The primary objective of this trial is to determine whether, compared to ARS, BRS can better maintain acid-based status as reflected by the change in standard base excess (SBE) levels in patients undergoing orthotopic liver transplantation.

Secondary objectives are to assess the impact of BRS on renal function and other clinical outcomes like the number of days alive and free of intensive care admission, invasive ventilation, vasopressors, and renal replacement therapy (RRT) to day 14 after operation. Laboratory results like bicarbonate, creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels will also be compared.

The present study is an investigator-initiated, single-centre, superiority, randomised controlled trial. This trial was registered at the Chinese Clinical Trials Registry (ChiCTR2100046889).

A Trial Management Committee (TMC) was formed, comprising the principal investigator and all the other co-investigators (clinical and non-clinical). The TMC is responsible for the day-to-day running of the trial. A writing and publication committee was organised for drafting the manuscript and submission of the manuscript to proper academic journals. It will also decide on the authorship of this study. An independent data safety and monitoring board (DSMB) consisting of a surgeon, an anesthesiologist, and a statistician will be organised to oversee all subjects' safety. The DSMB will review the safety report regularly and have the right to stop the trial early because of concerns about participant safety. DSMB members will not be involved in the study conduct, and all the processes will be independent of the investigators.

All adult patients undergoing orthotopic liver transplantation surgery admitted to the Jinling Hospital, Nanjing University, will be assessed for eligibility after admission. The inclusion and exclusion criteria are as follows:

The randomisation sequence will be generated by an independent statistician using SAS Version 9.4 with a fixed block size (block size = 4). Randomisation will be stratified by the surgical methods adopted (classical orthotopic liver transplantation vs. piggyback orthotopic liver transplantation). Allocation will be in a 1:1 ratio.

Due to the specific double-packaging of bicarbonated Ringer's solution for stabilising the concentration of bicarbonate radical, blinding to investigators will not be applicable. However, research personnel, ICU staff and other caregivers will not have access to the randomisation schedule. Allocation concealment will be maintained by using a secure, password-protected study website to randomise consenting patients.

The only difference between the two study groups exists in the choice of perioperative intravenous isotonic crystalloid: bicarbonated Ringer's solution (BRS group) vs. acetated Ringer's solution (ARS group). The compositions of each crystalloid solution are displayed in Supplementary Table S1. •

Group 1: BRS group

Patients will receive bicarbonate Ringer's solution for fluid therapy during and within 48 h post operation.

First, both groups received general standard of care involving the following key components (27). The operating room temperature will be set at 22°C and standard warming measures be used for all patients. All patients will receive standard general anaesthesia induced by midazolam, sufentanil, etomidate, cisatrcurium and maintained by propofol, remifentanil, sevoflurane and additional injection of sufentanil. An arterial line and a central venous catheter will be inserted before induction of anaesthesia. Mechanical ventilation will be performed routinely. During the perioperative period, all patients will receive intravenous fluids according to a standardised protocol, which includes basiliximab, antibiotics, esomeprazole and methylprednisolone. Transfusions will be administered at the discretion of the attending anaesthetist according to the National Blood Transfusion guidelines.

Throughout the operation, arterial blood gas will be measured every 60 min during the dissection phase, every 30 min during the anhepatic phase (including a 5-min pre-reperfusion blood gas) and every 30 min during the neohepatic phase for 1 h (including a 5-min post-reperfusion blood gas), then hourly until surgical closure. When pH is less than 7.2 or SBE is less than −10 mmol/L, additional 5% sodium bicarbonate will be infused with a total amount of 5% NaHCO₃(ml) = (−2.3-SBE)*weight (kg)*0.42 to correct acidosis. The infusion will be started at a rate of 90 ml/h and discontinued with a targeted pH level of 7.35.

When the operation is completed, all the patients will be transferred to the surgical Intensive Care Units for postsurgical care. Both groups will receive standard treatment according to the guidelines after admission (27), including continuous vital signs recording, adequate fluid therapy, routine medical treatment (blood glucose control, antibiotics if needed and sedatives if required), organ support measures, etc. Organ failure would be assessed on a daily basis according to the SOFA score.

Initiation of RRT should be based on the criteria described by Bellomo et al. (28). Patients who have AKI (at least 1.5 times increase in creatinine from known baseline value) and meet predefined specific criteria will be eligible for initiation of RRT.

A web-based electronic database (Unimed Scientific, Wuxi, China) is used for data collection and storage. All data are input by the designated coordinator. Training for data entry was arranged by the provider of the electronic database before study commencement. The data required to be collected during different phases are shown in Figure 1.

The principal investigator will be responsible for data management, safety, privacy, and quality. The reporting and presentation of this trial will follow the CONSORT guidelines (29). Based on the principle of intention to treat (ITT), a full-analysis set (FAS) will be performed on the population with outcome reporting. FAS will be used for the analysis of baseline characteristics and main therapeutic interventions. The safety set (SS) will include all enrolled patients to assess the safety profile of the study intervention.

According to the previous study (30) and our unpublished data, the change of SBE during operation is approximately −2 mmol/L with a standard deviation of 2.5 mmol/L in patients receiving ARS. We estimated that a sample size of 72 participants (36 per group) could provide 80% power at a two-sided alpha level of 0.05 to detect ≥1.7 mmol/L increase in the primary endpoint results from the use of BRS with a potential loss of 5% recruitments.

Descriptive statistics will be used to assess any marked baseline differences in demographics or outcome measures between the two groups. Comparisons of binary outcomes will be expressed as relative risk with 95% confidence intervals and comparisons of continuous outcomes as mean differences together with 95% confidence intervals. Comparisons will be made using t-test and ANOVA for repeated-measures or Wilcoxon rank-signed test and Kruskall-Wallis according to the underlying distribution for continuous data and Chi-square or Fisher's exact T test for categorical data, as appropriate. Two-sided 5% significance levels will be used to identify statistically significant results. All confidence intervals reported will be 95% confidence intervals.

All adverse events (AE) are required to be recorded and the DSMB will review all the safety profiles regularly during the study period. AEs will be reported in a uniform format through the electronic data capture system. The detection and report of the AEs will depend on the physicians involved in this trial.

Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research.