This single-centre, prospective randomized controlled study was conducted at Seoul St. Mary’s Hospital. Ethical approval was obtained from the Institutional Review Board and Ethics Committee of Seoul St. Mary’s Hospital (approval number: KC19MESI0573) on October 7, 2019. The trial was performed according to the Declaration of Helsinki. The protocol was prospectively registered at a publicly accessible clinical trial database recognized by the International Committee of Medical Journal Editors (Clinical Research Information Service, Republic of Korea; approval number: KCT0004351) on October 18, 2019. Written informed consent was obtained from all patients registered in the trial between October 2019 and June 2020. Our study complies with the Consolidated Standards of Reporting Trials (CONSORT) guidelines (CONSORT Checklist); a CONSORT flow chart is presented in Figure 1. The summary of our study protocol is presented in Supplemental file 1.
Adult donors (aged≥19 years) with an American Society of Anesthesiologists physical status (ASA-PS) I or II, who were suited for KT according to clinical practice guidelines (19) and were undergoing elective HALN at our hospital, were recruited to the study. We excluded patients who refused to participate or met the following exclusion criteria: emergency case, age<19 years, ASA-PS III or IV, intra-operative haemodynamic instability (massive haemorrhage, requirement for fluid resuscitation with colloid solution, blood product transfusion and/or an infusion of strong inotropic drugs), or not appropriate for intrathecal intervention (bleeding diathesis, neurologic dysfunction, history of lumbar spine surgery, recent systemic or local infection or drug allergy).
Among the 84 living donors registered in this trial, 4 were excluded based on the exclusion criteria: 2 had a history of spinal surgery and 2 refused to participate. Consequently, 80 living donors were included in the final analysis.
Living donors were randomly classified into two groups: an IV propofol group (n=40) and an IH sevoflurane group (n=40). We used sealed opaque envelopes to randomly assign the living donors to the groups. The envelopes were divided into groups of 10 and each group contained equal numbers of IV propofol and IH sevoflurane group allocations. Then a colleague not otherwise involved in this study randomly shuffled the envelopes within the group and stacked. When a participating donor entered the preoperative holding area, the uppermost envelope was opened by the attending anesthesiologist and the patient was offered the anesthetic management described therein.
The attending anesthesiologist and nurses were aware of the group allocations, but were not involved in patient care. The patients, surgical team, physicians, post-anesthetic care unit and ward nurses, and all researchers were blinded to the group allocation.
Surgery and anesthesia
An experienced urologic surgeon (Y.H.P.) performed HALN, which was comprehensively described in a previous article (20). Patients were offered balanced anesthesia by the experienced attending anesthesiologist. Induction of anesthesia was achieved using 1–2 mg kg-1 propofol (Fresenius Kabi, Bad Homburg, Germany) and 0.6 mg kg-1 rocuronium (Merck Sharp & Dohme Corp., Kenilworth, NJ, USA). Anesthesia in the IV propofol group was maintained by infusing propofol and remifentanil (Hanlim Pharm. Co., Ltd., Seoul, Republic of Korea) according to the effect-site concentration using a target-controlled infusion pump (Orchestra® Workstation; Fresenius Kabi). Schneider’s and Minto’s pharmacokinetic models were used for propofol and remifentanil, respectively. Anesthesia in the IH sevoflurane group was maintained using sevoflurane (Hana Pharm.) combined with medical air/oxygen. In both groups, anesthetic agents were titrated to maintain the bispectral index (BIS) at 40–60.
The participants all received intrathecal morphine (ITM) injection and intravenous patient-controlled analgesia (IV-PCA) for postoperative analgesia. Informed consent for ITM was acquired on the day before the surgery. The ITM injection was administered before the induction of general anesthesia without any sedative. The intrathecal space was approached through the L3-4 interspace. Once free flow of cerebrospinal fluid had been observed, a single bolus of 0.2 mg (0.2 ml) morphine sulphate (BCWorld Pharm. Co., Ltd., Seoul, Republic of Korea) mixed with 0.9% saline (1 ml) to a total volume of 1.2 ml was injected slowly.
All living donors were provided with the IV-PCA device (AutoMed 3200; Acemedical, Seoul, Republic of Korea) containing 1,000 μg of fentanyl (Dai Han Pharm.) and 0.3 mg of ramosetron (Boryung Co., Ltd., Seoul, Republic of Korea) in a total volume 100 ml. The IV-PCA device was programmed as follows: no basal infusion, 1 ml bolus injection, and a lockout time of 10 min. If the numeric rating scale (NRS) pain score was ≥7 despite ITM and IV-PCA, a rescue IV opioid was administered on approval by the attending physician in the post-anesthesia care unit (PACU) or ward.
Quality of early postoperative recovery outcomes
The quality of early postoperative recovery was evaluated with the QoR-40K questionnaire, which consists of the following five subscales: physical comfort (12 items), emotional state (9 items), physical independence (5 items), psychological support (7 items) and pain (7 items). All items are rated on a 5-point Likert scale, where scores range from 1 (“none of the time”) to 5 (“all of the time”) for positive questions; the anchor points are reversed for negative questions. The total score ranges from 40 to 200 and is calculated by summing the scores for all items. Better-quality recovery corresponds to a higher score (11). In this study, donors were asked to complete the QoR-40K questionnaire on postoperative day (POD) 1.
We assessed functional recovery using the objective measurements of ambulation success rate and number of footsteps. Donors were advised to attempt sitting, standing and walking only after at least 6 hours postoperatively, and only under the guidance of an attending physician. Ambulation was assessed at 6–12 hours after surgery and on POD 1. Successful ambulation was defined as walking more than 10 steps without any adverse event (nausea, vomiting or pain) or physical support from the attending physician. Ambulation at the former and latter time points was classed as successful early and late ambulation, respectively. The number of footsteps was counted using the EI-AN900 activity tracker (Samsung Electronics, Suwon, Republic of Korea).
A NRS was used to evaluate the intensity of postoperative pain at the wound site. Pain severity was measured at 6 hours and 24 hours after surgery, and during every nursing shift as a part of standard patient care. For each measurement, donors were asked to report the intensity of pain at rest and while coughing. We collected all pain scores during the initial 24 hours after surgery, and the highest NRS scores at rest and during coughing were analysed. The total IV-PCA use and number of rescue IV opioids used during the first 24 hours after surgery were also documented.
Other complications occurred on POD 1 were recorded, including nausea/vomiting, headache, shivering, respiratory depression and pruritus. The adverse events related to the surgery were graded using the Clavien–Dindo classification, which is used to evaluate the severity of postoperative complications after many surgeries (21). The length of hospital stay after surgery was compared between donors in the IV propofol and IH sevoflurane groups.
The preoperative findings included demographic and laboratory variables. The intraoperative findings included hemodynamic variables and total surgical duration. Laboratory variables measured on POD 1.
The required sample size was determined based on an unpublished retrospective pilot study conducted at Seoul St. Mary’s Hospital and including 20 patients. The number of patients needed in each group for a statistical power of 0.8 at a significance level of 5% was 36, when the standard deviation (SD) and the mean difference between groups were 30 and 20, respectively. We enrolled 40 subjects in each group assuming a drop rate of 10%.
We used the Shapiro–Wilk test to verify the normality of the data distribution. Normally distributed data were compared using an unpaired t-test, while non-normally distributed were analysed with the Mann–Whitney U test. Categorical data were analysed using Pearson’s χ2 test or Fisher’s exact test, as appropriate. Data are presented as mean ± SD, median and interquartile range or number (%), as appropriate. All tests were two-sided and a p-value<0.05 was considered significant. All statistical analyses were performed using SPSS for Windows (ver. 24.0; IBM Corp., Armonk, NY, USA) and MedCalc for Windows software (ver. 11.0; MedCalc Software, Ostend, Belgium).