Advances in the etiology, diagnosis, and treatment of intensive care unit-acquired weakness: a comprehensive narrative review

Introduction

Background

Intensive care unit-acquired weakness (ICU-AW) is a severe complication characterized by generalized, symmetric limb weakness that occurs in critically ill ICU patients. Its diagnosis requires the exclusion of primary neuromuscular diseases (1). With the development of critical care medicine, ICU-AW, as a core factor affecting short-term weaning and long-term functional recovery, has gained growing epidemiological and pathophysiological importance (2). Large-scale prospective cohort studies indicate that mechanically ventilated patients exceeding 7 days have an ICU-AW prevalence of over 50%, with higher incidence in patients with sepsis and multiple organ failure (3). This syndrome directly prolongs mechanical ventilation duration and ICU hospitalization, increases medical resource consumption, and independently predicts elevated 1-year mortality in critically ill patients. The related physical dysfunction can persist for up to 5 years after discharge, severely impairing patients’ long-term quality of life and self-care ability (4,5).

ICU-AW has heterogeneous pathological types, primarily encompassing two subtypes: critical illness polyneuropathy (CIP) and critical illness myopathy (CIM), which often coexist (6). CIP is characterized by peripheral nerve axonal degeneration, while CIM manifests as muscle fiber structural damage with myosin loss (7). Its pathogenesis is multifactorial, involving critical illness-induced systemic inflammation, metabolic and endocrine disorders, neuromuscular microcirculatory dysfunction, and iatrogenic factors including sedation, immobilization and drugs (8). Within this mechanism, pro-inflammatory cytokine storm, mitochondrial dysfunction, oxidative stress, and overactivation of the ubiquitin-proteasome and autophagy-lysosome systems collectively induce severe negative protein balance, ultimately causing skeletal muscle loss and axonal injury (9,10).

Despite its severe clinical consequences, early identification and accurate diagnosis of ICU-AW remain difficult (11). The core dilemma lies in the lack of an ideal diagnostic tool, particularly one for objectively assessing unconscious or sedated patients. Current clinical diagnosis primarily relies on the Medical Research Council (MRC) sum score; however, its application is strictly limited by the patient’s consciousness and cooperation, leading to diagnostic delays and missed diagnosis in the acute phase (12). Although neurophysiological testing is regarded as the objective gold standard for diagnosis and classification, its complexity, required professional interpretation, and limited ICU equipment accessibility restrict its routine screening value (13). Therefore, exploring high-sensitivity and high-specificity circulating biomarkers and bedside objective imaging methods for early identification and dynamic monitoring has become a research priority in this field (14,15).

Currently, no pharmacological agent has been validated by large randomized controlled trials (RCTs) to specifically reverse or improve established ICU-AW (16). Consequently, modern clinical management has shifted to a multidisciplinary comprehensive model focusing on prevention and early intervention (17). This includes rational administration of risky medications (e.g., corticosteroids and neuromuscular blocking agents), early goal-directed rehabilitation, and metabolism-based individualized nutrition (18). Safe and early physical intervention can alleviate muscle atrophy and accelerate functional recovery (19). Additionally, adequate high-quality protein intake is critical to reverse negative nitrogen balance and facilitate muscle protein synthesis (20). However, the optimal intervention window, intensity and duration of these measures, as well as individualized prognostic models, require further rigorous clinical trials for high-level medical evidence.

Rationale and knowledge gap

Although previous reviews on ICU-AW have been published, none have sufficiently focused on thoracic surgical patients or integrated the latest evidence on biomarkers, imaging, and perioperative management. Most existing summaries provide general overviews rather than targeted insights for high-risk surgical populations. This updated review is therefore necessary to fill this gap and provide a targeted, up-to-date reference for thoracic surgeons and intensivists.

Objective

This review summarizes recent advances in the etiology, diagnosis, and treatment of ICU-AW. Combining basic scientific discoveries with clinical translational evidence, it analyzes the pathophysiological mechanisms, objectively evaluates the clinical value and limitations of current diagnostic tools, and systematically summarizes evidence-based management strategies. This review intends to provide clinicians with updated practical references and clarify future research directions, thereby improving outcomes for ICU-AW patients, especially those undergoing major thoracic surgery. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-0019/rc).

Methods

A literature review was conducted using PubMed and Web of Science up to January 1, 2026. The search combined MeSH terms and keywords related to ICU-AW, including its pathogenesis, diagnosis, treatment, and thoracic surgery population. Detailed search strategy is shown in Table 1.

We included English original studies, reviews, and guidelines focusing on ICU-AW in adults, excluding case reports, abstracts, and non-full-text articles. Literature screening was performed independently by B.Z. and Y.Z., with final inclusion determined by consensus.

Etiological mechanisms of ICU-AW

The pathogenesis of ICU-AW is driven by synergistic multi-pathway interactions rather than single-factor linear effects under critical illness. This network covers systemic to cellular molecular events, including inflammation-immunity, metabolism-endocrine, microcirculation, electrophysiology, and iatrogenic factors, ultimately disrupting neuromuscular structure and function (2,4,6,9).

Inflammatory response and immune-mediated mechanisms

Systemic inflammatory response syndrome (SIRS) and sepsis are core drivers initiating ICU-AW pathogenesis. In this state, the innate immune system is excessively activated, releasing abundant pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) from monocytes/macrophages, forming a “cytokine storm” (21,22). These circulating inflammatory mediators induce distant organ damage and directly disrupt the neuromuscular microenvironment. TNF-α and IL-1β can act on skeletal muscle cells, activating nuclear factor-κB (NF-κB) and p38 MAPK signaling pathways to upregulate muscle-specific E3 ubiquitin ligases (MAFbx/Atrogin-1 and MuRF1), thereby activating the ubiquitin-proteasome pathway and promoting contractile protein degradation. This is the direct molecular mechanism underlying inflammation-induced muscle atrophy (23,24). A 2022 prospective clinical study conducted by Cacciani et al. demonstrated that early pro-inflammatory signaling activation in muscle tissue was synchronized with atrophy-related gene upregulation, providing important molecular evidence for inflammation-mediated CIM (25).

Simultaneously, inflammatory cytokines impair blood-nerve barrier (BNB) integrity and exacerbate nerve injury. IL-1β inhibits the endothelial Wnt/β-catenin pathway and disrupts barrier homeostasis. This mechanism was initially characterized in the blood-brain barrier (BBB) of transgenic zebrafish (26). Given the structural and functional similarities between the BBB and BNB, this finding is extrapolated to explain BNB dysfunction. Notably, unlike the BBB, the BNB lacks glial involvement; thus, zebrafish data should be cautiously translated to human neuromuscular pathophysiology. BNB disruption exposes the endoneurium to inflammatory mediators, worsening the axonal microenvironment. Oxidative stress, a critical inflammatory downstream effector, arises from NADPH oxidase activation and mitochondrial dysfunction, causing reactive oxygen species (ROS) accumulation. ROS damages biological macromolecules, impairing muscle myofibrils and mitochondrial respiratory function (27). Stressed mitochondria exhibit dysregulated dynamics, defective biogenesis and impaired autophagy, causing adenosine triphosphate (ATP) depletion and pro-apoptotic factor release to trigger programmed cell death (28,29). A 2023 mechanically ventilated rat model study by Barsotti confirmed that diaphragmatic weakness correlated with Drp1-mediated mitochondrial fragmentation, indicating mitochondrial dynamics as a promising therapeutic target (30).

The neuromuscular junction (NMJ) is a vital immune-mediated injury target. The complement-derived membrane attack complex deposits on the postsynaptic membrane and disrupts acetylcholine receptor clustering and stability (31). A landmark 2003 animal study by Rich and Pinter first demonstrated pathological inactivation of muscle voltage-gated sodium channels impairs action potential generation, namely “membrane inexcitability”, which is triggered by inflammatory stress (32). Furthermore, inflammatory cytokines interfere with presynaptic vesicle cycling and acetylcholine release. This dual structural and functional NMJ damage electrophysiologically explains clinical muscle weakness. Inflammatory, oxidative, and mitochondrial abnormalities collectively promote muscle atrophy and neuromuscular injury (Figure 1).

Figure 1 Schematic overview of inflammatory pathways leading to muscle atrophy in ICU-AW. ICU-AW, intensive care unit-acquired weakness; IL-1β, interleukin-1β; IL-6, interleukin-6; NF-κB, nuclear factor-κB; NMJ, neuromuscular junction; ROS, reactive oxygen species; SIRS, systemic inflammatory response syndrome; TNF-α, tumor necrosis factor-α.

Sepsis disrupts the balance between myoprotective and atrophy-related signaling, reducing protective factors and upregulating negative regulators. Beyond conventional interventions, several promising myoprotective molecules and regenerative strategies have been validated in preclinical studies. Insulin-like growth factor-1 (IGF-1) activates the Akt/PKB pathway to promote muscle protein synthesis and inhibit catabolism, thereby mitigating muscle atrophy (33). As an anti-inflammatory cytokine, interleukin-13 (IL-13) induces skeletal muscle metabolic reprogramming and mitochondrial adaptation, improving muscle endurance under stress with potential applicability in critical illness (34). Since myostatin is a sepsis-induced negative regulator, its inhibition suppresses muscle protein degradation to alleviate muscle wasting and improve survival (35). Furthermore, mesenchymal stem cell (MSC) therapy repairs sepsis-impaired mitochondrial function and muscle stem cell regeneration, serving as a novel ICU-AW therapeutic strategy (36). These preclinical findings provide promising targets for future clinical translation. Figure 2 summarizes the mechanistic association between sepsis-mediated signaling dysregulation and myoprotective interventions.

Figure 2 Mechanisms of sepsis-induced ICU-AW and promising preclinical interventions. ICU-AW, intensive care unit-acquired weakness; IGF-1, insulin-like growth factor-1; IL-13, interleukin-13; MSC, mesenchymal stem cell.

Neuromuscular pathology and electrophysiological alterations

ICU-AW mainly presents two histopathological subtypes: CIP and CIM. CIP is an axonal sensorimotor polyneuropathy characterized by axonal degeneration and secondary Wallerian degeneration of myelinated nerve fibers. Distal nerve segments are affected earlier and more severely, involving both sensory and motor nerves (37). Electron microscopy shows axonal mitochondrial swelling and disorganized neurotubules and neurofilaments. CIM is a primary myopathy characterized by myofibrillar destruction (especially selective myosin heavy chain loss), type II fast-twitch fiber atrophy, variable muscle fiber necrosis and regeneration, and dysregulated sarcolemmal excitatory proteins such as sodium channels (6). A classic 2013 study by Puthucheary et al. using serial quadriceps biopsies in ICU patients confirmed reduced muscle fiber cross-sectional area and early myosin loss within the first week of ICU admission; muscle wasting severity was correlated with illness severity and corticosteroid dosage (9).

Electrophysiological examinations provide objective functional evaluation and differential diagnosis for these structural pathologies. In CIP patients, nerve conduction studies (NCS) typically show decreased amplitudes of compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAP), indicating axonal loss; motor nerve conduction velocity remains preserved or mildly slowed, excluding primary demyelination (38). Needle electromyography (EMG) may detect abnormal spontaneous activity including fibrillation potentials and positive sharp waves. In cooperative patients, neurogenic motor unit potentials with high amplitude, long duration and increased polyphasicity can be detected, suggesting nerve reinnervation (39). CIM presents a distinct electrophysiological pattern: NCS shows reduced and prolonged CMAP amplitudes with normal SNAPs, while EMG reveals early recruitment of low-amplitude, short-duration motor unit potentials (40). Direct muscle stimulation (DMS) is valuable for differential diagnosis. CIP patients with absent nerve-stimulated CMAP, DMS can elicit intact muscle action potentials, indicating lesions located in the nerve or NMJ; conversely, unresponsive DMS suggests sarcolemmal or contractile impairment, namely CIM (41).

Besides intrinsic pathological lesions, iatrogenic immobilization and mechanical ventilation serve as independent potent muscle injury factors. Controlled mechanical ventilation induces early diaphragmatic dysfunction, characterized by accelerated proteolysis, enhanced oxidative stress, and inhibited diaphragmatic mitochondrial biogenesis; this condition is defined as ventilator-induced diaphragmatic dysfunction (VIDD) (42). For limb muscles, complete disuse eliminates mechanical tension and neural input, rapidly activating FoxO-mediated ubiquitin-proteasome and autophagy-lysosome pathways to trigger rapid muscle protein degradation (43,44). Therefore, the combination of primary illness and iatrogenic disuse constitutes a “double-hit” model of rapid muscle loss in ICU patients. These pathological and electrophysiological features distinguish CIP from CIM (Figure 3).

Figure 3 Key pathological and electrophysiological distinctions between CIP and CIM. CIM, critical illness myopathy; CIP, critical illness polyneuropathy; CMAP, compound muscle action potential; SNAP, sensory nerve action potential.

Metabolic abnormalities and medication effects

Metabolic disorders during critical illness create an unfavorable “soil” for neuromuscular injury. Stress hyperglycemia is a prominent metabolic disturbance with multiple detrimental mechanisms: persistent hyperglycemia promotes advanced glycation end products (AGEs) deposition in the endoneurium and muscle basement membrane (45). AGEs bind to receptor for advanced glycation end products (RAGE) and continuously activate inflammatory and oxidative stress pathways, causing direct tissue damage. The hyperglycemia-AGEs-RAGE axis impairs neuromuscular transmission by disrupting postsynaptic NMJ structural integrity (46). Concurrently, insulin resistance reduces skeletal muscle glucose uptake and blunts insulin-mediated muscle anabolism, suppressing protein synthesis and accelerating protein degradation in the hypercatabolic state (47,48). A 2024 systematic review by Van den Berghe et al. reaffirmed that early strict glycemic control reduces CIP incidence, highlighting the essential role of metabolic regulation (49).

Electrolyte imbalance rapidly and directly impairs neuromuscular function. Hypophosphatemia disrupts ATP and phosphocreatine synthesis, triggering an intracellular energy crisis, weakening muscle contractility and inducing respiratory muscle failure in severe cases (50). In mechanically ventilated patients, hypophosphatemia independently reduces diaphragmatic contractility via impaired mitochondrial oxidative phosphorylation (51). Hypokalemia alters the resting membrane potential, diminishing neuromuscular excitability and action potential conduction (52). Hypomagnesemia often accompanies calcium and potassium disturbances, interfering with neurotransmitter release and muscle excitation-contraction coupling (53). Furthermore, critically ill patients frequently develop protein-energy malnutrition; insufficient substrates further restrict tissue repair and regeneration (54).

Medications are critical iatrogenic triggers for ICU-AW. Corticosteroids induce myopathy via multiple mechanisms: suppressing the IGF-1 pathway to reduce protein synthesis, upregulating ubiquitin ligases to enhance protein degradation, triggering myocyte apoptosis, and impairing mitochondrial function (55). Neuromuscular blocking agents, especially combined with corticosteroids, may cause acute quadriplegic myopathy with CIM-like but more severe pathological manifestations (56). Additionally, antibiotics (e.g., aminoglycosides) and statins exhibit potential neuromuscular toxicity (57). Mitochondrial dysfunction serves as the final common pathway of diverse injury factors. Critical illness induces mitochondrial loss, structural abnormalities, suppressed respiratory chain activity, and excessive ROS production, ultimately resulting in energy depletion and apoptosis activation (58,59). Meanwhile, severe negative protein balance occurs: suppressed insulin/IGF-1 signaling and inadequate substrates inhibit protein synthesis, while hyperactivated ubiquitin-proteasome and autophagy pathways accelerate protein degradation, with preferential breakdown of muscle-specific proteins (60). This catabolic predominance drives rapid, extensive muscle wasting in ICU-AW patients (10). Metabolic disturbances and pharmacological insults interact synergistically to facilitate ICU-AW progression (Figure 4).

Figure 4 Interplay between metabolic disturbances and medication effects in ICU-AW pathogenesis. AGE, advanced glycation end product; ATP, adenosine triphosphate; ICU-AW, intensive care unit-acquired weakness; IGF-1, insulin-like growth factor-1; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species.

Diagnostic methods for ICU-AW

Accurate and timely diagnosis of ICU-AW is a prerequisite for initiating targeted management, assessing prognosis, and evaluating treatment efficacy. An ideal diagnostic system should combine objectivity, sensitivity, specificity, and clinical operability. Currently, diagnosis primarily relies on the combined application of clinical assessment, neurophysiological testing, and increasingly developed auxiliary techniques.

Clinical assessment tools

For conscious and cooperative ICU patients, bedside clinical assessment constitutes the diagnostic cornerstone. The MRC sum score is the most widely adopted and well-validated standardized tool globally. This scale evaluates six bilateral limb muscle groups (wrist flexion, elbow flexion, shoulder abduction, ankle dorsiflexion, knee extension, and hip flexion) with a 0–60 total score (13). A landmark 2002 multicenter study by De Jonghe et al. established an MRC score <48 (80% of the maximum score) as the ICU-AW diagnostic threshold, which remains valid today (61). Despite limited formal diagnostic accuracy data, the MRC score correlates well with electrophysiological results, supporting its application for bedside screening (61). Hermans et al. verified its favorable inter-observer reliability in a 2012 study, confirming high consistency among standardized-trained assessors (62). Importantly, the MRC score possesses prognostic value: lower MRC score at initial awakening correlates with higher mortality, prolonged mechanical ventilation, extended ICU and hospital stay, and poor post-discharge functional status (62).

However, the MRC score has undeniable limitations. Its fundamental flaw is absolute dependence on patient cooperation, intact cognition and sustained attention. This makes the score inapplicable to patients with deep sedation, coma, severe delirium, or neuromuscular blockade—the highest-risk ICU-AW population—creating a critical “diagnostic vacuum” in the acute disease phase (63). Furthermore, the scale has insufficient sensitivity to mild weakness (ceiling effect) and merely evaluates muscle strength, lacking assessments of muscle endurance, coordination and motor function (12).

To compensate for MRC limitations and optimize functional evaluation, supplementary functional assessment tools have been adopted in ICUs. The Functional Status Score for the ICU (FSS-ICU) and Chelsea Critical Care Physical Assessment Tool (CPAx) multidimensionally evaluate physical performance, including bed mobility, transfer, sit-to-stand and walking ability, to quantify overall disability. These functional scores correlate better with patients’ long-term post-discharge mobility capacity (64,65). The psychometric properties of the CPAx have been rigorously validated. Its original validation study confirmed excellent inter-rater reliability (ICC =0.94) and internal consistency (Cronbach’s α =0.87) (64). Similarly, the FSS-ICU presents favorable test-retest reliability (r=0.89) and dynamic responsiveness in ICU survivors (65). Handgrip dynamometry, a simple and rapid semi-objective quantitative tool, has been extensively investigated. A 2008 study by Ali et al. validated that decreased admission handgrip strength independently predicts higher ICU mortality (66). Nevertheless, its specific diagnostic accuracy for ICU-AW remains unconfirmed, serving only as an adjunct to the MRC score. Additionally, handgrip measurement mainly reflects distal upper limb strength and is susceptible to peripheral edema, pain, and limited joint mobility. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) specifically evaluate respiratory muscle strength. Reduced MIP and MEP indicate respiratory muscle weakness and weaning difficulty, and are closely correlated with generalized ICU-AW (67). Therefore, combined application of MRC score and functional assessments (e.g., FSS-ICU, handgrip strength, and respiratory muscle strength) can improve the sensitivity of neuromuscular dysfunction detection and provide prognosis consistent with patients’ daily living and rehabilitation demands (Table 2).

Electrophysiological examination

Early electrophysiological testing is critical for ICU-AW diagnosis. NCS and EMG can distinguish ICU-AW subtypes CIP and CIM, supporting clinical decision-making and prognostic evaluation (6).

NCS and EMG present shared and subtype-specific features in ICU-AW. Both CIP and CIM show decreased motor nerve conduction velocity and CMAP amplitude: CIP is caused by peripheral nerve axonal degeneration, whereas CIM arises from impaired muscle fiber excitability. On EMG, both subtypes manifest resting fibrillation potentials and positive sharp waves. During voluntary contraction, CIP shows prolonged, high-amplitude polyphasic MUPs indicative of axonal injury-induced reinnervation; CIM presents shortened, low-amplitude MUPs reflecting intrinsic muscle fiber damage (38,69).

CIM yields a more favorable long-term prognosis than CIP, with most CIM patients recovering full muscle strength, while CIP may cause persistent weakness or quadriparesis (70). Early subtype identification facilitates individualized rehabilitation and prognostic guidance.

Electrophysiological examination also evaluates disease severity and prognosis. Reduced CMAP amplitude at ICU day 8, independent of clinical weakness and normal MRC score, correlates with elevated 1-year mortality (71). Dynamic NCS/EMG monitoring reflects the effects of glycemic control and nutritional intervention on neuromuscular function, guiding therapeutic optimization. However, electrophysiology is equipment-dependent, and concurrent CIP-CIM overlap increases diagnostic difficulty. Comprehensive assessment combining clinical manifestations and other examinations is therefore necessary (2,72).

Muscle ultrasound (MUS) can quantify muscle edema and inflammation via standardized protocols (73). Based on global muscle echogenicity (GME), MUS differentiates patients from healthy individuals and serves as a pre-invasive screening tool (74). Serial GME monitoring also assesses disease progression in sedated or ventilated patients.

Magnetic resonance imaging (MRI) enables precise assessment of muscle structure and metabolism. It visualizes diaphragmatic and limb muscle morphology, quantifying muscle volume and fat infiltration—a key feature of muscle atrophy. With superior spatial resolution to ultrasound, MRI differentiates the distribution and atrophy of slow- and fast-twitch fibers. Magnetic resonance spectroscopy detects muscle ATP and phosphocreatine levels to reflect energy reserve status (75). Overall, MRI provides quantitative evidence for metabolic injury in ICU-AW.

Biomarkers

A prospective study by Klawitter et al. demonstrated that blood biomarkers are commonly elevated in critically ill patients yet have limited ability to distinguish patients with or without ICU-AW. Though correlated with disease severity, these biomarkers cannot effectively identify or monitor ICU-AW (68).

Patejdl et al. found that combined application of MUS and inflammatory biomarkers (syndecan-1 and serum procalcitonin) assists ICU-AW diagnosis and long-term outcome prediction in critically ill patients (73).

Moreover, miR-451a serves as a potential biomarker for elderly sarcopenia (76), and the muscle atrophy-related E3 ubiquitin ligase MuRF1/TRIM63 is pivotal in muscle wasting (77). These molecules are promising candidates for ICU-AW diagnostic research.

Treatment strategies for ICU-AW

Rehabilitation training and physical therapy (PT)

Early mobilization is a core strategy for ICU-AW prevention and treatment. Multiple studies have verified that early active or passive exercise effectively enhances skeletal muscle strength and functional recovery in critically ill patients. Ruo Yu et al.’s meta-analysis indicated that initiating mobilization within 24–72 hours of ICU admission optimally reduces ICU-AW incidence and related complications (78). Haylett et al. stressed the priority of rehabilitation for ICU-AW patients, recommending targeted personalized rehabilitation and resource allocation for patients unable to sit independently during initial mobilization (79).

Clinical trials have confirmed the feasibility and safety of early mobilization. Patel et al. found the 1-year ICU-AW incidence was 0% in the early mobilization group, much lower than 14% in conventional care, supporting its role in reducing long-term muscle weakness (80). Nevertheless, the large-scale TEAM trial showed that although early mobilization prolonged daily activity time, it failed to improve 180-day survival and functional independence, and was accompanied by more adverse events, suggesting the timing and intensity of early mobilization need further optimization (18). Rosa et al.’s systematic review concluded that active and passive exercise can strengthen muscle strength, shorten mechanical ventilation and ICU stay, and safely prevent ICU-AW; however, unified implementation standards are lacking, and nursing participation remains insufficient (81).

In conclusion, early exercise intervention benefits muscle strength recovery and reduces ventilation and ICU hospitalization duration. Future research should focus on establishing standardized exercise intensity and multidisciplinary collaboration protocols to balance efficacy and safety. Neuromuscular electrical stimulation (NMES) serves as a vital alternative for patients incapable of active exercise. Peripherally, NMES strengthens muscle contractility and fatigue resistance, increases muscle mass and relieves tissue edema, thereby reversing prolonged immobilization-induced muscle atrophy in critically ill patients (82,83). Centrally, targeted NMES modulates central motor regulation, promotes nerve terminal synchronization and facilitates motor relearning (82); NMES-evoked isometric contractions induce brain activation patterns similar to voluntary movement (84).

Kho et al. and Liu et al. verified that NMES combined with early rehabilitation markedly improved lower limb muscle strength, alleviated muscle atrophy and shortened mechanical ventilation duration, yielding better functional outcomes than rehabilitation alone (85,86). Campos et al.’s RCT demonstrated that early mobilization plus NMES enhanced ICU functional scores and muscle strength, lowered ICU-AW incidence without raising adverse events (83). For ICU patients receiving mechanical ventilation over 24 hours, Verceles et al. found that combined intervention with NMES, high-protein supplementation and PT reduced lower limb muscle loss, accelerated positive nitrogen balance and decreased delirium occurrence (87).

Patient discomfort restricts the clinical efficacy of NMES (84). Nevertheless, personalized stimulation protocols targeting impaired brain regions are expected to broaden its application in neuromuscular rehabilitation. Further mechanistic research and large-scale RCTs are required to clarify clinical benefits, optimize parameters, and validate its value in ICU-AW prevention.

Kayambu et al.’s RCT on septic patients showed that early comprehensive physical rehabilitation, including electrical stimulation, range-of-motion exercise and out-of-bed training, did not improve discharge functional indicators, but enhanced patients’ physical function and quality of life at 6 months and exerted anti-inflammatory effects (88).

Diaphragmatic dysfunction is a key component of ICU-AW in mechanically ventilated patients. Respiratory muscle training combined with NMES can improve diaphragmatic morphology and function and shorten ventilation duration. Liu et al. confirmed that NMES plus early rehabilitation elevated diaphragmatic thickening fraction, attenuated abdominal and femoral muscle atrophy, and reduced mechanical ventilation time (89). Respiratory and whole-body exercise training benefits ventilated patients by facilitating weaning and improving long-term prognosis. Wollersheim et al. verified the feasibility of whole-body vibration (WBV) therapy. WBV can safely activate muscles, elevate oxygen uptake and energy metabolism with no obvious hemodynamic disturbance, showing potential as an adjuvant early rehabilitation approach to prevent prolonged bed-rest-related muscle weakness in critical illness (90).

Photobiomodulation therapy [red/near-infrared light-emitting-diode (LED) therapy, PBMT] is an emerging non-pharmacological intervention for ICU-AW. A randomized triple-blind sham-controlled trial (91) found that limb PBMT reduced ICU stay by about 30% and better improved muscle strength and functional ability than sham intervention. PBMT thus serves as a promising adjunctive therapy for ICU-AW. ICU-AW rehabilitation relies heavily on multidisciplinary collaboration. In an extracorporeal membrane oxygenation (ECMO)-to-lung transplantation case, Salam et al. built a comprehensive team consisting of physicians, nurses, physical therapists, respiratory therapists, nutritionists and perfusionists. The team achieved notable preoperative functional recovery, rapid postoperative weaning and favorable long-term quality of life, verifying the critical role of multidisciplinary teamwork in ensuring rehabilitation adherence and therapeutic efficacy (92).

Egger et al.’s prospective cohort study demonstrated that comprehensive health assessment and follow-up for ICU survivors under neurorehabilitation settings facilitate the understanding of post-intensive care syndrome (PICS) and ICU-AW progression and prognosis. Such multimodal rehabilitation targets patients’ physical, cognitive and psychological impairments simultaneously (93).

A before-and-after study by Klein et al. showed that early progressive mobility protocols require multidisciplinary management. Patients’ highest activity levels significantly increased, neurological ICU length of stay shortened, and infection and pressure ulcer rates decreased (94). Furthermore, an RCT by Schweickert et al. provided high-quality evidence that daily sedation interruption combined with PT and occupational therapy (OT) significantly increased independent functional recovery, shortened delirium duration and mechanical ventilation time, and proved safe and feasible (19).

In summary, multidisciplinary team (MDT) participation in ICU-AW treatment improves rehabilitation adherence and safety, and realizes continuous management from early mobility to functional recovery via physical, nutritional, and psychological support.

Pharmacological treatment advances

Damage, inflammatory exacerbation, ferroptosis and apoptosis, leading to muscle mass and function loss (95). Antioxidant and mitochondrial protective strategies thus hold potential for ICU-AW therapy. Polyphenols, vitamins, coenzyme Q10 and mitochondria-targeted antioxidants are promising candidate agents (96). Relevant large-scale clinical trials remain insufficient. Irisin, a novel myokine, ameliorates muscle atrophy by inhibiting the ubiquitin-proteasome system. In a chronic kidney disease (CKD) mouse model, irisin suppressed FOXO3A activation to downregulate E3 ubiquitin ligases, reduce protein degradation and relieve muscle atrophy (97). Thus, irisin and its pathway may serve as promising therapeutic targets for ICU-AW.

A 2020 study found that short-term testosterone propionate could improve skeletal muscle function in septic rats without obvious side effects, providing a potential therapy for ICU-AW (98). A 2024 review further proposed that some anabolic supplements may help prevent muscle loss and facilitate recovery in ICU-AW patients, though clinical verification is still required.

A 2024 case report noted ICU-AW onset after cardiac transplantation in patients with JAK2 mutation-associated endocarditis. The Janus kinase (JAK) inhibitor ruxolitinib normalized eosinophil levels but failed to prevent ICU-AW (99), indicating the complicated role of immunomodulators that needs further study.

Testosterone and programmed death 1 (PD-1) inhibitors for ICU-AW are only supported by preclinical evidence. Their clinical efficacy, dosage, treatment window and long-term safety remain undefined, calling for high-quality RCTs (98).

As routine critical care medications, corticosteroids predispose to ICU-AW (100) by activating protein degradation, suppressing protein synthesis, damaging mitochondria and inducing insulin resistance (101). However, no solid evidence proves corticosteroid tapering or withdrawal can reverse severe muscle atrophy.

Nutritional support and metabolic management

Adequate nutritional support is essential for ICU-AW prevention and management. Zhou et al. reported that early mobilization significantly reduced the incidence of ICU-AW from 16% in the control group to 2%, with additional early enteral nutrition providing no further reduction in risk (102). Following European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines to optimize protein and energy supply, combined with electrolyte monitoring, promotes protein synthesis, muscle repair and functional recovery.

The finding that this intervention reduced ICU-AW incidence but not mortality highlights that the relationship between ICU-AW and death is likely associative rather than causal. ICU-AW frequently develops in the context of severe critical illness and multiple organ dysfunction, which independently drive mortality. To date, no clinical trial has demonstrated that specifically reversing ICU-AW improves survival.

Hyperglycemia-driven metabolic imbalance is a major risk factor for ICU-AW, underscoring the necessity of effective glycemic control (103). However, glycemic control should not be overly strict. Hyperglycemia is closely associated with the occurrence of ICU-AW. Intensive insulin therapy (IIT) may reduce the incidence of ICU-AW but significantly increases the risk of severe hypoglycemia and mortality; therefore, strict intensive insulin control is not recommended for routine prevention (49,104). Early attempts at strict glycemic control (81–108 mg/dL) significantly increased severe hypoglycemia and mortality risks (104).

Currently, the recommended glycemic target for most critically ill patients is 140–180 mg/dL (7.8–10.0 mmol/L) (104). This moderate control balances the adverse effects of hyperglycemia and hypoglycemia. Hypoglycemia may lead to brain injury, arrhythmias and elevated mortality (105). Meanwhile, glycemic variability serves as an independent predictor of poor clinical outcomes (106,107).

In the ICU, continuous intravenous insulin infusion is the mainstay to reach glycemic targets and requires frequent glucose monitoring and insulin titration to sustain glucose stability and avoid hypoglycemia (103). Emerging continuous glucose monitoring technologies can optimize the efficiency and safety of glycemic management (108).

A secondary analysis by Patel et al. among mechanically ventilated patients showed that early mobilization reduced insulin demand and was independently negatively associated with ICU-AW risk (109). Early mobilization may optimize metabolism by enhancing skeletal muscle glucose utilization, thereby benefiting both glycemic regulation and ICU-AW prevention (109).

Accordingly, glycemic and metabolic management should be integrated with exercise rehabilitation and nutritional support to jointly improve metabolic homeostasis and muscle function.

Beyond optimized nutrition and metabolic strategies, several interventions have failed to yield benefits or exerted adverse effects in ICU-AW RCTs. Anabolic growth hormone therapy, once considered for muscle wasting, increased mortality without functional benefits and is thus abandoned clinically (110). Early parenteral nutrition within 48 hours of ICU admission also failed to improve outcomes and may raise infection risks, supporting the current strategy of delayed parenteral nutrition (111). Combined with the disappointing results of IIT, these cases highlight the necessity of evidence-based metabolic and nutritional management to avoid ineffective or harmful ICU-AW interventions.

Future research directions

Current ICU-AW management remains challenging with multiple unresolved issues. Future research priorities are summarized as follows. First, individualized rehabilitation regimens should be formulated based on illness severity, comorbidities, age and neuromuscular impairment. Multidisciplinary collaboration can integrate nutritional and exercise interventions to enhance muscle anabolism, reduce metabolic complications and optimize prognosis. Second, high-quality trials are required to confirm the optimal timing, intensity and duration of early mobilization, NMES, inspiratory muscle training (IMT) and PBMT, and clarify their long-term functional mechanisms (112), supporting standardized clinical guideline development. Third, targeted strategies should address clinical barriers including patient instability, manpower and equipment shortages, and insufficient staff training (113), so as to improve the accessibility and adherence of physical interventions.

Special considerations in thoracic surgery patients

Despite extensive ICU-AW research in general critically ill patients, this condition merits specific attention in major thoracic surgery populations. Thoracic procedures including esophagectomy, lung resection and transplantation often require prolonged ventilation and trigger severe postoperative inflammation and sepsis—major ICU-AW drivers (2,4). ICU-AW impairs respiratory muscle function, delays weaning, prolongs ICU stay and increases postoperative morbidity (114).

The general ICU-AW incidence is approximately 40% (115). Epidemiological data focusing on thoracic surgical patients remain scarce, whereas advanced age, elevated Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, prolonged ventilation and glucocorticoid use are recognized risk factors. Targeted interventions include early postoperative mobilization, high-protein nutritional optimization, and rational sedative administration. For lung transplant recipients, ICU-AW-related ventilation delay exacerbates allograft complications such as ventilator-associated pneumonia and bronchial anastomotic injury (116).

Current prospective studies on thoracic surgical cohorts are insufficient. Further research is essential to clarify ICU-AW incidence, risk factors and long-term outcomes in this high-risk population, and formulate tailored perioperative protocols to reduce ICU-AW burden and improve surgical prognosis.

Outlook

Future ICU-AW research should pursue precision and integrated management. Mechanistically, further exploration is required to clarify pathways including mitochondrial dysfunction and NMJ instability. Diagnostically, sensitive bedside tools are imperative for early objective detection. Clinically, high-quality trials are needed to confirm the optimal rehabilitation regimens and establish individualized nutrition-rehabilitation protocols. Integrating basic research with clinical translation helps construct a precise ICU-AW management system, reducing disease burden and improving long-term outcomes for critically ill patients, particularly high-risk thoracic surgical populations.

Strengths and limitations of this review

Strengths

This review provides a comprehensive overview of ICU-AW covering etiology, diagnosis, and multidisciplinary management. It places specific emphasis on thoracic surgical patients, a high-risk group that has not been fully addressed in existing reviews. We also integrate recent advances in rehabilitation, imaging, and biomarkers to offer clinically practical information for daily practice.

Limitations

As a narrative review, this study does not systematically grade the level of evidence. Most available clinical data are observational, and high-quality RCTs remain limited. Research specifically targeting perioperative thoracic surgery populations is still insufficient, and conclusions for this group should be interpreted with caution. Some novel diagnostic and therapeutic approaches require further validation before widespread clinical use.

Conclusions

ICU-AW is a prevalent and severe complication characterized by generalized limb weakness, which prolongs ventilation and hospital stay, increases mortality, and impairs long-term functional prognosis.

Its pathogenesis is multifactorial, involving intertwined injury pathways. Systemic inflammation activates muscle protein degradation and disrupts the BNB. Metabolic disorders such as stress hyperglycemia suppress muscle anabolism. Neuromuscular injuries mainly manifest as CIP and myopathy. Iatrogenic factors including corticosteroids, neuromuscular blockers, and prolonged immobilization further aggravate muscle damage.

ICU-AW is diagnosed via combined clinical and auxiliary examinations. Conscious patients are assessed using MRC sum score and functional tests, whereas electrophysiological examinations serve as the diagnostic gold standard for sedated patients. Although MUS and circulating biomarkers exhibit diagnostic potential, their clinical applicability requires further validation.

Currently, no specific drugs are available for ICU-AW. Clinical management focuses on preventive multidisciplinary interventions, including rational medication use, early rehabilitation, individualized high-protein nutrition, and metabolic homeostasis regulation. This review provides a structured reference for ICU-AW prevention, diagnosis and management, aiming to optimize clinical care for critically ill patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-0019/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-0019/coif). C.C. serves as an unpaid Associate Editor-in-Chief of Current Challenges in Thoracic Surgery from October 2025 to September 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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