A Review of Muscle Relaxants in Anesthesia in Patients with Neuromuscular Disorders Including Guillain-Barré Syndrome, Myasthenia Gravis, Duchenne Muscular Dystrophy, Charcot-Marie-Tooth Disease, and Inflammatory Myopathies

Introduction

Neuromuscular diseases (NMDs) are a clinically and genetically diverse group of disorders characterized by muscle weakness and dystrophic changes. Due to the nature of these diseases, anesthesiologists may encounter challenges in providing appropriate analgesics, especially muscle relaxants, managing symptoms, and using other techniques necessary to properly anesthetize patients. When anesthetizing a patient with NMD, special attention should be paid to preoperative assessment, medical history, risk of intubation difficulties or cardiac incidents, respiratory failure, and frequent pulmonary infections. It should also be remembered that these patients are prone to prolonged paralysis, hyperkalemia, rigidity, malignant hyperthermia, cardiac arrest, rhabdomyolysis, and even death. With such awareness, it is necessary to use train-of-four (TOF) monitoring.

Anesthetic challenges in patients with NMD arise from both the nature of the condition itself and the interaction of anesthetics and neuromuscular conduction blockers with the anticholinergic drugs used in therapy. Before anesthesia, each patient’s individual risk should be assessed. Therefore, conducting a thorough preoperative examination is important (and even necessary, before major surgery) not only to determine perioperative risk, but also to ensure optimal perioperative monitoring.

The present review was based on the available literature and the authors’ experience. The aim of the study was to review the available methods of anesthesia for patients with NMD. An article search was conducted using important keywords in electronic databases such as PubMed, UpToDate, Web of Science, Cochrane Library, and Wiley Online Library, and then the most recent articles covering the years 1992–2024 were selected as possible sources of relevant information.

Nondepolarizing Neuromuscular Conduction Blocking Agents

Nondepolarizing neuromuscular conduction blocking agents (NMBAs), which do not induce depolarization, are a key component of medical procedures, especially in the context of endotracheal intubation [1]. They are divided into 2 main groups based on their structure: steroidal agents and benzylisoquinolines. Steroid agents, such as rocuronium and vecuronium, have a steroid-based structure. In contrast, benzylisoquinolines, including atracurium and cisatracurium, have a benzylisoquinoline-based structure. Both types of neuromuscular blockers achieve their effect by selectively blocking nicotinic receptors, leading to inhibition of nerve impulse transmission [2]. The choice of a particular nondepolarizing neuromuscular blocker depends on various factors, such as the individual characteristics of the patient, the type of procedure being performed or the duration of the muscle relaxation effect [3]. Steroid agents are often characterized by a rapid onset of action and a short half-life, which can be advantageous for short-term procedures. Benzylisoquinolines, on the other hand, may be more suitable for longer operations, as they have a longer duration of muscle relaxant action [2,3]. It should also be noted that the use of nondepolarizing neuromuscular blockers is not without risk. There is a potential risk associated with muscle paralysis, especially if their use not properly controlled [2–4]. Therefore, monitoring the degree of muscle relaxation and adjusting the dose of the blocker are crucial when using these substances [2,3].

Succinylcholine, a Depolarizing Agent

Succinylcholine, a depolarizing agent that blocks neuromuscular conduction, binds to postsynaptic cholinergic receptors on the motor endplate. This binding causes a continuous disturbance, leading to transient fasciculation or involuntary muscle contractions, followed by skeletal muscle paralysis [4].

It is imperative to exercise caution and consider potential risks before using succinylcholine, especially in patients affected by neuromuscular disease. Cases of malignant hyperthermia, hyperkalemia, rhabdomyolysis, and cardiac arrest have been reported in patients with underlying muscular disorders, reinforcing the need for careful evaluation of the patient’s medical history and condition [5–7].

Quantitative neuromuscular monitoring, such as TOF, is strongly recommended to reduce the risks associated with neuromuscular blockade, especially in patients with pre-existing neuromuscular conditions. Monitoring provides real-time assessment of neuromuscular function, enabling precise titration of NMBAs and reducing the likelihood of complications [2].

Reversal of the Effects of Muscle Relaxants: Neostigmine and Sugammadex

People struggling with neuromuscular pathologies face significant difficulties characterized by persistent paralysis and respiratory complexities resulting from prolonged exposure to nondepolarizing muscle relaxants. This underscores the need for meticulous monitoring of neuromuscular function and recognition of blockade reversal [2]. Neostigmine, which acts as an acetylcholinesterase inhibitor, plays a key role in the blockade reversal process by increasing the concentration of acetylcholine, thereby increasing the competition between the muscle relaxant and acetylcholine for receptors [4]. However, this intervention is not without potential complications.

The mechanism of action associated with neostigmine poses the risk of prolonged depolarization of acetylcholine receptors, thus causing potential risks such as myotonic crises in those affected by myotonic dystrophy, rhabdomyolysis in those with muscular dystrophy, and myotonia-induced muscle spasms in those affected by various neuromuscular diseases. Moreover, the reversal efficacy of neostigmine may be inconsistent with expectations, and in some cases cause additional complications. Consequently, some anesthesiologists are inclined to avoid the administration of muscle relaxants altogether or refrain from routinely reversing the blockade [8,9].

The advent of sugammadex heralds a different mechanism of action, promising a favorable route to reversing neuromuscular blockade in patients with neuromuscular disease, while reducing the likelihood of adverse effects and complications. A plethora of studies since its inception confirm its efficacy in a variety of patient cohorts, including both adult and pediatric populations in clinical settings. The triumph of sugammadex enables the safe use of steroid nondepolarizers in patients with neuromuscular disease, effectively reducing the risk of prolonged duration of action and residual paralysis [10]. This strategic modality not only improves the conditions for intubation and surgical procedures, but also serves as a safeguard against potential laryngeal injury, thus increasing the overall safety of anesthesia in people struggling with neuromuscular disease. The availability of such advanced reversal agents marks a commendable step forward in optimizing patient care and enhancing the well-being of this particular cohort of patients [11].

Epidemiology and Classification of Neuromuscular Diseases

Based on a study conducted in the UK in 2019, 28 230 patients were diagnosed with NMDs. Statistical analysis showed a higher prevalence of these conditions among men. The most commonly diagnosed types of neuromuscular diseases were Guillain-Barré syndrome (40.1%), myasthenia gravis (33.7%), muscular dystrophies (29.5%), Charcot-Marie-Tooth disease (29.5%), and inflammatory myopathies (25.0%) [12].

Guillain-Barré Syndrome

Guillain-Barré syndrome is a rare but serious neurological disorder characterized by acute inflammatory demyelinating polyradiculopathy. It includes progressive muscle weakness, areflexia, and increasing paralysis [13–15]. The incidence of this disease ranges from 0.81 to 1.91 cases per 100 000 people per year. Patients with Guillain-Barré syndrome often have a history of upper respiratory tract infections or gastritis, usually occurring up to 4 weeks before the onset of the disease [14].

Symptoms of the syndrome begin with weakness in the extremities, which can progress to affect the trunk, neck area, facial muscles, and even respiratory muscles. In severe cases, this can lead to respiratory failure. In addition, patients with Guillain-Barré syndrome may have sensory symptoms, such as cranial nerve deficits and autonomic nervous system dysfunction [14,15]. When surgical intervention is required in patients with Guillain-Barré syndrome, both regional and general anesthesia can be used. There is no definitive evidence to support the superiority of one method of anesthesia over the other, and both carry certain risks. In the case of general anesthesia, special caution should be exercised with succinylcholine because of the potential risk of hyperkalemia, which is additionally associated with a high probability of arrhythmia [16,17]. Nondepolarizing neuromuscular blockers should also be administered with caution because of the risk of prolonged neuromuscular blockade, requiring postoperative mechanical or assisted ventilation [18].

According to the clinical experience of the authors of this article and indications of other neuromuscular diseases during general anesthesia in patients with Guillain-Barré syndrome, monitoring TOF contractions is crucial from the beginning of anesthesia, despite its inadequacy in this group of patients [19]. This helps avoid an overdose of neuromuscular conduction blocking agent and allows the dose to be tailored to the individual patient. It is also worth noting that transferring the patient to a postoperative intensive care unit after confirming that the neuromuscular blockade has resolved may be essential for monitoring the patient’s condition after surgery.

In conclusion, Guillain-Barré syndrome poses challenges in both diagnosis and anesthesia planning during surgical procedures. Selection of the method of anesthesia, monitoring of the patient, and adjusting the dose of NMBAs require special attention and careful assessment of the patient’s condition to minimize the risk of complications. Transfer of the patient to the intensive care unit after surgery can be crucial to ensure adequate care during the recovery period [14,15].

Myasthenia Gravis

Myasthenia gravis is an autoimmune disease characterized by muscle fatigue and weakness of striated muscle strength [20,21]. Approximately 85% of patients develop antibodies to acetylcholine receptors at the neuromuscular junction. The estimated incidence of myasthenia gravis is 100–200 per million, with a higher prevalence in young women in their 20s and 30s and men over 60 [20]. The reason for this bimodal distribution is not fully understood [22]. In myasthenia gravis, skeletal muscle relaxants are used only when absolutely necessary due to contraindications arising from hypersensitivity and paradoxical resistance to neuromuscular conduction blockers. Patients with myasthenia gravis show resistance to depolarizing NMBAs in combination with paradoxical prolongation of their action [23]. This resistance is due to a reduced number of acetylcholine receptors at the neuromuscular junction, which increases the risk of prolonged, unpredictable nondepolarizing neuromuscular blockade, known as “phase II block”. The prolonged effect of these drugs is due to inhibition of succinylcholine metabolism by serum cholinesterases in myasthenia gravis, further increasing the risk of phase II block. The residual effect of even very low doses can lead to postoperative respiratory failure [21]. ED95 is a parameter developed to determine the dose of muscle relaxants, representing the dose that causes a 95% reduction in response to a single stimulus in half the population. Nondepolarizing NMBAs should be dosed by titrating small amounts in the range of 0.1 to 0.2 ED95 until the desired effect is achieved. Rocuronium and vecuronium are the preferred choice due to the possibility of reversing their effects with sugammadex (see below for details). In line with “Good Clinical Research Practice in Pharmacodynamic Studies of Neuromuscular Conduction Blocking Agents III: Geneva Revision 2023” [19], patient response should be monitored by TOF measurements during the administration of NMBAs. It should be noted that TOF measurements in patients with myasthenia gravis may be unreliable due to selective neuromuscular conduction abnormalities that vary widely from muscle to muscle [13,19]. However, given the available methods for assessing muscle relaxation, TOF measurement remains the preferred approach. The response to classical acetylcholinesterase inhibitors (IAChE) used to reverse skeletal muscle relaxation is highly unpredictable and, in extreme cases, can lead to cholinergic breakthrough. In cases requiring rapid intubation, full-dose muscle relaxants are recommended: rocuronium at 1.2 mg/kg or succinylcholine at 1.5 mg/kg lean body weight. No patient should be at increased risk of aspiration because of concerns about prolonged neuromuscular blockade [21]. Reversal of muscle relaxants: Sugammadex is the preferred agent for reversing the neuromuscular blockade induced by steroidal skeletal muscle relaxants (rocuronium and vecuronium) because its effect is not affected by IAChE. The effectiveness of blockade reversal should be confirmed by a TOF test value >0.9. Neostigmine, used to reverse the effects of depolarizing NMBAs, unlike sugammadex, is characterized by its action, especially in patients chronically treated with IAChE. In the absence of sugammadex and the use of neostigmine, careful dosing is necessary to minimize the risk of cholinergic breakthrough [24].

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy, caused by a mutation in the dystrophin gene located on chromosome Xp21. This mutation results in a deficiency of dystrophin, a key structural protein of the sarcolemma in muscle cells [25–27]. The clinical course of Duchenne muscular dystrophy is severe, and currently available therapies are not effective. The disease is characterized by progressive skeletal muscle weakness, usually manifesting in early childhood. Muscle reorganization with fatty infiltration and increased fibrous tissue leads to loss of walking ability by age 10. Most patients require corrective orthopedic surgery in the early stages of the disease because of foot deformities, and later, for severe scoliosis, to improve quality of life [25,28].

The main anesthetic concern in the treatment of patients with Duchenne muscular dystrophy is the use of depolarizing neuromuscular conduction blockers due to the potential risk of hyperkalemic cardiac arrest and rhabdomyolysis. The administration of various nondepolarizing NMBAs at different stages of the disease has been reported anecdotally. Documented responses to nondepolarizing NMBAs are inconsistent and range from normal to increased sensitivity. Therefore, reduction to standard NMBA doses is recommended. Nevertheless, reversal agents have been used in almost all cases, making full spontaneous recovery from neuromuscular blockade in patients with Duchenne muscular dystrophy unclear [25]. Rocuronium, usually characterized by a short onset time, may be a suitable alternative to succinylcholine in patients with Duchenne muscular dystrophy when clinical conditions require rapid muscle relaxation to protect the airway [25,26].

Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is the most commonly inherited disorder of the neuromuscular system. It is characterized by weakness and loss of sensation in the distal extremities, along with contractures, deformities, and reduced or absent deep tendon reflexes. Although Charcot-Marie-Tooth disease is usually inherited in an autosomal dominant manner, it can also be inherited in an autosomal recessive or X-chromosome-coupled manner, and different genes contribute to its clinical diversity. As the disease progresses, the upper extremities may become involved, and in severe cases, the respiratory muscles, diaphragm, and vocal cords may atrophy [29,30].

In the context of anesthesia, patients with Charcot-Marie-Tooth disease may have a delayed response to muscle relaxants and are at risk for malignant hyperthermia and respiratory problems due to weakened postoperative respiratory muscles [31]. The prolonged effects of muscle relaxants in Charcot-Marie-Tooth disease patients can theoretically be attributed to several factors: loss of motor units leading to muscle weakness and atrophy [32], as well as upregulation of acetylcholine receptors at the neuromuscular junction or increased sensitivity to nondepolarizing neuromuscular conduction blockers. Despite this, upregulation can also lead to a greater number of cholinergic receptors, which can result in normal or slightly increased resistance to these agents, and thus not always result in prolonged muscle relaxation [33]. For example, Pogson et al [31] reported prolonged neuromuscular blockade with vecuronium, while Baraka [33] found a normal response to the same drug despite extensive muscle weakness and areflexia. Ortiz-Gómez et al [34] reported no prolonged effects of rocuronium, and Schmitt et al [35] found no differences in the effects of mivacurium compared with healthy subjects. Patients with Charcot-Marie-Tooth disease are chronically denervated and are also at risk for a higher incidence of hyperkalemia and malignant hyperthermia. Succinylcholine should be used with extreme caution due to its adverse effects, including hyperkalemia. Although one study [32] reports the safe use of this muscle relaxant in patients undergoing surgery for Charcot-Marie-Tooth disease, it is recommended that plasma potassium levels be measured pre- and perioperatively and that ECGs be performed, especially in patients who have developed hyperkalemia.

Referring to the latest data according to the “Good Clinical Research Practice in Pharmacodynamic Studies of Neuromuscular Blocking Agents III: The 2023 Geneva Revision” [19], it is recommended to measure the degree of relaxation in the upper extremities due to a greater degree of disease involvement in the lower extremities than in the upper extremities. This is essential for convenient titration of NMBAs and identification of relevant reversible symptoms through effective nerve monitoring.

In summary, clinicians should be very alert to potential complications in Charcot-Marie-Tooth disease patients, including hyperkalemia, malignant hyperthermia, prolonged muscle relaxation, and respiratory failure. The selection of appropriate anesthetic techniques, including types and doses of anesthetics, along with the use of monitoring devices such as neuromuscular transmission monitors, is critical to ensure a rapid and effective response.

Inflammatory Myopathies

Inflammatory myopathies comprise a diverse category of chronic systemic autoimmune diseases, with an annual incidence ranging from 2 to 5 cases per million [36]. These diseases are characterized by muscle inflammation and progressive muscle weakness, and 3 major diseases fall into this classification: dermatomyositis, including a distinct juvenile subtype, polymyositis, and myositis with insertions [37].

Polymyositis manifests as a systemic disease involving inflammation and muscle degeneration [37]. Its symptoms often include muscle weakness, pain, swallowing disorders, shortness of breath, and hand tremors [38]. In addition, people with polymyositis may experience heart muscle problems, joint pain, and respiratory muscle weakness, leading to carbon dioxide retention. Weakness of the abdominal and neck muscles can contribute to complications such as gastroesophageal reflux disease (GERD) and aspiration of acidic gastric contents [38]. Recommendations for the management of patients with polymyositis, drawn from the literature, include awareness of potential aggravated or delayed reactions to drugs that block neuromuscular conduction, vigilance for pulmonary complications such as pneumonia and pulmonary fibrosis, and cardiac issues such as cardiomyopathy, arrhythmias, and even cardiac arrest [38,39]. It is crucial to recognize the possibility of pituitary-adrenal axis suppression and increased sensitivity to NMBAs due to previous steroid therapy [38].

The risk of skeletal deformity, limited joint mobility, and cervical spine disorders should be considered. Awareness of potential hyperkalemia and impaired temperature regulation is essential, along with caution regarding interactions between nondepolarizing muscle relaxants and immunosuppressants, which can lead to resistance and reduced efficacy of muscle relaxants [38].

It is recommended that succinylcholine be avoided because of its potential to cause malignant hyperthermia and hyperkalemia [38,39]. Neuromuscular blockers with shorter half-lives are suggested, with atracurium identified as safe, although with slightly increased sensitivity [40]. Monitoring neuromuscular blockade with peripheral nerve stimulators is recommended [38]. It is critical to recognize the potential for postoperative respiratory depression with opioid use. Avoidance of volatile anesthetics is emphasized because of the increased risk of malignant hyperthermia and their potential to enhance the effects of muscle relaxants. It is generally recommended to avoid all agents that can induce malignant hyperthermia in patients with elevated plasma creatine phosphokinase levels [38]. Considering epidural anesthesia in patients with polymyositis, especially if cardiopulmonary function is normal, is an important option to consider when determining treatment strategy [38].

Conclusions

In the context of anesthesia for patients with NMDs, a detailed preoperative evaluation plays a key role. Medical history, risk of difficulties during intubation, respiratory failure, and frequent pulmonary infections should be taken into account. These patients are at risk for a number of complications, such as prolonged paralysis, hyperkalemia, muscle rigidity, malignant hyperthermia, cardiac arrest, rhabdomyolysis, and even death. Problems with anesthesia in patients with NMD are due to the nature of the disease and the interaction of anesthetics and muscle relaxants with the drugs used in therapy. The selection of muscle relaxants should take into account the individual characteristics of the patient, the type of procedure being performed, and the duration of action of the muscle relaxant. Guillain-Barré syndrome is a rare but serious neurological disorder. It is critical to monitor TOF contractions during general anesthesia in patients with Guillain-Barré syndrome. Myasthenia gravis is an autoimmune disease characterized by fatigue and muscle weakness. Patients with myasthenia gravis are resistant to depolarizing muscle relaxants, which can lead to prolonged neuromuscular blockade. Rocuronium and vecuronium are preferred choices due to the possibility of reversing their effects with sugammadex. Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy, caused by a mutation in the dystrophin gene. The main anesthetic concern in patients with Duchenne muscular dystrophy is the risk of sudden cardiac arrest and rhabdomyolysis associated with the use of depolarizing muscle relaxants. Charcot-Marie-Tooth disease is the most common inherited neuromuscular disorder, characterized by weakness and abnormal sensation of the extremities. Patients with Charcot-Marie-Tooth disease may have a delayed onset of action of muscle relaxants. There is the possibility of prolonged muscle blocking, but responses to different muscle relaxants can be variable. Inflammatory myopathies are a diverse category of chronic systemic autoimmune diseases characterized by muscle inflammation and progressive muscle weakness. In patients with inflammatory myopathies, the possibility of increased or delayed response to muscle relaxants and the risk of complications such as pneumonia or cardiac disorders should be considered. In conclusion, the management of anesthesia in patients with NMD requires an individualized approach, taking into account the specific features of each disease and the risks associated with the use of muscle relaxants. Monitoring the effects of the drugs used and being aware of potential postoperative complications are key to providing safe and effective anesthesia care for these patients.

Future Directions

Key areas of focus should include establishing tailored dosing protocols based on individual patient characteristics, addressing drug interactions in this population, exploring alternative methods of anesthesia, longitudinal studies to assess long-term patient outcomes, and further research on sugammadex in the context of NMD patient safety. The invention of other similar drugs to reverse muscle relaxation that do not directly affect muscle tissue may prove invaluable. This research may be critical to addressing the complex challenges of anesthetizing patients with NMD, ultimately leading to improved care practices and increased patient safety. In addition, the use of alternative methods of anesthesia, such as regional techniques or total intravenous anesthesia, may offer benefits in specific NMD populations, necessitating comparative effectiveness studies. Longitudinal studies focusing on long-term patient outcomes, including postoperative complications, functional status, and quality-of-life measures, are necessary to gain insight into the broader impact of anesthetic interventions in patients with NMD. By addressing these multifaceted research avenues, the field can move forward toward more personalized, evidence-based anesthesia practices tailored to the unique needs of NMD patients, ultimately improving their perioperative care experience and clinical outcomes.