This single-center, 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 and a summary of the 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 suitable for kidney donation according to the clinical practice guidelines (21) and were undergoing elective HALN at our hospital, were recruited into 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, intraoperative hemodynamic instability (massive hemorrhage, requirement for fluid resuscitation with colloid solution, blood product transfusion and/or infusion of strong inotropic drugs), or not appropriate for intrathecal intervention (bleeding diathesis, neurological dysfunction, history of lumbar spine surgery, recent systemic or local infection or drug allergy).
Among the 84 living donors registered in this trial, four were excluded based on the exclusion criteria: two had a history of spinal surgery and two 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. A colleague not otherwise involved in this study randomly shuffled and stored the envelopes. When a participating donor entered the preoperative holding area, the uppermost envelope was opened by the attending anesthesiologist who was not a member of the investigational team and the patient was provided the anesthetic management described therein.
The attending anesthesiologist and nurses were aware of the group allocations, but were not involved in patient care after surgery. To prevent their further involvement, nurses from the postanesthetic care unit (PACU) were supervised by a member of the research team who was blinded to the group allocation. The patients, surgical team, physicians, PACU and ward nurses, and all researchers were blinded to the group allocation.
Surgery and anesthesia
HALN, which was comprehensively described in a previous article (22), was performed in all of the patients in both groups by one experienced urological surgeon (Y.H.P). Patients were provided 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. Neuromuscular blockade was maintained by additional bolus injection of rocuronium. The timing and dosage of injection were determined by the attending anesthesiologist. After the surgical procedure, neuromuscular blockade was reversed with 4 mg kg−1 sugammadex (MSD Korea Ltd., Seoul, Republic of Korea) in both groups.
All participants 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 sulfate (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; Ace Medical, Seoul, Republic of Korea) containing 1000 μg of fentanyl (Dai Han Pharm.) and 0.3 mg of ramosetron (Boryung Co., Ltd., Seoul, Republic of Korea) in a total volume of 100 ml. No other local anesthetic or opioid was added to the solution. The IV-PCA device was programmed as follows: no basal infusion, 1 ml bolus injection, and a lockout time of 10 min. If the numerical 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 PACU or ward.
Quality of early postoperative recovery outcomes
The quality of early postoperative recovery was evaluated using 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 can range from 40 to 200 and is calculated by summing the scores for all items. Better-quality recovery corresponds to a higher score (14). In this study, we compared the global and all sub-dimensional scores of QoR-40K between IV propofol and IH sevoflurane groups. 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 steps. 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, at least 24 hours after surgery. 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 steps was counted using the EI-AN900 activity tracker (Samsung Electronics, Suwon, Republic of Korea). We compared the rate of successful ambulation at early and late postoperative time points between IV propofol and IH sevoflurane groups. The numbers of steps during early and late ambulation and the total footsteps were also compared between the two groups.
An 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 analyzed. Total IV-PCA use and number of rescue IV opioids used during the first 24 hours after surgery were also documented.
Other complications that occurred on POD 1 were recorded, including nausea/vomiting, headache, shivering, respiratory depression and pruritus. 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 (23). The length of hospital stay after surgery was compared between donors in the IV propofol and IH sevoflurane groups.
Preoperative findings included demographic and laboratory variables. Intraoperative findings included hemodynamic variables and total surgical duration. Laboratory variables were measured on POD 1.
The required sample size was determined based on an unpublished retrospective pilot study conducted at Seoul St. Mary’s Hospital including 20 patients. The parameter used for the calculation of effective size was global QoR-40K score. 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 dropout rate of 10%.
We used the Shapiro–Wilk test to verify the normality of the data distribution. Normally distributed data were compared using the unpaired t-test, while non-normally distributed data were analyzed using the Mann–Whitney U test. Categorical data were analyzed 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. To control the overall family-wise error rate, p-value < 0.005 was taken to indicate statistical significance of primary outcomes. In other analyses, p-value < 0.05 was taken to indicate statistical significance. All statistical analyses were performed using SPSS for Windows (ver. 24.0; IBM Corp., Armonk, NY, USA) and MedCalc for Windows (ver. 11.0; MedCalc Software, Ostend, Belgium).