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

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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[5]. 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[6]. The development of AKI is due to multiple factors[7-14], one of which is intraoperative and postoperative infusion of supraphysiologic chlorinated liquids[15].

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[16]. 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.[17].

However, the ideal crystalloid during liver transplantation remains uncertain[18]. 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)[23], which, as shown in the SMART trial,  could reduce adverse kidney events in critically ill patients when compared with NS[24].

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)[25]. During liver transplantation, liver metabolism is suspended during the anhepatic phase and severely compromised during the early neohepatic phase[26], 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[26]. 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.

 

Population

Inclusion Criteria

  1. Recipients undergoing liver transplant surgery;
  2. Age≥18 years.

Exclusion Criteria

  1. Combined transplantation;
  2. Patients receiving RRT within 1 week before operation;
  3. 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);

References

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  2. Karapanagiotou, A., et al., Acute kidney injury after orthotopic liver transplantation. Transplant Proc, 2012. 44(9): p. 2727-9.
  3. 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.
  4. 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.
  5. Barri, Y.M., et al., Acute kidney injury following liver transplantation: definition and outcome. Liver Transpl, 2009. 15(5): p. 475-83.
  6. 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.
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  20. 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.
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  23. Yunos, N.M., et al., Bench-to-bedside review: Chloride in critical illness. Crit Care, 2010. 14(4): p. 226.
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  31. 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.