06 Jan Balanced Crystalloids versus saLine in prEdicted seVERe Acute Pancreatitis patients: a multicenter, stepped-wedge, cluster-randomized, controlled trial
Project abbreviation: clever-ap research
Overall trial start date: 01/04/2021
Overall trial end date: 31/3/2022
Background and Rationale
The leading determinant responsible for high mortality in patients with severe acute pancreatitis (SAP) is organ failure. Kidney tends to be involved in the early course of SAP due to both anatomical adjacency and early compromised renal perfusion caused by hypovolemia and persistent inflammation [2-3]. It has been reported that 25%-59.5% of patients developed acute kidney injury (AKI) during the course of SAP [4-5]. Previous guidelines for the management of AP suggested that timely and adequate fluid therapy in acute phase is pivotal for maintaining sufficient intravascular volume and perfusion in remote organs such as kidney [6-8]. Currently, saline (0.9% sodium chloride; “normal saline”) is the most commonly used isotonic crystalloid in fluid resuscitation for SAP patients all over the world . However, the chloride concentration of saline (154 mmol per liter) is significantly higher than that of human plasma (94 to 111 mmol per liter), which means infusion of saline could potentially cause hyperchloremic metabolic acidosis depending on the rate and volume of fluid infusion, which may increase inflammation and impair renal perfusion through multiple mechanisms. Although the clinical significance of these physiological effects is not fully understood yet, accumulating evidence suggests that the supraphysiologic chloride concentration of saline may contribute to kidney injury in critically ill patients [11-12], but no solid evidence exists in SAP patients.
Most guidelines for AP currently recommend balanced crystalloid solution like Lactated Ringers(LR) for early resuscitation, which are based on the studies showing that LR dampens the inflammatory response in acute pancreatitis as measured by SIRS and CRP at 24 hours[13-15]. However, studies focusing on the effect of different crystalloids on plasma chloride concentration, renal function in SAP patients are rare in the literature. In our previous study, we found that aggressive resuscitation and chloride exposure in the first 24 hours were risk factors of new-onset AKI in moderate-SAP and SAP patients . Therefore, a well-designed, sufficiently-powered clinical study assessing the impact of balanced crystalloids versus saline on plasma chloride concentration, renal function in SAP patients is warranted. As SAP can not be defined early during the disease, we use predicted severe acute pancreatitis(PSAP) patients as our study population.
Aims and hypothesis
We aimed to evaluate the effects of balanced crystalloids versus saline on plasma chloride concentration in predicted severe acute pancreatitis patients. Renal function and clinical outcomes will also be compared between groups. The hypothesis is that balanced crystalloids can reduce the plasma chloride concentration at day3 compared to saline.
Primary outcome measures
The primary outcome measure is plasma chloride concentration at day3 (the day of enrollment will be set as day 1).
- Symptoms and signs of acute pancreatitis based on abdominal pain suggestive of AP, serum amylase at least three times the upper limit of normal, and/or characteristic findings of AP on computed tomography;
- Within 72 hours from the onset of the disease;
- Age between 18 to 70 years old;
- APACHEII≥8 and CRP>150mg/L.
- Patients who are pregnant or lactating at the time of enrollment.
- Patients who receive percutaneous drainage for pancreatic necrosis or surgery before admission or require emergency surgery due to abdominal compartment syndrome, etc.
- Patients who undergo RRT before admission;
- Patients who need RRT at admission for life-threatening changes in fluid, electrolyte, and acid-base balance exist.;
- Patients who present with respiratory failure, severe systemic circulatory failure, coma, or other dangerous symptoms that were difficult to reverse and who were predicted to die within 24 hours (under full-fluid resuscitation and norepinephrine usage at a dose of 25 mg/min or more, with a systolic blood pressure <90mm Hg and serum pH values <7.0);
- Patients with a known history of severe cardiovascular, respiratory, renal, hepatic, hematologic, or immunologic disease defined as (1) greater than New York Heart Association class II heart failure, (2) active myocardial ischemia or (3) cardiovascular intervention within previous 60 days, (4) history of cirrhosis or (5) chronic kidney disease with creatinine clearance< 40 mL/min, or (6) chronic obstructive pulmonary disease with requirement for home oxygen;
- Nicolien J Schepers, Olaf J Bakker, Marc G Besselink. Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis. Gut. 2019, 68 (6) 1044-1051.
- Scurt FG, Bose K, Canbay A, et al.Acute kidney injury following acute pancreatitis (AP-AKI): Definition, Pathophysiology, Diagnosis and Therapy. Z Gastroenterol. 2020;58(12):1241-1266.
- Tareq I Nassar, Wajeh Y Qunibi. AKI Associated with Acute Pancreatitis. Clin J Am Soc Nephrol. 2019;14(7):1106-1115.
- Jiaojiao Zhou, Yi Li, Yi Tang, et al. Effect of acute kidney injury on mortality and hospital stay in patient with severe acute pancreatitis. Nephrology. 2015;20(7):485-91.
- Li H, Qian Z, Liu Z, et al. Risk factors and outcome of acute renal failure in patients with severe acute pancreatitis. J Crit Care 2010; 25(2):225-9.
- Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 2013; 13(4 Suppl 2):e1-15.
- SD Crockett, S Wani, TB Gardner, et al.American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. Gastroenterology. 2018;154(4):1096-1101.
- Yokoe M, Takada T, Mayumi T, et al. Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015. J Hepatobiliary Pancreat Sci. 2015;22(6):405-32.
- Myburgh JA. Fluid resuscitation in acute medicine: What is the current situation? J Intern Med 2015; 277: 58–68.
- Suetrong B, Pisitsak C, Boyd JH, et al. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care 2016; 20(1):315.
- Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med 2018; 378(9):829-839.
- Wesley H Self, Matthew W Semler, Jonathan P Wanderer, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018;378(9):819-828.
- Bechien U Wu 1, James Q Hwang, Timothy H Gardner, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-717.e1.
- Enrique de-Madaria, Gema Soler-Sala, José Sánchez-Payá, et al. Influence of fluid therapy on the prognosis of acute pancreatitis: a prospective cohort study. Am J Gastroenterol. 2011;106(10):1843-50.
- Alice Lee, Christopher Ko, Carlos Buitrago, et al. Lactated Ringers vs. Normal Saline Resuscitation for Mild Acute Pancreatitis: A Randomized Trial. Gastroenterology. 2020;S0016-5085(20)35362-2.
- Ye B, Mao W, Chen Y, et al. Aggressive Resuscitation Is Associated with the Development of Acute Kidney Injury in Acute Pancreatitis. Dig Dis Sci. 2019;64(2):544-552.
- Wenjian Mao, Jingyi Wu, He Zhang et al. Increase in serum chloride and chloride exposure are associated with acute kidney injury in moderately severe and severe acute pancreatitis patients. Pancreatology.2019;19(1):136-142.
- Bellomo R, Kellum J. A, Ronco C. Acute kidney injury. Lancet 2012, 380 (9843), 756-66.
- Karla Hemming, Monica Taljaard, Joanne E McKenzie et al. Reporting of stepped wedge cluster randomised trials: extension of the CONSORT 2010 statement with explanation and elaboration. BMJ. 2018;363:k1614.