Effect of Early Weight-based Aggressive Versus Non-aggressive Goal-directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis: an Open-label Multicenter Randomized-controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 249
- 试验地点
- 2
- 主要终点
- Moderate-to-severe acute pancreatitis
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Aggressive fluid resuscitation
Lactated Ringer Solution 20 ml/kg bolus (administered over 2 hours) followed by an infusion of 3 ml/kg/h.
At 12(±4) hours:
A) Hypovolemia: same bolus and infusion B) No hypovolemia: infusion of lactated Ringer Solution 1.5 ml/kg/h C) Fluid overload: infusion rate of lactated Ringer Solution will be decreased or stopped
Similar adjustments are repeated at 24(±4), 48(±4) and 72(±4) hours
Fluid resuscitation is maintained at least 48h, and then it can be stopped in case of tolerating oral feeding for at least 8 hours
干预措施: Lactated Ringer Solution (Drug)
Moderate fluid resuscitation
At recruitment:
A) Hypovolemia: Lactated Ringer Solution 10 ml/kg bolus (administered over 2 hours) followed by an infusion of 1.5 ml/kg/h.
B) No hypovolemia: infusion of lactated Ringer Solution of 1.5 ml/kg/h (no bolus).
At 12(±4) hours:
A) Hypovolemia: same bolus and infusion B) No hypovolemia: infusion of lactated Ringer Solution 1.5 ml/kg/h C) Fluid overload: infusion rate of lactated Ringer Solution will be decreased or stopped
Similar adjustments are repeated at 24(±4), 48(±4) and 72(±4) hours
Fluid resuscitation can be stopped before the first 48h in case of tolerating oral feeding for at least 8 hours
干预措施: Lactated Ringer Solution (Drug)
结局指标
主要结局
Moderate-to-severe acute pancreatitis
时间窗: From admission to discharge, up to 24 weeks
Moderate or severe category of the Revised Atlanta Classification (Banks et al, Gut 2013)
次要结局
- PAN-PROMISE scale(At 12, 24, 48 and 72 hours)
- Shock(From admission to discharge, up to 24 weeks)
- Local complications (acute peripancreatic fluid collections/ pancreatic necrosis/peripancreatic necrosis)(From admission to discharge, up to 24 weeks)
- C-reactive protein(48 and 72 hours)
- Death and/or persistent organ failure and/or infection of pancreatic necrosis(From admission to discharge, up to 24 weeks)
- Length of hospital stay(From admission to discharge, up to 24 weeks)
- Need for nutritional support(From admission to discharge, up to 24 weeks)
- Kidney failure(From admission to discharge, up to 24 weeks)
- Fluid overload(From admission to discharge, up to 24 weeks)
- Respiratory failure(From admission to discharge, up to 24 weeks)
- Intensive care unit stay(From admission to discharge, up to 24 weeks)
- Need for invasive treatment(From admission to discharge, up to 24 weeks)
- Systemic inflammatory response syndrome (SIRS)(Baseline, 12, 24, 48 and 72 hours)
研究者
Enrique de-Madaria
Principal Investigator of the AUGH Clinical Pancreatology Research Group
Hospital General Universitario de Alicante