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Pathophysiology and management of critical illness polyneuropathy and myopathy

Critical illness-associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into three major classifications based on the component of the neuromuscular system (i.e. peripheral nerves or skeletal muscle or both) that are affected. This includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and an overlap syndrome, critical illness polyneuromyopathy (CIPNM). It is a common complication observed in people with critical illness requiring intensive care unit (ICU) admission. Given CIAW is found in individuals experiencing grave illness, it can be challenging to study from a practical standpoint. However, over the past 2 decades, many insights into the pathophysiology of this condition have been made. Results from studies in both humans and animal models have found that a profound systemic inflammatory response and factors related to bioenergetic failure as well as microvascular, metabolic, and electrophysiological alterations underlie the development of CIAW. Current management strategies focus on early mobilization, achieving euglycemia, and nutritional optimization. Other interventions lack sufficient evidence, mainly due to a dearth of large trials. The goal of this Physiology in Medicine article is to highlight important aspects of the pathophysiology of these enigmatic conditions. It is hoped that improved understanding of the mechanisms underlying these disorders will lead to further study and new investigations for novel pharmacologic, nutritional, and exercise-based interventions to optimize patient outcomes.


INTRODUCTION
Critical illness-associated weakness (CIAW) refers to a group of neuromuscular disorders that may develop in patients with severe, typically acute, disease or trauma often resulting in admission to an intensive care unit (ICU). CIAW is a frequent complication of critical illness, affecting 30%-50% of critically ill patients who are admitted to ICU, and as high as 67% of those patients affected by sepsis (1). The typical description is symmetrical, flaccid limb weakness with sparing of facial and ocular musculature (2). Diaphragmatic involvement is common and is associated with important respiratory consequences (2). Limb and respiratory weakness often leads to prolonged ICU admissions, mechanical ventilator dependence, and increased long-term disability (2).
CIAW is a clinically descriptive, syndromal term that can be further categorized into two distinct clinical entities: critical illness polyneuropathy (CIP) and critical illness myop-athy (CIM), with an overlap syndrome, critical illness polyneuromyopathy (CIPNM). Further delineation is possible (e.g., sepsis-induced myopathy, steroid-denervation myopathy) but will not be the focus of this review (3). CIP refers to weakness related to dysfunction and degradation in multiple peripheral nerves. CIM includes weakness due to disease processes within skeletal muscle. CIPNM involves overlap between the two conditions. Although these subcategories are often conceptually collapsed into the unified CIAW, the divisions represent important differences in pathophysiology, prognosis, and perhaps distinct approaches for management. Multiple investigations have found CIP is associated with significantly worse outcomes compared with CIM (4). Many patients experience decreased functional capacity and compromised quality of life for months or years following resolution of their critical illness. Recently, substantial advances have been made to enhance the understanding of the mechanisms related to these conditions (5,6). This is relevant to the context of the COVID-19/SARS-CoV pandemic, given associated neuromuscular complications, including reports of an added CIAW incidence (7). The purpose of this article is to discuss CIP, CIM and CIPNM, with emphasis on their pathophysiologic underpinnings and how those mechanisms may relate to prognosis and management approaches.

PATHOPHYSIOLOGY
Although CIM, CIP, and CIPNM may have similar clinical presentations, there are differences in the underlying pathophysiology. CIP is an axonal sensorimotor polyneuropathy whereby the clinical deficits are a result of the loss of individual nerve fibers (8). In contrast, weakness in CIM is due to loss of thick myofilaments and subsequent myofiber death in skeletal muscle without a neurogenic etiology (8). Despite the recognized pathophysiologic differences between these two conditions, the underlying mechanisms and risk factors associated with their development are highly complex and remain a matter of ongoing study.
Multiple mechanisms have been identified that can theoretically result in CIAW (Fig. 1). These mechanisms likely include but are not limited to 1) reduced excitability of muscle and nerve; 2) death of peripheral nerve axons; 3) altered ionic (e.g., calcium, sodium) regulation; 4) myosin loss, myofiber atrophy and death; 5) bioenergetic failure; 6) neuromuscular transmission dysfunction; 7) altered catabolism to anabolism ratio; and 8) profound increases in systemic inflammation (3). To optimize disease prevention or therapy, it may be necessary to acknowledge and address multiple factors.
It is important to note there are ethical and practical challenges related to studying weakness due to critical illness. Individuals who are critically ill are typically unable to consent to being studied. Thus, the use of animal models forms a substantial proportion of our understanding of these conditions.

PATHOPHYSIOLOGY OF CIP
CIP is a result of peripheral nerve axonal dysfunction and death without a major demyelinating component such as seen in some other acute neuropathic conditions (e.g., typical Guillain-Barr e syndrome/acute inflammatory demyelinating polyneuropathy or mononeuritis multiplex) (9). One proposed mechanism underlying CIP is an alteration to the microvasculature to the axons of peripheral nerves. In some foundational work, Bolton et al. (1) hypothesized CIP could be due to increased permeability to the vasa nervorum. This increased permeability may be mediated by significantly increased expression of membrane activation Figure 1. Conceptual depiction of the pathophysiological factors underlying critical illness-associated weakness (CIAW). Please note, the evidence for these factors is derived from heterogeneous studies including investigations in both humans and animal models. This figure is meant to graphically illustrate 1) the inherent complexity of CIAW and 2) how various potential pathophysiologic mechanisms relate to one another and how they may lead to either, or both of, polyneuropathy and myopathy. ROS, reactive oxygen species. GH, growth hormone.
marker, E-selectin, found in human patients with CIP (4). The resultant transmigration of immune cells into nerve tissue, through the release of inflammatory mediators such as TNF-a and IL-1, represents an inflammatory response (10). The resulting edema may induce hypoxia, leading to impaired energy generation and an increase in the formation of reactive oxygen species (ROS) (11). Energy deficits can subsequently result in axonal degeneration, and increased ROS can further contribute to bioenergetic failure via structural damage to mitochondria (12). This inflammatory response, in absence of infection, has been recognized as systemic immune response syndrome (SIRS) (10).
Hyperglycemia, a common feature in people with critical illness, has been thought to have direct toxic effects to the axons (13) as has been established in diabetic polyneuropathy (14), and has been shown to negatively affect mitochondrial function (15). Although the underlying mechanism has yet to be determined, two possible hypotheses may explain why hyperglycemia may be more toxic in ICU patients compared with noncritically ill people with diabetes. The first theory is the direct toxic effect of cellular glucose overload in response to critical illness. There is upregulation of glucose transporters on various tissue types, including neurons, in response to increased hypoxia, cytokines, angiotensin II, endothelin-1, VEGF, and TGF-b stimulation (16). Thus, the classic systemic inflammatory "stress response" overrides normal glucose homeostatic measures, allowing for a greater, more rapid toxic intraneuronal glucose overload.
The second theory, which may be an extension of the first, hypothesizes that increased glucose levels lead to a subsequent increase in generation of ROS taking the form of superoxide produced through glycolysis and oxidative phosphorylation processes (16). Additionally, there is a deficiency in the scavenging of ROS in people who are critically ill (16). The marked increase in the generation of superoxide molecules overwhelm the cells native ROS protective mechanisms and unneutralized ROS can then go on to form complexes with nitric oxide, generating peroxynitrite (4). Peroxynitrites can theoretically suppress the mitochondrial electron transport chain creating a reactionary chain of events that ultimately lead to cell apoptosis (16).
Another hypothesis, with relatively limited evidence, related to CIP pathophysiology implicates membrane depolarization secondary to endoneurial hypoxia or systemic hyperkalemia (17), directly affecting nerve signal conductance. In renal failure, increased levels of endoneurial potassium contributes to membrane depolarization through an alteration in membrane subexcitability potential, ultimately leading to a depolarized state of the axonal membrane (17). However, this same altered membrane potential was also noted in human patients with CIP without renal failure and has been attributed to acute local ischemia at the level of the vasa nervorum (18). Therefore, the state of membrane depolarization is hypothesized to occur as a direct result of decreased oxygen levels (17) and may contribute to loss of peripheral neurons (15).

PATHOPHYSIOLOGY OF CIM
Of the two distinct entities that make up CIAW, CIM has been much more intensively studied, leading to a more detailed understanding of its pathophysiologic mechanisms when compared with CIP. CIM is structurally characterized by the selective loss of myosin causing myofiber atrophy and death (3). Some underlying causes may include systemic inflammation, structural skeletal muscle changes, metabolism, microcirculation at the muscle level, biological energy generation, autophagy, and dysfunction of membrane/ion channels (19).

Systemic Inflammation
Proinflammatory cytokines are greatly increased in the critically ill, across a wide variety of underlying etiologies, and this inflammation may be implicated in the development of weakness. Past studies have shown increased plasma levels of proinflammatory cytokines (e.g., TNF-a, IFN-c, IL-1, IL-6, IL-10) in a variety of critically ill states, including mechanical trauma (20), sepsis (21), severe burn injuries (22), and drug-induced organ failure (23).
TNF-a and IL-1 promote skeletal muscle atrophy with reduced protein content and reduced myotube diameter (24)(25)(26)(27) via NF-kB, intramyocellular ROS, and increased activity of ubiquitin-proteasome pathways (28). Past studies have shown selective inhibition of NF-kB prevents TNFa-related loss of muscle protein (26). Additionally, TNF-a and IL-1 impair muscle function (i.e., force per unit of muscle) through oxidative processes and alterations in sarcoplasmic reticulum calcium release (29)(30)(31). IL-6 may also lead to loss of muscle mass via an indirect path by interfering with IGF-1 signaling, an important anabolic promoter (32). Recently, Growth and Differentiation Factor-15 (GDF-15), a stressinduced cytokine, has also been identified as a mediator of critical illness-related muscle atrophy (33).

Prolonged Immobilization
In patients with CIM, there is a generalized loss of myofibrillar protein overall but a preferential loss of myosin within myofibers. This selective myosin loss may be related to prolonged immobilization (>5 days) (34) and, in the case of diaphragmatic myosin loss, due to the use of mechanical ventilation (35). Mechanical silencing, the state of absent external and internal strain, has been demonstrated to reproduce the CIM phenotype within animal models (36). The proposed underlying mechanism involves the upregulation of several proteolytic pathways in response to mechanical silencing that targets myosin specifically, with MuRF-1 ubiquitylation representing a particularly important step Key Points 1. CIP is a result of peripheral nerve axonal dysfunction and death, typically without significant demyelination. 2. Hyperglycemia is a potential driving force in the onset of CIP through direct glucose toxicity and mitochondrial disruption. 3. Altered membrane depolarization, secondary to hypoxia or hyperkalemia, may also play a role in the development of CIP, but evidence for this concept remains quite limited.
(36). Calpain-1 and caspase-3 pathways have also been shown to be activated in parallel to the ubiquitin-protease pathway (37). Additionally, myosin protein and myosin mRNA expression levels have been shown to be decreased in both ICU patients and those with acute quadriplegic myopathy (38), suggesting that immobilization and disuse can lead to myosin loss. Even relatively short-duration diaphragmatic inactivity can result in considerable muscle atrophy. This was demonstrated in a study showing a greater than 50% decrease in diaphragm muscle cross sectional area in organ donors who underwent muscle biopsies after being mechanically ventilated for periods ranging from 18 to 69 h when compared with clinical controls (39).

Metabolism
Experiencing a critical illness induces a systemic catabolic state, with decreased anabolic effector hormones and increased catabolic hormones (40). One upregulated catabolic pathway is the ubiquitin-proteasome system (41). Proteolytic activity of the proteasome pathways is higher in skeletal muscle in human patients with sepsis/organ failure versus controls (42). Local inflammatory responses may also contribute to the arrest of protein synthesis (43), and IL-1 has been shown to promote proteolysis via ubiquitylation in rodent models (44).
The hypothalamic-pituitary axis also plays a critical role in regulation of metabolic homeostasis during stress, in particular via growth hormone and cortisol (40). The pulsatile release of growth hormone is suppressed in chronic critically ill human patients, contributing to muscle wasting (40). Excess cortisol exerts catabolic effects on skeletal muscle within healthy volunteers, and inactivity exacerbates this process (45). Cortisol levels are dramatically increased during the acute phase of critical illness (40). Given the effect of endogenous cortisol, one may expect the use of exogenous corticosteroids could be a significant contributor to CIM; however, results were equivocal in human randomized control studies (46).

Microvascular
Microvascular vasodilation and increased permeability have been implicated in CIM pathophysiology. Patients with CIM have increased leukocyte extravasation and tissue infiltration, leading to local cytokine release resulting in edema (3,8,47). Edema within the muscle tissue compromises perfusion and oxygen delivery thus compromising energy production (48). These metabolic conditions cause an upregulation of catabolic and/or apoptotic pathways and thus muscle atrophy.

Bioenergetic Failure
Bioenergetic failure in CIM occurs because of three main factors: increased oxidative stress, mitochondrial dysfunction, and overall ATP depletion (49). Glutathione, an endogenous antioxidant, has been found to be depleted in critically ill patients (50,51). Depleting glutathione indicates increasing oxidative stress, with ROS scavengers being consumed in response to the increase in ROS. Oxygen insufficiency, as well as impaired oxygen utilization, can result in bioenergy production failure (3). Impaired oxygen utilization comes as a result of mitochondrial damage, which can be then further aggravated by inflammation, hyperglycemia, damage via ROS (3), as well as high levels of nitric oxide (NO) (49).

Membrane Inexcitability/Excitation Coupling
In patients with CIM, sodium channel dysfunction may result in sarcolemma inexcitability (52) leading directly to muscle weakness. In an experimental rodent model, altered calcium homeostasis was implicated in dysfunctional excitation contraction coupling (53). Changes to ryanodine receptors on the sarcoplasmic reticulum result in decreased contractile performance within a rat model of critical illness (53). Another study showed the serum of human patients with CIM exhibited toxic effects on muscle membrane excitability and transcellular calcium release of mammalian skeletal muscle in vitro (54), suggesting the potential presence of a low molecular weight humoral factor in the pathogenesis of CIM.

Autophagy Failure
Autophagy refers to the natural, ordered mechanism by which a cell degrades and recycles unnecessary or dysfunctional components (55). Autophagy is impaired in critically ill patients, leading to accumulation of damaged protein and damaged mitochondria within myofibres (56). The result is compromised muscle function secondary to bioenergetic failure, along with degenerative changes, such as fibrosis or increased intramuscular adipose tissue.

PATHOPHYSIOLOGICAL CONSIDERATIONS SPECIFIC TO COVID-19/SARS-COV
Over the course of the COVID-19/SARS2-CoV pandemic, there has been concern regarding the potential for neuromuscular complications. To begin, high rates of CIP and CIM are seen in patients with acute respiratory distress syndrome (ARDS) in general (25%-46% and 48%-96%, respectively) (57). And, in addition to a small case series of patients with CIAW and a single case report of CIM (9, 58) associated with COVID-19, there has now been a cohort study (7) that found a 9.8% rate of CIAW in their ICU population with COVID-19, although this excluded the 23% who died in the first 2 wk. This incidence was higher than the study historical control rate of 2.5% (7). Predictably, patients who developed CIP had longer ICU stays and relatively prolonged ventilation. Investigation into the relationship between COVID-19 and CIAW is still in its infancy, and there is clearly much to be explored.

Key Points 1. A profound systemic inflammatory response in peo-
ple who are critically ill is a common feature underlying both CIP and CIM. 2. Critical illness typically induces a catabolic state with systemically impaired neurotrophic and myotrophic signaling. 3. It is unknown why an individual may develop CIM versus CIP versus CIPNM despite sharing many common risk factors and systemic pathophysiological mechanisms.

EPIDEMIOLOGY AND RISK FACTORS
Three major agreed upon risk factors for CIAW include sepsis, multiorgan failure, and persistent systemic inflammation (3). These major risk factors are clearly linked with the current pathophysiologic understanding of CIM and CIP. Hyperglycemia has predictive value (59-61), as its presence is associated with increased risk of CIAW by 20% (59). The role of glucocorticoid usage as a risk factor remains unclear (62,63).
One report found females were four times more likely to develop CIAW, hypothesizing differences in baseline muscle strength, physiology, and pharmacokinetics as major contributing factors (63). A Sequential Organ Failure Assessment (SOFA) score over 7 for the Respiratory, Central Nervous, and Cardiovascular systems have been significantly associated with the development of CIAW (19). The Acute Physiology And Chronic Health Evaluation II (APACHE II) score, which includes measures of vitals, blood count differential, and Glasgow Coma Scale, under 10 has also been found to be a statistically significant predictor of CIAW (64). Duration of ICU stay (65), parenteral nutrition (66), and mechanical ventilation (63) have also been identified as risk factors.
Duration of stay, use of mechanical ventilation, premorbid health status, severity of acute disease, and plasma IL-6 levels are risk factors for CIM development (67), whereas duration of mechanical ventilation is a CIP-specific risk factor (19,68). Other independent risk factors for both CIP and CIM include chronic renal failure, liver dysfunction, diabetes, dyslipidemia, and impaired electrolyte homeostasis (68). Initial evidence suggested that neuromuscular blocking agents may be a risk factor for CIP and CIM (12); however, this has recently been refuted (69). Risk factors are illustrated in Fig. 2.

DIAGNOSIS
CIAW is typically diagnosed during recovery from a critical illness, where there was prolonged or failed weaning from mechanical ventilation or profound weakness in a conscious patient (70). An early clinical sign in a critically ill, unconscious person may include a limited or absent limb response to painful stimulation but with facial grimace present indicating intact sensory function (70). Diagnostic criteria, as adapted and modified from Bolton et al. and Lacomis et al. are described in Table 1. CIP, CIM, and CIPNM all share the major clinical sign of flaccid and usually symmetrical weakness. Deep tendon reflexes may be absent or reduced. A potential differentiating factor is people with CIP may show a distal loss of pain, temperature, and vibration sensitivity, whereas these functions would be intact in CIM. Additionally, CIM typically results in relatively more muscle atrophy, which may be difficult to detect given critically ill patients are often profoundly edematous (71). In the conscious patient, three muscles groups are tested bilaterally in each upper and lower extremities and graded using the Medical Research Council (MRC) scale (0-5 scale, with 5 being full strength). Somewhat arbitrarily, a combined score of <48 is diagnostic of CIAW (63). More detailed review of clinical diagnostic criteria can be found elsewhere (3,12,72).
Despite contextual technical challenges (e.g., the presence of profound edema), electrodiagnostics [both nerve conduction studies (NCS) and needle electromyography (EMG)] may be helpful in differentiating CIP and CIM. In both entities, typical motor nerve studies show reduced compound muscle action potential (CMAP), without significant slowing of conduction velocities or prolongation of latencies (which would be indicative of demyelination). However, in CIM the duration of the CMAP, from either nerve or direct muscle stimulation, is prolonged-believed to be a sign of muscle inexcitability (15). CIP may feature reduced or absent sensory nerve action potential (SNAP), whereas in isolated CIM, SNAP should be normal. Needle EMG performed at rest, in both CIM and CIP, often shows abnormal spontaneous activity (e.g., positive sharp waves and fibrillation potentials), a reflection of active, functional denervation which is nonspecific, as it can be associated with myopathic or neuropathic processes (6,73). When feasible, in the awake and cooperative patient, needle EMG during voluntary activity may show the classic pathologic recruitment profiles of myopathy or neuropathy in CIM and CIP, respectively (74).

Laboratory Investigation and Imaging
Standard laboratory tests and imaging have not been central to the diagnosis of CIAW. However, plasma IL-6 has been noted to be an early marker of membrane dysfunction  in CIM (75). Recent studies have demonstrated GDF-15, a stress-induced mediator of critical illness muscle atrophy, as a promising biomarker candidate (33). Muscle biopsy may be considered if the diagnosis is unclear following clinical and electrodiagnostic assessment (12).

PREVENTION AND MANAGEMENT
At present, the current standard of care for management includes reducing risk factors, supportive care of symptoms, and physical rehabilitation (12). Ongoing efforts are being made to develop new and improved strategies for prevention and treatment. Management strategies are listed in Fig. 3.

Pharmacological Interventions
At present, there are no recommended pharmacologic interventions in preventing or treating CIAW (76). The use of intravenous immunoglobulin (IVIG) was thought to be promising (77); however, it has since proven unhelpful (78). Hyperglycemia is an important predictor of death and complications in critically ill patients, and achieving euglycemia has been shown to improve a variety of outcomes in ICU patients (60), including those with CIAW. A Cochrane review provided evidence that intensive insulin therapy significantly reduced CIP and CIM rates, duration of mechanical ventilation, duration of ICU stay, and 180-day mortality rate (79).

Functional Electrical Stimulation
Functional electrical stimulation (FES) in the non-ICU patient population has been shown to increase muscle strength and exercise tolerance (80); however, FES for management of CIAW has demonstrated mixed findings. Trials of FES have been heterogeneous and underpowered, with various levels of bias in reporting (81)(82)(83)(84)(85)(86)(87), limiting ability to draw firm conclusions regarding its utility. Additional, higher-quality studies are required to determine the usefulness of FES.

Exercise-Based Interventions
Exercise has been the mainstay of CIAW management. Early mobilization following sepsis has been shown to be beneficial in preserving muscle fiber cross-sectional area (88), and importantly, is procedurally safe with a low risk of adverse events (89). A systematic review by Zhou et al. (72) revealed early mobilization leads to decreased incidence of CIAW, improved functional capacity, increased standing capacity, and increase in the number of ventilator-free days. This same review, however, did not see an exercise-related improvement in the ICU, hospital, or 28-day mortality rate in people with CIAW (72). Some exercise modalities studied to date included transfers (e.g., supine to sitting), walking, and Biomarkers such as IL-6 and GDF-15 have shown promise, however, require more study.
bedside cycle ergometry (90,91). Passive mechanical loading has been shown to preserve muscle function (34). Earlier initiation of mobilization has been shown to decrease overall length of stay and improve short-term and long-term functional outcomes, however without significant difference in weakness (91)(92)(93). It remains unclear whether long-term rehabilitation in post-ICU care facilities improves outcomes. A Cochrane review, examining physical rehabilitation following ICU discharge, reviewed six studies and was equivocal, with half reporting improvement and the other half showing no effect of treatment (94). These results likely indicate admissions to dedicated inpatient rehabilitation centers for intensive rehab following discharge from ICU is beneficial for some individuals with CIAW, at least in part related to the severity of their deficits.

Nutrition
When Bolton et al. (1) initially coined the term "critical illness polyneuropathy," they proposed malnutrition as the primary cause. It has since been suggested that parenteral nutrition has an overall detrimental effect on ICU patients and that enteral feeding should be started as soon as possible (64,95). To address the increasingly proteo-catalytic state of ICU patients, supplementation with specific amino acid blends has shown promise to increase muscle protein synthesis (96).
Although not studied specifically in CIAW, omega-3 fatty acid supplementation has been shown to enhance skeletal muscle anabolism (97) and have also been shown to have potent anti-inflammatory properties (98). Furthermore, supplementation has been shown to be effective in attenuation of skeletal muscle mass declines over 2 wk of unilateral lower limb immobilization (99). These findings are suggestive of potential promise in mitigating the effect of CIAW, particularly with CIM, but studies addressing this question are needed.

PROGNOSIS AND LONG-TERM CONSEQUENCES
CIAW is a marker and mediator of poor clinical outcomes (46). It is associated with prolonged ICU admissions, prolonged mechanical ventilation, and increased mortality (46,100). The functional recovery from CIAW can take weeks to months, with the most severe cases never regaining their previous level of function (101,102).
When comparing CIM and CIP, CIM is typically associated with better outcomes (103). Overall mortality and duration of mechanical ventilation was significantly higher for patients with CIP (66). Koch et al. (67) found complete recovery within 3-6 mo in CIM-only patients, whereas isolated CIP or CIPNM patients required 6-12 months. The difference in functional outcomes is likely related to the slow (1-3 mm/day) and often incomplete nature of axonal regeneration in CIP.

CONCLUSIONS
A deeper understanding of CIAW is important given its high prevalence and profound effect on patient outcomes. Unfortunately, this is also quite relevant in the context of COVID-19/SARS-CoV pandemic-related complications. There is value in recognizing the difference between CIP and CIM, due to the marked differences in prognosis. Although the prevalence of CIAW is generally Intensive physical therapy Early mobilizaƟon Figure 3. Summary of prevention and management strategies for critical illnessassociated weakness (CIAW). Interventions within solid lines are well supported by available evidence; interventions within hatched lines are theoretically supported but require further study.

Key Points
1. Intensive insulin therapy has been shown to have a protective effect regarding development of CIAW in ICU patients with hyperglycemia. 2. Functional electrical stimulation has mixed evidence as an effective mitigating treatment modality for CIAW; however, higher-quality studies are required to determine its usefulness. 3. Early mobilization is a key factor in CIAW prevention and leads to overall positive functional outcomes. 4. Nutritional intervention has limited data in critically ill patients but is known to promote muscle protein synthesis and ameliorate immobility-associated changes, and thus it is an important avenue for further research.
quite high, the early recognition and management of risk factors can help mitigate the severity of symptoms. Following diagnosis, early mobilization/exercise and nutritional optimization should be implemented. Other interventions require further study to better characterize their potential benefit. An understanding of the underlying pathophysiology will help direct future research to identify new diagnostic biomarkers and novel pharmacological and nutritional interventions.

ACKNOWLEDGMENTS
We thank Dr. J. Gordon Boyd (staff intensivist and neurologist at Queen's University) for his critical feedback and thoughtful comments.

DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.