de Pancreatología
Enrique de-Madaria
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients age greater or equal to 18 presenting to one of the collaborating centers * Diagnosis of acute pancreatitis according to the revised Atlanta classification which requires 2 of the following 3 criteria: A) Typical abdominal pain; B) Increase in serum amylase or lipase levels higher than 3 times the upper limit of normality; and C) Signs of AP in imaging.
Exclusion criteria
* Uncontrolled arterial hypertension (systolic blood pressure \>180 and/or diastolic blood pressure 100 mmHg); * New York Heart Association Class II hear 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); * Chronic kidney failure (basal glomerular filtration rate \<60 mL/min/1.73m2); * Clinical signs or symptoms of volume overload or heart failure at recruitment (dyspnea, peripheral edema, pulmonary rales, or evident increased jugular ingurgitation at 45º); * Shock or respiratory failure according to the revised Atlanta classification at recruitment (non-fluid responding systolic blood pressure\< 90 mmHg, PaO2/FIO2≤300 mmHg); * Time from pain onset to arrival to emergency room \>24h; * Time from confirmation of pancreatitis to randomization \>8h; * Severe comorbidity associated with an estimated life expectancy \<1 year; * Confirmed chronic pancreatitis (in case of recurrent alcoholic pancreatitis a recent (\<6 months) CT scan/MRI or endoscopic ultrasound is needed to rule out chronic pancreatitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Moderate-to-severe acute pancreatitis | From admission to discharge, up to 24 weeks | Moderate or severe category of the Revised Atlanta Classification (Banks et al, Gut 2013) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fluid overload | From admission to discharge, up to 24 weeks | Fluid overload is defined by the absence of Acute Respiratory Distress Syndrome and at least 2 of the following 3 criteria (based on Sharma et al, Lancet Diabetes Endocrinol 2016, with modifications): Criteria 1. Hemodynamic-imaging evidence (≥1): * Non-invasive diagnostic evidence of heart failure (i.e., echocardiographic, cardiac MRI) * Radiographic evidence of pulmonary congestion * Invasive cardiac catheterization suggesting evidence of heart failure (i.e., pulmonary capillary wedge pressure \[or left ventricular end-diastolic pressure\] \>18 mm Hg, right arterial pressure \[or central venous pressure\] \>12 mm Hg, or cardiac index \< 2·2 L/min per m2) Criteria 2. Heart failure symptoms (1): \- Dyspnea Criteria 3. Heart failure signs (≥1): * Peripheral edema * Pulmonary rales or crackles, or crepitation * Increased jugular venous pressure, hepatojugular reflux, or both |
| Shock | From admission to discharge, up to 24 weeks | Systolic blood pressure \<90 mmHg after fluid resuscitation |
| Respiratory failure | From admission to discharge, up to 24 weeks | PaO2/FIO2\<300 |
| Kidney failure | From admission to discharge, up to 24 weeks | Creatinine \>1.9 mg/dL |
| Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis) | From admission to discharge, up to 24 weeks | As described on the revised Atlanta classification, Banks et al, Gut 2013 |
| Length of hospital stay | From admission to discharge, up to 24 weeks | — |
| Death and/or persistent organ failure and/or infection of pancreatic necrosis | From admission to discharge, up to 24 weeks | Analyzed as a composite endpoint and each of its components, includes in-hospital mortality, persistent organ failure (according to the revised Atlanta classification, Banks et al, Gut 2013) or infection of pancreatic necrosis |
| Need for invasive treatment | From admission to discharge, up to 24 weeks | Endoscopic, percutaneous or surgical treatment of acute pancreatitis complications |
| Need for nutritional support | From admission to discharge, up to 24 weeks | Need for enteral/parenteral feeding |
| PAN-PROMISE scale | At 12, 24, 48 and 72 hours | Score on an acute pancreatitis Patient-Reported Outcome Measurement |
| C-reactive protein | 48 and 72 hours | Blood levels of C-reactive protein |
| Systemic inflammatory response syndrome (SIRS) | Baseline, 12, 24, 48 and 72 hours | SIRS at the different checkpoints. Presence of persistent (\>48h) SIRS |
| Intensive care unit stay | From admission to discharge, up to 24 weeks | Need for intensive care unit (ICU) admission, and days admitted in the ICU |
Countries
Spain
Outcome results
None listed