Introduction

Sugammadex rapidly reverses neuromuscular blockade via selective encapsulation of rocuronium and other nondepolarizing aminosteroid muscle relaxants. Since its 2010 launch in Japan, sugammadex has been administered to an estimated 12.32 million patients over 8 years. Sugammadex has contributed to safe and effective management of muscle function by reducing the risk of postoperative residual neuromuscular blockade (sugammadex 1–4% vs neostigmine 25–60%).¹ However, the Safety Committee of the Japanese Society of Anesthesiologists (JSA) released a warning in 2019 highlighting the need for correct sugammadex dosing.² This warning was based on 36 cases of recurrence of neuromuscular blockade (recurarization) reported by the end of 2018 in Japan. The appropriate dose of sugammadex should be determined based on the patient’s body weight and depth of neuromuscular blockade (Table 1). Moreover, the anesthesia professional should check for signs of anaphylactic reactions and recurarization after sugammadex injection while monitoring for full neuromuscular recovery.

Table 1. Recommended Doses of Sugammadex for Reversal of Neuromuscular Blockade Based on Neuromuscular Monitoring¹²

Level of Neuromuscular Blockade	Sugammadex Dose12 (mg/kg)
Moderate (Reappearance of T2 in response to TOF stimulation)	2
Deep (At reappearance of 1 or 2 PTCs)	4
Immediate reversal of neuromuscular blockade (3 minutes after an intubating dose of rocuronium bromide)	16

T2, second twitch. TOF, train-of-four. PTC, post-tetanic count.

Many incidents reported in Japan involved inappropriate dose determination (lack of neuromuscular monitoring) and insufficient postdose management. Perioperative neuromuscular monitoring with a quantitative device, which measures and displays a train-of-four (TOF) ratio, is the gold standard for avoiding postoperative residual neuromuscular blockade.³ Quantitative muscle relaxation monitoring is a method for evaluating the degree of muscle relaxation objectively using accelerometer, electromyograms, etc., in conjunction with electric nerve stimulation. Quantitative monitoring enables evaluation of whether the TOF ratio, which is an index of recovery from muscle relaxation, is greater than 0.9. Evaluation of a deeper degree of muscle relaxation, using the Post-Tetanic Count (PTC) is also possible. Qualitative monitoring is based on an anesthesia professional’s subjective judgment with palpating or observing muscle contractions using a device with only a nerve stimulation function. While it may be possible to obtain an approximate TOF count, it is not possible to obtain the precision crucial for distinguishing exact TOF ratios, for example, between 0.8 and 0.93.

However, a survey showed that quantitative monitors were available to only 22.7% of anesthesia practitioners in the United States.⁴ In addition, the use of qualitative or quantitative monitors is not common in Japan. In most cases, anesthesia professionals subjectively judge recovery of muscle relaxation based on clinical signs. Since the availability of neuromuscular monitors is likely to be similar in Japan and the United States, the lack of appropriate perioperative monitoring may be a major cause of inappropriate dosing of neuromuscular blockade.

Recurarization

Recurarization, or a rapid increase in neuromuscular blockade after a period of recovery, was reported in the past with the use of acetylcholinesterase inhibitors, but is increasingly being reported with sugammadex, where muscle strength appears to recover more reliably. Elveld et al. reported recurrence of neuromuscular blockade during reversal with a small dose of sugammadex at a PTC of 1 (i.e., deep muscle relaxation).⁵ In a subsequent clinical case report, an obese patient experienced recurarization due to an insufficient dose of sugammadex that necessitated tracheal re-intubation after a TOF ratio of 0.9 was observed prior to extubation for the first time.⁶

Mechanism of Recurarization

Even when muscle relaxant molecules occupy 75% of the nicotinic acetylcholine receptors at the neuromuscular junction, normal neuromuscular transmission is achieved because the remaining 25% of receptors allow for normal muscle strength.⁷ Thus, the neuromuscular junction has a large safety factor under various physiological conditions. In the case mentioned above, muscle strength was apparently normal. However, in the presence of low concentrations of muscle relaxants, recurarization may occur with the onset of respiratory acidosis, administration of magnesium or aminoglycoside antibiotics, or other factors that decrease the safety factor. Some rocuronium molecules remain unbound in the central compartment in some patients who receive an insufficient dose of sugammadex. These free molecules may redistribute to the peripheral compartment, migrate to the neuromuscular junction, and cause further muscle relaxation.

Two Cases of Recurarization

Case No. 1. A 70-year-old, 71-kg male patient underwent ureterectomy. The patient had chronic renal insufficiency. In total, 240 mg of rocuronium was administered during anesthesia, which lasted for 7 hours and 33 minutes. Sugammadex 200 mg was administered 87 minutes after the last 20-mg dose of rocuronium. The patient resumed spontaneous respiration. The patient was responsive to verbal communication and extubated. No neuromuscular monitoring was performed. Fifteen minutes after the patient was moved to the post-anesthesia care unit (PACU), he stopped breathing and reintubation was performed. The neuromuscular monitor displayed a TOF count of 3. Upon administration of another 200-mg dose of sugammadex, body movements reappeared, spontaneous respirations resumed, and no signs of recurarization were observed thereafter.

Case No. 2. An 80-year-old, 61-kg male patient underwent surgical abdominal aortic aneurysm repair. Rocuronium (50 mg) was administered for endotracheal intubation and 25-mg doses were injected at 30-minute intervals starting at 1 hour after intubation. No neuromuscular monitoring was performed. Fifty minutes after the last 25-mg dose of rocuronium was administered, 200 mg of sugammadex was injected in the absence of consciousness and spontaneous respirations. Following the administration of sugammadex, weak spontaneous breathing was noted. The patient was responsive to verbal communication, extubated, and transferred to the PACU. Fifteen minutes after extubation, breathing stopped. Spontaneous respiration was restored immediately after an additional 200-mg dose of sugammadex was injected.

Neuromuscular Monitoring and Correct Use of Sugammadex

Neuromuscular monitoring was not performed intraoperatively or before administration of sugammadex in either case. These cases show the occurrence of recurarization in elderly patients with presumably high rocuronium sensitivity due to pharmacokinetic and pharmacodynamic factors. Recently, there is a trend to administer relatively large doses of rocuronium to maintain deep relaxation because deep neuromuscular blockade may result in improved operative conditions for laparoscopic surgery compared with moderate blockade.⁸ Given the risk of rocuronium overdosing, deep neuromuscular blockade should be assessed using intraoperative neuromuscular monitoring. If rocuronium overdose results in profound muscle relaxation and disappearance of the twitch response, it is important to wait for spontaneous recovery (initially assessed based on PTC). In the two cases described earlier, one vial of sugammadex (200 mg) was administered on a routine basis in the absence of neuromuscular monitoring, which led to under dosing and eventual recurarization.

Revised JSA Guidelines for Monitoring During Anesthesia

As compared with earlier editions, the 2019 revision of the JSA Guidelines for Monitoring During Anesthesia included a more definitive recommendation on the use of neuromuscular monitoring: “Neuromuscular monitoring should be performed in patients receiving muscle relaxants and their antagonists.”⁹ This recommendation replaced the previous version: “Neuromuscular monitoring should be performed where appropriate.” Although no specific monitoring methods were mentioned in the latest edition, the use of a quantitative neuromuscular monitor is desirable in all cases. Qualitative and semi-qualitative neuromuscular monitoring methods, such as clinical muscle function tests (e.g., 5-second head lift and sustained hand grip), can only detect TOF ratios of 0.4 or less and do not correlate with a TOF ratio of 0.9, a threshold indicating the absence of residual paralysis.¹⁰ Perioperative evaluation and management of deep muscle relaxation during anesthesia requires neuromuscular monitoring based on PTC or other reliable parameters.³

Increasing the Use of Neuromuscular Monitoring

Japan’s national medical insurance system does not promote the use of neuromuscular monitoring in clinical settings because it does not reimburse for the medical expenses incurred by neuromuscular monitoring. In addition, the sale of the stand-alone portable acceleromyography (AMG)-based devices has been discontinued. This has significantly narrowed the range of options, discouraging the purchase of new monitors. However, several new quantitative neuromuscular monitors have been launched in the market and are attracting the interest of anesthesia professionals. New device types include electromyography-based monitors, AMG-based monitors that employ new measurement algorithms (3-dimensional accelerometer), and monitors that comprise a modified blood pressure cuff with neuromuscular electrodes on the inside.¹¹ The advantages of these new models include ease of calibration, ease of use, and presence of adaptive mechanisms to compensate for postural changes. However, given their short post-launch duration and high cost, the medical community is waiting for quality products with time-tested reputations and competitive prices.

Conclusions

The frequent absence of perioperative neuromuscular monitoring has increased the risk of recurarization due to inappropriate sugammadex dosing in Japan. In light of the increasing use of sugammadex worldwide, we acknowledge the need to warn the medical community that the risk of recurarization is high in many parts of the world. In conclusion, we invite medical device manufacturers to produce price-competitive and easy-to-operate neuromuscular monitors that can be used throughout perioperative care. We also encourage anesthesia professionals to administer sugammadex based on neuromuscular monitoring data. Moreover, we call for clinical attention to prevent recurarization, anaphylactic reactions, and other postoperative complications associated with the use of muscle relaxants and their antagonists.

 

Dr. Sasakawa is an associate professor in the Department of Anesthesiology and Critical Care Medicine at Asahikawa Medical University, Asahikawa, Hokkaido, Japan.

Dr. Miyasaka is a professor in the Department of Perianesthesia Nursing at St. Luke’s International University, Tokyo, Japan.

Dr. Sawa is a professor in the Department of Anesthesia at Teikyo University, Teikyo, Japan.

Dr. Iida is a professor and chair of the Department of Anesthesiology and Pain Medicine at the Gifu University Graduate School of Medicine, Gifu, Japan.

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The authors have no conflicts of interest. All authors are members of the Safety Committee of the Japanese Society of Anesthesiologists.

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