Sugammadex (SGX) is a modified cyclodextrin that antagonizes aminosteroidal neuromuscular blocking agents (NMBAs) through encapsulation.1,2 As the SGX-NMBA complex forms, NMBA is pulled into the plasma from its site of action at the neuromuscular junction because of a concentration gradient.3,4,5 The SGX-NMBA complex is hydrophilic and is excreted unchanged into the urine.4,6 As a result of this pharmacokinetic property, the United States Food and Drug Administration does not recommend using SGX as an NMBA antagonist in patients with a creatinine clearance < 30 mL·min−1.7

Sugammadex antagonizes neuromuscular blockade faster than neostigmine and reduces the risk of postoperative residual neuromuscular blockade.8,9 It also has the novel ability to reverse deep levels of neuromuscular blockade (train-of-four count < 1) and 16 mg·kg−1 SGX can rapidly restore neuromuscular function after 1.2 mg·kg−1 rocuronium has been administered.9 As a result of this drug’s novel applications and clinical efficacy, clinicians have expanded its use in various off-label scenarios such as in patients with significant renal impairment.2,5,10,11,12,13,14,15,16

In patients with reduced renal function, theoretical concerns include the effects of prolonged exposure to the SGX-NMBA complexes that remain within circulation. Cammu et al. have shown that standard convective and diffusive dialysis techniques can remove this complex.17 Nevertheless, neuromuscular blockade could recur if the circulating SGX-NMBA complex dissociates, allowing free NMBA to reach the neuromuscular junction. Additionally, delayed clearance of SGX-NMBA complex may increase the risk of hypersensitivity reactions.18 The use of neostigmine in patients with end-stage renal disease (ESRD) is also concerning as 50% of this drug is renally cleared, a characteristic that prolongs exposure to its undesired muscarinic effects.19

Anecdotally, we were familiar with SGX being used to successfully antagonize neuromuscular blockade in patients with ESRD. As such, we designed the current study to review all instances of patients receiving SGX with ESRD within our institution’s health system and to describe their clinical outcomes.

Methods

After obtaining Institutional Review Board approval (22 August 2019), electronic medical records of adult (age ≥ 18 yr) patients with chronic kidney disease stage 5 (CKD5) who underwent general anesthesia and received intraoperative SGX were identified and reviewed (Figure). The list of patients with CKD5 identified through hospital International Classification of Diseases (ICD)-9/ICD-10 codes was cross-referenced with patients receiving SGX via pharmacy data from 7 March 2016 (when SGX became available on our institution’s formulary) until 1 August 2019. Subjects who signed a waiver to exclude their medical records from research studies were excluded. CKD5 was defined, as per the National Kidney Foundation,20 as patients with glomerular filtration rate (GFR) ≤ 15 mL·min−1, with or without the need for renal replacement therapy (RRT) at the time of the procedure. Each medical record was reviewed for preoperative, intraoperative, and postoperative data up to 30 days after surgery. Patient demographics, perioperative data, and postoperative events were collected and managed using REDCap electronic data capture tools hosted at our institution.21

FIGURE
figure 1

Selection process of final study population. CKD = chronic kidney disease; NMBA = neuromuscular blocking agent; SGX = sugammadex.

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The primary outcome of the study was defined as complications that could be related to delayed clearance of SGX within 30 days following its administration. These complications included hypersensitivity reactions, the need for reintubation, hypoxemia, and pneumonia. Hypersensitivity reactions were defined as a constellation of clinical symptoms (rash, flushing, difficulty breathing, nausea, stomach discomfort, palpitations, tachycardia, hypotension, paresthesia, and visual disturbance) after administration of SGX. Need for reintubation was defined as any patient requiring endotracheal intubation within the next 30 postoperative days. Hypoxemia was defined as an oxygen saturation (< 92%) for more than five minutes measured by pulse oximetry while in the recovery room, evidence of hypoxemia discussed in hospital progress notes and discharge summaries, or oxygen arterial pressure ≤ 75 mmHg measured in an arterial blood gas analysis. Pneumonia was defined as clinical signs and symptoms suggestive of respiratory infection and confirmed by laboratory or imaging studies (e.g., sputum culture and/or chest x-ray). Each electronic medical record of a patient who had any of these complications was examined to identify the cause and the possible association with SGX use. The secondary outcome was the identification by manual chart review of any other complication that could possibly be related to SGX administration and/or patient death up to 30 days after the procedure, independent of possible association with SGX.

Statistical analysis

An analysis was conducted using descriptive statistics. Continuous variables are presented using central tendency values, including mean (standard deviation [SD]) for normally distributed data and median [interquartile range (IQR)] for skewed distribution data. Categorical data are reported as frequencies and percentages (%).

Results

There were 543,142 general anesthesia cases performed throughout our health system at three distinct geographic locations (Scottsdale, AZ; Jacksonville, FL, USA; Rochester, MN, USA) during the period from 7 March 2016 to 1 August 2019. Sugammadex was used in 73,958 cases (7.3%), 565 of which also had a diagnosis of CKD5 listed in their medical record. After excluding patients who did not have CKD5 at the time of the surgery or were < 18 yr old, and one patient with an obvious charting error, 219 patients with CKD5 who received SGX were identified as our final study population (Figure).

The mean (SD) age in our study was 61.5 (14.1) yr and 82 (37.4%) were female. Mean body mass index was 28.9 (6.8) kg·m−2. A total of 171 (78.1%) patients required routine renal replacement therapy (RRT) at the time of the procedure, 143 patients (83.6%) were on hemodialysis (HD), and 28 patients (16.4%) were on peritoneal dialysis. The mean (SD) dose of SGX was 217 (106) mg or 2.7 (1.2) mg·kg−1 (Table 1).

TABLE 1 Demographics
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Eighteen (8.2%) of the 219 patients receiving SGX experienced 25 complications included in our primary outcome (Table 2) (Appendix 1). Thirteen (5.9%) patients developed hypoxemia, 3 (1.4%) developed pneumonia, and 9 (4.1%) required reintubation within 30 days of the surgical procedure. No patients experienced a hypersensitivity reaction.

TABLE 2 Complications within 30 days after surgery
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Five of the eight patients developed hypoxemia not requiring reintubation that appeared unrelated to SGX. Three of these patients developed hypoxemia not requiring reintubation after discharge and presented to the emergency room on postoperative day 17, 18, and 26, respectively. One patient developed hypoxemia secondary to septic shock after undergoing emergent bowel resection. One patient developed hypoxemia not requiring reintubation on postoperative day 9 due to a large pleural effusion. Two patients developed hypoxemia not requiring reintubation after receiving SGX and before being dialyzed (Table 3). The etiology of hypoxemia in these patients was thought to be pulmonary edema and prolonged apnea, respectively.

TABLE 3 Patients with complications occurring after sugammadex administration and prior to next scheduled dialysis
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Two of three patients developed pneumonia that appeared unrelated to SGX. One of these patients developed airway hemorrhage from an aortoesophageal fistula on postoperative day 4. One patient developed encephalopathy, septic shock, and aspirated on postoperative day 12. One patient developed hospital-acquired pneumonia three days after the procedure. While no evidence of aspiration was noted, adequate recovery from neuromuscular blockade was not confirmed as no quantitative monitor was utilized and residual weakness could be not excluded (Table 3).

Nine patients required reintubation that appeared to be unrelated to SGX in six patients. One patient developed hypoxemia after a tracheal stent became occluded. Two patients developed septic shock six and 14 days after the procedure, respectively. One patient developed hemorrhagic shock ten hours postoperatively. As previously mentioned, one patient had airway hemorrhage after a ligation of an aortoesophageal fistula on postoperative day 4. One patient developed a myocardial infarction on postoperative day 22.

Three of the nine reintubations occurred before the patients were dialyzed. Although a careful chart review suggested that SGX was not implicated, this could not be definitively excluded (Table 3). One patient underwent a skin graft for a knee wound. The patient received 50 mg of rocuronium at induction. At the conclusion of the operation 88 min later, 2 mg·kg−1 of SGX were administered. In the postanesthesia care unit (PACU), the patient was reported to be unresponsive with an inadequate respiratory drive. Arterial gas analysis revealed hypercapnic respiratory failure and the patient needed to be reintubated 61 min after the initial extubation. A second patient underwent an inguinal hernia repair. After 40 mg of rocuronium at induction, 5.6 mg·kg−1 of SGX dose was administrated 120 min later. After extubation, the patient was noted to be somnolent and developed hypoxemia requiring reintubation 64 min after the initial extubation. The anesthesia providers documented that this respiratory failure may have been due to “residual anesthesia.” In both cases, residual neuromuscular blockade could not be definitively excluded as a contributor to respiratory failure as no quantitative monitor was utilized to confirm adequate recovery. A third patient was reintubated after undergoing a kidney transplant that required significant volume administration intraoperatively. After extubation, the patient developed hypoxemia and had to be reintubated 212 min after extubation. Chest radiograph was consistent with pulmonary edema. A quantitative neuromuscular monitor was utilized in this patient and although the anesthesia record documented train-of-four count of 4 at the conclusion of the operation, adequate recovery could not be verified as the train-of-four ratio from this quantitative monitor was not linked into the electronic medical record.

Fifty (23%) patients developed our secondary outcome of any postoperative complication within the first 30 days following surgery. The most common included bleeding (5%), need for transfusion of red blood cells (4.5%), pulmonary edema (3.2%), and arrhythmias (1.8%) (Appendix 2). Finally, nine patients (4.1%) died within 30 days of their operation (Appendix 3).

Discussion

In the current study, we found 18 of 219 patients (8.2%) with CKD5 and SGX administration that required reintubation, developed hypoxemia, or pneumonia within the first 30 postoperative days. No patients experienced a hypersensitivity reaction. A careful review determined that complications related to neuromuscular blockade management could not be excluded in six of the 18 patients; however, the authors felt it to be unlikely. These results suggest that SGX can be used as an agent for reversing aminosteroidal-induced neuromuscular blockade in patients with CKD5.

The efficacy and safety profile of SGX in CKD patients has been evaluated in several small studies.2,10,11,17 Panhuizen et al. showed a complete, rapid, and well-tolerated reversal of deep rocuronium blockade in patients with both normal renal function (n = 35) and ESRD (n = 35).2 While train-of-four ratio (TOFR) recovery from SGX is slower in patients with CKD when compared with patients with normal renal function [median recovery to TOFR 0.9 was 3.1 (95% CI, 2.4 to 4.6) vs 1.9 (95% CI, 1.6 to 2.8) min, respectively; P = 0.0002], reversal still occurs faster than with neostigmine. De Souza et al. also evaluated the efficacy and safety of SGX in 20 patients undergoing kidney transplants who had CKD stages 4 and 5, compared with 20 patients without renal failure and concluded that although the mean (SD) recovery was slower in the CKD population [5.6 (3.6) min vs 2.7 (1.3) min; P = 0.003], SGX was still effective and safe, reporting zero complications.10 While we cannot comment on the speed of reversal in our study, our results suggest a similar safety profile of SGX.

Sugammadex-induced hypersensitivity reactions have been reported and the concern has been raised about this being increased in patients with delayed renal clearance.11,18,22,23,24,25 Nevertheless, a large retrospective review from Japan of 15,479 patients found an extremely low (0.039%) incidence of anaphylaxis possibly related to SGX use.18 Similarly, Adams et al. conducted a retrospective observational study to evaluate SGX safety in 158 surgical patients with ESRD requiring RRT, and the results showed no cases of anaphylaxis.11 Our results are consistent with these previous efforts.

The recurrence of neuromuscular blockade has been described via possible dissociation of SGX from NMBA in the plasma.11 Sugammadex has a high association constant (Ka) with rocuronium (17,000–20,400 M−1), and a low dissociation rate constant (K2 = 0.00216 min−1).1,26 Such pharmacokinetics suggest that even if dissociation occurs, a rapid re-association is likely because of its strong binding force, leaving little free rocuronium available for restoring neuromuscular blockade.1,11,27 There is no evidence that this pharmacology is significantly altered in ESRD patients and prior work has failed to show recurrence of neuromuscular blockade 48 hours after SGX administration.2,5,12 We did not identify any cases of neuromuscular blockade recurrence in our study, although universal quantitative monitoring was not utilized in our study population.

Pulmonary complications, including hypoxemia, the need for reintubation, and pneumonia, are frequently related to residual NMB.5,28 Our incidence of 5.9% was slightly higher than the reported incidence of 3.1% in patients with GFR < 30 mL·min−1·1.73 m.2,29 Moreover, the general incidence of any postoperative complication in CKD patients ranges from 15% to 64%.30,31 Our incidence of 22.8% is comparable with reported data of 23.5% of complications after 30 days of a major abdominal surgery in patients requiring hemodialysis.32 The overall reported mortality of CKD patients ranges from 1% in non-cardiac patients to up to 20% for cardiac patients.29,32,33,34,35 Our postoperative mortality of 4.1% was lower than previous descriptions of ESRD patients. While the present work cannot attribute reduced mortality to the use of SGX instead of neostigmine, SGX use has been associated with reductions in postoperative complications in patients with normal renal function.8,36

This study was conducted at three distinct geographic locations within one health system. One site had a higher utilization of SGX in CKD5 patients per total number of anesthetics compared with the other two sites. Of note, this site frequently uses quantitative neuromuscular monitoring as a result of local interest and investigations related to NMBA and monitoring. Unfortunately, such objective measurements were not automatically transferred into the medical record at the time of the study, a shortcoming that has since been remedied. The authors agree with a recent consensus statement that recommends quantitative monitoring whenever a NMBA is administered.36 This practice would significantly reduce the risk of residual blockade-related complications, especially in vulnerable populations such as CKD patients.

There are multiple limitations to our study. First, the use of SGX in CKD5 patients should be considered “off-label”. In March 2016, SGX was introduced to our hospital formulary and became a frequently utilized NMBA antagonist, even in patients with CKD. Additionally, this retrospective review is subject to the limitations of any chart review and we indeed discovered one obvious charting error, in which the provider documented 1/10 of the normal dose of SGX, and had to be excluded from the final data analysis. Also, this study is limited by a relatively small sample size (n = 219), and we investigated infrequent outcomes such as reintubation. Nevertheless, to our knowledge, this study represents the largest cohort and longest follow-up of patients with CKD5 receiving SGX. Finally, the lack of a historical cohort for comparison limits the ability to assess the complication rate of CKD5 patients who received SGX compared with those who received conventional reversal with neostigmine.

In conclusion, 18 of 219 (8.2%) patients with ESRD developed postoperative pneumonia, hypoxemia, or required reintubation after SGX administration. While the majority of these complications appeared unrelated to neuromuscular blockade management, we could not definitively exclude SGX as a contributing factor in six of the 18 patients. Nonetheless, we felt that it was unlikely that administering SGX to these patients with ESRD significantly contributed to their postoperative complications. We recommend the routine use of quantitative neuromuscular monitoring when NMBA are employed, an effective practice to reduce postoperative complications associated with NMB.37 Prospective studies are needed to make recommendations about the clinical impact of SGX in ESRD. We provide incremental evidence that SGX could be considered as a neuromuscular blockade reversal agent in patients with ESRD.