Introduction
The remarkable advancements in intensive care medicine have significantly boosted survival rates for critically ill patients over the past few decades. However, this progress has also brought to the forefront the complications associated with prolonged intensive care treatment, notably neuromuscular complications like critical illness myopathy (CIM). CIM has garnered increasing attention due to its strong correlation with heightened morbidity and mortality, leading to extended stays in the intensive care unit (ICU), protracted and intensive rehabilitation needs, and challenges in patients returning to their pre-illness lives. The impact of CIM became especially pronounced during the COVID-19 pandemic, where elevated CIM rates were reported, placing immense strain on healthcare systems already grappling with resource limitations and surging patient numbers requiring prolonged care and rehabilitation. This situation underscores the urgent need for deeper understanding of the pathophysiological mechanisms driving CIM and the development of effective preventive and therapeutic strategies.
Before the term CIM gained widespread acceptance, a variety of descriptive names were used, reflecting clinical, pathophysiological, or histological features, including acute quadriplegic myopathy, thick filament myopathy, acute necrotizing myopathy of intensive care, acute corticosteroid myopathy, acute myopathy in severe asthma, and acute corticosteroid- and pancuronium-associated myopathy.
Critical illness myopathy is defined as an acute primary myopathy that develops in patients during critical illness. Clinically, it manifests as flaccid paresis or plegia, often involving the respiratory muscles, with significant muscle atrophy. Histologically, CIM is characterized by a general reduction in muscle fiber cross-sectional area and a disproportionate loss of myosin, a key motor protein, without inflammatory infiltrates but with evidence of cytokine activation [1–3]. Early histological changes can occur as early as day 5 of ICU admission [4, 5], with muscle fiber cross-sectional area diminishing by approximately 4% daily in the initial stages [6–8]. Muscle fiber necrosis is another histological feature, though its presence is not consistently reported [1, 6].
Determining the precise incidence of CIM remains challenging due to variations in diagnostic methods and criteria employed across studies [9]. Reported incidence rates vary widely from 9% to 86% [10–13]. A comprehensive systematic review estimated the approximate incidence at around 40% [14], highlighting that purely clinical assessments are more prone to diagnostic failures (26%) compared to electrophysiological approaches (2%). Recent studies focusing on critically ill COVID-19 patients have reported CIM incidences ranging from 50% to 64% [15–17], suggesting a potentially higher prevalence in this population compared to non-COVID-19 cohorts. CIM can also coexist with critical illness polyneuropathy, sharing overlapping clinical features and associated with poorer patient outcomes [18]. The combined prevalence in patients with sepsis, multi-organ failure, or prolonged mechanical ventilation has been estimated at nearly 50% [9, 19, 20], although more recent data suggests that the prevalence of critical illness polyneuropathy may be lower than previously thought [21].
The clinical trajectory of patients with CIM is diverse, but generally, CIM is linked to significant long-term consequences for patients and their families [22–24]. CIM development is associated with a 15–25% increase in mortality, both in-hospital and over a 5-year period [23, 25–27]. In-hospital mortality rates increase with the severity of muscle weakness, even when adjusted for the overall severity of illness [28]. A recent study highlighted that both clinical and electrophysiological indicators of muscle dysfunction are independently linked to increased 5-year mortality [29•]. Furthermore, the complications arising from CIM and the subsequent prolonged ICU and hospital stays contribute to a 30.5% increase in healthcare costs [23]. Even one year post-hospital discharge, 14% of critical illness survivors exhibit persistent muscle weakness, with 9% still experiencing weakness after two years [30]. In a subset of patients with acute respiratory distress syndrome, 50% experienced muscle weakness over a 5-year follow-up, which correlated with reduced survival rates [27]. Six months after critical illness, patients who received mechanical ventilation and developed profound muscle weakness reported lower health-related quality of life compared to those without weakness, with muscle strength being positively correlated with physical function [31].
Despite extensive research into risk factors for CIM, its exact etiology remains unclear. CIM development is believed to be multifactorial, with proposed risk factors including pre-existing health conditions, duration of ICU stay and mechanical ventilation, use of neuromuscular blocking agents or sedatives, and the severity of acute illness, especially in cases of multi-organ failure [1, 32–34]. Multi-organ failure is consistently identified as a significant risk factor [33, 35–37], leading to the hypothesis that CIM may be another manifestation of multi-organ dysfunction [33, 38]. Data regarding the impact of corticosteroids, neuromuscular blockers, or sedatives are inconsistent and sometimes conflicting [9, 10, 37, 39–44]. Hyperglycemia is common in critically ill patients, particularly those with sepsis and septic shock. While early research suggested intensive insulin therapy might reduce CIM incidence [45], later studies revealed a higher risk of severe hypoglycemia and increased 90-day mortality with intensive insulin therapy compared to liberal glucose control [46, 47]. However, lower serum glucose and higher insulin levels still appear to be protective against CIM [48–50]. Recent studies in both patients and animal models highlight the role of profound systemic inflammatory response and bioenergetic failure, including microvascular, metabolic, and electrical muscle membrane alterations, in CIM pathogenesis [51, 52]. Muscle atrophy in CIM arises from decreased protein synthesis and increased protein degradation, largely mediated by the ubiquitin–proteasome system (detailed in [52]).
Clinical Presentation and Advancements in Critical Care Myopathy Diagnosis
CIM typically becomes clinically evident in the subacute phase of critical illness. As patients stabilize and sedation is reduced, muscle weakness and difficulties in weaning from mechanical ventilation become apparent. Neurological examination usually reveals muscle atrophy and symmetrical flaccid paresis. Cranial and facial muscles are often less affected or spared. Deep tendon reflexes are typically reduced or, in some cases, absent. Sensory function is often difficult to assess in ICU patients but is generally found to be within normal limits.
Current guidelines for a definite Critical Care Myopathy Diagnosis rely on a combination of clinical, electrophysiological, and muscle biopsy criteria [1]. The clinical criteria include (i) a history of critical illness involving multi-organ dysfunction and/or failure, and (ii) limb weakness or ventilator weaning difficulties not attributable to non-neuromuscular causes. Electrophysiological assessment involves motor and sensory nerve conduction studies on at least two nerves, along with needle electromyography. Motor nerve conduction studies in CIM typically show a reduction of compound muscle action potential amplitudes by more than 20% below the lower limit of normal. The duration of these potentials may be prolonged but can also be normal [53, 54•]. Importantly, nerve conduction blocks must be excluded. Sensory nerve conduction studies are usually normal or show only minor amplitude reductions (less than 20% below the lower limit of normal). Needle electromyography, when feasible in cooperative patients, reveals short-duration, low-amplitude motor unit potentials. Spontaneous activity, such as fibrillation potentials and positive sharp waves, may be present. If recruitment can be assessed, it is generally normal. In unconscious or uncooperative patients, direct muscle stimulation can be performed, comparing the compound muscle action potential elicited by nerve stimulation versus direct muscle stimulation via a monopolar needle electrode. Reduced or absent responses to both stimulation modalities are indicative of myopathy [55, 56]. Neuromuscular transmission deficits must be ruled out using repetitive motor nerve stimulation. Muscle biopsy findings, as previously mentioned, include myosin loss and muscle fiber atrophy. Less invasive fine needle biopsies can be used to measure the myosin:actin ratio [57•], with reduced ratios supporting CIM diagnosis. Definite CIM diagnosis requires fulfillment of all these criteria. In cases where patient examination or muscle biopsy are not feasible, but other criteria are met, a diagnosis of probable CIM is considered. When only clinical criteria are used, the term ICU-acquired weakness is employed.
Over recent years, many studies have moved away from the comprehensive multimodal approach for definite CIM diagnosis, focusing instead on ICU-acquired weakness as the primary endpoint. Consequently, more specific recommendations for ICU-acquired weakness diagnosis have emerged, emphasizing muscle strength assessment using the Medical Research Council (MRC) score across 12 muscle groups: shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion bilaterally. A sum score below 48 out of 60 indicates ICU-acquired weakness [58, 59]. However, ICU-acquired weakness remains a purely clinical diagnosis, lacking specificity regarding the etiology of weakness and encompassing a broad differential diagnosis including critical illness polyneuropathy, Guillain-Barré syndrome, Myasthenia gravis, and myositis, in addition to CIM [60]. This lack of specificity makes ICU-acquired weakness less suitable as a primary outcome measure in interventional and pharmacological trials, as the underlying pathophysiologies, prognoses, recovery patterns, and potential treatments differ significantly across these conditions.
A major limitation of current critical care myopathy diagnosis criteria is that they often only allow for diagnosis at an advanced stage of the disease, when substantial muscle damage has already occurred. These criteria are not ideal for early screening, identifying at-risk patients, or monitoring disease progression from its earliest phases. This late diagnosis impedes the timely conduct of preventive and therapeutic trials and interventions.
Pioneering work in 1971 by Cunningham et al. using invasive measurements of absolute muscle membrane potential in severely ill patients demonstrated muscle membrane depolarization (resting membrane potential − 66.3 ± 9.0 mV compared to − 88.8 ± 3.8 mV in healthy volunteers) alongside increased intracellular Na+ concentration [61]. Although CIM was not recognized at the time, this study laid the groundwork for the hypothesis that alterations in electrical properties precede structural changes and represent an early marker of disease onset, potentially serving as a tool for early diagnosis and monitoring. In 2008, Allen et al. using single muscle fiber recordings in CIM patients, found significantly slowed muscle-fiber conduction velocities, increased refractoriness (suggestive of membrane depolarization), and muscle-fiber conduction block [53]. Conduction block likely explains the reported muscle inexcitability upon direct muscle stimulation [62, 63]. Rat models of CIM have linked altered muscle membrane excitability to a hyperpolarized shift in the voltage dependence of inactivation of Nav1.4 sodium channels [64–66]. Muscle membrane depolarization in CIM is associated with a significant reduction in available sodium channels, consequently decreasing muscle fiber excitability. In vitro studies by Haeseler et al. [67] revealed that lipopolysaccharide endotoxin from Escherichia coli interacts with Nav1.4 Na+ channel alpha-subunits, reducing Na+ channel availability specifically at depolarized resting potentials [67].
Given the technical challenges and time-consuming nature of single muscle fiber recordings, a novel technique for measuring muscle excitability has been developed as a more practical diagnostic tool [68, 69]. This method involves direct needle muscle stimulation to excite a small cluster of muscle fibers, with recordings obtained using a concentric EMG electrode [70]. Following an initial evoked action potential, the muscle membrane’s excitability to a second action potential is assessed based on the interstimulus interval. Short interstimulus intervals result in membrane in- or hypoexcitability (absolute or relative refractory period). During the relative refractory period, an action potential can only be elicited with higher stimulation intensities and exhibits slower conduction velocity. This refractory phase is succeeded by a period of altered excitability influenced by the depolarizing afterpotential that follows a muscle action potential. This afterpotential depends on the charge remaining on the membrane capacitance [71]. A second stimulus applied during the afterpotential period will propagate faster along the muscle membrane (supernormality phase). Both the afterpotential and refractory period are strongly dependent on the membrane potential. Multi-fiber muscle velocity recovery cycle measurements allow for the assessment of refractoriness and supernormality alterations, thus enabling the detection of relative changes in muscle membrane potential [68, 69]. Studies using this technique in patients with probable CIM have confirmed changes consistent with muscle fiber membrane depolarization and/or heightened sodium channel inactivation [54•, 72]. Porcine sepsis models have shown similar alterations within 6 hours of sepsis onset, indicating that muscle membrane changes may indeed be an early indicator of CIM development [73], and that sepsis-induced microcirculatory changes influence muscle excitability alterations [74]. A recent prospective cohort study in COVID-19-associated ARDS patients demonstrated that muscle excitability measurements taken 10 days post-intubation effectively differentiated between patients who developed CIM according to diagnostic criteria and those who did not, with a diagnostic accuracy of 90%. This study further confirmed that muscle membrane depolarization occurs very early in CIM progression. Muscle excitability parameters measured within 24 and 48 hours of intubation showed diagnostic accuracies of 73% and 82%, respectively, in predicting CIM development. These findings strongly support muscle excitability measurements as a promising approach for early and confirmatory critical care myopathy diagnosis. Regarding risk factors, this study did not find an association between neuromuscular blocking agents or other medications (sedatives, vasoactive drugs, glucocorticoids) and CIM development, but confirmed that patients who developed CIM had longer mechanical ventilation durations and greater overall disease severity. Interestingly, patients with CIM exhibited higher serum potassium levels and greater potassium variability during the first 10 ICU days, as well as a higher incidence of renal failure [Rodriguez et al. under review].
Treatment Options and Emerging Therapies
Currently, there is no specific treatment for CIM beyond supportive care and rehabilitation. This lack of targeted therapies underscores the critical importance of developing and implementing preventive strategies during intensive care and identifying patients at increased risk of developing CIM early on. Addressing the underlying critical illness, such as treating severe infections and multi-organ failure, remains central to CIM prevention. A Cochrane review of interventional trials indicated that intensive insulin therapy modestly reduced the prevalence of CIM and critical illness polyneuropathy in some studies (as mentioned previously) [11, 45, 75]. Recently, a novel preventive treatment approach has emerged. Cacciani et al. [76•] reported that BGP-15, a chaperone co-inducer, heat shock protein, and insulin-sensitizer drug candidate, may protect muscle fiber force and improve survival in the initial 5 days of critical illness. However, beyond this timeframe, BGP-15 lost its protective effect, particularly once myosin loss, a hallmark of CIM, became established [76•]. Vamorolone, a novel class of dissociative glucocorticoids, offers similar anti-inflammatory effects to prednisolone but with fewer adverse hormonal effects on muscle tissue. Originally developed for Duchenne muscular dystrophy [77], vamorolone has shown promise in experimental studies, reducing muscle mass loss, myosin loss, and muscle dysfunction in response to 5 days of mechanical ventilation and immobilization [78•]. The JAK/STAT inhibitor ruxolitinib also demonstrated similar protective effects against ICU-related muscle damage as BGP-15 and vamorolone [79•]. BGP-15, vamorolone, and ruxolitinib all possess anti-inflammatory properties, acting at different points in inflammatory pathways. In addition to improving muscle function, reducing muscle wasting, and mitigating myosin loss, these agents also improved survival in experimental ICU models involving immobilization and neuromuscular blockade for 5 days or longer [76•, 78•].
Conclusion and Future Directions in Critical Care Myopathy Research
The continuous improvement of modern intensive care has led to increased patient survival, but has also highlighted the significance of complications like CIM. Patients with CIM require prolonged intensive care and hospitalization, necessitating extensive rehabilitation. CIM is not only associated with higher morbidity and mortality but also hinders patients’ reintegration into their former lives, leading to substantial long-term socioeconomic burdens for patients and their families, in addition to increased healthcare costs. The heightened incidence of CIM during the COVID-19 pandemic has further emphasized the critical need for research into CIM pathophysiology and the development of both preventive and therapeutic interventions. Promising advancements in early critical care myopathy diagnosis methods have been made in recent years, particularly with muscle excitability testing, but these require validation in larger patient populations. Early diagnostic tools are crucial for advancing our understanding of CIM pathophysiology and for monitoring the effectiveness of therapeutic interventions. Novel pharmacological treatments evaluated in experimental models, such as BGP-15, vamorolone, and ruxolitinib, show encouraging preventive potential. Future clinical trials are essential to rigorously assess the effectiveness and safety of these and other emerging drugs in preventing and treating CIM, ultimately improving outcomes for critically ill patients.
Funding
Open access funding provided by University of Bern.
Declarations
Conflict of Interest
Belén Rodriguez declares that she has no conflict of interest. Lars Larsson declares that he has no conflict of interest. Werner J. Z’Graggen declares that he has no conflict of interest.
Footnotes
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