Effect of Perioperative Dexmedetomidine on Delayed Graft Function Following a Donation-After-Cardiac-Death Kidney Transplant

This randomized clinical trial compares outcomes among patients who received a donated-after-cardiac-death kidney allograft and either dexmedetomidine or placebo during and after the surgical procedure.


Introduction
The point prevalence of end-stage kidney disease in the US increased from 727 per million in 1990 to 2206 per million in 2016. 1 Kidney transplant is an established effective treatment for end-stage kidney disease, 2,3 with the number of US patients who received kidney allografts increasing from 10 011 in 1991 to 19 355 in 2016. 1 However, various complications can emerge during the posttransplant course, such as delayed graft function (DGF). 4,5The incidence of DGF is about 4% to 10% in living-donor kidney transplant and 20% to 50% in deceased-donor kidney transplant. 6layed graft function has been associated with ischemia-reperfusion injury 7 as well as a higher risk of acute rejection and reduced long-term allograft survival. 6,8xmedetomidine is a selective α 2 -adrenoreceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic effects. 9Dexmedetomidine may be renoprotective, which is likely associated with the attenuation of ischemia-reperfusion injury. 10,11A recent meta-analysis suggested an association between perioperative dexmedetomidine and reduced acute kidney injury after cardiac surgery. 12A retrospective cohort study suggested that dexmedetomidine use was associated with decreased incidence of DGF after isolated kidney transplant or multiorgan transplant. 13wever, to date, no randomized clinical trial has investigated the effect of dexmedetomidine on kidney allograft function.
In this single-center, double-blind, placebo-controlled randomized clinical trial, we investigated the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant.We hypothesized that perioperative dexmedetomidine infusion reduces the incidence of DGF after DCD kidney transplant.We compared the incidence of DGF between patients with kidney allograft who received dexmedetomidine and patients who received normal saline (placebo) during and after surgery for a total of 24 hours.

Methods
This randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China.The trial was approved by the ethics committee of The First Affiliated Hospital of Soochow University.Written informed consent was obtained from all patients.We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.The trial protocol and statistical plan are provided in Supplement 1.

Organ Donation and Procurement
The procedures of organ donation and transplant conformed to the National Guidelines for Donation after Cardiac Death in China. 14All of the donors were controlled donors after cardiac death. 15,16nea test was performed to determine donor suitability for DCD. 17,18Details of organ donation and procurement are presented in the eMethods in Supplement 2.

JAMA Network Open | Anesthesiology
Effect of Perioperative Dexmedetomidine on Delayed Graft Function

Donor Data Collection and Risk Assessment
Donor data were obtained from the Organ Procurement Organization records.The time between withdrawal of life-sustaining treatment and asystole, asystolic warm ischemic time (defined as the interval from asystole to the start of cold preservation), 18 and cold ischemic time (defined as the interval from the start of cold preservation to the start of graft reperfusion) were collected. 19[23]

Patients, Randomization, and Blinding
Patients who were 18 years or older, diagnosed with end-stage kidney disease, undergoing kidney replacement therapy, and scheduled for DCD kidney transplant were eligible for inclusion.Patients who had sick sinus syndrome, an atrioventricular block, a left ventricular ejection fraction less than 30%, or a multiorgan transplant were excluded.
All of the patients were of Han Chinese ethnicity.Race and ethnicity data were not collected because, we believe, they would have had no impact on the perioperative care and study outcomes.
Eligible adults were enrolled from September 1, 2019, to January 28, 2021.Patients were randomized to either dexmedetomidine or normal saline (Figure 1) using a 1:1 ratio and permuted block sizes of 2 and 4. Randomization was concealed using identical opaque envelopes that were sealed and stored in a locked cabinet.An independent research nurse prepared the medications according to the randomization results.Dexmedetomidine and normal saline were each kept in syringes that were labeled only with the patient number.There was no way to distinguish the contents of the syringes because both dexmedetomidine and saline are colorless and the syringes were identical.The patients, clinicians, and outcome assessors were all blinded to the randomization.

Anesthesia and Dialysis Treatment
Intraoperative monitoring included noninvasive cuff blood pressure, electrocardiography, pulse oximetry, end-tidal carbon dioxide, radial artery blood pressure, central venous pressure, and bispectral index.Intravenous infusion of lactated Ringer solution was provided.After anesthesia induction, patients were endotracheally intubated and mechanically ventilated.Anesthesia was The perioperative care of patients who underwent kidney transplant was based on the Kidney Disease: Improving Global Outcomes guideline. 4,24The perioperative dialysis treatment is presented in the eMethods in Supplement 2.

Interventions and Outcomes
The dexmedetomidine group received an intravenous infusion of dexmedetomidine, 0.4 μg/kg/h, immediately after anesthesia induction and continued throughout the procedure.After surgery, all patients were transferred to the designated transplant unit and received dexmedetomidine, 0.1 μg/kg/h.Dexmedetomidine was administered for a total of 24 hours.The dose regimen of dexmedetomidine was based on the dose used in previous studies in cardiac surgery 25 and older patients who underwent noncardiac surgery. 26The control group received an intravenous infusion of normal saline administered in the same dose regimen as dexmedetomidine.
The primary outcome was the incidence of DGF, defined as the need for dialysis during the first posttransplant week. 4,5The prespecified secondary outcomes were in-hospital repeated dialysis during the first posttransplant week; in-hospital acute rejection; and serum creatinine, serum cystatin C, estimated glomerular filtration rate (eGFR), need for dialysis, and patient survival on posttransplant day 30.Repeated dialysis was defined as 2 or more dialysis sessions during the first posttransplant week. 27Acute rejection was confirmed by biopsy of the kidney allograft.The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. 28veral in-hospital and long-term outcomes were assessed post hoc: (1)  (defined as the return to regular dialysis, graft removal, or patient death), 6,31 and patient survival at 1 posttransplant year.

Perioperative Data
The perioperative data were ( 1

Statistical Analysis
According to the literature, the incidence of DGF after DCD kidney transplant was 45% to 55%. 31 The (unpublished) pilot study we conducted showed that 9 of 20 patients (45%) who did not receive dexmedetomidine experienced DGF, which was in line with the previous report.The therapeutic effect of dexmedetomidine on DGF is unknown.We hypothesized that dexmedetomidine would reduce the incidence of DGF by 50%.Therefore, this trial required 54 patients in each group with a power of 80% at a significance of α = .05.We decided to recruit 114 patients (with 57 in each group) with consideration of a possible dropout rate of 5%.
Continuous variables were presented as means (SDs) or medians (IQRs), depending on data distribution.The categorical variables were presented as numbers (percentages).The betweengroup difference in the DGF incidence was analyzed using the χ 2 test, and the therapeutic effect was assessed with odds ratios (ORs) and 95% CIs.A 2-sided P < .05indicated a statistically significant difference.As appropriate, the secondary outcomes were analyzed with the unpaired, 2-tailed t test; Mann-Whitney rank sum test; χ 2 test; or Fisher exact test.The therapeutic effect was assessed using the OR (or difference) and 95% CI.Multiple testing was corrected using the Bonferroni method, with P < .007regarded as statistically significant.Because multiple testing corrections were not planned for the nonoutcome perioperative data and post hoc analyses, these results should be considered exploratory. 34The effects of interventions on DGF and 1-year postoperative acute rejection, allograft failure, and patient survival were assessed using the Kaplan-Meier curve and the log-rank test, and the therapeutic effect was analyzed with the hazard ratio (HR) and 95% CI.
All analyses were based on the modified intention-to-treat population principle, which included any randomized patient who had undergone kidney transplant and for whom the result of the primary outcome was available.Neither an interim analysis nor missing data imputation was planned a priori.Statistical analyses were performed using the SPSS software, version 23.0 (IBM SPSS).

Results
Of the 122 patients screened for eligibility, 8 were excluded and 114 were randomized (Figure 1).One patient did not undergo the planned transplant because of intraabdominal infection, and 2 patients withdrew their informed consent.The remaining 111 patients (56 in the dexmedetomidine group, and 55 in the normal saline group) underwent the scheduled transplant and had available primary outcome data.One patient in the normal saline group was lost to the 1-year postoperative follow-up.
Approximately 80% of donors after cardiac death became unstable during the 10-minute apnea test.
The panel reactive antibody was less than 10% for all patients.No patients had previous transplants or a preemptive transplant.The median (IQR) time between treatment withdrawal and asystole was 8.0 (6.0-11.8)minutes and 9.0 (7.0-13.0)minutes (ranging from 4 to 48 minutes), and the median (IQR) asystolic warm ischemic time was 9.5 (8.0-10.0)minutes and 10.0 (6.0-11.0)minutes, in the dexmedetomidine and normal saline groups, respectively.
The blood gas and electrolyte parameters at the end of surgery were within the normal ranges in both groups (

JAMA Network Open | Anesthesiology
Effect of Perioperative Dexmedetomidine on Delayed Graft Function

Discussion
To our knowledge, this trial was the first to show that 24-hour perioperative dexmedetomidine administration reduced the incidence of DGF after DCD kidney transplant.Decreased need for repeated dialysis further suggested the favorable effects of dexmedetomidine on kidney allograft during the first posttransplant week, a higher creatinine clearance rate on PODs 1 and 2, and increased urine output on PODs 2 and 7 and at hospital discharge.The dexmedetomidine infusion neither led to concerning adverse events nor adversely affected postoperative recovery.
Delayed graft function is associated with an increased risk of acute rejection, inferior graft function, prolonged hospital stay, and reduced long-term graft survival and patient survival. 6,8,357][38][39] A retrospective cohort study found an association between dexmedetomidine and decreased incidence of DGF, overall complications, infection, acute rejection in the early posttransplant phase, and length of hospital stay. 13That study had several limitations, however, including its cohort design, the heterogenous donor sources, the mixture of kidney-only and combined kidney-pancreas transplants, lack of multiple testing corrections, and potentially inadequate confounder control.
In contrast, the present trial was based on a randomized design and showed the DGF reduction effect exerted by dexmedetomidine in DCD kidney transplant.The finding was corroborated by previous studies reporting that dexmedetomidine decreased acute kidney injury in cardiac surgery. 25,40Dexmedetomidine has a favorable safety profile and is currently used in perioperative and critical care.A recent study found an association between dexmedetomidine and improved 5-year survival after cardiac surgery. 34The infusion rate and duration of dexmedetomidine in this trial were in concordance with those in current practice.Dexmedetomidine infusion (0.4 μg/kg/h intraoperatively and 0.1 μg/kg/h postoperatively) has been used in the perioperative setting. 25,26,40e low infusion rate may enhance postoperative recovery via anxiolysis, analgesia, sleeping promotion, and delirium reduction. 26The pilot study and this trial found neither concerning adverse effects nor delayed postoperative recovery associated with dexmedetomidine.The 1-year postoperative outcomes suggested that the dexmedetomidine treatment may improve longer-term kidney allograft function.The dexmedetomidine group had lower serum creatinine and cystatin C levels, higher eGFR, and a lower allograft failure rate up to 1-year postoperatively, although these between-group differences were not statistically significant.The present trial was likely underpowered for these long-term outcomes.The overall risk-benefit profile supports the use of dexmedetomidine in kidney transplants.
Several potential mechanisms may underlie the favorable effects of dexmedetomidine on kidney transplants.As an α 2 -adrenoreceptor agonist, dexmedetomidine engages in the α 2 -adrenoreceptors that are widely populated in kidney tubules and peritubular vascular structures.
The activation of the α 2 -adrenoreceptor pathway decreases sympathoadrenal hyperactivity.It induces vasodilatation via endothelial nitric oxide regulation, leading to enhanced glomerular filtration and increased urine output. 41,42 cell death signaling, and enhanced cell survival signaling. 10,11,43,44A meta-analysis found that dexmedetomidine as an adjuvant during anesthesia attenuated surgical stress and inflammation, 45 which may enhance postoperative recovery and improve overall outcomes.

Limitations
This trial has several limitations.First, although the sample size agreed with the result of the power analysis, including more patients would have enhanced the power.Second, the long-term outcomes were based on post hoc analysis.Third, although dexmedetomidine may reduce the length of hospital stay after kidney transplant, 13 we did not observe such an effect.9][50] This difference may be attributed to the different health care systems in various countries.Fourth, as a single-center trial based on controlled donors after cardiac death and characterized by a relatively short warm ischemic time, the generalizability of its findings should be tested in future studies.

Conclusions
In this randomized clinical trial, the 24-hour perioperative dexmedetomidine infusion reduced the incidence of DGF without incurring adverse effects after DCD kidney transplant.The findings of this trial support the use of dexmedetomidine in kidney transplants.Further trials are needed to determine the effects of dexmedetomidine on long-term outcomes and on different kidney transplant scenarios.
) graft function-related parameters: baseline serum creatinine and serum cystatin C before surgery as well as serum creatinine, serum cystatin C, creatinine clearance rate, and urine output on postoperative days (PODs) 1, 2, 3, 5, and 7, and at the time of hospital discharge; (2) arterial blood gas and electrolytes at the end of surgery; (3) visual analog scale pain score (range: 0-10, with 0 indicating no pain and 10 indicating most severe pain) at 30 minutes, 24 hours, and 48 hours postoperatively; (4) sufentanil consumption over 24 hours and 48 hours postoperatively; (5) perioperative bradycardia and hypotension; (6) transplant induction therapy and immunosuppressive medications; (7) duration of surgery, anastomosis time, time to extubation, and length of hospital stay; (8) intraoperative infusion of lactated Ringer solution; (9) furosemide use in the first posttransplant week; (10) level of postoperative nursing care (level I indicating intensive care, and level II indicating conventional care) on PODs 1 to 3; and (11) level of physical activity assessed using the Barthel index score (range, 0-100, with lower scores indicating increased disability) 32,33 on PODs 1 to 3. The creatinine clearance rate, urine output, and immunosuppressive medications are presented in the eMethods in Supplement 2. A single multidisciplinary team provided perioperative care to ensure consistency and efficiency.Adherence by clinicians and outcome assessors to the study protocol was achieved by training the research personnel and reviewing the case report forms.

a
VAS pain score range: 0 to 10, with 0 indicating no pain and 10 indicating most severe pain.b Level of postoperative nursing care: I indicating intensive care and II indicating conventional care.c Barthel index score range: 0 to 100, with lower scores indicating increased disability.

Figure 2 .B
Figure 2. Serial Changes in Graft Function Parameters During the Hospitalization Period

Table 2 .
Perioperative Data SI conversion factors: To convert PCO 2 and PO 2 levels to kilopascal, multiply by 0.133; hemoglobin level to gram per liter, multiply by 10.0; potassium, sodium, and bicarbonate levels to millimoles per liter, multiply by 1.0.