Sugammadex Compared to Neostigmine for Reversal of Neuromuscular Block in Patients Undergoing Kidney Transplantation. A Retrospective Cohort, Case-Control Study.


 Background: The impact of sugammadex in patients with end-stage renal disease undergoing kidney transplantation is still far from being defined. The aim of the study is to compare sugammadex to neostigmine for reversal of rocuronium- and cisatracurium-induced neuromuscular block (NMB), respectively, in patients undergoing kidney transplantation.Methods: A retrospective, observational study was performed. A total of 350 patients undergoing kidney transplantation, equally divided between a sugammadex group (175 patients) and a neostigmine group (175 patients), were considered. Postoperative kidney function, evaluated by monitoring of serum creatinine and urea and estimated glomerular filtration rate (eGFR), was the endpoint. Other endpoints were anaesthetic and surgical times, post-anaesthesia care unit length of stay, postoperative intensive care unit admission, and recurrent NMB or complications.Results: No significant differences in patient or, with the exception of drugs involved in NMB management, anaesthetic and surgical characteristics were observed between the two groups. Serum creatinine (median [interquartile range]: 596.0 [478.0-749.0] vs 639.0 [527.7-870.0] μmol/L, p=0.0128) and serum urea (14.9 [10.8-21.6] vs 17.1 [13.1-22.0] mmol/L, p=0.0486) were lower, while eGFR (8.0 [6.0-11.0] vs 8.0 [6.0-10.0], p=0.0473) was higher in the sugammadex group than in the neostigmine group after surgery. The sugammadex group showed significant lower incidence of postoperative severe hypoxemia (0.6% vs 6.3%, p=0.006), shorter PACU stay (70 [60-90] min vs 90 [60-105] min, p<0.001), and reduced ICU admissions (0.6% vs 8.0%, p=0.001).Conclusions: Compared to neostigmine for reversal of NMB, sugammadex resulted in a better recovery profile in patients undergoing kidney transplantation.


Introduction
Kidney transplantation represents the best option to improve survival and quality of life in patients with end-stage renal disease (ESRD) (Kellar et al. 2015).
The surgical procedure of kidney transplantation is generally performed under general anaesthesia and presents signi cant challenges for the anaesthesiologist (Martinez et al. 2013). A careful anaesthetic approach is highly recommended to improve outcomes (Martinez et (Kirmeier et al. 2019). Benzylisoquinolinium compounds, such as cisatracurium, and aminosteroid NMBAs, such as rocuronium, are commonly used during general anaesthesia for kidney transplantation. Cisatracurium seems to bene t from certain favour among anaesthesiologists because it is inactivated by Hofmann elimination and hydrolysis by esterases independent of renal function, whereas rocuronium is characterized by organ-independent elimination. However, both are associated with slightly prolonged duration of action and require careful neuromuscular function monitoring for safe recovery at the end of surgery (Della Rocca et al. 2003;Martinez et al. 2013;Mittel et al. 2017). While proper neuromuscular function monitoring is crucial in avoiding postoperative complications, particularly respiratory complications (Blobner et al. 2020), the choice of reversal drug seems to be no less important (Kheterpal et al. 2020). Compared to neostigmine, an acetylcholinesterase inhibitor traditionally used for reversal of NMB, the use of sugammadex, a modi ed γ-cyclodextrin developed for the reversal of NMB induced by aminosteroid NMBAs, particularly rocuronium, was associated with a signi cant lower incidence of major pulmonary complications (Kheterpal et al. 2020).
Sugammadex is a highly hydrophilic drug and acts in the plasma by encapsulating and inactivating unbound rocuronium to form a 1:1 water-soluble complex. Urinary excretion is the main route of elimination of sugammadex and the sugammadex-rocuronium complex. At this time, sugammadex administration is not recommended by the manufacturer for subjects with severe renal impairment So, the aim of our study is to evaluate the impact of sugammadex, given at recommended doses for reversal of a moderate or deep rocuronium-induced NMB, compared to neostigmine, administered for reversal of moderate cisatracurium-induced NMB, on renal function in a large cohort of patients undergoing kidney transplantation.

Materials And Methods
Ethical statement and study approval All procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. STROBE recommendations for cohort, case-control studies were followed. This retrospective observational study was approved by our Institutional Review Board (Ethics Committee in Clinical Research-CESC of Padova, Italy, prot.n.42587, 16 July 2020), which waived the requirement to obtain patients' written informed consent (the data were analysed retrospectively and anonymously).

Patients
A total of 350 patients with ESRD undergoing kidney transplantation at our hospital were evaluated.
Patients were recruited consecutively until the sample size was achieved.
The anaesthesia and medical records and the information system's computer database were used to retrieve data about all patients (age ≥18 years) with ESRD who received sugammadex or neostigmine to reverse rocuronium-or cisatracurium-induced NMB, respectively, during inhalational or intravenous anaesthesia for kidney transplantation. Each anaesthesia and medical record were reviewed for preoperative, intraoperative, and postoperative data up to 5 days after surgery. Patient demographics, comorbidities (e.g., history of neurological, respiratory, cardiac, abdominal, and metabolic disease), perioperative data including kidney function (serum creatinine and urea, estimated glomerular ltration rate [eGFR]), and postoperative events were considered.
Standard monitoring was adopted, including deep anaesthesia and neuromuscular function monitoring. All patients received antibiotic prophylaxis (piperacillin 2 g) before surgery, immunosuppression (thymoglobulin 1-1.5 mg/kg or basiliximab 20 mg, and methylprednisolone 500 mg) at the start of surgical procedure, and diuretics (furosemide 100 mg and mannitol 18% 80 mL) during surgery after anastomosis of the renal artery.
After surgery, patients were transferred to the post-anaesthesia care unit (PACU). Level of consciousness, respiratory rate, pulse oximetry, heart rate, and arterial blood pressure were monitored until discharge to the surgical ward. Pain and postoperative nausea and vomiting (PONV) were assessed using a numeric rating scale (NRS) from 0=no pain or nausea to 10=worst possible pain or nausea. Patients were also assessed for clinical evidence of residual or recurrent NMB (e.g., muscle weakness, oxygen desaturation, hypoventilation, critical respiratory event). Patients with a pain NRS score of >3 in the PACU received rescue analgesics (paracetamol 1 g and tramadol 1 mg/kg intravenously). Patients with a PONV NRS score of >3 received a rescue dose of droperidol 0.625-1.25 mg intravenously.

Endpoints
Serum creatinine (primary endpoint) and serum urea and eGFR (secondary endpoints) for monitoring kidney function after surgery for up to 5 postoperative days represented the main endpoints of the study. Other endpoints were anaesthetic and surgical times, length of PACU stay, intensive care unit (ICU) admission, clinical evidence of postoperative respiratory complications (e.g., hypoxemia with peripheral arterial blood oxygen saturation [SaO 2 ]<90%, critical respiratory event) or cardiovascular event (e.g., stroke, myocardial ischemia, heart failure, hypertension, arrhythmia), PONV NRS score of >3, pain NRS score of >3, residual or recurrent NMB, and presence of any other postoperative complications within 24 h after surgery that required treatment.
For respiratory function, gas exchange analysis of arterial blood (pH, arterial partial pressures of oxygen [PaO 2 ] and carbon dioxide [PaCO 2 ]) performed 15-20 minutes after tracheal extubation was considered.
For cardiac function, heart rate (HR) and systolic (SBP) and diastolic (DBP) arterial blood pressures evaluated 15-20 minutes after tracheal extubation were considered. Data were collected by researchers without any involvement in the management of patients. They created a dataset with anonymized data for statistical analysis performed by researchers not involved with data collection.

Statistical analysis
The sample size was based on the following assumptions: a mean difference of 44. Descriptive analysis was used to summarize the sample's characteristics. Normality of distribution of quantitative characteristics was analysed using the Shapiro-Wilk test. Continuous normally distributed variables are expressed as mean ± standard deviation (SD). Median and interquartile range (IQR) values are reported for non-normally distributed variables. The two-tailed Student's t-test or two-tailed Mann-Whitney U test was used to compare normally or non-normally distributed variables, respectively, between the sugammadex and neostigmine groups. Categorical data were reported as absolute number and percentage (%) and compared using χ 2 or Fisher's exact tests. To determine the strength and direction of association between two variables, Bravais-Pearson's correlation test was used for normally distributed variables, and Spearman's rank correlation test was used for non-normally distributed variables. Multiple linear regression analysis was used to examine the relationship between one dependent variable and independent variables. Using the Akaike information criterion, backward and forward stepwise regression was performed to select the best model. Correlation coe cients (CCs), estimate coe cients (ECs), standard errors (SEs), t-values, and p-values were determined. Statistical signi cance was set at p-values <0.05. All statistical analyses were performed using R version 3.4.0 (2017-04-21).

Results
No signi cant differences in demographic or other patient characteristics were observed between the sugammadex and neostigmine groups (Table 1). With the exception of NMBAs and reversal drugs, no differences in anaesthetic and surgical characteristics were observed between the two groups ( Table 2).
Sugammadex was administered for reversal of moderate and deep NMB in 57.7% and 42.3% of cases, respectively. In the postoperative period, the sugammadex group showed signi cantly lower incidence of hypoxemia, shorter PACU stay, and reduced ICU admissions ( Table 2). No patient in either group exhibited clinical evidence of major postoperative complications.    (Table 3, Fig. 1). Serum urea remained signi cantly lower in the rst 3 postoperative days (Table 3). No differences in kidney function were observed between the moderate and deep groups of sugammadex patients ( Table 3). The proportion of patients with an increase in serum creatinine to > 44 µmol/L was higher in the sugammadex group than in the neostigmine group ( rst postoperative day:

Discussion
In this study, sugammadex administered to reverse a rocuronium-induced NMB has been shown to improve recovery after kidney transplantation. Compared to the cisatracurium-neostigmine strategy, the rocuronium-sugammadex strategy resulted in lower incidence of postoperative respiratory events, faster discharge to the surgical ward, lower ICU admission, and better values of kidney function after surgery.
In patients with renal impairment, sugammadex was shown to effectively reverse both moderate (Staals were not considered to be clinically relevant (Sorgenfrei et al. 2006).
The impact on renal function of sugammadex compared to neostigmine for reversal of NMB also deserves consideration. A study designed to evaluate the cytotoxic, genotoxic, and apoptotic effects of different dosages of both reversal drugs on human embryonic renal (HEK-293) cells showed that neostigmine administered in vitro at 50, 100, 250, and 500 µg/mL had greater cytotoxic, genotoxic, and apoptotic effects on HEK-293 cells than the equivalent dosages of sugammadex (Büyükfırat et al. 2018).
In adult patients undergoing des urane/opioid anaesthesia that received neostigmine 40 µg/kg and sugammadex 4 mg/kg to reverse rocuronium-induced NMB, renal glomerular ltration and tubular functions were minimally affected. However, these effects were greater with neostigmine than with sugammadex. No signi cant changes were observed for serum creatinine and urea levels between the two groups. Instead, in urinalysis, the postoperative value of cystatin C, a speci c marker of glomerular function, was found to be signi cantly higher in the neostigmine group compared to the sugammadex group (Isik et al. 2016). Comparing the rocuronium-sugammadex strategy to the cisatracuriumneostigmine strategy in adult patients, signi cant differences were found only in urinalysis, with N-acetylglucosaminidase higher in the rocuronium-sugammadex group, and β 2 -microglobulin higher in the cisatracurium-neostigmine group .
A comparison of the rocuronium-sugammadex and cisatracurium-neostigmine strategies was retrospectively evaluated in kidney transplantation, but the sample size was not large enough to draw a conclusion on the impacts of sugammadex and neostigmine on renal function in such population of patients, and no data are included on sugammadex administered to reverse deep rocuronium-induced NMB (Vargas et al. 2020). This study con rmed the advantage of the rocuronium-sugammadex over the This study has two main limitations. First, it is not a randomized controlled study and therefore has the drawbacks of all observational studies. Second, more speci c markers (e.g., cystatin C, N-acetylglucosaminidase; α 1 -microglobulin; β 2 -microglobulin) were not available for a targeted analysis of postoperative renal function.
In conclusion, sugammadex should be considered for reversal of rocuronium-induced NMB in patients undergoing kidney transplantation.