Experimental participants and controls
We enrolled patients in 18 centers in four countries (India, Italy, Mexico, and Spain) in this multicenter, open-label, parallel-group, randomized, controlled, superiority trial. A previously published full trial protocol;16 The full text of this article is available at NEJM.org.
Consecutive patients (≥18 years) with a diagnosis of acute pancreatitis according to the modified Atlanta classification (which requires fulfilling two of the following three criteria: typical abdominal pain, serum amylase or lipase level greater than 3 times the upper limit. than the normal range or acute on imaging symptoms of pancreatitis) were assessed for eligibility.17 The trial included patients who presented to the emergency room no later than 24 hours after the onset of pain and who received a diagnosis no later than 8 hours before enrollment. At baseline (shock, respiratory distress, and renal failure) or incipient heart failure (New York Heart Association functional class II, III, or IV), uncontrolled arterial hypertension, hypernatremia, patients meeting criteria for moderate or severe disease, hyponatremia , hyperkalemia, hypercalcemia, life expectancy less than 1 year, chronic pancreatitis, chronic renal failure, or debilitating cirrhosis were excluded (see the Supplementary Appendix, available at NEJM.org).
The trial protocol followed the SPIRIT (Standard Protocol Materials: Recommendations for Interventional Trials) guidelines.18 and the principles of the Declaration of Helsinki.19 All patients provided written informed consent. An independent data and safety monitoring board consisted of a clinical pharmacologist, a gastroenterologist and a cardiologist.16
The first three authors and the last author designed the experiment. The first three authors and the fifth and seventh authors obtained the data and performed the data analysis. The first author vouches for the completeness and accuracy of the data and the fidelity of the trial to the protocol.
Patients were randomly assigned in a 1:1 ratio to receive aggressive fluid resuscitation (aggressive-respiratory group) or moderate fluid resuscitation (moderate-respiratory group) using a computerized central randomization system integrated in a web-based electronic database. -Report form (REDCap).20 The order of randomization was concealed from the experimental group. Randomization was performed by trial center, presence or absence of SIRS, and presence or absence of baseline hypovolemia.16 The patients and the investigators were aware of the assigned experimental groups.
In the aggressive-resuscitation group, 20 ml of Ring’s solution per kilogram of body weight was administered over a period of 2 hours, then 3 ml per kilogram per hour. In the intermediate rehabilitation group, patients were given 1.5 ml of Ringer’s solution per kilogram per hour (without a bolus in patients without hypovolemia or after receiving a bolus of 10 ml per kilogram administered over a period of 2 hours in patients with hypovolemia). Fluid doses and doses were based on a previous randomized trial in acute pancreatitis.13
Patients with acute pancreatitis were randomized to goal-directed intensive or moderate fluid sedation with infused Ringer’s solution.
To evaluate fluid overload in both experimental groups, we performed an initial physical evaluation at 3 hours and then biochemical and physical evaluations at 12, 24, 48, and 72 hours. At these checkpoints, goal-directed resuscitation is modulated (Figure 1) hypovolemia, normovolemia, or suspicion of fluid overload (see definitions in the Supplementary Appendix). In both groups, if there is a suspicion of fluid overload, hydration is reduced or stopped; This strategy is tailored to the extent of fluid overload and patient-specific characteristics.
In acute pancreatitis (PAN-PROMISE), the severity of abdominal pain as measured by the patient-reported score scale begins at 12 hours after oral feeding.21 It was below 5 (range, 0 to 10 for each symptom; total range 0 to 70, with higher symptoms having higher symptoms). Liquid sedation can be stopped if the patient can tolerate oral feedings for 8 hours; In the moderate-resuscitation group, this could occur within 20 hours of randomization and 48 hours after randomization in the aggressive resuscitation group.
The primary outcome was the development of moderate or severe acute pancreatitis (according to the revised Atlanta classification) during hospitalization. Moderate or severe acute pancreatitis was defined as meeting at least one of the following criteria in the revised Atlanta classification: local complications, worsening of a preexisting condition, creatinine level of at least 1.9 mg per deciliter (170 μmol per liter). A systolic blood pressure and arterial oxygen partial pressure (Pa) below 90 mmHg despite fluid resuscitation.oh2) to inspired oxygen fraction (FAyo2) not exceeding 300 (see the Supplementary Appendix).17
Secondary outcomes described included organ failure and environmental complications after the emergency and in-hospital (see Supplementary Appendix).16, 17 Additional defined secondary outcomes were length of hospital stay; Intensive care unit (ICU) admission; Number of days in the ICU; Use of nutritional support or invasive treatment after an accident and during hospitalization; The presence of SIRS at each inspection site (see below).14; persistent SIRS (lasting > 48 hours in the first 72 hours after randomization); The amount of C-reactive protein in the blood at 48 hours and at 72 hours; death Concomitant death results, persistent organ failure (lasting more than 48 hours), or infected necrotizing pancreatitis.10; And signs are measured using the PAN-PROMISE meter at the entrance and at each checkpoint.21 SIRS is defined as meeting at least two of the following criteria: a white cell count less than 4000 per cubic millimeter or a heart rate greater than 12,000 greater than 90 beats per minute, a respiratory rate greater than 20 breaths per minute, or a partial pressure of carbon dioxide less than 32 mmHg. or a body temperature below 36°C or above 38°C.14
The primary safety outcome – post-randomization and in-hospital fluid overload – required to meet at least two of the following three criteria: disease symptoms, physical symptoms and imaging evidence of hypervolemia; In addition, acute respiratory distress syndrome had to be excluded (see the Supplementary Appendix). Inconsistently obtained or interpreted criteria at individual trial sites to ensure reproducibility, including S auscultation.3 or S4, orthostatic variables and effusions on chest radiography (often suggestive of acute pancreatitis) were not used. If the fluid overload is responsive to medical therapy or if it reduces the amount of moisture and the ratio of Paoh2 For FAyo2 It never dropped below 300; If it is moderately responsive to medical therapy or decreased hydration, but paoh2 For FAyo2 At least once it was below 300; and if severe mechanical ventilation or hemophilization is indicated.
The predicted incidence of moderate or severe acute pancreatitis is 35%.1 A sample size of 744 with 372 patients in each group provides 80% power for the test to detect a difference of 10 percentage points between groups (between 35% and 25%) with a two-sided significance level (alpha) of 0.05, with 10% of patients expected to drop out. Two interim analyzes were planned after enrollment of one-third and two-thirds of patients (248 and 496, respectively); Therefore, the sample-size calculation was calculated using the O’Brien-Fleming cost function for three consecutive experiments. There were three a priori stopping rules: a two-sided P value of less than 0.0002 in the primary outcome in the first interim analysis or less than 0.012 in the second interim analysis, clear evidence of harm in one experimental group over the other (safety) as defined by the Data and Safety Monitoring Board. and slow recruitment rates.16
The intended-to-treat population included all patients who were randomized, and the trial data were analyzed according to the planned-to-treat principle. Normality was assessed by the Shapiro-Wilk test. Categorical variables are reported as counts and percentages, and continuous variables as means with standard deviations or interquartile ranges. Differences in continuous variables were compared using Student’s t-test or Mann–Whitney U test. Categorical results were compared using the chi-square test (with Fisher’s correction when required) and expressed as relative risk with corresponding 95% confidence intervals. As a post-hoc analysis, the Cochran–Mantel–Hanszel method was used for randomization stratification conditions (center, presence or absence of baseline, and presence or absence of baseline) for a more robust analysis.22 with adjusted relative risks and corresponding 95% confidence intervals.
A two-sided P value of less than 0.05 was considered to indicate statistical significance for the primary efficacy outcome and safety outcome. Because the statistical analysis plan did not include a provision for multiplicity adjustment when tests of secondary or other outcomes were performed, results were reported as point estimates with 95% confidence intervals. The widths of the confidence intervals were not adjusted for multiplicity, so the intervals should not be used to distinguish between true treatment effects for secondary outcomes.
Variables with missing values were subjected to both complete case analysis and imputation analysis after applying the multiple-imputation technique (see the Supplementary Appendix). All results and statistical analyzes are described in the experimental protocol;16 Except for multiple assumptions to correct for missing data and randomization conditions of the Cochran–Mantel–Haenszel method. Prespecified subgroup analyzes of efficacy and safety outcomes16 They were performed to determine the impact of baseline hypovolemia and SIRS, because an early fluid resuscitation strategy may have a greater impact in patients with or without these factors.13:23 Analyzes were performed with SPSS software, version 28.0 (IBM); SAS software, version 9.4 (SAS Institute); and R software, version 4.1.2.