Differences of Recovery from Rocuronium-induced Deep Paralysis in Response to Small Doses of Sugammadex between Elderly and Nonelderly Patients

POSTOPERATIVE residual muscle paralysis is reported to lead to postoperative critical respiratory complications and severe hypoxemia.^1,2  Therefore, neuromuscular function should adequately recover after surgery through spontaneous elimination of the neuromuscular blocking agents or administration of reversal drugs such as neostigmine and sugammadex. However, tidal volume and respiratory rate may be normal, despite a clinically significant neuromuscular weakness at the hand and pharyngeal muscles.^3–5  Neostigmine has been reported to be difficult for the deep neuromuscular block reversal process because of its ceiling effect.⁶  Furthermore, neostigmine has also been reported to have muscle relaxant action when administered in patients with shallow neuromuscular paralysis or recovered neuromuscular function,^7–9  although this has not been supported by other studies.^10,11  Considering the controversial effects of neostigmine, sugammadex may be considered to be the optimal drug for selection to produce complete recovery of neuromuscular function.¹² 

Sugammadex is a modified γ-cyclodextrin designed to selectively encapsulate plasma molecules of the nondepolarizing neuromuscular blockers, such as rocuronium and vecuronium, and facilitate reduction of neuromuscular blockers at neuromuscular junctions as a result of increased gradient of the neuromuscular blocker concentration between plasma and neuromuscular junctions, leading to complete reversal of the neuromuscular blockade.¹³  However, Kotake et al., reported a 5% incidence of postoperative residual paralysis after reversal with sugammadex without neuromuscular monitoring,¹⁴  and critical cases with recurarization after recovery with sugammadex are reported.^15–19  Notably, recurarization was reported in a 78-yr-old male with mild to moderate renal dysfunction receiving sugammadex 3.6 mg/kg after confirming train-of-four count 2 with a continuous neuromuscular monitor.¹⁹  Despite its clinical importance, we lack knowledge of the mechanisms and risk factors of residual paralysis and recurarization after low-dose sugammadex administration. From the pharmacokinetics standpoint, it is expected that recurarization occurs when low dose of sugammadex is administered to patients with deep muscle paralysis as demonstrated in previous studies.^20–25  Other studies demonstrated that the elderly patients respond differently to rocuronium^26,27  and sugammadex^28,29  in comparison with nonelderly patients, suggesting age-related differences in the pharmacodynamics and pharmacokinetics of rocuronium and sugammadex. We considered that potential pharmacodynamics/pharmacokinetics differences may be assessible by the change of the train-of-four ratio (primary outcome variable) between age groups. Moreover, these differences may be magnified and revealed by administrating a low dose of sugammadex while securing the airway and ventilation under general anesthesia. Accordingly, while measuring train-of-four ratio in anesthetized elderly and nonelderly patients, we tested the hypotheses that (1) recovery from deep neuromuscular block with a low dose of sugammadex is slower (primary hypothesis); and (2) incidence of recurarization is higher in elderly patients than in nonelderly patients (secondary hypothesis).

This nonrandomized interventional observation study was approved by the institutional ethics committees (#1712: Graduate School of Medicine, Chiba University, Chiba, Japan; #262: Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan) and registered in University Hospital Medical Information Network Clinical Trial Registry (UMIN000012658). Written informed consent was obtained from each subject after the aim and potential risks of the study were fully explained. Subject enrollment in this study was started on December 24, 2013, and terminated on March 31, 2016. Inclusion criteria were adult patients older than or equal to 70 yr (elderly group) and those younger than 70 yr (nonelderly group) undergoing surgeries under general anesthesia with total intravenous anesthesia at Kimitsu Chuo Hospital. Exclusion criteria were (1) patients with severe comorbidities; (2) patients with high risk of aspiration; (3) patients with allergies to muscle relaxants, propofol, or sugammadex; (4) patients undergoing surgeries undesirable for administration of rocuronium and sugammadex; and (5) patients taking drugs that influence rocuronium and sugammadex such as antiepileptic agents, estrogen preparation, rifampicin, and verapamil.

No medication was administered before induction of anesthesia. In the operating room, an intravenous cannula was inserted in a forearm vein for administration of lactated Ringer’s solution and all drugs. Vital signs were continuously monitored with an electrocardiogram, noninvasive arterial pressure measurements, and pulse oximetry. General anesthesia was induced with fentanyl 0 to 4 µg/kg^-1, remifentanil 0.1 to 0.5 µg · kg^-1 · min^-1, and propofol target controlled infusion 3 to 5 µg/ml^-1 while patients received 100% oxygen through an anesthesia facemask. All patients received rocuronium 0.6 mg/kg^-1 intravenously, and tracheal intubation was performed after confirming train-of-four count 0. Anesthesia was maintained with propofol target controlled infusion 2 to 3 µg/ml^-1 and continuous infusion of remifentanil 0.05 to 0.7 µg · kg^{-1 ·} min^-1 while monitoring the anesthesia depth with Bispectral Index 40 to 60 (Bispectral Index, Power Link, M1034B#B01; Ireland). Oxygen saturation was maintained above 98%, and normocapnia was ensured by adjusting ventilator settings. Bladder temperature was maintained above 36°C using forced-air warming system (Bair-Hugger; Arizant Healthcare Inc., USA) and skin temperature over the adductor pollicis muscle was maintained above 32°C. Normal hemodynamics was maintained by fluid infusion and vasopressor when necessary.

Neuromuscular monitoring was performed by an acceleromyograph (TOF-Watch SXTM; Organon Ltd, Ireland). Before induction of general anesthesia, the acceleration sensor was attached to the tip of the thumb to assess contractions of the adductor pollicis muscle in response to supramaximal electrical stimulation of the ulnar nerve by using a hand adapter. All data were collected through a computer and monitored throughout the study. After loss of consciousness, the ulnar nerve was stimulated through an automatic calibration mode 2 to determine the supramaximal current intensity and to calibrate the device. Train-of-four stimulation was repeated every 15 s throughout the experiment except when deep block was assessed by the posttetanic counts mode.

After we measured spontaneous change of the neuromuscular block up to train-of-four ratio greater than 50%, we administered rocuronium 0.4 mg/kg^-1 intravenously. As illustrated in figure 1, posttetanic counts were repeated every 5 min until the target posttetanic count range (posttetanic counts between 2 and 10) was achieved. At posttetanic count greater than 10, rocuronium 0.2 mg/kg^-1 was administered, and at posttetanic count less than 2, posttetanic count recovery was observed. When the target posttetanic count range was confirmed, sugammadex was continuously infused at a rate of 50 µg · kg^-1 · min^-1 but terminated when the train-of-four count of 3 was achieved. Train-of-four ratio was repeatedly measured every 15 s for at least 30 min after cessation of sugammadex infusion. These measurements were performed while the patient was mechanically ventilated and the airway was secured by a tracheal tube under propofol anesthesia. Additional sugammadex was injected at the end of the study, and train-of-four ratio greater than 100% was confirmed before emergence from anesthesia and tracheal extubation.

As illustrated in the figure 1, we assessed train-of-four responses to the initial rocuronium injection by calculating time to train-of-four count of 0 (time to train-of-four count of 0 after initial rocuronium injection), time to the first train-of-four count of 1 emergence after initial rocuronium injection (spontaneous recovery time to train-of-four count of 1 after initial rocuronium injection), and train-of-four ratio recovery rate estimated by the slope of the train-of-four ratio linear regression for 5 min after emergence of train- of-four ratio (spontaneous train-of-four ratio recovery rate). To assess train-of-four responses to low-dose sugammadex, time to the first train-of-four count of 1 emergence after sugammadex infusion initiation (recovery time to train-of-four count of 1 in response to low-dose sugammadex), early-phase train-of-four ratio change rate estimated by the slope of train-of-four ratio linear regression for 2 min after emergence of train-of-four ratio (early-phase train-of-four ratio change rate in response to low-dose sugammadex), and late-phase train-of-four ratio change rate estimated by the slope of train-of-four ratio linear regression for 5 min after the flexion point of train-of-four ratio changes (late-phase train-of-four ratio change rate in response to low-dose sugammadex: primary variable) were used.

Previous studies reported worsening of the train-of-four ratio recurarization pattern after initial train-of-four ratio recovery.^21,24,25  In this study, we considered the late-phase train-of-four ratio change rate in response to low-dose sugammadex to be the result of pharmacokinetics/pharmacodynamics of rocuronium and low-dose sugammadex in the body, which were the primary outcome variable for testing our primary hypothesis that the recovery from deep neuromuscular block with low dose of sugammadex is slower in elderly patients than in nonelderly patients. Our secondary hypothesis was that incidence of recurarization is higher in elderly patients than in nonelderly patients. Recurarization (secondary outcome variable) was defined as a situation with negative change of the train-of-four ratio after sugammadex. Initial complete recovery of train-of-four ratio was not included in the definition because complete train-of-four ratio recovery was not expected at the low-dose administration of sugammadex.

There has been no previous study examining the change rate of rocuronium-induced muscle paralysis with a low dose of sugammadex. Murphy et al. reported train-of-four ratio to be 0.67 ± 0.2 at tracheal extubation after reversal with neostigmine.³⁰  Previous studies demonstrating upper airway dysfunctions in subjects with train-of-four ratio less than 0.8 indicates the clinically meaningful train-of-four ratio difference to be 0.2.^31,32  In order to detect the 0.2 train-of-four ratio difference between the groups with α = 0.05 (two-tailed) and β = 0.8, the suitable sample size was calculated to be 17 subjects for each group (SigmaPlot 12.0; Systat Software Inc., USA). Accordingly, 20 patients were selected for each group.

For baseline variables, summary statistics were constructed using frequencies and proportions for categorical data, and means and SDs for continuous variables. Baseline variables were compared using Fisher exact test for categorical outcomes, and Student’s t test for continuous variables. Mann–Whitney rank-sum test was used for comparisons of the neuromuscular variables between the groups. Wilcoxon signed-rank test was used to assess changes of the neuromuscular variables in the group. To assess group differences of train-of-four ratio change rate, multiplicity between the groups was adjusted by using Holm correction for multiple comparisons. The association between late-phase train-of-four ratio change rate in response to low-dose sugammadex (primary variable) and baseline variables were assessed by Spearman rank-order correlation coefficient. To determine independent explanatory variables for Late-phase train-of-four ratio change rate in response to low-dose sugammadex (primary variable), a multiple linear regression analysis was performed through the use of 4 clinically-significant background variables (SAS 9.4; SAS Institute, USA). Background variables such as patient characteristics, anesthesia and surgical procedures and results of blood biochemical examination were prospectively collected to assess potential candidates for the independent explanatory variables. The estimated glomerular filtration rate (ml/min) was calculated using the following formula: ([140 – age {years}] × ideal body weight [kg]) / (72 × serum creatinine [mg/dl]) (× 0.85 if women),³³  in which the ideal body weight is defined for men (kg) as: 50 + 0.9 × (height [cm] – 152); and ideal body weight for women (kg) as: 45.5 + 0.9 × (height [cm] – 152). All values are expressed as either mean ± SD or median (the first quartile, the third quartile). All P values were two-sided, and a value of P < 0.05 was considered statistically significant.

The study was successfully completed in 20 nonelderly and 20 elderly patients. Informed consents were obtained from 45 patients; however, two nonelderly patients were excluded because of technical failure (n = 1) and shortage of time to complete the protocol (n = 1) and three elderly patients were unable to complete the protocol because of a lack of time. No adverse events relating to the study protocol occurred during the measurements, and none had cardiorespiratory complications such as hypoxemia and hypotension during the perioperative period. Table 1 presents patient characteristics, anesthesia and surgical procedures, and results of the blood biochemical examination. Elderly patients had more comorbidities and impaired renal function than did nonelderly patients.

Figure 2 illustrates results of the neuromuscular monitoring during the study protocol in a nonelderly patient (fig. 2A: 55-yr-old female; body mass index, 18.3 kg/m^-2) and an elderly patient (fig. 2B: 76-yr-old female; body mass index, 27.3 kg/m^-2). Spontaneous recovery of rocuronium-induced muscle paralysis was delayed and slower in the elderly patient. It is notable that recurarization occurred after cessation of low doses of sugammadex infusion (37 mg) in the elderly patient, while the early-phase recovery from muscle paralysis by sugammadex was faster than spontaneous recovery in both patients. Additional sugammadex successfully normalized the train-of-four ratio in both patients.

Table 2 presents group comparison of the recovery profiles regarding time and amount of rocuronium and sugammadex required to achieve the study protocol. At same initial dose of rocuronium (0.6 mg/kg^-1), spontaneous recovery of train-of-four count of 1 was significantly delayed in the elderly group. Although a significantly lower total dose of rocuronium was administered before sugammadex infusion in the elderly group compared with the nonelderly group, the target posttetanic count range was achieved at initiation of sugammadex infusion in both groups. Furthermore, a longer period and a larger dose of sugammadex were required to achieve train-of-four count of 3 in the elderly group.

Figure 3 demonstrates mean changes of train-of-four ratio during spontaneous (fig. 3A) and low-dose sugammadex-induced (fig. 3B) recovery from muscle paralysis for each group. Slower spontaneous recovery from muscle paralysis in the elderly compared with the nonelderly group is clearly presented. While initial recovery induced by sugammadex overlaps between the groups, a recovery rate decrease was observed in both groups but was more evident in the elderly group.

Figure 4 presents group differences of train-of-four ratio change rate during recovery from rocuronium-induced deep paralysis with adjustments for multiplicity between the groups by using Holm correction for multiple comparisons. Spontaneous train-of-four ratio recovery rate was significantly slower in the elderly group (P = 0.024). While early-phase train-of-four ratio change rate, in response to low-dose sugammadex, did not differ between groups (P = 0.820), late-phase train-of-four ratio change rate in response to low-dose sugammadex was significantly slower in the elderly group (P = 0.024), which supports the primary hypothesis. Recurarization in response to low-dose sugammadex was more frequent in the elderly group (35%; 7 of 13) than in the nonelderly group (5%; 1 of 19; P = 0.044), which supports the secondary hypothesis of this study (table 2).

Table 3 presents results of univariate correlation analyses between late-phase train-of-four ratio change rate in response to low-dose sugammadex and variables of the patient’s background and neuromuscular monitoring by use of Spearman rank-order correlation. It should be noted that body mass index, renal function, spontaneous recovery time to train-of-four count of 1 after initial rocuronium injection, and spontaneous train-of-four ratio recovery rate were associated with slower recovery from muscle paralysis after low-dose sugammadex. In particular, a significant indirect association between spontaneous train-of-four ratio recovery rate and late-phase train-of-four ratio change rate in response to low-dose sugammadex is illustrated in figure 5, which also demonstrates higher incidence of recurarization in the elderly group.

Results of the multiple linear regression analysis to determine independent risk factors for late-phase train-of-four ratio change rate in response to low-dose sugammadex are presented in table 4. It is interesting that slower spontaneous train-of-four ratio recovery rate and impaired renal function are the two most contributing factors for reduction of the late-phase train-of-four ratio change rate in response to low-dose sugammadex.

We conducted a study of recurarization after low-dose sugammadex administration in anesthetized humans. We found that (1) the train-of-four ratio recovery rate after low-dose sugammadex administration was slower in elderly patients than in nonelderly patients; (2) recurarization more frequently occurred in elderly patients; and (3) slower spontaneous train-of-four ratio recovery and impaired renal function are the two most contributing factors for reduction of the train-of-four ratio change rate in response to low-dose sugammadex.

Although residual paralysis after sugammadex administration is not rare, as evident in Kotake et al.’s study,¹⁴  recurarization after sugammadex administration is not common. Table 5 presents summary of previously reported 33 cases with recurarization after sugammadex administration including 6 clinical cases with critical clinical symptoms (cases 1 to 6),^15–19  and 27 patients participating in clinical researches for determining optimal sugammadex dose (cases 7 to 33).^20–25  In the latter clinical researches, recurarization occurred in 10 to 40% of nonelderly patients after bolus injection of low-dose sugammadex. It is interesting that the recurarization incidence was much higher than that (5%) found in our nonelderly patients receiving continuous infusion of low-dose sugammadex. No previous study has compared differences of recovery characteristics after low-dose sugammadex between nonelderly and elderly patients, nor identified risk factors for recurarization or residual muscle paralysis. This study identified obesity, slower spontaneous train-of-four ratio recovery, and renal dysfunction as independent risk factors for reduction of the train-of-four ratio change rate in response to low-dose sugammadex. In agreement with this study, three of the six clinical cases were obese (cases 3, 4, and 5) and three had chronic renal dysfunction (1, 2, and 5). It is notable that muscle paralysis was irreversible even after more than the recommended dose of sugammadex was administered (cases 1, 2, and 3). Two elderly patients (cases 1 and 6) had recurarization. Administration of 3.6 mg/kg sugammadex for train-of-four count of 2 failed to reverse muscle paralysis, resulting in sustained muscle weakness and hypoxemia in the 78-yr-old patient with chronic renal dysfunction (case 1). Clinical features of the reported recurarization cases well agree with the risk factors identified in this study, supporting significance of the experimental model developed in this study for exploring mechanisms and risk factors of recurarization after sugammadex administration.

The results demonstrate that elderly patients are at greater risk for recurarization or residual muscle paralysis when low doses of sugammadex are administered. In a series of clinical studies performed by Suzuki et al., recovery from rocuronium-induced muscle paralysis is reported to be significantly slower in the elderly patients than in the nonelderly patients,²⁷  and complete reversal of deep muscle paralysis with a full dose of sugammadex takes longer in elderly patients.²⁹  Our results are consistent with their findings and add new information on possible recurarization after low-dose sugammadex administration in elderly patients.

Use of sugammadex in patients with renal dysfunction is controversial. Ninety-six percent of sugammadex molecules are excreted in urine and clearance of sugammadex and sugammadex–rocuronium complex significantly decreases in patients with moderate to severe renal dysfunction.³⁴  However, sugammadex 4 mg/kg effectively reverses rocuronium-induced deep paralysis without dose adjustment although time to complete recovery is prolonged,^35,36  and larger dose of rocuronium is necessary to paralyze patients with renal dysfunction after reversal with sugammadex. In contrast, we found the reduced estimated glomerular filtration rate to be an independent risk factor for the reduced train-of-four ratio recovery rate and recurarization when low-dose sugammadex was administered. These discrepant responses to sugammadex strongly indicate clinical importance of neuromuscular monitoring of sustained complete reversal with full dose sugammadex particularly in patients with renal dysfunction.

Despite the clinically meaningful findings in this study, there are several methodologic limitations. First, the recurarization experimentally produced by low-dose sugammadex in this study may differ from the actual clinical setting, while the risk factors appear to be overlapped as suggested by the clinical cases. Dose of sugammadex alone may not be the cause of critical recurarization as evident from the variable responses to low-dose sugammadex among the elderly patients and the recurarization cases irreversible with the recommended dose of sugammadex.^15,18,19  Second, we did not directly measure the plasma rocuronium concentration in this study. Precise pharmacokinetics/pharmacodynamics analyses are beyond the scope of this study, and we refrain from any speculations of the mechanisms of recurarization observed in this study. Future studies should measure plasma rocuronium concentration and explore detailed mechanisms of recurarization after low-dose sugammadex.

In conclusion, our study demonstrated that elderly patients are one of the high-risk population for recurarization and residual muscle paralysis as a result of low-dose sugammadex. Sugammadex dose should be determined by the neuromuscular monitoring, not by the clinical signs particularly in elderly patients with impaired renal function.

The authors thank Sara Shimizu, M.D. (Shimizu Orthopedic Plastic Surgery Clinic, Tokyo, Japan), for greatly helping to improve the language of this article.

This study was supported by Japan Society for the Promotion of Science KAKENHI Grant No. 15H04967.

Dr. Isono received payments for his lectures from MSD Japan that distributes sugammadex in Japan. The other authors declare no competing interests.