Comprehensive Review of Anesthetic Strategies for Patients With Neurodegenerative Diseases

Introduction

Neurodegenerative diseases (NDDs), leading causes of disability worldwide, pose substantial challenges in aging populations [1]. Over the past 3 decades, the number of individuals affected by NDDs has greatly increased, and their prevalence and societal burden are expected to at least double over the next 20 years [2]. The presence of an NDD adds risk factors concerning the fragility of a patient’s neurological condition to those already associated with anesthetic procedures in the general population. General anesthesia is not merely an “instantly reversible state”; it can exert acute and potentially long-lasting effects on the central nervous system [3,4]. Neuroinflammation is a proposed mechanism underlying these effects [4]. Glial cells play an active role in regulating neuronal physiology [5]. Their functions include guiding synapse formation and development, modulating synaptic transmission, releasing gliotransmitters that influence neuronal activity, and contributing to metabolism by supplying lactate as an energy source [6]. For this reason, the use of general anesthesia itself – regardless of surgical intervention – is a factor that induces neuroinflammation, which may worsen the neurological status of patients with NDDs [7,8]. Extensive literature exists regarding perioperative complications in Parkinson disease (PD) and Alzheimer disease [8,9]; a few reviews have addressed amyotrophic lateral sclerosis [10] or selected neurological conditions [11]. Published guidance remains largely limited to these common disorders. Even the 2020 perioperative management guidelines from the Society for Perioperative Assessment and Quality Improvement focus only on PD and the most prevalent dementias, including Alzheimer disease [12]. Reports detailing anesthesiologists’ real-world experiences in managing patients with NDDs are generally scarce, and virtually no review articles address practical perioperative considerations for rare NDDs. This article aims to review the perioperative anesthetic management of patients with selected NDDs, including Huntington disease, (spino)cerebellar ataxia, Friedreich ataxia, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.

General Preoperative Evaluation in Patients With NDDs

GENERAL REMARKS:

A thorough preoperative assessment remains a cornerstone in minimizing anesthesia-related complications during surgery. This process heavily relies on meticulous patient history taking; careful review of current medications; and specialized consultations in cardiology, pulmonology, and neurology [12]. Importantly, the evaluation must also address the specific neurological disorder and its potential systemic implications, given that NDDs are not confined to the central nervous system but exert widespread multisystem effects. In addition to progressive neuronal loss, NDDs commonly involve autonomic dysfunction [13], gastrointestinal dysmotility [14], skeletal muscle atrophy [15,16], metabolic dysregulation [17,18], and chronic inflammatory activation [19]. Overall, these systemic manifestations reduce physiological reserve, alter pharmacokinetic and pharmacodynamic responses to anesthetic agents, and substantially increase perioperative and postoperative risk. Further diagnostic steps might include laboratory investigations, pulmonary function tests, chest imaging, and electrocardiograms, which may provide valuable information for perioperative planning. Collection of a detailed medical history – including the patient’s understanding of their diagnosis, any coexisting conditions, and the duration of their illness – is essential to guide anesthetic planning and select appropriate monitoring strategies [20], among several methods recently reviewed by other authors [21]. Particular attention should be given to the duration of disease presence, its severity, and any resulting physical limitations the patient may have developed [21]. Additionally, it is crucial to assess neurological status, including cranial nerve involvement, as well as the functionality of other organ systems, especially the heart and lungs [20]. In most cases that involve patients with NDDs, there is generally no need for additional or disease-specific laboratory tests. However, when a patient shows decreased muscle mass, careful monitoring of body temperature and blood glucose regulation is recommended [22,23].

DISEASE-SPECIFIC CONSIDERATIONS:

Some NDDs, notably PD, are associated with a higher risk of malignant hyperthermia (MH) – a potentially fatal hypermetabolic response to triggers such as succinylcholine or volatile anesthetics [22]. In rare diseases, it is important to consider the potential coexistence of additional genetic predispositions beyond the primary disorder, including alleles associated with MH susceptibility [24]. Timely identification of at-risk individuals, rapid detection of MH symptoms, and swift administration of dantrolene are crucial steps that can greatly enhance survival rates [23]. Regarding Creutzfeldt-Jakob disease, it is essential to consider measures for preventing the transmission of this fatal prion disease before surgery. Prion proteins are highly resistant to autoclaving and standard disinfectants; their presence on airway equipment or surgical instruments may pose a risk of disease transmission [25]. Preoperative preparation should therefore also include additional operating room arrangements (eg, removing unnecessary equipment) and providing the surgical team with enhanced personal protective equipment, such as liquid-repellent gowns, face masks, and double gloves [26]. Diseases that affect the neuromuscular junction or motor neurons – including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis – frequently involve cranial nerves, leading to bulbar symptoms such as slurred speech and difficulty swallowing [20]. Recurrent respiratory infections, especially pneumonia, or signs of impaired swallowing may suggest weakness of the throat muscles or cranial nerve dysfunction, raising concerns about increased aspiration risk [27]. Such findings are commonly observed in SMA and amyotrophic lateral sclerosis [20]. Collection of this clinical information – particularly regarding recent respiratory infections – is critical for determining whether surgery can proceed electively or must be postponed [28]. Furthermore, certain NDDs may slow gastrointestinal motility and impair swallowing, causing patients to retain food in the stomach despite adequate fasting periods before surgery. In these cases, some experts recommend gastric ultrasound to estimate stomach content volume and inform the safest anesthetic approach [28].

Cardiopulmonary Risk Assessment in Patients With NDDs

CARDIAC ABNORMALITIES IN NDDS:

The neural and cardiovascular systems are strongly interconnected through anatomical, physiological, and pathophysiological mechanisms. In patients with NDDs, damage may also occur to the heart’s electrical conduction pathways, which can substantially increase the risk of perioperative and postoperative complications [20]. Consequently, a thorough cardiovascular evaluation is essential in all patients with NDDs before surgery. For example, in Huntington disease, the mutant protein is expressed in both systems, resulting in clinical manifestations that affect each system [29]. Certain NDDs, such as Friedreich ataxia, are particularly susceptible to cardiac involvement as part of their disease progression [30]. Patients with these conditions frequently exhibit cardiac conduction abnormalities, including conduction blocks, ventricular tachyarrhythmias, premature beats (extrasystoles), and ST-segment changes on electrocardiography [30]. To adequately assess cardiac function and identify potential risks before surgery, transthoracic echocardiography and continuous 24-hour Holter monitoring are recommended [20]. However, because of physical limitations inherent to NDDs, exercise-based stress testing typically is not feasible in this patient population [20].

AIRWAY ASSESSMENT:

A crucial component of pulmonary risk assessment in patients with NDDs is thorough evaluation of the airway. Disease-related changes in the anatomy and function of the thorax, jaw, and cervical spine can strongly increase the likelihood of difficult intubation [31]. These alterations often result from disease progression and may include restricted mobility, skeletal deformities, or abnormal positioning of anatomical structures. Muscle weakness (central or peripheral), as well as conditions such as obstructive or central sleep apnea, impaired swallowing, spinal deformities, and distinctive craniofacial features, all contribute to an elevated risk of restrictive lung disease [31]. Over time, these factors can predispose patients to complications such as cor pulmonale (right heart failure secondary to lung disease) [32]. Imaging techniques, particularly chest computed tomography, can provide valuable insight into the presence of spinal curvature (eg, scoliosis) that may alter tracheal anatomy. When difficult airway management is anticipated, anesthetic teams must follow established clinical guidelines to effectively prepare for and manage these challenges.

In addition to airway considerations, patients with NDDs frequently face heightened pulmonary risks due to respiratory insufficiency and recurrent chest infections [33]. Identification of these risks requires a combination of clinical assessment and diagnostic tests, including physical examination, pulse oximetry, arterial blood gas analysis, lung function testing, and chest imaging. However, it is important to recognize that a normal chest X-ray does not rule out all pulmonary complications [34]. Thus, a comprehensive evaluation using multiple diagnostic tools is necessary; any previously acquired images should be carefully reviewed for signs of tracheal displacement or evidence of aspiration.

Recurrent aspiration is a common problem in some NDDs, such as amyotrophic lateral sclerosis or SMA. In these conditions, impaired cranial nerve function often leads to swallowing difficulties and increases aspiration risk [35]. This vulnerability extends to the perioperative period, when aspiration risk further increases. Additionally, structural abnormalities – such as macroglossia, mandibular deformities, or impaired tongue control – can complicate airway management during anesthesia. These issues may not only hinder intubation and ventilation but also predispose patients to acute respiratory failure due to airway obstruction by the tongue or aspiration events during sedation or anesthesia procedures. In patients with spinocerebellar ataxia, anesthesia-induced vocal cord paralysis has been reported; for this reason, video laryngoscopy to confirm the absence of vocal cord paralysis or upper airway obstruction appears reasonable [36].

Intraoperative Management in Patients With NDDs

SELECTION OF APPROPRIATE ANESTHETICS IN NDDS:

Etomidate, a short-acting nonbarbiturate hypnotic agent, is commonly used for induction because of its hemodynamic stability [40]. However, it may induce myoclonus in up to 50% to 80% of cases, likely due to disinhibition of extrapyramidal motor pathways, although the precise mechanism remains unclear [40]. Premedication with agents such as benzodiazepines or opioids can reduce the incidence of etomidate-induced myoclonus [41]. Emerging evidence suggests that remimazolam represents a promising alternative due to its cardiovascular stability and the availability of a specific antagonist [42].

Certain inhalational anesthetics have been reported to exacerbate motor symptoms in patients with PD during surgery [43]. In particular, halothane should be avoided in patients receiving long-term levodopa therapy because it may enhance myocardial sensitivity to circulating catecholamines, thus increasing the risk of cardiac complications [44]. Nitrous oxide provides effective analgesia and can be used either as a component of balanced anesthesia or in total intravenous anesthesia. Nevertheless, caution is required in patients with preexisting cardiac damage, given that the negative inotropic effect of nitrous oxide may worsen cardiac function.

Propofol, commonly used in the anesthetic management of patients with PD, has demonstrated potential neuroprotective and antiparkinsonian properties [45]. Nevertheless, clinicians should remain vigilant for propofol-induced extrapyramidal side effects, including tremors, athetotic movements, and dystonia. In certain individuals, even low-dose administration may be sufficient to induce adequate sedation or loss of consciousness [46]. Propofol and volatile agents have been successfully administered without complications in patients with amyotrophic lateral sclerosis or Friedreich ataxia [47,48]. This safety profile is likely attributable to the anti-inflammatory properties of propofol at low doses, including inhibition of astrocyte activation and reduction of pro-inflammatory mediators such as tumor necrosis factor-α [8]. Additionally, propofol may protect astrocytes against oxidative stress by inducing autophagy [8].

Opioid analgesics require cautious use due to the increased risk of postoperative respiratory depression in some diseases, such as spinocerebellar ataxia [36]. Remifentanil effectively suppresses the physiological responses to tracheal intubation and skin incision in patients with PD; however, dosage adjustment is recommended to avoid adverse effects [49]. Although fentanyl may induce bradykinesia and muscular rigidity in this population, these side effects do not impact its concomitant use with propofol.

MUSCLE RELAXANTS AND REVERSALS IN NDDS:

Among patients with NDDs, the use of muscle relaxants during anesthesia should be approached with caution and only when clearly indicated, given the increased risk of severe complications in this population. Administration of these agents to individuals with underlying disease can provoke adverse outcomes, including prolonged muscle paralysis, dangerous elevations in serum potassium levels, muscle stiffness, MH, cardiac arrest, rhabdomyolysis, or even fatal events. This adverse outcome risk is particularly high with depolarizing muscle relaxants such as succinylcholine, which can trigger a sudden efflux of potassium from damaged or unstable muscle cells into the bloodstream. This potassium surge, which follows an initial brief contraction, can precipitate life-threatening cardiac arrhythmias. Consequently, succinylcholine is generally avoided in most patients with NDDs. Nondepolarizing agents – such as rocuronium, vecuronium, atracurium, cisatracurium, and mivacurium – do not provoke potassium release and are considered safer alternatives. Nevertheless, due to reduced body mass in some of these diseases, patients with NDDs require careful dose reduction and vigilant monitoring. Acidosis is typical in certain NDDs, such as PD or multiple sclerosis [50], and may occur in some patients with amyotrophic lateral sclerosis [51], influencing the pharmacodynamics of neuromuscular blocking agents in these patients [52].

Neuromuscular blockade reversal in patients with NDDs presents additional challenges. The response to conventional reversal agents, such as acetylcholinesterase inhibitors, is highly unpredictable and carries a risk of inducing a cholinergic crisis [53]. Thus, sugammadex is the preferred agent for reversing blockade induced by steroidal muscle relaxants such as rocuronium or vecuronium, given that its mechanism of action does not impact acetylcholinesterase activity. Additionally, sugammadex has been associated with a reduced incidence of perioperative neurocognitive dysfunction relative to neostigmine [54]. Known risk factors for this complication include PD and advanced age [11].

Up to 82% of patients with spinocerebellar ataxia type 1 may develop peripheral neuropathy, which can alter the pharmacodynamics of neuromuscular blocking agents, potentially leading to a prolonged duration of action [55]. Careful titration and extended monitoring of muscle relaxant effects are advised. The reliability of train-of-four monitoring may be compromised if neuropathy is present at the site of peripheral nerve stimulation. To optimize signal accuracy, assessment for asymmetrical neurological findings, followed by electrode placement on the limb less affected by neuropathy, may be helpful [49].

Renal failure frequently co-occurs with NDDs, not only due to the age-related overlap between certain NDDs and kidney disorders but also because of shared pathogenetic mechanisms, including genetic mutations [56]. Renal impairment requires dosage adjustments for all medications – especially neuromuscular blocking agents – and careful selection of the appropriate drug. This topic was thoroughly examined by Radkowski et al [57]. Briefly, outside the context of NDD-related neuromuscular pathology, research generally supports the safety of succinylcholine in individuals with renal failure; however, reports of postoperative hyperkalemia highlight the need for continued scrutiny [57]. Certain neuromuscular blockers, such as atracurium and mivacurium, undergo elimination processes that are largely unaffected by reduced kidney function [57]. In contrast, drugs such as cisatracurium and rocuronium exhibit altered pharmacokinetics in the context of renal impairment, often requiring careful dose modifications [57]. Reversal agents, including neostigmine and sugammadex, have been shown to influence renal biomarkers; however, cystatin C levels tend to remain stable after sugammadex administration, suggesting a less pronounced effect on glomerular filtration compared with neostigmine [58]. Importantly, animal studies involving the concurrent use of rocuronium and sugammadex indicate a risk of nephrotoxicity, underscoring the need for caution when these agents are used together [57].

In some cases, anesthesiologists may choose to perform tracheal intubation without administering muscle relaxants to patients with NDDs, in an attempt to avoid pharmacological risks. However, this approach can complicate the intubation process and may increase the likelihood of injury to laryngeal structures. The decision to omit neuromuscular blocking agents should be individualized and balanced against the anticipated difficulty of airway management.

REGIONAL ANESTHESIA IN NDDS:

In patients with NDDs, no single anesthetic technique can be considered universally optimal. The choice between general and regional anesthesia should be individualized and based on the type and stage of underlying disease, the extent of central or peripheral nervous system involvement, the planned surgical procedure, and the patient’s respiratory and cardiovascular reserve. Both general and regional anesthesia may be appropriate in selected patients, provided that disease-specific risks are carefully considered and appropriate precautions are taken. Procedures performed with regional anesthesia are often considered a suitable alternative to those requiring general anesthesia, particularly in patients with increased risks of respiratory or pharmacological complications.

Initial concerns have been raised regarding the use of regional anesthesia in patients with Guillain-Barré syndrome and multiple sclerosis who experienced worsening neurological symptoms during the procedure. Guillain-Barré syndrome is an acute autoimmune-mediated demyelinating neuropathy of the peripheral nervous system [59], whereas multiple sclerosis is characterized by immune-driven demyelination within the central nervous system. Regarding demyelinated nerve fibers, increased sensitivity to local anesthetics and theoretical neurotoxicity have been suggested as potential mechanisms underlying neurological deterioration [60]. Consequently, the use of neuraxial anesthesia in demyelinating disorders remains controversial; it should be approached with caution and individualized risk assessment, rather than considered an absolute contraindication.

Although regional techniques are often favored, general anesthesia may be unavoidable or preferable in many patients with NDDs. Evidence supporting the safe use of general anesthesia in neurologically vulnerable populations has increased in recent years. A study reporting 13 years of experience from a single tertiary center specializing in surgical procedures among pregnant women with neurological disorders included 239 pregnant women with preexisting neurological conditions, of whom 10% had a demyelinating disease of the central nervous system [61]. Across all cesarean sections, 73 patients (31.2%) received general anesthesia; the remaining 161 patients (68.8%) were managed via neuraxial techniques. Videolaryngoscopy was used for tracheal intubation in 71% of general anesthesia cases, and neuromuscular blockade was reversed with sugammadex in 85% of patients; there were no reported cases of residual neuromuscular block [61]. These findings suggest that, when appropriate precautions and modern anesthetic strategies are utilized, general anesthesia can be safely administered even in high-risk neurological populations.

In PD, regional anesthesia allows monitoring of motor symptoms during surgery and enables earlier postoperative resumption of oral antiparkinsonian medications. However, this approach also has limitations. PD-related tremor may interfere with intraoperative monitoring, and dysphagia may increase aspiration risk even during regional anesthesia. Consequently, enhanced airway vigilance and protective strategies remain necessary in this population [62].

A distinct clinical scenario is presented by patients with Creutzfeldt-Jakob disease. Given the risk of prion transmission, minimizing exposure to cerebrospinal fluid is a key consideration. In this context, general anesthesia may be preferred over neuraxial techniques to reduce the potential risk of contaminating surgical staff and equipment.

Postoperative Monitoring of Patients With NDDs

Postoperative care involves ensuring access to an intensive care unit (ICU) with the capacity to provide mechanical ventilation and continuous 24-hour monitoring. Outpatient anesthesiology is typically recommended only in exceptional cases. Because specific guidelines for postoperative care in NDDs have not been established, decisions should be guided by the disease’s pathophysiology, severity, available resources, as well as the expertise of the healthcare team.

Close attention must be given to cranial nerve involvement and any decline in cardiopulmonary function. Reducing postoperative stress to lower oxygen demand can be advantageous. Efforts to minimize postoperative stress, including careful control of metabolic demand, are essential. Prevention of MH is particularly important in susceptible patients. MH is a genetic condition in which exposure to certain anesthetic agents triggers excessive calcium release from the sarcoplasmic reticulum via defective ryanodine receptors, leading to uncontrolled muscle metabolism, increased oxygen consumption, acidosis, rhabdomyolysis, hyperkalemia, and potentially life-threatening complications. Effective pain management and maintenance of normal body temperature are key strategies to reduce physiological stress.

Pain control should be tailored to each individual, incorporating a wide range of medications and regional anesthesia options. Some nonsteroidal anti-inflammatory drugs have demonstrated efficacy in the management of PD [63]. Given that many individuals with PD experience chronic pain and may already be taking analgesics, careful dosing is necessary to prevent accumulation and toxicity.

Pharmacological considerations extend beyond analgesia. Antiemetic agents with dopamine receptor–antagonistic properties, such as metoclopramide and promethazine, should generally be avoided in patients with PD because they may exacerbate motor symptoms [64]. In this context, effective postoperative care integrates close monitoring, tailored pain management, and avoidance of medications that could worsen neurological function, ensuring the best possible recovery for patients with NDDs.

Patients With NDDs in the ICU and Recovery Room

Standardized management protocols for patients with NDDs have not been established; therefore, awareness of potential high-risk events in this population is essential. Patients with PD are susceptible to acute clinical deterioration in the perioperative period, often triggered by intercurrent illness or alterations in pharmacotherapy. Such changes may exacerbate both motor and nonmotor symptoms. Individuals who show the highest risk include those with advanced PD requiring high-dose levodopa, genetically determined forms of the disease, or early-onset PD. Potential complications include severe “off” period manifestations such as orthostatic hypotension, intestinal pseudo-obstruction, acute psychosis, delirium, pronounced motor fluctuations, disabling dyskinesia, and akinetic crisis [65]. Akinetic crisis – also termed parkinsonism-hyperpyrexia syndrome – occurs in approximately 0.3% of cases and poses considerable therapeutic challenges because of transient unresponsiveness to dopaminergic agents [66,67]. It is commonly precipitated by abrupt discontinuation or impaired enteral absorption of dopaminergic drugs, or by administration of dopamine antagonists such as metoclopramide, haloperidol, or phenothiazines. Additional perioperative precipitants include infections, trauma, dehydration, malnutrition, and heightened sympathoadrenal activity. Clinical features may include pronounced rigidity, profound bradykinesia or akinesia, hyperthermia, elevated creatine kinase levels, rhabdomyolysis, autonomic instability, and altered mental status. Management focuses on prompt identification and removal of the underlying trigger, aggressive fluid resuscitation, temperature regulation, thromboembolic prophylaxis, and reintroduction or escalation of dopaminergic therapy [66]. These disease-specific perioperative risks highlight the need for vigilant monitoring in the ICU and recovery room, particularly concerning respiratory function and neurological status.

There is no clear guideline for predicting the need for postoperative ventilation. However, it is important to discuss the potential requirement for postoperative ventilation with patients, especially those who have preexisting respiratory impairment. The primary goal, as previously mentioned, is to achieve extubation as early as possible [9]. In the recovery room, all patients – regardless of procedure severity – are closely monitored and provided with appropriate care, ensuring that experienced medical support is available to address any issues that may arise.

Prophylactic postoperative ventilation is generally not recommended; the primary goal remains early extubation whenever feasible, considering the patient’s respiratory reserve. However, in patients with severe respiratory compromise – such as those with amyotrophic lateral sclerosis, SMA, or Friedreich ataxia – extubation may be delayed, and ventilatory support should be carefully planned.

Long-Term Complications of General Anesthesia in NDDs

Preclinical studies suggest that general anesthetics, particularly propofol, can impair mitochondrial function by inhibiting the respiratory chain, promoting mitochondrial fission, suppressing mitophagy, and increasing oxidative stress, thus potentially leading to neuronal dysfunction or death [68]. However, clinical evidence confirming long-term neurological harm remains limited.

In multiple sclerosis, a systematic review revealed no statistically significant difference in postpartum relapse rates between patients who underwent neuraxial anesthesia or analgesia and those who did not [69]. Similarly, in patients with dementia, reports of postoperative neurological deterioration after general anesthesia are inconsistent; systematic reviews have not demonstrated conclusive evidence of harm [70,71]. In PD, outcomes among patients undergoing subthalamic nucleus deep brain stimulation did not significantly differ between general and local anesthesia groups in terms of safety or therapeutic efficacy [72].

In Alzheimer disease, general anesthesia has been associated with postoperative sleep disturbances, which may persist for several days and recur weeks after surgery [73,74]. Approximately 23% of patients experience reduced sleep quality lasting up to 4 days postoperatively; nearly one-quarter of these patients require pharmacological sleep support, and approximately 25% report recurrence of sleep deprivation 15 days after surgery [74]. Sleep disruption itself may exacerbate neuroinflammation and potentially worsen neurodegenerative processes [75,76]. Although general anesthesia has been linked to alterations in amyloid-β metabolism [77], preclinical studies indicate that propofol does not affect amyloid precursor protein and may even inhibit the Aβ42 oligomer formation induced by inhalational anesthetics such as isoflurane [78].

Experimental data suggest that propofol can induce dyskinesias via GABAA receptor activation and NMDA receptor inhibition [78]; however, these effects have not been confirmed in clinical studies [79–82]. Older patients with cognitive impairment exhibit increased sensitivity to propofol, as reflected by lower bispectral index values, underscoring the need for careful dose adjustment in this population [81].

Future Directions

A promising direction for further research concerning anesthesia in patients with NDDs is the potential introduction of a new class of anesthetic drugs with neuroprotective properties. This emerging group of drugs is particularly important given the conflicting results of studies that examined the effects of currently available anesthetic agents on neural tissue affected by neurodegeneration. The new drugs include neurosteroids, which are more commonly recognized as antidepressants and anticonvulsants but also possess nerve conduction–inhibiting properties. Although Althesin (a mixture of alfaxalone and alfadolone) was used in clinical practice in the 1980s, its approval for human use was withdrawn due to adverse effects [82]. Subsequent research revealed that these effects were attributable to the excipient Cremophor EL [83]. An investigational formulation, Phaxan – an updated version of alfaxalone containing a cyclodextrin excipient – has emerged as a promising alternative. In a comparative study involving rats [84], Phaxan induced anesthesia more rapidly and allowed faster recovery relative to propofol. Moreover, its therapeutic index – a measure of drug safety – was considerably higher than that of both Althesin and propofol, indicating a wider margin between effective and toxic doses. Additionally, Phaxan exhibited substantially milder cardiovascular depressive effects compared with propofol, suggesting a more favorable hemodynamic profile. In a randomized, double-blind phase 1c trial involving human participants [85], Phaxan demonstrated recovery times comparable to those of propofol but was associated with significantly reduced cardiovascular suppression. Notably, airway obstruction requiring intervention occurred in the majority of individuals receiving propofol (9 of 12), whereas no such incidents were reported among those given Phaxan. These divergent effects on cardiovascular and respiratory function, despite equivalent hypnotic potency, are likely attributable to distinct off-target pharmacological actions of the 2 agents. From the perspective of this drug’s safety in patients with NDDs, its most important property is its additional anti-inflammatory effect. This property is particularly relevant because neuroinflammation (ie, microglial activation) is considered a key mechanism underlying anesthesia-induced cognitive and psychiatric disturbances in older adults [86]. One mechanism by which neurosteroids exert anti-inflammatory effects in the nervous system involves enhancement of brain-derived neurotrophic factor, which plays a crucial role in supporting neuronal viability, promoting axonal and dendritic regeneration, and maintaining efficient synaptic transmission and plasticity [87]. Levels of this substance are negatively correlated with neuroinflammation [86]. The neuroprotective effect of alfaxalone has been demonstrated in NDDs [88]. A key randomized controlled trial in humans evaluating Phaxan, propofol, and sevoflurane during hip replacement surgery [89] revealed that patients receiving Phaxan exhibited superior postoperative cognitive function. This cognitive benefit was paralleled by elevated plasma levels of brain-derived neurotrophic factor, suggesting a neuroprotective advantage of Phaxan over both propofol and sevoflurane.

Future research directions could include comparisons with other anesthetic agents; monitoring of cognitive and neurological function in patients with different NDDs; evaluation of whether alternative anti-inflammatory interventions can reduce postoperative cognitive dysfunction risk in this population; and long-term follow-up to determine whether the observed cognitive benefits are sustained over time.

Conclusions

The criteria for qualifying patients for postoperative ICU management have not been standardized across the entire population of individuals with NDDs. Decisions regarding postoperative ICU monitoring should be based on individualized clinical assessment, considering disease pathophysiology and progression, the degree of cranial nerve involvement, and any decline in cardiopulmonary function. For instance, patients with SMA or amyotrophic lateral sclerosis have an increased risk of respiratory complications, and postoperative mechanical ventilation may be necessary. Furthermore, in certain diseases, such as Friedreich ataxia, cardiovascular involvement can lead to perioperative complications that require advanced monitoring. In summary, although standardized guidelines have not been established, the most important criteria for ICU admission include severe respiratory impairment, the need for postoperative ventilation, and a high risk of cardiovascular complications.