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 et al. 2008; Staals et al. 2010) and deep (Cammu et al. 2012; de Souza et al. 2015; Panhuizen et al. 2015) rocuronium-induced NMB. No complications definitely, probably, or possibly related to the reversal drug have been reported (Staals et al. 2008; Staals et al. 2010; Cammu et al. 2012; de Souza et al. 2015; Panhuizen et al. 2015). In patients undergoing kidney transplantation, successful use of sugammadex for reversal of moderate rocuronium-induced NMB has been reported by retrospective observational studies (Unterbuchner, 2016; Ono et al. 2018; Arslantas and Cevik, 2019; Adams et al. 2020; Paredes et al., 2020; Vargas et al. 2020). Potential effects of sugammadex, or sugammadex-rocuronium complex, on renal function and the risk of postoperative recurrence of NMB are the main concerns about the rocuronium-sugammadex strategy in subjects with ESRD, including those undergoing kidney transplantation.
After administration, sugammadex (and sugammadex-rocuronium complexes) is renally excreted (Bom et al. 2009; Staals et al. 2010). In a pharmacokinetic study, excretion of (14)C-labeled sugammadex was rapid, with around 70% of the dose excreted within 6 h and around 90% within 24 h. Consequently, the major route of elimination of rocuronium changes from the hepatic to the renal route (Peeters et al. 2011). In patients with ESRD, total plasma clearance of sugammadex was 17 times lower and mean elimination half-life was 16 times higher in the renal failure group compared to control (Staals et al. 2010). Therefore, administration of sugammadex after rocuronium results in lengthened exposure of renal glomeruli and tubules to sugammadex and sugammadex-rocuronium complexes, leading to their hypothesized role in the renal impairment after surgery (Bostan et al. 2011). However, cyclodextrins are highly water-soluble cyclic oligosaccharides without intrinsic biological activity; it is therefore unlikely that side effects will occur after administration (Staals et al. 2011). Toxicity studies on γ-cyclodextrins have shown that the drugs are well tolerated and elicit no toxicological effects (Munro et al. 2004). Also, sugammadex, belonging to the family of γ-cyclodextrins, is biologically inactive and, administered at the recommended dose, has been shown to be well tolerated in patients with renal impairment (Staals et al. 2008; Staals et al. 2010; Cammu et al. 2012; de Souza et al. 2015; Adams et al. 2020; Paredes et al., 2020). In an experimental study, only sugammadex administered at a higher dose (96 mg/kg) than recommended (≤ 16 mg/kg) resulted in a significant increase of histopathological changes in the rat kidney (dilatation, vascular vacuolation and hypertrophy, lymphocyte infiltration, and tubular cell sloughing) compared to the control group (Bostan et al. 2011). Similar findings were reported in streptozotocin-induced diabetic rats. Diabetic nephropathy predisposes to changes in kidney tissues, including inflammation, degeneration, necrosis, tubular dilatation, tubular cell degeneration, dilatation in Bowman’s space, tubular hyaline casts, and lymphocyte infiltration. In renal tissue samples, a significant increase in histopathological changes was found after sugammadex 96 mg/kg but not sugammadex 16 mg/kg treatment compared to diabetic control (Kip et al. 2015). These results suggest that, at recommended doses, sugammadex does not significantly impact renal function (Bostan et al. 2011), also in case of diabetic nephropathy (Kip et al. 2015). In a dose-finding and safety study in adult patients, abnormal levels of N-acetyl-glucosaminidase were only found in 5 of 20 patients included in the intent-to-treat population and safety population (Sorgenfrei et al. 2006). However, changes in urinalysis were reported in the active treatment groups (sugammadex 0.5-4.0 mg/kg) as well as in the placebo group but 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 desflurane/opioid anesthesia who received neostigmine 40 μg/kg and sugammadex 4 mg/kg to reverse rocuronium-induced NMB, renal glomerular filtration and tubular functions were minimally affected. However, these effects were greater with neostigmine than with sugammadex. No significant changes were observed for serum creatinine and urea levels between the two groups. Instead, in urinalysis, the postoperative value of cystatin C, a specific marker of glomerular function, was found to be significantly higher in the neostigmine group compared to the sugammadex group (Isik et al. 2016). Comparing the rocuronium-sugammadex strategy to the cisatracurium-neostigmine strategy in adult patients, significant differences were found only in urinalysis, with N-acetyl-glucosaminidase higher in the rocuronium-sugammadex group, and β2-microglobulin higher in the cisatracurium-neostigmine group (Flockton et al. 2008).
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 confirmed the advantage of the rocuronium-sugammadex over the cisatracurium-neostigmine strategy not only in improving postoperative kidney function (Vargas et al. 2020) but also in promoting a better general recovery, independently from the level of NMB at the end of surgery. This may be explained by different impacts of the two reversal drugs on renal function (Munro et al. 2004; Sorgenfrei et al. 2006; Flockton et al. 2008; Staals et al. 2011; Bostan et al. 2011; Kip et al. 2015; Isik et al. 2016; Büyükfırat et al. 2018; Vargas et al. 2020), a restoration of glomerular filtration after surgery that minimizes the stasis of the sugammadex (and rocuronium-sugammadex complex) in the glomeruli and tubules (Bostan et al. 2011; Kip et al. 2015; Vargas et al. 2020), and a potential protective effect of sugammadex against ischemia-reperfusion injury (Vargas et al. 2020). In an experimental study, sugammadex 16 mg/kg and 100 mg/kg, administered to evaluate the benefit of cyclodextrins against transient global cerebral ischemia, showed a dose-dependent neuroprotective effect in a transient global cerebral ischemia/reperfusion rat model (Ozbilgin et al. 2016). In the postoperative period, the transient increase of serum urea, which peaked on the third day after surgery, may be due to the catabolic effects of corticosteroids administered perioperatively to prevent graft rejection and of diuretics (Vargas et al. 2020).
Serum creatinine level significantly decreased over time after kidney transplantation. The recipient’s age was negatively associated with their postoperative serum creatinine values. No significant association was found between serum creatinine levels and the recipient’s BMI, gender, or history of dialysis (Younespour et al. 2016). On the basis of our analysis, postoperative serum creatinine significantly depends on preoperative values. Most importantly, the drugs involved in NMB management had no effect on serum creatinine. A positive association has been shown between serum creatinine levels and graft failure, which means that graft failure is more likely to occur in patients with higher postoperative serum creatinine levels (Younespour et al. 2016; Maraghi et al. 2016). A one-unit increase in the serum creatinine level was found to be associated with a four- (Younespour et al. 2016) or five-times (Maraghi et al. 2016) higher risk of graft failure.
A high affinity of rocuronium to sugammadex allows the guest-host complex to exist in equilibrium with a very high association rate (an association constant of 107 M−1) and a very low dissociation rate, so the complex is tight, and recurrence of NMB is highly unlikely (Bom et al. 2009). The absence of recurrences of NMB observed in our large cohort of patients supports the safety of the rocuronium-sugammadex strategy in kidney transplantation and confirms the findings from other observational studies. Ono et al. (2018) reported a successful use of sugammadex in 99 consecutive patients undergoing kidney transplantation, Adams et al. (2020) in 48 patients, and Vargas et al. (2020) in 30 patients, without recurrences of NMB. Interestingly, among 158 patients with ESRD undergoing a surgical procedure, sugammadex was administered to 24 patients (18%) who had initially been reversed with a standard dose of neostigmine (70 μg/kg up to a maximum dose of 5 mg) for residual NMB, with immediate and full reversal of muscle strength loss and successful tracheal extubation at the end of surgery (Adams et al. 2020). A more favorable recovery after sugammadex compared to neostigmine is supported by the literature. Recovery to TOFR > 1.0 is recommended when acceleromyography is used (Eikermann et al. 2007). Although TOFR ≥ 0.9 indicates adequate recovery from NMB, it does not necessarily mean that neuromuscular function has returned to normal and may increase the risk of upper airway obstruction, hypoventilation, hypoxia, and other postoperative respiratory complications (Eikermann et al. 2007; Blobner et al. 2020). Tracheal extubation in patients with TOFR > 0.95 has been shown to reduce the adjusted risk of postoperative pulmonary complications compared to extubation at TOFR > 0.9 (Blobner et al. 2020). Both quantitative monitoring of neuromuscular function and an appropriate dosage of reversal drug titrated to the level of NMB concur with a full reversal (TOFR ≥ 1.0) and an improvement of patient outcomes (Eikermann et al. 2007; Blobner et al. 2020). Compared to neostigmine, sugammadex has been associated with lower risk of postoperative complications (Carron M, Baratto F 2016) and a better recovery profile that allows faster discharge from the operating theater and PACU (Carron et al. 2020) and reduced risk of ICU admission (Carron M, Baratto F 2016).
This study has some limitations. First, it is not a randomized controlled study and therefore has the drawbacks of all observational studies. The evidence of non-inferiority may warrant a specific prospective, randomized clinical trial. Second, the temporal factor may be a potential bias, even if the majority of patients were recruited close to the change in strategy for NMB management and no changes in the surgical team or perioperative care were adopted in the study period. Third, we were unable to compare the exact values of TOFR ≥ 0.90 before extubation, which might cause an unmatched level of recovery after reversal of neuromuscular block at the time of extubation between the two study groups. Fourth, more specific markers (e.g., cystatin C, N-acetyl-glucosaminidase, α1-microglobulin, β2-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.
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