Depression is a common mental health problem that is associated with significant disability and mortality. According to the National Institute of Mental Health, 7.1% of adults in the United States experienced at least one major depressive episode in 2017 [1]. Depression is not only expensive [2], but it is associated with substantial impairment in role functioning at work and in personal life, poor physical health, increased mortality due to various physical disorders, and suicide [3]. Electroconvulsive therapy (ECT) has been successfully used to treat severe and treatment-resistant depression [4]. Modern ECT guidelines recommend the use of muscle relaxants to modify convulsive motor activity and enhance airway management. For many decades, succinylcholine (Sch), with its visible and rapid onset, short duration of action, and spontaneous recovery, has been the preferred neuromuscular blocking agent (NMBA) for ECT. Non-depolarizing muscle relaxing agents such as mivacurium, atracurium, rapacuronium, and rocuronium have been used for ECT, but with limited enthusiasm. With the widespread availability of sugammadex, a modified γ-cyclodextrin that can rapidly and predictably reverse the effect of steroidal non-depolarizing NMBAs, we are presented with a muscle relaxation strategy that can altogether replace the use of Sch for ECT, thus alleviating some of the side effects associated with Sch, such as myalgia, bradycardia, prolonged blockade, and allergic reactions [5]. This narrative review focuses on the clinical practice of muscle relaxation, its monitoring as it pertains to ECT, and current evidence for the use of sugammadex to further improve the safety profile of ECT.

In the clinical setting, the effect of NMBAs is commonly assessed by measuring the motor response to peripheral nerve stimulation, typically focusing on the adductor pollicis muscle through ulnar nerve stimulation (Fig. 1). Single-twitch stimulation is a straightforward method applicable to both depolarizing and non-depolarizing NMBAs (Fig. 2A). A single twitch depression (T1) of 11%–25% has been observed to reduce muscle contractions during ECT; however, the optimal endpoints remain uncertain [6]. In a series of studies comparing Sch to rocuronium-sugammadex for ECT, Hoshi et al. [7] and Kadoi et al. [8] utilized both rocuronium (0.6 mg/kg) and Sch (1 mg/kg) and applied electroshock stimulus after confirming that the single-twitch height (T1) was zero. Different dosages of rocuronium (ranging from 0.3 mg/kg to 1.25 mg/kg) have been utilized by various investigators, while relying on a combination of clinical signs (such as eye opening, hand grip, head lift) and peripheral nerve stimulation to assess the adequacy of neuromuscular blockade [9]. In a dose-finding crossover randomized controlled trial conducted by Mirzakhani et al. [10], the authors established that a twitch suppression > 90% is necessary for controlling motor contractions during ECT. This level of suppression was achieved using doses of Sch ranging from 0.77 to 1.27 mg/kg in 50% to 90% of patients undergoing ECT, and at doses of 0.36–0.6 mg/kg when administering rocuronium [10].

Train of four (TOF) is another neurostimulation pattern with extensive clinical applications. In this pattern, four supramaximal electrical stimuli (T₁, T₂, T₃, and T₄) are delivered at a frequency of 2 Hz, and the number of succeeding detectable muscle contractions, known as the TOF count (TOF-C; Fig. 2B) is assessed. The disappearance of responses to electrical stimuli correlates with the depth of the neuromuscular blockade. A TOF-C of 0 corresponds to optimal conditions for intubation, indicating sufficient laryngeal muscle relaxation [11]. However, studies with a similar design investigating the correlation between TOF-C and the quality, safety, and outcomes of ECT are lacking, and the optimal level of neuromuscular blockade for ECT remains unknown [12]. The degree of pharmacological muscle relaxation is more quantitatively expressed in terms of the TOF ratio (TOF-R; Fig. 2B), in which the amplitude of the fourth response (T₄) is compared to that of the first response (T₁) [13]. As the neuromuscular block intensifies, the TOF-R diminishes, and fades are said to be present. The return of the TOF-R to 0.9 is representative of adequate recovery from neuromuscular blockade. Table 1 shows the criteria for assessing the neuromuscular blockade depth in terms of the TOF-C and TOF-R [13]. Although the effect of Sch at commonly used doses of 1–1.5 mg/kg is short-lived, it can be prolonged in certain situations (e.g., butyrylcholinesterase deficiency and liver disease). In most cases, neuromuscular blockade can be managed without objective neuromuscular monitoring. However, when using non-depolarizing NMBAs, neuromuscular monitoring in the form of TOF-C (qualitative) or TOF-R (quantitative) should be routinely performed [14]. To prevent residual neuromuscular blockade, intermediate-acting non-depolarizing NMBAs, such as rocuronium, need to be pharmacologically antagonized after their desired effect is no longer needed. The extremely short interval between achieving an adequate depth of neuromuscular blockade, completion of ECT, and reversal of the neuromuscular blockade allows for minimal time for spontaneous recovery from the effect of non-depolarizing NMBAs.

Neuromuscular monitoring in the form of the TOF-R helps in determining the readiness, dosing, and adequacy of pharmacological antagonism of the neuromuscular blockade. For sugammadex, adequate reversal dosing should be established through objective neuromuscular monitoring. This includes administering 4 mg/kg at a post-tetanic count of 1–2, providing 2 mg/kg upon the reappearance of two twitches during TOF stimulation, administering 1 mg/kg when four twitches reappear during TOF stimulation, dispensing 0.49 mg/kg at a TOF-R ≥ 0.2, and offering 0.22 mg/kg at a TOF-R ≥ 0.5 [15].

The key components of the neuromuscular junction involved in neuromuscular blockade and reversal are illustrated in Fig. 3A. Mechanism of action and termination of of action of Sch is illustrated in Fig. 3B. When using non-depolarizing NMBAs such as rocuronium, two commonly available pharmacological approaches to reverse neuromuscular blockade are as follows: 1) cholinesterase inhibitors such as neostigmine and 2) γ-cyclodextrin (i.e., sugammadex). The traditional approach of using cholinesterase inhibitors (Fig. 3C) is limited by their inability to reverse deep levels of neuromuscular blockade and the need for partial spontaneous recovery of neuromuscular blockade before pharmacological antagonists can be administered. Simultaneous administration of muscarinic antagonists, such as glycopyrrolate, is required to block the unwanted muscarinic effects (bronchospasm, bradycardia, and intestinal hypermotility) of cholinesterase inhibitors. Administration of “full dose” cholinesterase inhibitors in patients who have spontaneously recovered or who are close to full recovery (defined as a TOF-R > 0.90) can also have detrimental effects and provoke paradoxical weakness. This highlights the need for judicious execution of neuromuscular blockade reversal guided by objective monitoring of neuromuscular blockade depth.

Another approach to neuromuscular blockade antagonism is the use of sugammadex, a synthetic molecule specifically designed to form high-affinity host–guest inclusion complexes with steroidal NMBAs (Fig. 3D). The binding affinity between sugammadex and steroidal non-depolarizing NMBAs depends on the blockers used in the following order from highest to lowest: rocuronium > vecuronium > pancuronium. Sugammadex binds to rocuronium in the plasma, rendering it unavailable for binding to acetylcholine (Ach) receptors in the synaptic cleft. For every 25 million rocuronium molecules bound in a rocuronium–sugammadex inclusion complex, only one complex is estimated to disassociate [15]. As the free drug concentration decreases in the plasma, a concentration gradient that moves the steroidal NMBA out of the neuromuscular junction and away from the nicotinic Ach receptors is established, terminating the effect of the NMBA [16,17]. These complexes are then renally excreted. Other categories of NMBAs, such as Sch and benzylisoquinoliniumes (i.e., atracurium, cisatracurium, and mivacurium) lack the molecular framework to bind and form host–guest complexes with sugammadex; therefore, sugammadex-induced reversal of these medications does not occur [15].

With the widespread use of sugammadex, the muscle relaxation achieved by rocuronium can be predictably and effectively reversed in patients undergoing ECT. This is a safe and effective muscle relaxation approach with a clinical effectiveness comparable to that of Sch. Even profound neuromuscular blockade achieved with rocuronium can be rapidly reversed with an appropriate dose of sugammadex. Table 2 presents the results of studies comparing the clinical effectiveness of rocuronium-sugammadex (ROC-SUG) to Sch for ECT [7,8,18–21]. Rocuronium administered at a dose of 0.6 mg/kg provides muscle relaxation comparable to Sch at a dose of 1 mg/kg both in terms of time to onset and depth of blockade. This was demonstrated by Hoshi et al. [7] in a non-randomized crossover trial and later by Kadoi et al. [8] in a trial with a similar design. Time to adequate muscle relaxation, as assessed by T1 0%, was similar between the two groups in both trials. Kadoi et al., in a separate trial, compared the effect of three different dosages of sugammadex on the antagonism of rocuronium and noted that the recovery time with sugammadex was statistically shorter than that with Sch at a dose of 16 mg/kg sugammadex but statistically longer at a dose of 4 mg/kg sugammadex. In a separate study, Kadoi et al. [19] noted prolonged recovery times after the administration of sugammadex in patients aged > 70 years compared to those aged < 50 years; however, this trial lacked a comparative Sch arm. In the non-ECT setting, a dose of 4 mg/kg sugammadex to antagonize muscle relaxation achieved with 0.6 mg/kg rocuronium has been found to provide depth, onset, and recovery characteristics of neuromuscular blockade similar to that with Sch [22,23]. Methodological variability in the assessment of muscle relaxation and subsequent antagonism endpoints limit our ability to compare findings from the trials listed in Table 2. Some investigators utilized clinical endpoints, such as spontaneous eye opening or time to first spontaneous breath, while others utilized objective neuromuscular monitoring to determine the adequacy and antagonism of neuromuscular blockade. Two inferences can be drawn from these trials. First, the muscle relaxation and recovery profile of ROC-SUG is comparable to that of Sch and meets the muscle relaxation requirement of the ECT procedure. Second, objective neuromuscular monitoring should be performed to determine the dosage of sugammadex and adequacy of recovery from muscle relaxation.

Sch is the NMBA of choice for ECT. Unfortunately, its side effects preclude its use in certain clinical situations, such as pseudocholinesterase deficiency, hyperkalemia, malignant hyperthermia, neuroleptic malignant syndrome (NMS), and catatonia. Sch has the potential to cause dangerous elevations in serum potassium levels related to the upregulation of Ach receptors and increased efflux of potassium during depolarization in cases of immobility and neuromuscular disorders, such as direct muscle injury, upper or lower motor neuron damage, neuromyopathies, and toxic muscle injury [24]. Of significant relevance is catatonia, which can lead to short-term and prolonged immobility. Sch-induced hyperkalemia has been reported to occur within as little as 5 days of immobility, which can then trigger fatal arrhythmias, such as torsade de pointes and ventricular fibrillation, leading to cardiac arrest [25,26]. Sch is metabolized by butyrylcholinesterase, and its use in patients with both congenital and acquired butyrylcholinesterase deficiency can result in prolonged neuromuscular blockade [27–29]. In patients with NMS, the use of Sch can induce hyperkalemia, and given the overlapping pathogenetic mechanisms between NMS and malignant hyperthermia, patients with NMS could be susceptible to malignant hyperthermia; thus, avoiding administration of Sch in patients with NMS is recommended [30–33].

Alternatives to Sch include mivacurium, a short-acting non-depolarizing NMBA; however, its side effects (hypotension and bronchospasm) and metabolism by pseudocholinesterase limit its usefulness [34]. It is also not a viable option in cases of butyrylcholinesterase deficiency, where the use of Sch is also contraindicated. Atracurium has been used as an alternative to Sch, but the termination of its effect does not align with the duration of the average ECT procedure [6]. Rapacuronium, a short-acting non-depolarizing NMBA, was withdrawn from the market because of the extremely high incidence of bronchospasm [35]. On the other hand, sugammadex, with its ability to reverse even profound rocuronium-induced neuromuscular blockade, is a more appropriate alternative when the use of Sch is unfavorable.

Table 3 provides data on neuromuscular blockade with rocuronium and antagonism with sugammadex when Sch is contraindicated [27–31,36–39]. Although the published data are mostly in the form of case reports, they demonstrate that ECT can be safely performed using rocuronium followed by the sugammadex muscle relaxation approach. As noted in Table 3, the dosages of both rocuronium and sugammadex used by the authors in these case reports vary widely. In addition, the means used to assess the adequacy of neuromuscular blockade and the effectiveness of reversal is widely variable, with only a few studies utilizing objective neuromuscular monitoring. Consistent with expert consensus [14,40], we advocate for the use of weight-based dosing of the NMBA followed by objective neuromuscular monitoring to guide sugammadex dosing and to determine the adequacy of antagonism (i.e., TOF-R of 0.9).

The adverse effects of ECT can be broadly classified into general medical adverse effects (dental and tongue injuries, headaches, and myalgia) and cognitive adverse effects (amnesia, confusion, and agitation) [41,42]. Myalgia is commonly experienced post-ECT and can occasionally be severe and debilitating. Myalgia, headache, and sore throat are the known side effects of Sch. The exact mechanism of myalgia after ECT is unclear; however, both Sch-induced fasciculations and ECT-induced seizures have the potential to cause muscle damage and associated pain. Data regarding the role of Sch in post-ECT myalgia are conflicting. In a study comparing serum myoglobin levels as a marker of muscle injury, investigators unexpectedly found higher levels of myoglobin in patients receiving Sch for intubation compared to patients receiving Sch before undergoing ECT [43]. In the non-ECT setting, the use of rocuronium and sugammadex has been associated with a significantly lower incidence of sore throat compared to the use of Sch [23]. In a randomized controlled trial comparing the incidence of headaches and myalgia in patients undergoing ECT, Saricicek et al. noted a significantly lower incidence of myalgia and headaches in patients receiving ROC-SUG compared to patients receiving Sch [21]. Table 4 provides a list of other studies on the role of rocuronium and sugammadex use on reducing ECT-related adverse events [21,29,44].

The incidence of other ECT-related adverse effects, such as arrhythmia and postictal agitation, may be reduced with ROC-SUG compared to Sch [39,44]. However, these potential benefits have only been described in case reports and need to be substantiated in larger trials.

The introduction and adoption of sugammadex for the reversal of neuromuscular blockade during general anesthesia has been heavily influenced by drug costs and economic evaluations. Data available from numerous randomized clinical trials indicate that rocuronium-sugammadex use results in a faster and more predictable return to adequate neuromuscular function [61]. The use of sugammadex, in comparison with neostigmine, has been shown to result in shorter operating room and recovery room stays and decreased rates of intensive care admissions related to residual neuromuscular blockade [62]. As the clinical benefits of sugammadex have begun to be recognized, cost-effectiveness modelling has evolved to incorporate these benefits [63]. The economic benefits of sugammadex are particularly evident when considering the overall costs associated with operating room time. As our understanding and clinical experience with sugammadex has expanded, its broader implications for healthcare efficiency and patient safety have become clearer. Shifting costs of alternative medications (cholinesterase inhibitors and Sch), either driven by industry or resulting from changes in health policy, can impact the cost-effectiveness of one muscle relaxation approach to another [64]. Budgetary constraints in hospitals and pharmacies may lead to decisions favoring cheaper drugs, overlooking indirect benefits such as improved patient throughput, reduced postoperative complications, and enhanced overall patient safety. A recent budgetary impact analysis in the United States on the net costs of reversal agents and overall cost offsets via a reduction in postoperative pulmonary function with the use of sugammadex demonstrated a cost saving of up to $309 with the use of sugammadex vs neostigmine or spontaneous recovery [65]. Although sugammadex is more expensive per dose compared to neostigmine, the time saved in the operating room can offset the higher drug cost: using sugammadex can translate to $50–$100 saved per minute, depending on the type and complexity of surgery. The rapid recovery and cumulative time savings of rocuronium-sugammadex translate into enhanced operational efficiency and productivity along with improved patient outcomes. These factors collectively highlight sugammadex as a valuable and cost-effective option for neuromuscular blockade reversal [63,65].

Muscle relaxants were introduced to clinical medicine almost 80 years ago [13]. Since then, our understanding of these agents and their antagonists has greatly increased. Sugammadex is a welcome addition to the anesthesiologist’s armamentarium. Its role in managing neuromuscular blockade and safe anesthesia practice is increasing. In terms of ECT, preliminary work has been conducted to determine how rocuronium, when antagonized with sugammadex, compares to the well-established muscle relaxant Sch (Table 2). In side-by-side trials comparing Sch with ROC-SUG, longer seizure durations were noted in the ROC-SUG group with similar doses of hypnotic agents. Although the exact reason for this difference has not been elucidated, the longer time required to achieve adequate muscle relaxation when rocuronium is used compared with Sch provides both an opportunity to manually hyperventilate the patient for a longer period and a decline in hypnotic-induced electroencephalogram suppression as the muscle relaxant takes effect [66]. Future randomized controlled trials comparing muscle relaxants in ECT are necessary to elucidate whether rocuronium reversed by sugammadex is consistently and substantially better tolerated than Sch. Such trials will provide higher-quality data on the incidence of post-ECT myalgia, headaches, and postictal agitation for rocuronium-sugammadex vs. Sch and data regarding the difference in the length of recovery according to these muscle relaxation approaches.

While many unknowns still remain, the advent of sugammadex in ECT has been a welcome development, allowing practitioners to use rocuronium when Sch is contraindicated or otherwise problematic (Table 3). For decades we have allowed patients to tolerate the known side effects of ECT, including at times intolerable myalgia. Now we can offer patients the option of a different medication during the procedure to ease their discomfort. Indeed, it may be time to re-evaluate our approach to muscle relaxation during ECT altogether. ECT has progressively become safer and more tolerable over the decades. The next step in the development of this highly effective procedure could be that rocuronium reversed by sugammadex becomes the new standard of care. Larger studies are required to explore the use of rocuronium in combination with sugammadex in practice. We also need psychiatrists and anesthesiologists practicing ECT to become more comfortable with administering and monitoring these medications in combination.