02 Jan The effects of bicarbonated versus acetated Ringer’s solutions on acid-base state and kidney injury following orthotopic liver transplantation: protocol for a single-center, randomized controlled trial
Project abbreviation: BETTER trial
Overall trial start date: 01/06/2021
Overall trial end date: 01/03/2022
Background and Rationale
Acute kidney injury (AKI) is a common complication following liver transplantation, occurring in 29% to 60% of pateints[1-4]. Once it develops, regardless of the severity of AKI, it is significantly associated with increased mortality. A long-term cohort study conducted by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) showed that, compared with patients with normal renal function, those with AKI had a hazard ratio of one-year mortality up to 3.59. The development of AKI is due to multiple factors[7-14], one of which is intraoperative and postoperative infusion of supraphysiologic chlorinated liquids.
During liver transplantation, fluid therapy, including crystalloid and colloids, is considered the cornerstone of perioperative management to maintain normal blood volume and preserve renal perfusion. The RELIEF study shows that patients undergoing liver transplantation and other major abdominal surgeries had an average fluid infusion of 3500ml intraoperatively and 6146ml within 24 hours after the operation, respectively, and most of the intravenous fluids are crystalloid..
However, the ideal crystalloid during liver transplantation remains uncertain. By now, normal saline (NS, 0.9% sodium chloride) is most frequently used[19, 20]. Nevertheless, the chloride concentration of NS (154 mmol/L) is significantly higher than that of plasma (94-111 mmol/L), which may cause hyperchloric metabolic acidosis and impaired renal perfusion[21, 22]. A possible alternative is balanced solution(chloride limited crystalloid), which, as shown in the SMART trial, could reduce adverse kidney events in critically ill patients when compared with NS.
In practice, the most commonly used balanced crystalloids are buffered with organic anions, such as lactate, acetate, or malate, all of which require liver metabolism to increase strong ion difference(SID). During liver transplantation, liver metabolism is suspended during the anhepatic phase and severely compromised during the early neohepatic phase, thus organic anions based solution can not function properly, thereby inducing metabolic acidosis.
On the contrary, bicarbonated Ringer’s solution (BRS), introduced 11 years ago, directly replaces chloride with bicarbonate. It can increase SID regardless of liver metabolism. Previous pharmacokinetic studies showed that BRS could correct metabolic acidosis faster than lactated or acetated Ringer’s solution(ARS) in shock models. Taken together, compared with conventional organic anion based balanced solutions, BRS may better maintain acid-base status during liver transplantation, but no evidence exists in the literature.
In this study, we aim to compare the effect of BRS and ARS on acid-base status and renal function in patients undergoing liver transplantation. The results of this study could also provide data to power a confirmatory Phase III study in the future.
Aims and hypothesis
We aim to test the hypothesis that, in patients undergoing orthotopic liver transplantation, compared with acetate Ringer’s solutions(ARS), perioperative fluid therapy with bicarbonated Ringer’s solutions(BRS) would better maintain the acid-base state and protect renal function.
Primary outcome measures
The primary outcome is the difference of standard base excess(SBE) before and after operation.
- Recipients undergoing liver transplant surgery;
- Age≥18 years.
- Combined transplantation;
- Patients receiving RRT within 1 week before operation;
- Patients with increased serum creatinine (SCr) levels within 1 week before operation (Defined as SCr increased by more than 1.5 times or 26.5μmol/L (0.3mg/dL) from baseline. Baseline was defined as SCr levels obtained within six months, if not availablethe upper limit of normal was set for baseline at 90μmol/L for female /110μmol/L for male);
- Zhu, M., et al., Strong impact of acute kidney injury on survival after liver transplantation. Transplant Proc, 2010. 42(9): p. 3634-8.
- Karapanagiotou, A., et al., Acute kidney injury after orthotopic liver transplantation. Transplant Proc, 2012. 44(9): p. 2727-9.
- O’Riordan, A., et al., Acute renal disease, as defined by the RIFLE criteria, post-liver transplantation. Am J Transplant, 2007. 7(1): p. 168-76.
- Hu, J., et al., Global Incidence and Outcomes of Adult Patients With Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-Analysis. J Cardiothorac Vasc Anesth, 2016. 30(1): p. 82-9.
- Barri, Y.M., et al., Acute kidney injury following liver transplantation: definition and outcome. Liver Transpl, 2009. 15(5): p. 475-83.
- Watt, K.D., et al., Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant, 2010. 10(6): p. 1420-7.
- Wang, Y. and R. Bellomo, Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol, 2017. 13(11): p. 697-711.
- Pawarode, A., D.M. Fine and P.J. Thuluvath, Independent risk factors and natural history of renal dysfunction in liver transplant recipients. Liver Transpl, 2003. 9(7): p. 741-7.
- Chen, J., et al., Postliver transplant acute renal injury and failure by the RIFLE criteria in patients with normal pretransplant serum creatinine concentrations: a matched study. Transplantation, 2011. 91(3): p. 348-53.
- Sanchez, E.Q., et al., Preoperative and perioperative predictors of the need for renal replacement therapy after orthotopic liver transplantation. Transplantation, 2004. 78(7): p. 1048-54.
- Bilbao, I., et al., Risk factors for acute renal failure requiring dialysis after liver transplantation. Clin Transplant, 1998. 12(2): p. 123-9.
- Lima, E.Q., et al., Risk factors for development of acute renal failure after liver transplantation. Ren Fail, 2003. 25(4): p. 553-60.
- Lebron, G.M., et al., Risk factors for renal dysfunction in the postoperative course of liver transplant. Liver Transpl, 2004. 10(11): p. 1379-85.
- Cabezuelo, J.B., et al., Risk factors of acute renal failure after liver transplantation. Kidney Int, 2006. 69(6): p. 1073-80.
- Nadeem, A., et al., Chloride-liberal fluids are associated with acute kidney injury after liver transplantation. Crit Care, 2014. 18(6): p. 625.
- Myles, P., et al., Restrictive versus liberal fluid therapy in major abdominal surgery (RELIEF): rationale and design for a multicentre randomised trial. BMJ Open, 2017. 7(3): p. e015358.
- Myles, P.S., et al., Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. N Engl J Med, 2018. 378(24): p. 2263-2274.
- Schumann, R., et al., Intraoperative fluid and pharmacologic management and the anesthesiologist’s supervisory role for nontraditional technologies during liver transplantation: a survey of US academic centers. Transplant Proc, 2013. 45(6): p. 2258-62.
- IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology, 2013. 13(4 Suppl 2): p. e1-15.
- Rhodes, A., et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med, 2017. 43(3): p. 304-377.
- Suetrong, B., 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): p. 315.
- Ke, L., et al., Systemic and renal haemodynamic effects of fluid bolus therapy: sodium chloride versus sodium octanoate-balanced solution. Crit Care Resusc, 2014. 16(1): p. 29-33.
- Yunos, N.M., et al., Bench-to-bedside review: Chloride in critical illness. Crit Care, 2010. 14(4): p. 226.
- Semler, M.W., et al., Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med, 2018. 378(9): p. 829-839.
- Guidet, B., et al., A balanced view of balanced solutions. Crit Care, 2010. 14(5): p. 325.
- Satoh, K., et al., Pharmacological study of BRS, a new bicarbonated Ringer’s solution, in haemorrhagic shock dogs. Eur J Anaesthesiol, 2005. 22(9): p. 703-11.
- Millson, C., et al., Adult liver transplantation: UK clinical guideline – part 2: surgery and post-operation. Frontline Gastroenterol, 2020. 11(5): p. 385-396.
- Ronco, C., R. Bellomo and J.A. Kellum, Acute kidney injury. Lancet, 2019. 394(10212): p. 1949-1964.
- Hemming, K., et al., Reporting of stepped wedge cluster randomised trials: extension of the CONSORT 2010 statement with explanation and elaboration. BMJ, 2018. 363: p. k1614.
- Weinberg, L., et al., Sodium bicarbonate infusion in patients undergoing orthotopic liver transplantation: a single center randomized controlled pilot trial. Clin Transplant, 2016. 30(5): p. 556-65.
- Chowdhury, A.H., et al., A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg, 2012. 256(1): p. 18-24.