INTRODUCTION
Since the introduction of neuromuscular blocking agents (NMBAs) into general anesthesia, they have reduced patient movement, anesthetic requirements, and airway responsiveness, thereby facilitating tracheal intubation, mechanical ventilation, and microsurgery. However, complications related to residual neuromuscular blockade (rNMB) during ventilator weaning and postoperative recovery remain serious concerns. Postoperative rNMB can not only lead to pulmonary complications but also increase hospital costs because of longer postanesthesia care unit (PACU) stays, increased staffing requirements, reintubation, unexpected intensive care unit transfers, and prolonged hospitalization [1,2].
Intermediate-acting NMBAs and sugammadex have been developed and are widely used to prevent rNMB, and neuromuscular monitoring (NMM) devices are now available for intraoperative use. Although anesthesiologists are fully aware of the seriousness of complications related to rNMB, they still tend to underestimate its incidence [3]. Over the 60-year history of NMBA use, the definitions of rNMB and postoperative pulmonary complications have varied widely across studies, making it difficult to develop clinical guidelines. Since 2020, practical guidelines have been published in the United States and Europe, and here we describe methods of intraoperative NMBA management for safe recovery without rNMB in adult patients.
rNMB ASSESSMENT
Assessment for rNMB during recovery after NMBA use under general anesthesia can be broadly divided into clinical tests and NMM (Table 1). Clinical tests involve evaluation of the degree of neuromuscular blockade (NMB) reversal by an anesthesiologist based on clinical findings such as the patient’s respiratory function, hand grip, head lift, and airway reflexes. Many anesthesiologists still use clinical tests alone or in combination with NMM [4]. However, clinical tests should not be used to assess rNMB because their results are reliable only when performed before extubation and therefore do not accurately reflect actual recovery of respiratory function [5,6]. By contrast, NMM evaluates innervated muscle responses through peripheral nerve stimulation. NMM was developed in the 1950s and includes both subjective qualitative and objective quantitative methods. Since the introduction of train-of-four (TOF) monitoring in the 1970s, qualitative monitoring using TOF has been widely adopted. Similar to clinical tests, qualitative NMM has limitations in objectively identifying rNMB because TOF counts and fade are evaluated by anesthesiologists using tactile or visual assessment. Even when qualitative NMM is used together with clinical tests, multiple studies have consistently shown that it is insufficient for identifying rNMB compared with quantitative NMM [4,7,8].
Currently, the most effective quantitative method for monitoring rNMB during NMBA reversal is measurement of the TOF ratio at the ulnar nerve [4,9,10]. Four consecutive stimulations of the ulnar nerve cause adduction of the adductor pollicis, and the TOF ratio objectively indicates the degree of NMB by comparing the amplitude of the fourth response with that of the first response (T4/T1). The site of peripheral nerve stimulation in quantitative NMM is also important for assessing rNMB. Ulnar nerve stimulation is considered the most reliable method because the adductor pollicis recovers more slowly from NMB than the corrugator supercilii, orbicularis oculi, diaphragm, laryngeal adductors, and posterior tibial nerve [11,12]. In particular, facial muscles recover faster than respiratory muscles; therefore, performing NMM at the face before extubation can lead to overestimation of the TOF ratio. Thus, when TOF is monitored at the face or leg during surgery, the monitoring site should be changed to the ulnar nerve at the end of surgery. Measuring the TOF ratio at the ulnar nerve before extubation is an appropriate method for preventing rNMB [13,14]. In addition, when NMM is applied to a paretic limb, resistance to nondepolarizing NMBAs may be observed because of upregulated acetylcholine receptors, which may lead to overestimation of the TOF ratio. Therefore, monitoring should be performed on a limb with normal motor strength [15].
Commercially available monitors that display the TOF ratio for use in operating rooms include acceleromyography (AMG), electromyography (EMG), and kinemyography (KMG). Their clinical application differs according to their measurement mechanisms, requiring education and understanding of each device (Table 2). Mechanomyography is used primarily in laboratory settings and is difficult to use in operating rooms because the apparatus occupies considerable space [12]. AMG, a commercial technology that has long been in use, requires the thumb to be positioned freely for accurate measurements. However, it can be difficult to use during surgery because of arm immobilization or interference from surgical drapes. Among previously used TOF monitors, EMG, which required attachment of five electrodes, was cumbersome and therefore rarely used. However, recently developed EMG devices have the advantages of integrated electrode sensors for easy application and fewer restrictions related to patient positioning [8,11]. Furthermore, unlike AMG, EMG does not exhibit the staircase effect, in which muscle contraction increases with repeated stimulation at a fixed frequency, thereby allowing reliable measurements even in awake patients [16]. Similar to AMG, KMG values can vary according to patient position, potentially limiting the accuracy of NMB depth assessment during surgery. The KMG piezoelectric sensor is positioned across the thumb and index finger, and its measurement direction differs from the actual direction of thumb movement toward the palm during contraction. In a study comparing KMG with 5-lead EMG, the TOF ratio measured by KMG was on average 0.11 higher than that measured by EMG and was 0.08 higher at a TOF ratio of 0.9 [17]. However, studies of KMG are scarce, and future comparative studies using other NMM methods are needed.
rNMB DEFINITION USING THE TOF RATIO
According to the American Society of Anesthesiologists (ASA) and European Society of Anaesthesiology and Intensive Care guidelines published after 2020, a quantitative TOF ratio < 0.9 after use of a nondepolarizing NMBA is considered indicative of rNMB [4,9,10]. In recent clinical studies, even at TOF ratios between 0.7 and 0.9, symptoms of rNMB such as airway obstruction, generalized weakness, and diplopia have still been observed despite the absence of abnormalities in tidal volume or muscle power on clinical testing [18,19].
Because measured values vary according to the TOF monitoring mechanism, extubation is recommended at a TOF ratio of ≥ 1.0 when NMB depth is monitored using AMG. Because AMG typically shows a baseline value > 1.0 before NMBA administration (1.1-1.4), the normalized TOF ratio, defined as the measured TOF ratio divided by the baseline twitch response, should be ≥ 0.9 to indicate acceptable recovery. If the anesthesiologist chooses not to normalize the TOF ratio, the measured TOF ratio should be > 1.0 to indicate adequate recovery [4,11]. Although the timing of rNMB assessment varies across studies, most studies measure the TOF ratio immediately before extubation or after PACU admission [4].
rNMB-RELATED CLINICAL PRESENTATIONS
In a study of healthy volunteers without anesthesia [20] in whom mivacurium was administered to maintain a TOF ratio of 0.65 to 0.75 using EMG, participants experienced blurred vision and muscle weakness that made it difficult to produce facial expressions, clench a fist, or sit up independently. They also reported impaired speech and difficulty drinking. Although muscle strength recovered gradually as the TOF ratio increased to 1.0, blurred vision and generalized weakness persisted even at TOF ratios > 0.9, which are not generally considered indicative of rNMB [20,21]. Conversely, symptoms of rNMB may be absent at low TOF ratios and present at higher values. Therefore, clinical assessment together with TOF ratio measurement is important when evaluating rNMB in the PACU (Table 3).
Complications associated with rNMB after general anesthesia can be difficult to distinguish because of the residual effects of anesthetic agents, such as opioids, benzodiazepines, inhalational agents, or sedatives, as well as the effects of the surgical procedure and the patient’s underlying medical conditions. Therefore, regardless of TOF ratio-based assessment, the actual incidence of complications related to rNMB varies widely across studies, making comprehensive evaluation difficult. Symptomatic pulmonary complications such as hypoxia and reintubation are extremely rare, and further research is needed to clarify the effects of rNMB in PACU patients in the context of evolving NMBA management practices.
INCIDENCE OF rNMB
The incidence of rNMB varies widely according to NMBA type, timing of NMM, use of reversal agents, type and dose of reversal agent, and method of measurement. Reported rates range from 2% to 88%, with rates as high as 65% in elective abdominal surgery [2]. In most studies [2], the high incidence of rNMB appears to be attributable mainly to the use of long-acting NMBAs and anticholinesterase reversal agents. A meta-analysis published in 2020 and based on 40 years of studies found that the incidence of rNMB with intermediate-acting NMBAs and quantitative NMM was 11.5%, which was significantly lower than that with qualitative NMM (30.6%) or no NMM (33.1%) [7].
In studies conducted since 2000, the incidence of rNMB has similarly been reported to range from 2.2% to 53.3%, which is relatively lower than in earlier studies [7,22]. This may be due to the use of intermediate-acting NMBAs, sugammadex, and TOF ratio monitoring. However, the overall incidence of rNMB remains high when confirmed by NMM in the PACU, and the usual criterion for incidence is a TOF ratio < 0.9 measured in the PACU after recovery [4,9-11].
PREVENTION OF rNMB
NMBAs
Concerns regarding complications associated with rNMB increased after the use of long-acting NMBAs. Since the development of intermediate-acting NMBAs in the 1980s, choosing an NMBA with a shorter duration of action has become a key strategy for preventing rNMB. Even with intermediate-acting NMBAs, repeated administration increases the risk of accumulation and may prolong the duration of action. Therefore, when repeated NMBA doses are administered after the initial dose, the dose and timing should be determined by assessment of NMB depth with NMM rather than by routine administration based only on expected duration of action. With recent advances in laparoscopic and robotic surgery, the number of procedures requiring deep NMB to secure an adequate surgical field is increasing [23,24]. Failure to adequately reverse excessive blockade required for surgical conditions can lead to recurarization in the PACU after extubation or to development of rNMB [25].
Patient characteristics are also associated with rNMB, with a higher incidence in patients who are hypothermic, older, male, or obese [22,25]. Hypothermia and age ≥ 65 years can prolong the effects of NMBAs because of delayed drug metabolism and excretion. In male patients and those with obesity, dosing based on actual body weight is thought to contribute to this risk. Patients with underlying liver or kidney disease and impaired organ function may also experience prolonged drug action because of decreased metabolism and excretion, depending on the type of NMBA [25]. Succinylcholine, the only depolarizing NMBA, is naturally degraded by pseudocholinesterase and does not require reversal agents. However, its effect can be prolonged in patients with hepatic dysfunction or genetic pseudocholinesterase deficiency. In addition, inhalational agents, aminoglycosides, magnesium, acute use of antiepileptic drugs, antidepressants, and some chemotherapeutic agents may interact with NMBAs and increase the risk of rNMB [11,22,25-27].
Reversal agents
To achieve reliable reversal of NMB, selecting the appropriate reversal agent and administering it correctly are essential (Table 4). First, the appropriate antagonist should be selected according to the type of NMBA intraoperatively used and the depth of blockade at the time the reversal agent is administered [4,9,10]. If a steroidal NMBA is used, sugammadex can be selected as the reversal agent. When given in doses adjusted to the depth of blockade, sugammadex can reverse steroidal NMBA-induced blockade at all stages, from deep to shallow depth of NMB. If a steroidal NMBA is not used or sugammadex is unavailable, an anticholinesterase can serve as a reversal agent for both types of nondepolarizing NMBAs. Reversal with anticholinesterases is most effective during minimal blockade (TOF ratio, 0.4-0.9), and neostigmine can be an appropriate substitute for sugammadex in this setting. In patients receiving rocuronium, when neostigmine was administered during deep blockade with 1 or 2 post-tetanic counts (PTCs), recovery to a TOF ratio > 0.9 required more than 50 min with AMG monitoring [28]. During deep blockade, the NMBA concentration at the neuromuscular junction is already high, and increasing acetylcholine concentration by inhibiting acetylcholinesterase has limited effectiveness; therefore, acetylcholine cannot adequately compete at nicotinic receptors. Thus, waiting until a TOF ratio is present before administering an anticholinesterase is a practical way to maximize its effect.
Second, routine institutional or individual dosing should not be used; rather, the dose of the antagonist should be based on NMB depth confirmed by the TOF ratio [4,29]. The U.S. Food and Drug Administration (FDA) recommends sugammadex 4 mg/kg from PTC 1 to TOF count 1, 2 mg/kg from TOF count 2 to TOF ratio < 0.9, and 16 mg/kg when emergency reversal is required after an intravenous bolus of rocuronium 1.2 mg/kg for intubation [4,30]. Although sugammadex can reverse NMB at all depths, use of a low dose that does not match the depth of blockade, or underdosing based on ideal body weight rather than actual body weight, may prolong recovery time and increase the risk of rNMB [31]. The neostigmine dose is reduced from 30 to 15 μg/kg as NMB depth decreases within the minimal blockade range, and the maximum administered dose should not exceed 40 μg/kg at minimal blockade [4,29].
Third, even when an anticholinesterase is administered during minimal NMB, approximately 10 min are required for maximal effect [32,33]. If the TOF ratio remains < 0.9 even 10 min after neostigmine administration, the NMB depth at the time of administration should be considered inadequate. In such cases, further spontaneous recovery, use of sugammadex, or administration of additional neostigmine up to the maximum dose may be considered. However, excessive neostigmine can produce a ceiling effect and may result in temporary depolarizing NMB; therefore, it is not recommended [29,34,35].
Finally, regardless of the time elapsed since the last NMBA dose, quantitative NMM should be performed, and the decision to administer a reversal agent should be based on the monitoring results [4,9,10]. If sufficient time has passed after administration of a depolarizing NMBA, spontaneous recovery is often assumed and reversal agents may be omitted without checking the TOF ratio. However, rNMB can occur as long as 4 h after even a single intubating dose of an NMBA [29]. Conversely, rNMB may still occur after apparently appropriate anticholinesterase administration. Therefore, rather than relying on the time since the last NMBA dose, clinicians should confirm blockade depth using quantitative NMM and select a reversal agent appropriate for that depth.
In addition, several precautions should be considered regarding reversal agents. Side effects caused by muscarinic receptor activity after anticholinesterase administration, such as bronchospasm and bradycardia, can be counteracted by coadministration of anticholinergic agents. As of 2020, only six cases of anticholinesterase-induced anaphylaxis had been reported [36]. Sugammadex is not related to anticholinesterase and therefore does not require coadministration of an anticholinergic agent. However, with increased use of sugammadex, adverse effects such as bradycardia, bronchospasm, and anaphylaxis have also been reported, leading to concern about their incidence. The reported incidence of sugammadex-induced anaphylaxis ranges from 0.0016 to 0.02%, and the exact mechanism remains unclear [36]. Furthermore, because sugammadex may reduce contraceptive efficacy in females taking oral contraceptives, the FDA recommends additional contraception for 7 days after administration of sugammadex [30].
Both anticholinesterases and sugammadex are excreted by the kidneys, and renal function can affect their elimination [36]. Specifically, sugammadex is not yet approved by the FDA for use in patients with creatinine clearance ≤ 30 ml/min [30]. Studies using rocuronium and sugammadex in patients with end-stage renal disease found that the time required to reach a TOF ratio of 0.7 to 0.9 was longer than in healthy individuals, but clinical muscle recovery time and symptoms did not differ significantly [36-38]. Furthermore, despite delayed excretion of the sugammadex-rocuronium complex, no patient experienced recurarization due to circulating sugammadex and unbound rocuronium. However, most of these studies had small sample sizes, and some did not perform TOF monitoring, making it difficult to determine the true incidence of rNMB. In addition, the presence, timing, and rate of dialysis may affect clearance of the sugammadex-NMBA complex. Long-term data on the association between rNMB and sugammadex use in patients with end-stage renal disease remain unavailable. Therefore, concurrent use of quantitative NMM is essential in patients with impaired renal function, and close observation is necessary when determining the dose and evaluating the efficacy of sugammadex [37-39].
According to the ASA guidelines [4], comparisons between anticholinesterases and sugammadex have shown mixed results regarding rNMB-related pulmonary complications and postoperative nausea and vomiting. However, compared with anticholinesterases, sugammadex consistently shortens the time to a TOF ratio of 0.9 at all depths of NMB [4]. Although not all studies have shown that sugammadex completely prevents rNMB, current practice guidelines strongly recommend its use during deep, moderate, and shallow NMB [4,9,10].
Quantitative NMM
Practical guidelines published over the past five years have consistently recommended quantitative NMM in patients receiving NMBAs and have included it as standard monitoring throughout the anesthetic period [4,9,10]. If TOF cannot be used intraoperatively, TOF monitoring should be performed when the patient awakens so that the timing and dose of the reversal agent can be determined based on the TOF ratio and the appropriate timing of extubation can be confirmed. Clinical tests and qualitative NMM cannot reliably detect fade when the TOF ratio is > 0.4 [40]. The ASA practice guidelines reported the proportion of rNMB in studies of neostigmine and sugammadex according to whether TOF was confirmed before extubation [4]. When neostigmine was used, the incidence of rNMB was 5.3% when a TOF ratio ≥ 0.9 was confirmed before extubation, but it was substantially higher at 44.9% when the TOF ratio was not confirmed before extubation. When sugammadex was used and extubation was performed after TOF confirmation, the incidence of rNMB was 0.5%; however, when the TOF ratio was not confirmed, the incidence was 2.2%. In other words, administration of sugammadex cannot replace quantitative NMM in determining whether recovery is sufficient for extubation. Regardless of the type of reversal agent used, confirmation of a TOF ratio ≥ 0.9 immediately before extubation has moderate- to high-strength evidence for preventing rNMB [4].
Even with depolarizing NMBA, assessment of muscle recovery with NMM is necessary if the duration of blockade exceeds the expected duration of action. Normally, succinylcholine gradually recovers to the same level as the NMM twitch without fade, and recovery usually occurs within approximately 10 min without reversal agents. rNMB can be assessed by comparing the baseline single-twitch height with the recovered single-twitch height as a percentage. Delayed return of the first twitch response indicates prolonged NMB due to abnormal pseudocholinesterase activity [41,42].
Despite the significant advantages of NMM, concerns about increased medical costs and the need for training remain barriers to its clinical implementation. Considering the increased rates of reintubation, pulmonary complications, and prolonged hospitalization associated with rNMB, TOF monitoring is relatively inexpensive and should be used more actively [43]. Another challenge is training anesthesiologists to change established clinical practice. A Spanish multicenter study published in 2023 was the first to evaluate a video-based educational intervention [44]. Despite training, the incidence of rNMB was not reduced. The authors speculated that this may have been due to limited feedback and the low rate of NMM use, which reached only up to 50%. However, the incidence of postoperative pulmonary complications, such as respiratory depression and chest radiography-confirmed pulmonary disease, decreased. A single-center observational report that included feedback and education found that, before training, two to four patients per year required reintubation because of rNMB in the PACU; after training, none of the patients who underwent adequate quantitative NMM required PACU reintubation [45]. As this report suggests, further observational studies are needed to evaluate the impact of effective and continuous NMM education on prevention of rNMB.
Surveys conducted in Korea over the past two decades found that although approximately 80% of hospitals had NMM devices, most were AMG devices and not all operating rooms were equipped with them [46,47]. These surveys were conducted before the introduction of current single-sensor EMG monitors. Although approximately 80% of anesthesiologists recognized the need for NMM, assessments of rNMB using quantitative NMM were performed in fewer than 5% of patients. Clinical tests were used by 75% to 86% of anesthesiologists to assess NMB recovery, and only approximately 40% were aware of the pre-extubation TOF criterion (TOF ratio ≥ 0.9). Another analysis showed that overconfidence in personal knowledge and experience with NMBA use, as well as the belief that clinical tests alone are sufficient to determine NMB recovery, hinders routine use of quantitative NMM [3].
CONCLUSION
Guidelines for preventing rNMB primarily emphasize appropriate administration of NMBAs and reversal agents guided by quantitative NMM, along with confirmation of the TOF ratio before extubation. Although sugammadex is an effective reversal agent for steroidal NMBAs, intermediate-acting NMBAs and sugammadex cannot replace quantitative NMM. Furthermore, sugammadex cannot replace the anesthesiologist’s responsibility to apply quantitative NMM in order to achieve safe emergence without rNMB.
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