Ggressive or Moderate Fluid Resuscitation in Acute Pancreatitis

Clinical Question In patients with acute pancreatitis, does early aggressive fluid resuscitation with lactated Ringer’s solution improve clinical outcomes?

Bottom Line Early aggressive fluid resuscitation with lactated Ringer’s solution did not reduce the incidence of moderate or severe pancreatitis and increased the risk of hypervolemia compared to moderate fluid resuscitation.

Major Points Pancreatitis is the result of inflammation of the pancreas leading to persistent abdominal pain and elevation in pancreatic enzymes, most commonly in response to gallstones or chronic alcohol use. Pancreatitis is the leading cause of gastrointestinal related hospitalization in the United States with a mortality rate approaching 5%1,2. Management is focused on fluid resuscitation, pain control, and close monitoring of laboratory values and hemodynamics. Previous clinical trials and case reports have demonstrated conflicting evidence comparing the effective volume of fluid administration in the treatment of pancreatitis.

WATERFALL is a randomized, multicentered, open label trial comparing aggressive and moderate fluid resuscitation in the treatment of pancreatitis. Aggressive fluid resuscitation was defined as a bolus of 20 ml per kilogram of body weight, followed by 3 ml per kilogram per hour, whereas moderate fluid resuscitation was defined as a bolus of 10 ml per kilogram in patients with hypovolemia or no bolus in patients with normovolemia, followed by 1.5 ml per kilogram per hour. During hospitalization, patients were assessed at 12, 24, 48, and 72 hours, and fluid resuscitation was adjusted according to the patient’s clinical status including monitoring for signs of fluid overload. The primary outcome was the development of moderately severe to severe pancreatitis according to the Revised Atlanta Classification. The primary safety outcome was the development of fluid overload as determined by signs or symptoms consistent with hypervolemia.

The trial was stopped early due to safety concerns involving the development of fluid overload and no significant difference between groups in the progression to moderately severe or severe pancreatitis. The primary outcome occurred in 22.1% with aggressive resuscitation versus 17.3% with moderate resuscitation (ARR 1.30; 95% CI 0.78-2.18; P=0.32). The primary safety outcome occurred in 20.5% with aggressive resuscitation versus 6.3% with moderate resuscitation (ARR 2.85; 95% CI 1.36-5.94; P=0.004). Criticisms of the paper include being statistically underpowered due to not meeting sufficient patient enrollment and low incidence of moderately severe to severe pancreatitis among both groups. Future studies are warranted to investigate objective measures of volume status in order to optimize adequate fluid resuscitation without causing volume overload.

Guidelines As of April 2023, no guidelines have been published that reflect the results of this trial.

Design Trial type: multicenter, open-label, parallel-group, randomized, controlled, superiority trial N= 249 Experimental arm: 122 Standard: 127 Setting: 18 centers across four countries (India, Italy, Mexico, and Spain) Enrollment: January 2020-December 2022 Mean follow-up: 72 hours Analysis: Intention to treat Primary outcome: Development of moderately severe or severe acute pancreatitis according to the Revised Atlanta Classification during the hospitalization

Population 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 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) 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 Baseline Characteristics Demographics: Age 56, 51% female, BMI 27 Comorbidities: Diabetes 18.9% Median BISAP score: 1 Median PAN-PROMISE score: 31 (aggressive fluid resuscitation) and 27 (moderate fluid resuscitation) Median Urea: 32 mg/dL (aggressive fluid resuscitation) and 36 mg/dL (moderate fluid resuscitation) Median Hematocrit: 44% Median Creatinine: 0.8 mg/dL SIRS: 35 (aggressive fluid resuscitation) and 29 (moderate fluid resuscitation) Hypovolemia: 64 (aggressive fluid resuscitation) and 65 (moderate fluid resuscitation)

Interventions Aggressive fluid resuscitation consisted of a bolus of 20 ml per kilogram of body weight, followed by 3 ml per kilogram per hour. Moderate fluid resuscitation consisted of a bolus of 10 ml per kilogram in patients with hypovolemia or no bolus in patients with normovolemia, followed by 1.5 ml per kilogram per hour in all patients in this group.

Patients were randomly assigned 1:1 to receive aggressive fluid resuscitation or moderate fluid resuscitation

Patients were assessed at 12, 24, 48, and 72 hours, and fluid resuscitation was adjusted according to the patient’s clinical status.

Outcomes Primary Outcome Development of moderate to severe pancreatitis 22.1% with aggressive resuscitation versus 17.3% with moderate resuscitation (ARR 1.30; 95% CI 0.78-2.18; P=0.32)

Primary Safety Outcome Development of fluid overload 20.5% with aggressive resuscitation versus 6.3% with moderate resuscitation (ARR 2.85; 95% CI 1.36-5.94; P=0.004)

Secondary Outcomes Development of organ failure: 7.4% with aggressive resuscitation versus 3.9% with moderate resuscitation (ARR 1.23; 95% CI 0.47-3.23) Development of persistent organ failure 6.6% with aggressive resuscitation versus 1.6% with moderate resuscitation (ARR 2.69; 95% CI 0.56-12.88) Local complications 20.5% with aggressive resuscitation versus 16.5% with moderate resuscitation (ARR 1.28; 95% CI 0.74-2.22) Necrotizing pancreatitis 13.9% with aggressive resuscitation versus 7.1% with moderate resuscitation (ARR 1.95; 95% CI 0.87-4.38) Respiratory failure 7.4% with aggressive resuscitation versus 2.4% with moderate resuscitation (ARR 2.19; 95% CI 0.63-7.64) Admittance to Intensive Care Unit 6.6% with aggressive resuscitation versus 1.6% with moderate resuscitation (ARR 2.71; 95% CI 0.64-11.51) Subgroup Analysis Baseline hypovolemia and baseline SIRS did not differ significantly between groups. Persistence of SIRS >48 hours was not performed due to low number of patients (n=17). Adverse Events Median time to fluid overload 34 hours with aggressive resuscitation versus 46 hours with moderate resuscitation (P=0.18) Symptoms of fluid overload (dyspnea) 18.0% with aggressive resuscitation versus 7.9% with moderate resuscitation (ARR 1.85; 95% CI 0.95-3.61; P=0.08) Signs of fluid overload (peripheral edema, pulmonary rales, increased jugular venous distension) 26.2% with aggressive resuscitation versus 11.0% with moderate resuscitation (ARR 2.36; 95% CI 1.33-4.19; P=0.003)

Criticisms Open label bias in which blinding of treatments cannot be performed and reliance upon clinician assessment of volume status rather than objective measures Inadequate patient enrollment with goal of 350 patients per group to achieve 80% power Low incidence of moderate to severe pancreatitis with an anticipation of >35% of patients meeting this criteria prior to start of the trial Minimal separation between groups of 1.72 L of total volume received in 72 hours

Funding Supported by grants from Instituto de Salud Carlos III, the Spanish Association of Gastroenterology, and ISABIAL (Instituto de Investigación Sanitaria y Biomédica de Alicante).

Further Reading 1. Peery AF, Crockett SD, Murphy CC, et al. Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2018. Gastroenterology. 2019;156(1):254-272.e11. 2. Banks PA, Freeman ML, Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-2400.