Mapping the current evidence on the anesthetic management of adult patients with neuromuscular disorders—a scoping review

Our study population comprised adult patients with an NMD, who needed sedation or anesthesia for an operation or a nonsurgical intervention. Neuromuscular disorders included motor neuron diseases, poly(radiculo)neuropathies, neuromuscular junction disorders, and muscle disorders including acquired and inherited myopathies, muscular dystrophies, and (non)dystrophic myotonias. This study population represented a broad spectrum of NMDs, with one general research question: what is the current evidence on the anesthetic management of patients with an NMD?

We searched PubMed and EMBASE for clinical studies, retrospective studies, case series/reports, and systematic/narrative reviews on the anesthetic management of patients with NMDs.

We searched the following databases on 14 July 2021:

The search was developed in collaboration with the information specialist from the medical library at the Radboud University in consultation with the authors. We used a broad search strategy, comprising three main categories: neuromuscular disorders, anesthesia, and perioperative complications. For each main category, relevant Medical Subject Headings terms, keywords, and synonyms were combined using “OR” within the categories. These three separate main categories were combined using “AND.” No limitation, except for the date, was applied. We did not search other databases or gray literature.

Details of the search strategy can be found in the Electronic Supplementary Material (ESM), eAppendix 1.

Eligibility assessment was performed by two authors (L. B. and M. G.) in a blinded and standardized manner using a two-step model. For the first step, all studies were reviewed for eligibility based on title and abstract. In case of discrepancy between the reviewing authors, consensus was reached by discussion. When no consensus was reached, a third author (N. V.) was asked to make the final decision.

We included articles on anesthetic management of NMDs from four different levels of evidence criteria:

Articles matching the following criteria were excluded:

For the second step, we reviewed the full texts of the studies considered eligible to make a final decision about inclusion. After exploring the available literature, inclusion and exclusion criteria for the second step were tightened for the review articles and clinical studies as outlined in detail below.

All case reports and case series reporting the anesthetic management and outcome of patients with NMDs matching the inclusion criteria were included. Since most literature focused on the association of perioperative complications in patients with an NMD with AIR, MH, and pharmacological strategies, we included studies and reviews if least one of the following topics was studied:

During the second step of study selection, the following articles were excluded:

We developed a separate data extraction sheet for clinical/retrospective studies, case studies, and review articles. The data extraction sheets were pilot tested on five randomly selected clinical/retrospective studies, case studies, and review articles and subsequently refined accordingly. Data were extracted independently by two authors (L. B. and M. G.).¹⁷ For each study, we extracted the perioperative complication rate of patients with a specific NMD or NMDs in general, and the use of cholinesterase inhibitors (in patients with MG), NMBAs, volatile anesthetics, and sugammadex in the study population.

For each case study, we extracted the age, sex, publication date, neuromuscular diagnosis (including information if the diagnosis was known before surgery), type of surgery (including emergency or elective), anesthesia technique, anesthetic agents used, administration of NMBAs and their antagonists, whether neuromuscular monitoring was used, and the perioperative disease course (complicated or uncomplicated). In the patients with MG, we registered the perioperative use of cholinesterase inhibitors. In the patients with a complicated disease course, we registered the specific complications. All perioperative complications were registered, without distinction between complications, that were very likely caused by the anesthesia or by a more uncertain etiology. A case was classified as complicated when an adverse event or unexpected condition of a patient occurred during or following a medical action resulting in irreversible damage and/or need for medical treatment.

For each review article, we extracted which NMDs were associated with MH or AIR when exposed to volatile anesthetics and/or succinylcholine, and which NMBAs and antagonists appear to be safe in patients with a specific NMD, or NMDs in general.

Since there are no high-quality methodologies for an objective quality assessment of narrative reviews, selection based on quality of the review articles would lead to a significant selection bias. Therefore, we did not perform a quality assessment, and information regarding the authors’ opinion on the topics described in stage 3 is presented as categorical data without triage.

We did not identify any prospective clinical studies on the effect of anesthetic interventions on perioperative complications in patients with NMDs. The only three prospective clinical studies identified investigated the pharmacodynamics of nondepolarizing NMBAs in NMD patients. These studies showed that the train-of-four (TOF) ratio before administration of an NMBA is a good predictor for atracurium and rocuronium requirement in patients with MG.^18,19 Another pharmacodynamic study showed that, in patients with oculopharyngeal muscular dystrophy (OPMD), the onset time of cisatracurium was prolonged while the duration of action was normal compared with healthy controls.²⁰

We identified 21 retrospective studies matching our inclusion criteria of which eight studied described perioperative complications in MG patients undergoing thymectomy.^21‐28 Patients with MG had more preoperative complications and a higher frequency of reintubation following thymectomy than non-MG patients did.²¹ Postoperative myasthenic crisis (POMC) occurred in 0–18.2% of patients^22,25‐27 and was shown to be associated with a history of a previous myasthenic crisis and unstable MG.²² Prolonged mechanical ventilation varied between 4.5–13.1% (> 24 hr)^23,25 and 3.7% (> 48 hr).²¹ Apart from the study of Mouri et al.,²⁶ which reported less POMC when sugammadex was used, perioperative complications could not be associated with specific anesthetic agents/management.

Other studies were on the anesthetic management of patients with myotonic dystrophy type I (DMI)^29,30 and II,^31,32 amyotrophic lateral sclerosis,^33‐35 Duchenne muscular dystrophy,³⁶ glycogen storage disease,³⁷ inclusion body myositis,³⁸ Lambert–Eaton myasthenic syndrome,³⁹ mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes mitochondrial encephalomyopathy⁴⁰ and OPMD.⁴¹ Opioid use was possibly associated with postoperative complications in a small retrospective study on the anesthetic management of DMI.³⁰ In this group of “other studies” the complication rates varied from 0% to 54%. Respiratory complications were frequently reported. Because sample sizes were small, lack of any complications or a control cohort perioperative complication could not be associated with specific anesthetic agents/management. Results of the retrospective studies included are summarized in Table 1.

We included 168 case reports or case series reporting a total of 212 anesthetics in 197 different patients. There was a slight female predominance in the reported cases (117/212; 55%). Median [interquartile range] age was 41 [27–57] yr. Myasthenia gravis was a frequent neuromuscular diagnosis (67/212; 32%), followed by DMI (38/212; 18%) and McArdle’s disease (22/212; 10%). The neuromuscular diagnosis was known before surgery in 176/194 (91%) cases. The neuromuscular diagnosis may have been more frequently known before surgery in the uncomplicated group than in the complicated group (adjusted odds ratio [OR], 18.6; 95% confidence interval [CI], 4.06 to 85.0; P < 0.001). Nevertheless, this analysis lacks validity because of the small proportion of patients in which the neuromuscular diagnosis was unknown before surgery in the group of patients with an uncomplicated disease course (unadjusted relative risk, 6.4; 95% CI, 1.7 to 23.9). Gastrointestinal surgery (46/212; 22%), gynecological surgery (35/212; 17%), and thymectomy (29/212; 14%) were frequent indications for surgery. In 155/187 (83%) cases, surgery was elective. Surgery may have been more frequently elective in the uncomplicated group than in the complicated group (adjusted OR, 2.34; 95% CI, 1.07 to 5.1; P = 0.03). Demographics and details regarding the neuromuscular diagnosis and type of surgery are summarized in Table 2.

In 145/212 (68%) of the reported cases, surgery, anesthesia, and perioperative course of disease were uncomplicated. At least one complication was reported in 67/212 (32%) cases. Death was reported in 5/212 (2%) patients. Unexpected postoperative intensive care unit (ICU) admission (19/212; 9%), unplanned postoperative reintubations (18/212; 9%), and unplanned postoperative need for mechanical ventilation (17/212; 8%) were frequently reported complications. All reported complications and their frequencies are summarized in Table 3.

Succinylcholine may have been more frequently used in patients with a complicated disease course (adjusted OR, 0.05; 95% CI, 0.01 to 0.39; P = 0.004). Nevertheless, this analysis lacks validity because of the small proportion of patients in which the neuromuscular diagnosis was unknown before surgery in the group of patients with an uncomplicated course of disease (unadjusted relative risk, 0.13; 95% CI, 0.20 to 0.86). Volatile anesthetics may have been more frequently used in patients with a complicated disease course (adjusted OR, 0.38; 95% CI, 0.20 to 0.73; P = 0.004). Based on the available data from all included cases, there was no significant difference in the use of NMBAs (adjusted OR, 0.62; 95% CI, 0.31 to 1.24; P = 0.17) and the use of neuromuscular monitoring between the patients with a complicated (adjusted OR, 1.90, 95% CI, 0.82 to 4.43; P = 0.14) and uncomplicated course of disease. There was no significant difference in the use of NMBA antagonists between patients with an uncomplicated and complicated disease course (adjusted OR, 0.58; 95% CI, 0.25 to 1.36; P = 0.21). Sugammadex was associated with an uncomplicated perioperative disease course in univariate analysis (OR, 3.40; 95% CI, 1.25 to 9.3; P = 0.02). Based on the available data from all included cases, there was no significant difference effect after adding publication year as a covariate (adjusted OR, 2.57; 95% CI, 0.86 to 7.7; P = 0.09). Propofol infusion syndrome was not reported. Details regarding the anesthetic technique, use of NMBAs, NMBA antagonists, and neuromuscular monitoring can be found in Table 4.

Although the level of evidence identified in this scoping review was considerably low, we were able to identify some evidence on the use of NMBAs and its antagonists in patients with NMDs.

First, succinylcholine may have been associated with a complicated perioperative course of disease in the reported cases (unadjusted relative risk, 0.13; 95% CI, 0.20 to 0.86), and there was consensus among all but one of the authors of the review articles. We did not identify any clinical studies or retrospective studies on this topic. Therefore, the true severity and prevalence of life-threatening side effects such as hyperkalemia, rhabdomyolysis, and myotonia remain uncertain. Due to the association of severe side effects of succinylcholine in patients with NMDs and the availability of alternative NMBAs, prospective clinical studies on this topic are probably not feasible and future research on this topic will be limited to retrospective studies. Until more evidence on the risks of succinylcholine becomes available, the use of succinylcholine should probably be avoided when feasible.

Except for pharmacokinetic and pharmacodynamic studies, we did not identify any clinical studies or retrospective studies on the effect of nondepolarizing NMBAs or neuromuscular monitoring on perioperative disease course in patients with NMDs.²⁰ Future research should focus on pharmacokinetic and pharmacodynamic studies on different nondepolarizing NMBAs and NMDs to give more insights into whether and how pharmacodynamics and pharmacokinetics are altered for each specific NMBA and/or NMD. This might help guide personalized dose adjustments in patients with specific NMDs. Furthermore, the effect of nondepolarizing NMBAs and neuromuscular monitoring on perioperative disease course in patients with NMDs might be interesting areas for future studies. Especially considering the results from studies in the healthy population.⁶⁵ Until these studies have been conducted, nondepolarizing NMBAs can probably be used with caution (use of neuromuscular monitoring and dose adjustments in individual cases). Although reliable evidence in favor of using of neuromuscular monitoring in patients with NMDs is missing, neuromuscular monitoring is harmless and has been shown to be associated with less postoperative residual paralysis in the general population.⁶⁵ If available, use of neuromuscular monitoring is therefore recommended whenever muscle relaxation is required by NMBAs in NMD patients.

Third, the use of sugammadex was associated with less POMC after thymectomy in a large cohort of MG patients.²⁶ Other studies did not show beneficial effect of sugammadex in patients with NMDs. But due to the small sample size and lack of a control cohort or sometimes even lack of any complication, the methodology and power of these studies was insufficient to answer this research question. Furthermore, sugammadex was only introduced a few years ago in the USA and Canada. Therefore, large and well-performed clinical studies in this specific subgroup of patients are not yet available. In the case reports included in this scoping review, there was no statistically significant difference in the use of sugammadex between NMD patients with a complicated versus uncomplicated disease course. Nevertheless, its use has only been reported in 30 case reports, which is an inadequate sample size to draw conclusions as reflected in the wide confidence interval (adjusted OR, 2.57; 95% CI, 0.86 to 7.7; P = 0.09).

We identified two cases of incomplete reversal of rocuronium-induced neuromuscular blockade with sugammadex in MG patients.^66,67 In both cases, the TOF ratio was restored sufficiently after administration of neostigmine. Exacerbation of MG symptoms, sometimes leading to a myasthenic crisis, occurs frequently after transsternal thymectomy.²⁴ Worsening of myasthenia status with increase in muscle weakness might be caused by the interruption of immunosuppressive agents, perioperative sepsis, surgical stress, pregnancy, or interference from anesthetic drugs (volatile anesthetics or opioids). Acetylcholinesterase inhibitors are an effective treatment for MG, and complete recovery of the TOF ratio by neostigmine administration after prior use of sugammadex may therefore be explained by its anticholinergic effect rather than by its reversal of the neuromuscular blockade by rocuronium.

Apart from one large retrospective study in MG patients,²⁶ there is currently insufficient evidence on the risks and benefits of sugammadex in NMD patients. Future pharmacokinetic and pharmacodynamic studies could offer clarification of cases of incomplete reversal of muscle relaxations as discussed above. Given the beneficial effect of sugammadex on pulmonary complications in the general population,⁶⁸ this might be an interesting area for future prospective clinical studies and/or retrospective studies. Until these studies have been conducted, the effect of sugammadex on reversal of neuromuscular blockade should be appropriately monitored with TOF ratio recovery and specific attention to the 100% twitch recovery before extubation.

Several authors have expressed concerns regarding the AIR risk in patients with NMDs in general and in muscular dystrophy patients in particular.^{11‐13,44,51,54,55} Nevertheless, although AIR is a well-known perioperative complication in patients with muscular dystrophies, a causal relationship of AIR with volatile anesthetics has never been unequivocally proven. We identified only one report of an 18-year-old obese patient with Becker muscular dystrophy who suffered a hyperkalemic cardiac arrest and rhabdomyolysis after the use of isoflurane for a six-hour procedure.⁶⁹ To test for susceptibility to MH, an in vitro caffeine halothane contracture test (IVCT) was performed three months later that turned out to be positive. In the absence of clear symptoms of hypermetabolism and RYR1/CACNA1S/STAC3 variants, AIR might be a better diagnostic description indicating potential harmfulness of long-term exposure of volatile anesthetics. The IVCT has high false-positive rates in dystrophic patients.⁷⁰

Since we identified a very limited number of AIR cases, the risk of AIR in adult patients with NMDs seems low (Table 3). This rare occurrence within our cohort is probably due to the pediatric age group being excluded, where muscular dystrophy and AIR are frequently described. In spite of the low number of AIR cases, the use of volatile anesthetics was possibly associated with a complicated disease course rather than by AIR. There are several explanations for this finding. In animal studies, sevoflurane has been shown to reduce the contraction force of the diaphragm.^71,72 In addition, volatile anesthetics enhance the effect of nondepolarizing NMBAs, as illustrated by a prolonged duration of rocuronium action if coadministered with sevoflurane.^73‐75 This may lead to residual relaxation and reduced muscle force in NMD patients. Future studies or setting up a registry of all NMD patients exposed to volatile anesthetics might help to create an unbiased cohort and examine the prevalence and severity of AIR, residual paralysis, and pulmonary complications in NMD patients exposed to volatile anesthetics.

Although associated with serious complications and risks, volatile anesthetics do have desirable pharmacokinetic properties. Since evidence on this topic is limited, the risks and benefits of volatile anesthetics in patients with NMDs should be weighed on a case-by-case basis, taking into account the extent and duration of the surgery, the degree of muscle weakness (which may be enhanced by NMBAs), and/or disease-specific considerations such as the association with AIR and MH susceptibility of some NMDs. Neuromuscular monitoring should probably be used whenever NMBAs are used in combination with volatile anesthetics.

Although patients with mitochondrial myopathies are at increased risk of propofol infusion syndrome, we did not identify any studies or case reports in the body of literature we examined. Propofol infusion syndrome occurs mainly when patients are exposed to propofol for > 48 hr in the ICU.^76,77 Propofol seems safe when used for procedural sedation and/or general anesthesia lasting for shorter time periods, even if those last up to several hours. In addition to our observation, there is international consensus concerning the safety of propofol in patients with mitochondrial disorders.⁷⁸ The choice between intravenous and volatile anesthesia must be made on a case-by-case basis. Based on current available evidence, we cannot recommend completely avoiding the use of either one in patients with NMDs.

We did not identify any clinical/retrospective studies on this topic, possibly because of the low prevalence of NMDs and MH, excluding laboratory and pediatric studies and ethical limitations of prospective studies on this topic. There is consensus regarding the association of MH with RYR1-related myopathies (CCD, KDS, and MmD). Nevertheless, there are concerns about a potential relation with MH in a large number of NMDs without consensus among authors in the field of NMDs and anesthesiology (Table 6). The association of MH and some NMDs has been proven through direct genetic evidence in patients with NMDs due to mutations in RYR1,^79,80 and, less frequently, in CACNA1S^81‐83 and STAC3.^84,85 Patients with an NMD associated with variants in these genes might therefore be at risk for MH when exposed to triggering agents and should be referred to an MH unit to counsel and test for MH susceptibility.

There is currently no evidence for an association of other NMDs with MH. The association of some muscular dystrophies with MH made by some authors of the included review articles is probably based on misdiagnosed cases of AIR.⁸⁶ Of course, patients with any Mendelian NMD may have an additional RYR1/CACNA1S/STAC3 variant resulting in MH susceptibility. Nevertheless, this risk is similar to the low MH risk in the general population.

Our scoping review has a number of limitations. First, the level of evidence we identified was very low. There is a lack of prospective studies on the relationship between anesthetic management and perioperative complications in patients with NMDs. Such studies are difficult to conduct because of the low prevalence of most NMDs. Many retrospective studies had a small sample size, high bias risk, and insufficient methodology to study specific effects of perioperative anesthetic management on disease course. Furthermore, due to the explorative nature of our study design and the small number of case reports, we were not able to draw reliable conclusions as reflected in the remarkable ORs and wide confidence intervals. For the same reasons, we were not able to perform multivariate analysis and/or meaningful subgroup analysis for specific NMDs. While patients with different NMDs have different complications, anesthetic management should be adapted accordingly. We were not able to compare complication type, complication rate, or anesthetic management with data from a control cohort. Additionally, the cohort included in the case report/case series section is a very selective patient population since more highly complex cases with significant and clinically relevant perioperative risks are published. Finally, it was not possible to perform an objective quality assessment of the review articles, and although all reviews had been peer-reviewed before publication, quality and evidence for the statements made were variable.