Sugammadex, a neuromuscular blockade (NMB) reversal agent, binds strongly with neuromuscular blocking agents (NMBAs), including rocuronium, by encapsulating them in the blood and is excreted by the kidney in the form of a stable complex, resulting in the rapid and complete reversal of the NMB [1].

Concomitant renal dysfunction in patients with end-stage renal disease (ESRD) affects the pharmacokinetics (PKs) of non-depolarizing NMBAs, making neuromuscular function recovery prolonged or unpredictable. Therefore, when sugammadex is administered to patients with severe renal impairment, sugammadex or sugammadex–rocuronium complex is not excreted by the kidneys, posing a high risk of long-term exposure to the free sugammadex or complex (continuously present in high concentrations in the blood). The use of sugammadex is not currently recommended in this patient group due to the risk of prolonged NMB state (presence of residual NMB) and recurarization or anaphylactic reactions in the postoperative period [2]. Sugammadex is not recommended by the US Food and Drug Administration for patients with a creatinine clearance of less than 30 ml/min [3]. Furthermore, the Korean Ministry of Food and Drug Safety does not recommend the administration of sugammadex to patients with severe renal impairment (creatinine clearance of less than 30 ml/min) or patients requiring dialysis.

Nevertheless, there are cases where a combination of rocuronium and sugammadex is necessary for proper NMB management under anesthesia in surgical patients with chronic kidney disease in various clinical situations (such as surgery with very short operation time, including laryngeal microsurgery). Additionally, there are problems associated with the supply of benzylisoquinolinium-type NMBAs, their side effects and limitations. For these reasons, recently, it is common for patients with ESRD to be prescribed a combination of rocuronium and sugammadex. Therefore, considering this situation, it is necessary to comprehensively review and analyze studies on the administration of sugammadex in patients with ESRD.

Several prospective case-control studies, retrospective cohort studies, and case reports on the administration of sugammadex in patients with ESRD (or patients undergoing kidney transplantation) have been reported. A systematic review and meta-analysis [4], presented data analysis results on its efficacy and safety by synthesizing and integrating the results of studies reporting the use of sugammadex, and a retrospective study that investigated relatively long-term mortality [5], were reported. Table 1 shows the characteristics and results of the relevant studies.

Several prospective case-control studies on the administration of sugammadex in patients with ESRD have been reported, with some administrating sugammadex 2.0 mg/kg for reversal of moderate NMB [6,7], while others administered sugammadex 4.0 mg/kg for reversal of deep NMB [8,9]. Staals et al. [6,7] reported the results of a phase III trial conducted to determine the efficacy, safety, and PKs of sugammadex in patients with ESRD by dividing them into pharmacodynamic and safety findings [6] and PK findings [7], respectively.

Staals et al. [7] investigated the effect of ESRD on the PKs of sugammadex and rocuronium, and on the elimination of rocuronium encapsulated by sugammadex in patients with ESRD and controls using plasma and urine sampling at various times up to 48–72 h after sugammadex administration. Panhuizen et al. [9] collected blood samples from patients with ESRD and controls to assess rocuronium and sugammadex concentrations at various times up to 24–48 h after sugammadex injection. Min et al. [10] compared PKs of a single IV dose of sugammadex in patients with moderate and severe renal impairment to healthy patients.

Total plasma clearance of sugammadex in patients with ESRD was significantly lower than that in healthy controls [7,10]. Total plasma clearance of rocuronium in patients with ESRD was significantly lower than that in healthy controls [4]. Additionally, the effect of renal impairment on total plasma clearance was found to be greater with sugammadex than with rocuronium [7].

Staals et al. [7] reported significant differences in the PKs of sugammadex and rocuronium between patients with ESRD and healthy controls, with ESRD having a greater effect on sugammadex PK variables than those of rocuronium. The reason is that extrarenal clearance of rocuronium can occur in patients with ESRD, and even after encapsulating rocuronium with sugammadex, unbound rocuronium undergoes hepatic metabolism and elimination. Therefore, the total plasma clearance of rocuronium is less affected by renal impairment than sugammadex. The greater effect of renal impairment on total plasma clearance of sugammadex compared to rocuronium suggests that plasma concentrations of sugammadex remain relatively high in patients with ESRD during the postoperative period. Therefore, the possibility of the existence of unbound rocuronium is reduced, and in this situation, if the stability of the sugammadex–rocuronium complex is guaranteed, the risk of recurarization with free rocuronium may be low [4].

In addition, the plasma concentration of rocuronium 12 h after sugammadex injection was significantly higher in patients with ESRD [7,9]; however, this was due to the limitations of liquid chromatography–mass spectrometry to measure the plasma concentration of sugammadex and rocuronium. Because this assay cannot distinguish between encapsulated rocuronium (sugammadex–rocuronium complex) and free rocuronium, high plasma concentrations of rocuronium in patients with ESRD measured after sugammadex administration do not represent plasma concentrations of pure unbound (free) rocuronium [7,9,11,12]. Fortunately, a sugammadex–rocuronium complex may exist in equilibrium with a low dissociation constant because of strong binding [13]. However, it is unknown how long sugammadex–rocuronium complexes stably exist in the blood and whether changes in the binding force occur in patients with ESRD. If the internal environment in which the binding force of the sugammadex–rocuronium complex is reduced in these patients, the risk of fatal complications, including recurarization, still exists. Furthermore, given that the sugammadex–rocuronium complex was found in the body for a longer period in patients with ESRD (when considering the report for prolonged sugammadex–rocuronium complex exposure in patients with ESRD [9]), and there are no reported clinical data for the long-term distribution and elimination of this complex in their body, further PK studies with longer follow-up periods should be conducted.

In a situation where the stability of the sugammadex–rocuronium complex and the PK process in the body are unclear in patients with ESRD, the following study results related to the dialysability of this complex by high-flux dialysis in patients with severe renal impairment are encouraging. Cammu et al. [14] evaluated the dialysability of sugammadex and the sugammadex–rocuronium complex in six patients with acute severe renal impairment in the intensive care unit (ICU). All patients received rocuronium 0.6 mg/kg, followed by sugammadex 4.0 mg/kg 15 min later. Rocuronium and sugammadex concentrations in the plasma and dialysate were measured before, during, and after high-flux dialysis. The reduction ratio (the reduction extent of the plasma concentration at the end of a dialysis episode compared to that before dialysis) and dialysis clearance in plasma and dialysate were calculated for each dialysis episode. They reported that the mean plasma concentrations of sugammadex and rocuronium were reduced by 69% and 75% during the first dialysis episode, respectively, with reductions of approximately 50% during subsequent dialysis episodes. The mean dialysis clearance of sugammadex and rocuronium in the blood were 78 and 89 ml/min, respectively. Therefore, they concluded that in patients with severe renal impairment, hemodialysis using high-flux dialysis could be effective in removing sugammadex and sugammadex–rocuronium complex. According to the findings of this study, in patients with ESRD who have been receiving renal replacement therapy, including hemodialysis before surgery, if hemodialysis using a high-flux dialysis method is performed in the patients within 24–48 h after surgery, the sugammadex–rocuronium complex can be effectively removed, which further reduces the risk of postoperative complications, such as recurarization [4].

Reliable and sufficient reversal of NMB is important in patients with ESRD undergoing renal transplantation, to prevent microaspiration because of their perioperative immunosuppressed status. Therefore, there is no doubt about selecting a more effective and safer NMB reversal agent and providing proper NMB management using quantitative neuromuscular monitoring to measure neuromuscular function during anesthesia and to reduce postoperative residual NMB or recurarization [18].

Ono et al. [19] studied 99 consecutive patients who had undergone living renal transplantation. They investigated the efficacy and complications of sugammadex in the first 48–72 h in the surgical ICU and during 6 months follow-up period. In their study, no AEs, including recurarization, were recorded during the observation period following sugammadex administration. Although 14 (14.3%) patients had severe renal impairment (eGFR < 30 ml/min) on postoperative day 5, there were no signs of recurarization. Therefore, they concluded that the sugammadex–rocuronium complex may be excreted without detachment in their setting after renal transplantation and may remain stable for a long time in patients with renal transplants. In addition, considering that no patients required additional sugammadex injection at a dose of more than 4 mg/kg in their study, they recommended a dose of sugammadex 4 mg/kg to achieve complete recovery from deep NMB in patients with ESRD. Moreover, they emphasized that anesthesiologists should pay attention to the titrating amount of sugammadex while avoiding unnecessary overdoses, although no allergic reaction was observed in their study.

Sugammadex’s effect on grafted (transplanted) kidney function is important and warrants further investigation, in addition to its efficacy and safety in patients undergoing renal transplantation. Given that sugammadex can interact with corticosteroids, which play an important role in immunosuppression in patients undergoing renal transplantation, Arslantas et al. [20] retrospectively investigated whether there are any differences in grafted kidney function in recipients of renal transplantation when sugammadex or neostigmine is administered to the recipient. They reported no significant differences in serum creatinine values, the incidence of acute rejection episodes, graft failure, length of hospital stay, mortality, and graft survival rates until postoperative day 28 between recipients reversed with sugammadex and those reversed with neostigmine. Nevertheless, they suggested that considering the sugammadex–corticosteroid interaction and its long-term effects on immunosuppression and grafted kidney function, current safety data are insufficient to support the recommendation of routine sugammadex use in patients undergoing renal transplantation.

Vargas et al. [21] compared the effects of rocuronium and sugammadex on transplanted kidney function to cisatracurium and neostigmine. They reported that blood creatinine levels at 6, 12, and 24 h were significantly lower in the rocuronium–sugammadex group than in the cisatracurium–neostigmine group and that there were no significant differences between the two groups in blood sodium and potassium, diuresis, urinary sodium, and potassium levels before and after transplantation. They concluded that the administration of rocuronium and sugammadex during renal transplantation did not affect the grafted kidney function in the first week after transplantation.

Recently, Carron et al. [22] reported a single-center, 2014–2017 retrospective cohort case-control study that compared the impact of rocuronium–sugammadex versus cisatracurium–neostigmine on grafted kidney function in patients with renal transplants. The study included 350 patients who underwent renal transplantation and were equally divided into a sugammadex group (175 patients) and a neostigmine group (175 patients). The study showed that serum creatinine and serum urea levels were lower, while eGFR was higher in the sugammadex group than in the neostigmine group after transplantation. The sugammadex group showed a significantly lower incidence of severe postoperative hypoxemia, shorter post-anesthesia care unit stay, and reduced ICU admissions. They concluded that the rocuronium–sugammadex combination for NMB management showed a better-grafted kidney function and recovery profile and fewer AEs than cisatracurium–neostigmine in patients undergoing kidney transplantation.

A few prospective observational studies using sugammadex in patients with ESRD have been reported [6-10]. Regarding the method of evaluating safety-related results, each study had various reporting outcomes and observation periods related to adverse reactions. In some studies, there was insufficiently detailed mention of safety results. Thus, more prospective observational studies are needed to evaluate sugammadex-related efficacy and safety in patients with ESRD. Although several high-quality retrospective cohort studies have been reported recently [15,16,19], additional large-scale retrospective studies, including more robust safety-related data, such as, data associated with recurarization, anaphylactic reactions, long-term morbidity and mortality, and sugammadex-related cardiovascular complications, including bradycardia associated with hyperkalemia, which can occur frequently in patients with ESRD, are needed.

Magoon et al. [23] hypothesized that sources of concern with sugammadex in patients with ESRD include the possible instability of rocuronium-sugammadex binding, prolonged clearance times for rocuronium and sugammadex, difficult dosing of sugammadex for deep NMB, and sugammadex-related bradycardia. The cardiovascular adverse effects of sugammadex include corrected QT interval prolongation, atrioventricular block, atrial fibrillation, hypotension, and asystole associated with sugammadex warrant caution and further studies to examine its safety [24]. Most importantly, when administering rocuronium and sugammadex to patients with ESRD, it is essential to determine the depth of NMB during surgery using a quantitative neuromuscular monitoring device and to determine the appropriate dose of sugammadex accordingly. If such quantitative neuromuscular monitoring is not performed, it is difficult to rule out the possibility of residual NMB [23].

Comparing and observing the sugammadex-administered group and the neostigmine-administered control group in patients with ESRD would be a more efficacious for identifying sugammadex-related complications.

The use of several types of sugammadex, including many generic sugammadex, will gradually increase as only rocuronium is available in the supply of NMBAs worldwide. Considering the current limitations in terms of the effectiveness and safety of sugammadex in patients with ESRD, close patient monitoring through quantitative neuromuscular monitoring is more important. In addition, various international societies of anesthesiologists and pharmaceutical companies need to solve the supply problem of benzylisoquinolinium-type NMBAs (e.g., mivacurium, atracurium, and cisatracurium).

Recently, an experimental study showed the histochemically detectable nephroprotective effect of sugammadex in an ischemia-reperfusion rat model [25]. Considering the effect of sugammadex on renal function in patients with reduced renal function or in those undergoing renal transplantation, experimental and clinical studies on the renal protective effect of sugammadex will be valuable in the future.

Based on this review, we intend to present the minimum recommendations applicable to actual clinical settings for patients with ESRD undergoing general anesthesia as follows:

1. Quantitative NMB monitoring is mandatory for patients with ESRD because their responses to rocuronium and sugammadex may be more unpredictable and incomplete than those of healthy patients.

2. Considering the unresolved issue of sugammadex dosing, especially for deep NMB, moderate NMB and the corresponding sugammadex dose are recommended.

3. In patients with ESRD who have undergone hemodialysis before surgery, hemodialysis using a high-flux dialysis method within 24–48 h after surgery may be helpful. Patients who do not undergo hemodialysis require closer monitoring for a longer period to prevent postoperative complications.

4. Considering the potential risk of cardiopulmonary complications in patients with ESRD, close monitoring, including electrocardiogram, oxygen saturation, blood pressure, and blood tests for electrolytes, are required during the perioperative period.

5. A rocuronium-sugammadex combination is feasible for NMB management in patients undergoing renal transplantation. Nevertheless, routine sugammadex use is not yet recommended because of the unresolved issues of sugammadex-corticosteroid interaction and its long-term effects on immunosuppression and grafted kidney function.

Considering real clinical situations, including the discontinuation of the benzylisoquinolinium-type NMBAs, the use of sugammadex in clinical practice for NMB management cannot be avoided to achieve safe and complete neuromuscular recovery in patients with ESRD or patients with renal transplants after rocuronium administration.

Sugammadex can effectively and safely reverse rocuronium-induced NMB in patients with ESRD; however, the recovery of neuromuscular function in these patients is significantly slower than that in patients with normal renal function. However, the difference in the recovery rate was insufficient to be clinically significant. Considering the insufficient amount of reported data to date, more extensive data are required on the efficacy and safety of administration of sugammadex in patients with ESRD, especially safety-related results, including postoperative residual NMB, recurarization, and incidence of cardiopulmonary complications, and a problem in the dosing for reversal of deep NMB. Furthermore, it is important to perform appropriate quantitative neuromuscular monitoring during general anesthesia of patients with ESRD in actual clinical settings. Anesthesiologists should remember that it is essential to confirm the depth of perioperative NMB through neuromuscular monitoring, administer an appropriate dose of sugammadex, and closely monitor the recovery of neuromuscular function.