Impact On Grafted Kidney Function Of Rocuronium-sugammadex Vs Cisatracuriumneostigmine Strategy For Neuromuscular Block Management.

Abstract Background: The impact of sugammadex in patients with end-stage renal disease undergoing kidney transplantation is still far from being defined. The study aims to compare sugammadex to neostigmine for the reversal of rocuronium- and cisatracurium-induced neuromuscular block (NMB), respectively, in patients undergoing kidney transplantation. 

Methods: A single-center, 2014-2017 retrospective cohort case-control 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 anesthetic and surgical times, post-anesthesia care unit length of stay, postoperative intensive care unit admission, and recurrent NMB or complications. Results: No significant differences in patient or, except drugs involved in NMB management, anesthetic, 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 a significantly 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).

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Conclusions: Compared to cisatracurium-neostigmine, the rocuronium-sugammadex strategy for reversal of NMB showed a better recovery profile in patients undergoing kidney transplantation. 

Keywords: Anesthesia, Neuromuscular block, Rocuronium, Cisatracurium, Sugammadex, Neostigmine, End-stage renal disease, 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, 2015). The surgical procedure of kidney transplantation is generally performed under general anesthesia and presents significant challenges for the anesthesiologist (Martinez et al. 2013). A careful anesthetic approach is highly recommended to improve outcomes (Martinez et al. 2013; De Gasperi et al. 2014; Mittel and Wagener, 2017; Wagener et al. 2020). The management of neuromuscular block (NMB) deserves particular attention (Martinez et al. 2013; Mittel and Wagener, 2017) to reduce the incidence of complications due to postoperative residual NMB (De Gasperi et al. 2014; Miskovic and Lumb, 2017). Patients receiving, compared to those not receiving, neuromuscular blocking agents (NMBAs) during general anesthesia are at significantly increased risk of postoperative respiratory complications (adjusted odds ratio [aOR]: 1.86) (Kirmeier et al. 2019). Benzylisoquinolinium compounds, such as cisatracurium, and aminosteroid NMBAs, such as rocuronium, are commonly used during general anesthesia for kidney transplantation. There is no evidence supporting the superiority of a specific NMBA. Cisatracurium seems to benefit from certain favor among anesthesiologists 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 a 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 and Wagener, 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 the reversal of NMB, the use of sugammadex, a modified γ-cyclodextrin developed for the reversal of NMB induced by aminosteroid NMBAs, particularly rocuronium, was associated with a significantly 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 (creatinine clearance [CrCl] < 30 mL/min), including those undergoing standard forms of dialysis (EMA 2021). The safety profile of sugammadex observed in clinical studies involving subjects with severe renal impairment (Staals et al. 2008; de Souza et al. 2015) has encouraged its use in clinical practice in patients with ESRD (Adams et al. 2020; Paredes et al., 2020), particularly in those undergoing kidney transplant (Unterbuchner, 2016; Ono et al. 2018; Arslantas and Cevik, 2019; Adams et al. 2020; Vargas et al. 2020). However, only retrospective analyses including reports (Unterbuchner, 2016) or small cohorts of patients are available in the literature (Ono et al. 2018; Arslantas and Cevik, 2019; Adams et al. 2020; Vargas et al. 2020). Furthermore, no data exist on the use of sugammadex administered for the reversal of deep NMB in patients undergoing kidney transplantation. So, our study aims 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 by 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 analyzed 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 anesthesia 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 anesthesia for kidney transplantation. Each anesthesia and medical record was 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 filtration rate [eGFR]), and postoperative events were considered.

Two distinct periods that define the matched exposure groups were considered: the pre-sugammadex period, 2014-2015 (from which cisatracurium-neostigmine-treated patients were identified), and the sugammadex period, 2016-2017 (from which rocuronium-sugammadex-treated patients were identified). Sugammadex was introduced in Padua University Hospital in January 2013 and was initially restricted to emergency reversal and routine reversal of rocuronium-induced NMB in selected high-risk patients undergoing anesthesia (Carron M, Baratto F 2016). In January 2016, sugammadex use was allowed for routine reversal. This resulted in a switch from the utilization of the cisatracurium-neostigmine to the rocuroniumsugammadex strategy. Neostigmine was administered to reverse only moderate cisatracurium-induced NMB, while sugammadex was used for both deep and moderate rocuronium-induced NMB at the end of surgery. Standard monitoring was adopted, including deep anesthesia and neuromuscular function monitoring. A train-of-four ratio (TOFR) ≥ 0.90 was adopted as the criterion for tracheal extubation (Brull and Kopman, 2017). All patients received antibiotic prophylaxis (piperacillin 2 g) before surgery, immunosuppression (thyroglobulin 1-1.5 mg/kg or basiliximab 20 mg, and methylprednisolone 500 mg) at the start of the 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-anesthesia 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 for up to 5 days after surgery represented the main endpoints of the study. Other endpoints were anesthetic 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 [SaO2] < 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 [PaO2] and carbon dioxide [PaCO2]) performed 15-20 min after tracheal extubation was considered. For cardiac function, heart rate (HR) and systolic (SBP), and diastolic (DBP) arterial blood pressures evaluated 15-20 min 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 44.2 μmol/L of serum creatinine in the first postoperative day between the sugammadex group and the neostigmine group as clinically relevant in the postoperative period (Kork et al. 2015; Gameiro et al. 2018), type I error equal to 0.05, and type II error equal to 0.2 (power [1−β] = 0.8). Considering these assumptions, the sample size was calculated as 350 patients, equally divided between the sugammadex group (175 patients) and the neostigmine group (175 patients). Descriptive analysis was used to summarize the sample's characteristics. The normality of the distribution of quantitative characteristics was analyzed 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 and non-normally distributed variables, respectively, between the sugar-made and neostigmine groups. Categorical data were reported as an absolute number and as a percentage (%) and compared using a χ2 or Fisher's exact test. 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 the independent variables. Using the Akainformationtion criterion, backward and forward stepwise regression was performed to select the best model. Correlation coefficients (CCs), estimate coefficients (ECs), standard errors (SEs), t values, and p values were determined. Statistical significance was set at p values < 0.05. All statistical analyses were performed using R version 3.4.0 (2017-04-21).