 Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 1 - Intensive care unit-acquired weakness: A review from molecular mechanisms to its impact in COVID-2019 Andrea González (1,2,3), Johanna Abrigo (1,2,3), Oscar Achiardi (4), Felipe Simon (2,5,6), Claudio Cabello-Verrugio (1,2,3) (1) Laboratory of Muscle Pathology, Fragility and Aging, Department of Biological Sciences, Faculty of Life Sciences. Universidad Andres Bello, Santiago, Chile; (2) Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile; (3) Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile; (4) Escuela de Kinesiología, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile; (5) Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago, Chile; (6) Laboratory of Integrative Physiopathology, Department of Biological Sciences, Faculty of Life Sciences. Universidad Andres Bello, Santiago, Chile. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Abstract Intensive Care Unit-Acquired Weakness (ICU-AW) is a generalized and symmetric neuromuscular dysfunction associated with critical illness and its treatments. Its incidence is approximately 80% in intensive care unit patients, and it manifests as critical illness polyneuropathy, critical illness myopathy, and muscle atrophy. Intensive care unit patients can lose an elevated percentage of their muscle mass in the first days after admission, producing short- and long-term sequelae that affect patients’ quality of life, physical health, and mental health. In 2019, the world was faced with coronavirus disease 2019 (COVID-19), caused by the acute respiratory syndrome coronavirus 2. COVID-19 produces severe respiratory disorders, such as acute respiratory distress syndrome, which increases the risk of developing ICU-AW. COVID-19 patients treated in intensive care units have shown early diffuse and symmetrical muscle weakness, polyneuropathy, and myalgia, coinciding with the clinical presentation of ICU-AW. Besides, these patients require prolonged intensive care unit stays, invasive mechanical ventilation, and intensive care unit pharmacological therapy, which are risk factors for ICU-AW. Thus, the purposes of this review are to discuss the features of ICU-AW and its effects on skeletal muscle. Further, we will describe the mechanisms involved in the probable development of ICU-AW in severe COVID-19 patients. Key Words: ICU-acquired weakness (ICU-AW); coronavirus disease 2019; skeletal muscle atrophy; critical illness. Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 Patients in a critical state frequently require admission to the intensive care unit (ICU), generally, for extended periods.1 During the ICU stay, mechanical ventilation (MV) is usually an invasive treatment required to save the patient’s life.2 These patients can develop ICU- acquired weakness (ICU-AW), a neuromuscular dysfunction, generalised and symmetric disorder, without an identified etiology other than the critical illness and its treatments.1,3,4 ICU-AW has a high impact on the length of ICU stay and the time of the patient’s recovery. The adverse consequences of ICU-AW also affect patients’ reinsertion to daily living activities and represent a high economic cost for the patients and the health care services.5 In 2019, a global pandemic began due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which led to millions of people falling ill with coronavirus disease 2019 (COVID- 19), many of them in critical condition.6 There are similarities between the clinical conditions of patients with COVID-19 and those patients who develop ICU- AW (prolonged MV, ICU interventions, myalgias, muscle loss, and inflammation),6-8 suggesting that severe COVID-19 patients could have a high chance of developing ICU-AW during their ICU stay. Thus, the purposes of this review are to discuss the characteristic Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 2 - of ICU-AW and its effects on skeletal muscle to describe the probable development of ICU-AW in severe COVID- 19 patients. ICU-acquired weakness Muscle weakness is a frequent problem in ICU patients, and it can be induced due to primary or secondary causes. Primary causes (< 0.5% of all ICU admissions) include neuromuscular pathologies that need intensive care, such as myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, and Guillain–Barré Syndrome, among other neurological disorders. Secondary causes correspond to treatment for other life-threatening conditions in the ICU.4,9 ICU-AW affects the proximal rather than distal area of the limbs’ muscles and the respiratory muscles.1 Muscle tone become diminished, and tendon reflexes may be reduced or normal. ICU-AW does not strain the face and eyes muscles.1,10-13 The incidence of ICU-AW is approximately 80% in ICU patients. It is associated with a longer duration of MV and hospitalisation along with a significant functional impairment for survivors.2 The prevalence of ICU-AW oscillates between 25 and 75%. Still, it could vary depending on the studied patient population, risk factors, timing of assessment (hospitalisation days and severity of the patients), and the methods used for diagnosis.12,14,15 Risk factors for ICU-acquired weakness The risk factors for ICU-AW are classified as modifiable and non-modifiable (Figure 1). The modifiable risk factors include hyperglycaemia and drugs used to treat critically ill patients.4,16-18 The ICU- AW patient’s hyperglycaemia is an independent risk factor for ICU-AW, which could be developed by parenteral nutrition or depending on the patients’ high severity state.10,16,17 Regarding drugs for treating ICU patients, a high risk of ICU-AW has been associated with vasoactive medication duration and doses (β-agonists mainly).19 The use of corticosteroids has shown contradictory results: when focusing exclusively on patients with sepsis, it has been associated with the risk of ICU-AW, but in patients with hyperglycaemia, a protective effect has been suggested.16,17 Although it is not yet clear, the use of neuromuscular blocking agents, such as cisatracurium has shown adverse effects in muscle weakness. These agents have been considered an independent risk factor for ICU-AW.16,20 Certain antibiotics, such as aminoglycosides and vancomycin, develop muscle weakness.21-23 Lastly, continuous sedation has a more pronounced effect on muscle atrophy and weakness than patients in a conscious state but immobilised in the absence of sedation.24 The non-modifiable risk factors for developing ICU-AW are the severity of critical illness and mortality prediction. The severity of disease score and mortality prediction scores are often determined by the scale Acute Physiology and Chronic Health Evaluation (APACHE) II score, which estimates ICU mortality, and Sequential Organ Failure Assessment (SOFA) score, which evaluates the overall function and dysfunction of each organ system based on the degree of dysfunction of six organ systems. Higher scores on these scales indicate greater severity of clinical evolution, including a greater risk of death. Other non-modifiable risk factors include sepsis, inflammation (systemic inflammatory response syndrome, SIRS), multiple organ failure, longer duration of MV, and stay in the ICU.16,19,25,26 Prolonged MV is an independent risk factor for ICU-AW.16 MV increases the risk of ICU-AW and diaphragmatic weakness dysfunction, increasing the risk of failed ventilation and weaning, thus extending the MV and making up a vicious circle.14,16 Other risk factors are high levels of pro- inflammatory cytokines, an elevated lactate level, being a woman and/or older person, a premorbid state, and frailty conditions that may predispose to the severity of the weakness.16,26 Clinical manifestations of ICU-acquired weakness ICU-AW corresponds to nerve and muscle dysfunction due to generalized systemic inflammation and the risk factors mentioned above.27 ICU-AW commonly manifests in three different ways: polyneuropathy, myopathy, and muscle atrophy (Figure 1).25 These three conditions can contribute to varying proportions of this pathological condition and manifest alone or in combination.5,12,28 Critical illness polyneuropathy (CIP) is defined as a distal sensory-motor polyneuropathy that affects limb and respiratory muscles and autonomic nerves in symmetric form.12,29 There is a loss of axons in CIP and reduced nerve excitability with preserved myelin sheets. 1,12 The aetiology could include loss of the blood-nerve barrier, inexcitability of the endoneurial membrane, and direct toxic effects from ICU therapies, including hyperglycaemia or lipids derived from parenteral nutrition, which would induce muscle denervation and atrophy.12,29 Critical illness myopathy (CIM) is a primary acute myopathy with loss of myosin filaments, loss of muscle membrane excitability, and possible necrosis.1,12 CIM is characterised by limb and respiratory muscle weakness with retained sensory function, which is not related to denervation.2,12 The proposed CIM aetiology includes chemokine-induced autophagy of muscle fibre, muscle membrane inexcitability, acquisition of channelopathies, or direct toxic effects of ICU care, including corticosteroids or neuromuscular blockade.29 Muscle atrophy is a typical feature of ICU-AW. Pronounced muscle wasting in ICU patients could be explained by mechanical unloading due to immobilisation/denervation and the catabolic state of critical illness, with reduced anabolism.5,14 Activated proteolytic systems have been observed in type II fibres, together with myosinolysis (proteolytic degradation of Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 3 - myosin), consistent with primary myopathy and neurogenic muscle atrophy.2,25 These pathological disorders translate clinically into loss of strength and muscle mass, weakness, and significant functional disorders in activities of daily living, which are independent predictors of mortality in critically ill patients. 2 Patients with ICU-AW have significantly decreased handgrip strength and reported worse physical performance. 29 Despite improvements in overall strength in the timeline, physical function-related quality of life remained significantly below the expected age-adjusted indicators at all time points.29 Fig 1. Features of ICU-acquired weakness. ICU-AW commonly manifests in three different manners: Critical Illness Polyneuropathy (CIP), Critical Illness Myopathy (CIM), and muscle atrophy. The modifiable risk factors include hyperglycaemia (an independent risk factor for ICU-AW); common drugs for the treatment of intensive care unit (ICU) patients (such as vasoactive medications); neuromuscular blocking agents (such as citraturia); antibiotics (such as aminoglycosides and vancomycin); continuous sedation; and corticosteroids (with contradictory results). The non-modifiable risk factors include prolonged mechanical ventilation (MV) (an independent risk factor for ICU-AW) and stay in ICU; multiple organ failure; the presence of sepsis; the presence of Systemic Inflammatory Response Syndrome (SIRS); premorbid state: to be a woman and/or older; and frailty conditions. The diagnosis of ICU-AW will depend on whether the patient is conscious or not. In awake/cooperate patients, the evaluation tests are handgrip dynamometry and six grades MRC-SS (the gold standard for the diagnosis of ICU-AW). Also, some tests or scores provide information about the patients’ functional abilities: functional status score for the ICU and Chelsea Critical Care Physical Assessment tool; 6-minute walking distance (6-MWD) (assesses functional walk capacity post ICU); and maximum inspiratory and expiratory pressure (in respiratory muscles). In unconscious/uncooperative patients, the evaluation consists of electroneurography test (to evaluate nerve conduction velocities and amplitude of nerve action potentials) and, electromyography (to evaluate activity at rest, motor unit potentials and maximal effort); imaging techniques (computed tomography (CT), ultrasonography, magnetic resonance imaging, dual- energy X-ray absorptiometry, neutron activation analysis, bioelectrical impedance); and nerve and muscle biopsies (used mainly in research). ICU-AW: ICU-acquired weakness; ICU: intensive care unit; SIRS: systemic inflammatory response syndrome; MV: mechanical ventilation; CIP: Critical Illness Polyneuropathy; CIM: Critical Illness Myopathy; MRC-SS: Medical Research Council sum score; 6-MWD: 6-minute walking distance; CT: computed tomography: MIP: maximum inspiratory pressure; MEP: maximum expiratory pressure Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 4 - ICU-acquired weakness diagnosis ICU-AW diagnosis requires both clinical assessments of muscle strength (peripheral and/or respiratory muscles) and complete electrophysiological evaluation of peripheral nerves and muscles (Figure 1).4,12 Diagnosis in awake/cooperative patients The gold standard for ICU-AW diagnosis is handgrip dynamometry and the Medical Research Council sum score (MRC-SS).12 Handgrip dynamometry evaluates the dominant hand’s isometric muscle strength.12,18 In ICU- AW, the cut-off scores are less than 11 kg (interquartile range [IQR] 10–40) in males and less than 7 kg (IQR 0– 7.3) in females.18,24,30 The handgrip is a non-invasive test with quick and easy bedside testing. Besides, it has high inter-rater reliability and increased sensitivity and specificity. Its disadvantages are that patients must be awake, cooperative, and must comprehend the assessor’s instructions. In general, these conditions are difficult for ICU patients because they could be in a coma, have pain, or use sedative drugs; therefore, it is uncertain whether the outcome is representative of global muscle strength or not.4,12,24,31 The six-grade MRC-SS is a strength test that allows assessment of muscle strength in 12 muscle groups (shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and foot dorsiflexion).4,12,31 Individual scores are combined into a total score, which allows for an estimated overall motor function. Its advantages are that it is a bedside non-invasive test with high reliability and validity. However, it requires the patient to be alert, cooperative, and motivated, which is not always possible; it may be affected by the positioning of the patient and availability of limbs for assessment (immobilisation, for example); and it has a low sensitivity to changes in muscle function. 4,12,31 There is also a modified score MRC-SS of 4-grade, but it still requires further validation.4,24 Other less commonly used tests are functional status score for the ICU, scored physical function in intensive care test, and Chelsea critical care physical assessment tool, which provide information about the patients’ functional abilities. The 6-minute walking distance (6- MWD) assesses functional walking capacity, but it is mainly used to evaluate how patients perform at discharge and at post-ICU follow-up.24,32-34 In respiratory muscles, the determination of maximum inspiratory and expiratory pressure represents the strength of the general respiratory muscles. Still, they require the patient to be awake and cooperative. The measurement of transdiaphragmatic pressure or endotracheal tube pressure in response to phrenic nerve stimulation could be a good option, but it is an invasive technique that requires magnetic stimulation and qualified staff. Imaging techniques, such as chest X-rays or ultrasonography, can be used, but they have low sensitivity and specificity.4,35-38 Diagnosis in unconscious/uncooperative patients The strategies applied to unconscious/uncooperative patients, such as electrophysiological and imaging techniques, have been incorporated to the diagnosis of ICU-AW. Electrophysiological studies are primarily aimed at differentiating between CIM and CIP in unconscious patients. However, they can also be used when the patient is cooperative and voluntary muscle activation is possible. Among the most used tests are electroneurography which evaluates nerve conduction velocities and amplitude of nerve action potentials, as sensory nerve action potentials and compound muscle action potentials; and electromyography (which includes activity at rest, motor unit potentials and maximal effort). These tests provide a measure of muscle function regardless of whether the patient is awake and cooperative, which allows assessment of the contractile properties of skeletal muscles without the need for voluntary muscle activation.1,12,13,39,40 The imaging techniques can assess muscle mass and body composition with different precision grades and costs. Among these, the skeletal muscle area at the third lumbar vertebra level measured through computed tomography (CT) on admission is more exact. It allows a better diagnosis of patients in the ICU state. Its disadvantages are that it is expensive, requires specialised staff and software, and exposes patients to a high radiation level.4,41 Other techniques include ultrasonography, magnetic resonance imaging, dual- energy X-ray absorptiometry, neutron activation analysis, and bioelectrical impedance.42-44 Nerve and muscle biopsies could provide essential and precise information of muscle states but are invasive, expensive, and specialised techniques, so they are used mainly in research.39,42,45 Skeletal muscle atrophy in ICU-acquired weakness Skeletal muscle atrophy is characterised by decreased structural proteins essential for muscle function (such as myosin heavy chain and myosin light chain).46,47 Some reports show that ICU patients can lose as much as 20% of their muscle mass in the first 10 days after ICU admission, depending on the disease severity.5,48 This mass loss is caused by an increase in a catabolic state in the muscle in these first days. Beyond this specific muscle damage, ICU-AW patients show significant impairments in body structure and function. These alterations produce a critical limitation of physical activity, even offering complete immobilisation.10,29,49,50 In ICU-AW, several causes can produce muscle wasting. Some studies have proposed disturbed metabolism, sepsis, and/or malnutrition as inductors of muscle wasting.48,51 It has also been attributed to immobilisation and chronic disease.52,53 There is evidence that part of ICU patients’ treatment, such as drug administration, muscle relaxants, corticosteroids, and even intravenous sedation, can exacerbate the effect produced by Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 5 - immobilisation. Thus, the same therapy for ICU patients can decrease the muscle mass.52,53 At the physiopathological level (Figure 2), one of the muscle wasting features in the critical illness is the loss of myosin and myosin-related proteins due to the imbalance between muscle protein synthesis and degradation.52,54 Studies performed in animal models of ICU-AW and critically ill patients present increased ubiquitin-proteasome system (UPS) activity as the dominant regulator of muscle proteolysis.39 UPS activation is induced by oxidative stress, energy stress, pro-inflammatory cytokines (tumour necrosis factor- alpha [TNF-α], interleukin 1 [IL-1], and interleukin 6 [IL-6]), mechanical silencing (defined as loss of external muscle strain (weight-bearing), and internal muscle strain (contraction), and sepsis conditions that could increase the gene expression of crucial UPS players.39,52,55,56 Moreover, dysregulated autophagy has been found in muscles from critically ill patients, contributing to the degradation of muscle fibre and inducing muscle loss.45,57 Furthermore, in critical illness conditions with prolonged bed stay resulting in minimal mechanical load stimuli, protein synthesis is decreased, reinforcing muscle loss for reducing mTOR1 pathway activity.39,52 Calpain, an enzyme that participates in sarcomere disassembly, could lead to Z-band disintegration and myofibrillar protein breakdown in critical illness. However, the antecedents that support this possibility are minimal.39 Fig 2. Physiopathology mechanisms associated to high chance of developing ICU-acquired weakness and its severe consequences in COVID-19 patients. Dysregulated control of skeletal muscle mass and other factors induce muscle weakness and skeletal muscle atrophy in ICU-AW. There is increased ubiquitin-proteasome system (UPS) activity, dysregulated autophagy, decreased protein synthesis, and increased calpain activity. Other factors that induce muscle weakness and skeletal muscle atrophy in ICU-AW patients are impaired excitation- contraction coupling, hypoperfusion, mitochondrial dysfunction, and inflammation. In COVID-19, the possible pathophysiological mechanisms for developing ICU-AW in patients treated in ICU include the cytokine storm, deregulation of the renin-angiotensin system (RAS), and inflammatory myopathy. ICU-AW: ICU-acquired weakness; COVID-19: coronavirus disease 2019; UPS: ubiquitin-proteasome system; mTOR: mammalian target of rapamycin; ICU: intensive care unit; TNF-α: tumour necrosis factor- alpha; IL-1: Interleukin 1; IFN: Type I interferon; IL-6: Interleukin 6; RAS: Renin-angiotensin system; SARS- CoV-2: severe acute respiratory syndrome coronavirus 2; ACE2: angiotensin-converting enzyme 2; MV: mechanical ventilation. Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 6 - Muscular mitochondrial dysfunction has been observed in critical patients. They show a vicious cycle of macromolecules and organelle damage due to mitochondrial damage compromises energy provision and increases the production of free radicals and reactive oxygen species, which can induce proteolysis.39,52 Regulation of mitochondrial size and morphology may play a critical role in muscle atrophy and is determined by an imbalance between mitochondrial fission and fusion.58,59 Furthermore, impaired excitation-contraction coupling due to altered intracellular calcium homeostasis for sodium channel inactivation has been reported in muscle of ICU-AW patients.39 This alteration could fail to coordinate repetitive firing within the motor neurons that can precede electrical failure in axons and nerve-muscle coupling or neuromuscular junction (NMJ) degradation, as observed in aging.60,61 Under ICU-AW conditions, hypoperfusion, probably caused by oedema formation because of vasodilation and increased permeability, may favour axonal degeneration, neuronal injury, and a chronic membrane depolarisation of terminal motor axons in skeletal muscle.13,39 Inflammation is an essential factor that induces muscle atrophy in several patients. The systemic inflammatory- mediated pathology is considered the most significant risk factor for ICU-AW.62 Inflammation has a higher impact on ICU-AW development than inactivity when evaluating patients with critical diseases.63 A recent meta-analysis concluded that lower muscle strength and skeletal muscle mass are significantly associated with higher levels of circulating inflammatory markers.64 In ICU patients, muscle biopsies have shown signs of inflammation, pronounced infiltration with adipose tissue, and fibrosis, which could also lead to muscle mass loss.39,45 Due to the early appearance of muscle atrophy and the impact of muscle dysfunction in the ICU outcome, the development of persistent post-ICU complaints, and low quality of life, research about ICU-AW has increased. The researchers have focused on studying the mechanisms and factors that influence muscle dysfunction in a patient chronically ill, which promotes the development of possible therapies or treatments for ICU patients to avoid and/or improve this muscular condition. Therapeutic strategies in ICU-acquired weakness patients Substantial loss in muscle mass develops in the first stage of ICU; however, its impact on muscle function is extended to the period after the patients are discharged.48 These antecedents indicate that implementing some strategies to avoid impaired muscle structure and function in the early ICU stage is essential to prevent impaired status after ICU stay. As immobilisation is the most common feature in ICU patients, several studies have focused on finding treatments considering immobilisation as the leading cause of skeletal muscle wasting in these patients. The development of treatment for ICU-AW is based on three strategies: pharmacological, nutritional, and mechanical loads (physical therapy and/or electrostimulation). Pharmacology treatment of ICU-acquired weakness: There are several drugs for ICU-AW treatment: anabolic steroid oxandrolone and growth hormone (to increase muscle mass), propranolol (to decrease muscle loss), immunoglobulin (to control inflammation), and glutamine therapy (to improve nutritional status). However, the evidence is not yet sufficient to recommend their use. Insulin therapy could be a promising treatment because it has shown significant preventive effects upon CIP/CIM, but it is not yet possible to recommend it as a common strategy due to the substantial risk of hypoglycaemia.4,65,66 Nutrition treatment: Concerning the contribution of nutrition to the clinical outcome of ICU-AW patients, randomised controlled clinical trials have not shown an apparent effect.48 The recommendations in the initial phase in ICU stay (1–4 days) are to deliver calories and proteins progressively, and from day five onward, to deliver a high-caloric supplementation.67 Few studies have assessed the impact of nutritional strategies on muscle mass or function in ICU-AW patients, and their results are inconclusive.48,67-70 Protein supplementations in the early phases of dysfunction have been used to treat muscle mass loss, but the results are contradictory. Some authors indicate that protein administration does not improve the catabolic state during the early phase of critical illness, and protein synthesis does not change to increased protein delivery.5,71,72 Other authors indicate that exogenous nutrients supplemented as part of the dietary protein during critical illness reach the skeletal muscle and can induce the synthesis of muscle protein and, at the same time, can inhibit proteolysis 73 It has been demonstrated that immobilisation can induce an inflammatory condition in the muscle, altering muscle energy and nutrient metabolism. Considering this analysis, some researchers have focused on studying the effects of enhanced protein provision, specific substrate delivery, and physical exercise in the prevention of muscle mass loss in ICU patients.48 This reaffirms that the loss of muscle mass in ICU patients in the first phase should be considered a multifactorial condition. Thus, the prevention of muscle wasting in ICU patients should be focused on the control of all the associated risk factors,74 such as immobility or nutrient deficits that are key for avoiding protein loss and metabolic alterations.75-77 Mechanical loads Physical therapy: It is well established that physical therapies can improve health in different ways, including neurological, metabolic, and morphological adaptation.78-81 Training, exercise, and movement are essential stimuli for the induction of protein synthesis, Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 7 - mainly via direct activation of the mTOR pathway and, consequently, increasing muscle mass under normal conditions.82 Physical therapy is considered an essential field in critical care,83 because it may improve muscle function by targeting different aspects: anti- inflammatory effects, potentially reducing local cytokine expression, and increasing the expression of anti- apoptotic factors. 84 Patients with muscle wasting are commonly referred to physical therapy when they are discharged from the ICU, but physical rehabilitation must begin early in the ICU stay.85 Anekwe et al. developed an analysis to evaluate the effects of rehabilitation in two subgroups of ICU patients, screened and randomised, with 49% and 36% lower odds of developing muscle wasting, respectively.85 The sub- analysis based on the time of onset of rehabilitation suggests that in the first 72 hours after ICU admission, the rehabilitation programme is protective against ICU- AW development compared to beginning rehabilitation later (more than 72 hours). However, these beneficial effects may be explained by the preventive protocol working better or by the patients being able to participate more actively in its rehabilitation in the early stage of the disease. In this line, Hickmann et al. previously demonstrated that mobilisation attenuated the muscle atrophy induced by disuse in the early or catabolic phase of critically ill patients, maintaining the muscle fibre cross-sectional area.86 Electrical stimulation: Evidence suggests that beneficial effects in ICU patients are observed with neuromuscular electrical stimulation (NMES) treatments. The NMES could reduce skeletal muscle atrophy in ICU patients.87 However, controversial results are observed on whether NMES could reduce ICU-AW risk compared to usual care in ICU.88 NMES have been shown to improve other conditions, such as time on a mechanical ventilator, hospital length stay, and acute mortality associated with ICU-AW, but it does not enhance global muscle strength.50,88-90 The main reasons NMES intervention are not recommended yet are the low quality of the experimental evidence due to the limited number of participants, differences in the NMES parameters, such as frequency, intensity, and duration, and limiting the pooling and interpretation of data.88 Potential therapies One of the vasoactive peptides with a beneficial effect on structure and function in skeletal muscle is angiotensin- (1–7) [Ang-(1–7)] which belongs to the non-classical axis of the renin-angiotensin-system. Ang-(1–7) has anti- atrophic activity in skeletal muscle, posing a potential treatment for ICU-AW. Ang-(1–7) produces its effects through the G-protein-coupled transmembrane receptor Mas.91 The actions of Ang-(1–7) include the inhibition of cell proliferation, vasodilation, and antihypertensive effects.92-94 In skeletal muscle, Ang-(1–7) reportedly acts in the prevention of fibrosis and autonomic dysfunction associated with Duchenne muscular dystrophy, as well as the decrease in angiotensin II (Ang II)-induced insulin resistance and transforming growth factor (TGF)-β signaling.95-97 Ang-(1–7) also has anti-atrophic effects in skeletal muscle, counteracting the muscle wasting induced by Ang II, immobilisation, and sepsis through a mechanism dependent on the Mas receptor and protein kinase B (PKB/Akt) activity. Furthermore, at the catabolic level, studies in mice have shown that systemic administration of Ang-(1–7) prevents the myosin heavy chain (MHC) decrease and increases atrogin-1 and MuRF-1 in skeletal muscle. Lastly, Ang-(1–7) can prevent the reduction in the diameter of muscle fibres and avoid the transition in their type.98-101 Thus, Ang-(1–7) could be an exciting candidate for possible future therapies to curb muscle mass loss in patients with ICU-AW. ICU-acquired weakness and COVID-19 Since 2019, the world has faced a complex health situation due to the COVID-19 pandemic. COVID-19 is an infectious disease caused by SARS-CoV-2. The World Health Organization (WHO), in April 2022, reported 497057239 infected people and 6179104 deaths from the virus in the world.102 The clinical manifestation of this viral infection includes asymptomatic or symptomatic patients. The common symptoms are cough, sore throat, headache, fever, gastric discomfort, fatigue, dyspnoea, and muscle and joint pain. 103 In symptomatic patients, the condition’s severity is highly variable and can be managed on an outpatient basis, requiring hospitalisation or admission to intensive care units (ICU). Severe COVID-19 patients usually need access to the ICU and, in many cases, the use of mechanical ventilation (MV) and other invasive treatments to save their lives. In this context, the risk of developing ICU-AW is high.6 There is still little information regarding COVID-19 patients developing ICU-AW. However, there are several similarities between patients with severe COVID-19 and CIM patients, such as prolonged MV, classical ICU interventions, myalgias, significant muscle loss, and hyper-inflammation.7,8 Considering that COVID-19 produces severe respiratory disorders, such as pneumonia (75%) and acute respiratory distress syndrome (ARDS) (15%), these patients have a high probability of developing ICU- AW.104 Hence, SARS-CoV-2 could cause neuromuscular symptoms like another coronavirus previously reported such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). In these viruses, patients reportedly develop several neuromuscular alterations, such as myalgia, rhabdomyolysis, and polyneuropathy.105-107 About 75% of COVID-19 patients admitted to the ICU require MV,108-110 and the median length of stay in the ICU and hospital is 14 and 17 days, respectively.111 Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 8 - High probability of developing ICU-acquired weakness in COVID-19 patients Still, not many clinical studies describe the development of ICU-AW in COVID-19 patients treated in ICU. However, the current information shows that a high percentage of these patients developed early diffuse and symmetrical muscle weakness (CIM)112-115 or polyneuropathy (CIP)116 with absent deep tendon reflexes,117 and myalgia,114 coinciding with the clinical manifestations of ICU-AW. These patients present several risk factors of ICU-AW, such as required intensive care, invasive mechanical ventilation, pharmacological therapy for ICU (corticosteroids, sedatives drugs, neuromuscular blocking agents), hyperglycaemia, and prolonged ICU stays.118 The ICU-AW diagnosis in patients with COVID-19 has been developed through clinical tests that show lower scores in mobility scales, decreased handgrip strength, and Barthel index. 112,118 Electrodiagnostic findings have shown normal sensory conduction, low amplitude, and increased distal latency of compound muscle action potentials (CMAP), and electromyography (EMG) showed signs of critical illness myopathy (CIM), 112,114,116,117 which would confirm the presence of ICU- AW in patients with more severe COVID-19. Thus, when COVID-19 patients require prolonged ICU stays, it is highly probable that they develop ICU-AW. However, the impact on functional status and long-term consequences of ICU-AW in these survivors remain unclear. Despite a lack of evidence, the median and extended time consequences can have severe adverse effects on daily life activities. The rehabilitation programmes could effectively reverse muscle weakness caused by ICU-AW in COVID-19 patients. Mechanisms for the development of ICU-acquired weakness in COVID-19 patients treated in ICU At the pathophysiological level (Figure 2), in COVID-19 exhibits a “cytokine storm,” with increases in cytokine and chemokine levels119 and triggers coagulopathy and thrombosis.120 The principal cytokines identified in COVID-19 patients are TNF-α, IL-1, type I interferon (IFN), and IL-6,121 the same cytokines that are increased in critically ill patients.39 A high correlation between the level of IL-6 in the blood and mortality and severity has been described in patients with COVID-19.122,123 It is known that there may be an imbalance in muscle metabolic homeostasis that exacerbates the loss of muscle mass due to a systemic increase in IL-6.124,125 Furthermore, in a Syrian hamsters model injected with SARS-CoV-2, the animals developed typical COVID-19 and weight loss signs associated with increases in interferon δ and TNF-α.126 The IFN dysregulated release in COVID-19 could produce a maladaptive immune response with hyperactivity of innate immunity and immunosuppression.127 This COVID-19 cytokine storm could aggravate the patient’s condition and promote the development of ICU-AW. In COVID-19 patients, deregulation of the renin- angiotensin system (RAS) can also play a role in ICU- AW development.128 RAS can modulate skeletal muscle mass through two pathways: classical and non-classical. Angiotensin (Ang) I is converted to Ang II by angiotensin-converting enzyme (ACE) in the classical axis. If Ang II is bound to angiotensin type 1 (AT1R), the adverse effects are inflammation, vasoconstriction, atherogenesis, fibrosis, and skeletal muscle atrophy.129 In the non-classical axis, angiotensin-converting enzyme 2 (ACE2) converts Ang II into Ang (1-7). Positive skeletal muscle consequences include anti-inflammatory, anti- atrophic, and antifibrotic effects.130,131 The SARS-CoV-2 receptor is ACE2. When the virus binds to its receptor, it downregulates the ACE2 protein,132 which could lead to deregulation of RAS with increased activity of the classical axis and decreased activity of the non-classical axis,128 affecting the muscle mass balance. In coronavirus disease, post-mortem muscle samples of SARS-CoV patients showed muscle atrophy and necrosis;132 thus, it cannot be ruled out that SARS-Cov-2 might have similar effects on skeletal muscle. However, COVID-19 patients may develop an inflammatory myopathy called immune-mediated necrotising myopathy (IMNM) or necrotising autoimmune myopathy. The myopathy in severe COVID-19 patients may be explained by immune mechanisms (due to massive cytokine release than the direct invasion of the virus into muscle tissue), immune myositis infection with the virus, electrolyte disturbances, drugs, hypo-excitability of the membrane, necrosis, or hypoxia.114,133 Inflammatory myopathy is characterised by proximal muscle weakness accompanied by elevated serum muscle enzyme levels, such as creatine kinase (CK), scattered necrosis of myofibers, few infiltrated lymphocytes, size variation of muscle fibres, and central nuclei.134 This condition must necessarily be diagnosed by muscle biopsy,134,135 but CK could be a good and more accessible alternative. CK has generally been considered an indicator of muscle damage and inflammatory response.136 Patients with severe COVID-19 reportedly have higher CK serum levels and muscle injury than ICU patients.105 However, it is crucial to consider that CK is nonspecific and can be elevated by prolonged bed rest and medications instead of a direct muscle injury from COVID-19.137 Treatment of ICU-acquired weakness in COVID-19 patients The current treatments applied to COVID-19 patients in the ICU are: “conservative intravenous fluids, empirical intravenous antibiotics for suspected bacterial coinfection, consideration for early, invasive endotracheal intubation and ventilation to maintain adequate oxygenation and carbon dioxide elimination, lung-protective ventilation strategies, such as limiting tidal volumes and inspiratory pressures, periods of prone positioning while mechanically ventilated to decrease the Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 9 - risk of mechanical lung injury and consideration of extracorporeal membrane oxygenation”.138 After discharge from ICU, these patients could present similar long-term sequelae of ARDS, such as multiorgan impairment, pulmonary dysfunctions, dyspnoea, fatigue, reduced exercise capacity, exertional hypoxemia, reduced muscle strength, shoulder dysfunction, dysphagia, anxiety symptoms, and cognitive and mental health dysfunction.139,140 These sequels could affect functionality in daily activities and require rehabilitation. In addition, another aspect to consider and that could have important negative effects on the subsequent functional recovery of ICU and COVID-19 patients is the lack of mobilization during hospitalization. In this regard, a study by Liu et al. (2022)141 conducted with data from 135 ICUs, with a total of 1,229 patients in 33 countries around the world, showed that more than 90% of patients with MV (positive or negative for COVID-19) during the pandemic, remained completely immobile most of the time. These results are worrying considering the enormous number of sequelae that these patients can have and, without a doubt, it is essential to change the therapeutic approach to one where mobility is a fundamental element of the rehabilitation.141 Regarding post-ICU rehabilitation in COVID-19 patients, given the limited information, more research is needed.139,142 Patients with physical function sequelae of ICU-AW and COVID-19 need physical therapy to reverse the disability associated with cardiopulmonary dysfunction and muscle atrophy. The physical treatment includes earlier mobilisation, exercise training, neuromuscular electrical stimulation, and respiratory rehabilitation, which can consist of respiratory care and respiratory training.143-145 Therefore, developing rehabilitation programmes for post-COVID-19 patients treated in the ICU for medium- and long-term treatments are essential. Although it is a topic that is beginning to be studied and understood, considering the relevance for patient recovery and the associated health costs, it is relevant to explore the possible factors that influence the risk of ICU-AW in COVID-19 patients. Conclusions and perspectives In the future, it is necessary to investigate the pathophysiological process that favours possible myopathy and the development of ICU-AW in patients with COVID-19.133 In this regard, biopsy, despite being an invasive procedure, could be essential,114 as well as nerve conduction and EMG studies.116 A detailed neurological and muscular evaluation is also essential because many ICU-AW patients with COVID-19 may have early deficits.146 If the long-term physical consequences of COVID-19 on skeletal muscle are added to the effects of ICU-AW,147- 156 recovery is complex, along with the high health care costs that this entails.117 It is crucial to start a nutritional intervention and preventive physical and respiratory therapy to delay the accelerated loss of skeletal muscle mass and maintain respiratory function during the ICU stay. After ICU discharge, it is essential to include multidisciplinary therapy that considers muscle function treatment from nutritional, pharmacological, and physical rehabilitation aspects. The target could be the progressive recovery of mass and general muscle strength and the function of the respiratory muscles and, with it, the generalised recovery of physical function. All these interventions that are used post-ICU-AW patients must be adapted to the needs of patients with COVID-19 exhibiting long-term persistent symptoms, such as fatigue, dyspnoea, pain, and cough.139,145 List of acronyms 6-MWD - 6-minute walking distance ACE - angiotensin-converting enzyme ACE2 - angiotensin-converting enzyme 2 Akt - protein kinase B Ang II - angiotensin II Ang-(1–7) - angiotensin-(1–7) APACHE - acute physiology and chronic health evaluation ARDS - acute respiratory distress syndrome ( AT1R - angiotensin type 1 CIM - critical illness myopathy CIP - critical illness polyneuropathy COVID-19 – Corona virus disease 2019 CT - computed tomography ICU -intensive care unit ICU-AW - intensive care unit - acquired weakness IFN - type I interferon IL-1 - interleukin 1 IL-6 - interleukin 6 IQR - interquartile range MEP: maximum expiratory pressure MIP - maximum inspiratory pressure MRC-SS - medical research council sum score mTOR - mechanistic target of rapamycin MuRF-1 - muscle-specific RING finger protein 1 MV - mechanical ventilation NMES - neuromuscular electrical stimulation NMJ - neuromuscular junction PKB - protein kinase B RAS - renin-angiotensin system SARS-CoV-2 - severe acute respiratory syndrome Coronavirus 2 SIRS - systemic inflammatory response syndrome SOFA - sequential organ failure assessment TNF-α - tumour necrosis factor-alpha UPS - ubiquitin-proteasome system WHO - world health organization MERS-CoV - Middle East respiratory syndrome coronavirus Contributions of Authors All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 10 - for this article, take responsibility for the work's integrity as a whole. Conceptualization: JA, OA, AG and CC-V; validation: JA, OA, and AG; formal analysis: JA, OA, AG, FS and CC-V; investigation: JA, OA, AG, and C C- V; original draft preparation: JA, OA, AG, and CC-V; revision and editing: C C-V and FS; supervision: C. C-V; project administration: C C-V; funding acquisition: C C- V, and FS. All authors have read and approved the final edited typescript. Acknowledgments None Funding The manuscript was supported by research grants from the National Fund for Science and Technological Development (FONDECYT 1200944 [CCV], 1201039 [FS]), Agencia Nacional de Investigación y Desarrollo (ANID) - Millennium Science Initiative Program - ICN09_016 / ICN 2021_045: Millennium Institute on Immunology and Immunotherapy (ICN09_016 / ICN 2021_045; former P09/016-F [CCV, FS]), Basal Grant CEDENNA (AFB180001 [CCV]). The Millennium Nucleus of Ion Channel- Associated Diseases (MiNICAD) is supported by the Iniciativa Científica Milenio ANID, Chile Conflict of Interest The authors declare no conflict of interests. Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Corresponding Author Claudio Cabello-Verrugio. Laboratory of Muscle Pathology, Fragility, and Aging. Department of Biological Sciences. Faculty of Life Sciences. Universidad Andres Bello, Santiago, 8370146, Chile. ORCIDciD: 0000-0001-7273-2102 E-mail: claudio.cabello@unab.cl E-mails and ORCID iD of co-authors Andrea Gonzalez: a.gonzalezrojas@uandresbello.edu ORCID iD: 0000-0001-5003-7109 Johanna Abrigo: j.abrigoleon@uandresbello.edu ORCID iD: 0000-0002-5598-513X Oscar Achiardi: oscar.achiardi@pucv.cl ORCID iD: 0000-0003-3623-0994 Felipe Simon: fsimon@unab.cl ORCID iD: 0000-0002-2653-9798 References 1. Stevens RD, Marshall SA, Cornblath DR, Hoke A, Needham DM, de Jonghe B, Ali NA, Sharshar T. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med. 2009 Oct;37(10 Suppl):S299-308. doi: 10.1097/CCM.0b 013e3181b6ef67. 2. Jolley SE, Bunnell AE, Hough CL. ICU-Acquired Weakness. Chest. 2016 Nov;150(5):1129-1140. doi: 10.1016/j.chest.2016.03.045. 3. Griffiths RD, Hall JB. Intensive care unit-acquired weakness. Crit Care Med. 2010 Mar;38(3):779-87. doi: 10.1097/CCM.0b013e3181cc4b53. 4. Vanhorebeek I, Latronico N, Van den Berghe G. ICU-acquired weakness. Intensive Care Med. 2020 Apr;46(4):637-653. doi: 10.1007/s00134-020- 05944-4. 5. Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, Chan P, Hopkinson NS, Phadke R, Dew T, Sidhu PS, Velloso C, Seymour J, Agley CC, Selby A, Limb M, Edwards LM, Smith K, Rowlerson A, Rennie MJ, Moxham J, Harridge SD, Hart N, Montgomery HE. Acute skeletal muscle wasting in critical illness. JAMA. 2013 Oct 16;310(15):1591-600. doi: 10.1001/jama.2013. 278481. Erratum in: JAMA. 2014 Feb 12;311(6):625. Padhke, Rahul [corrected to Phadke, Rahul]. 6. McClafferty B, Umer I, Fye G, Kepko D, Kalayanamitra R, Shahid Z, Ramgobin D, Cai A, Groff A, Bhandari A, Aggarwal CS, Patel R, Bhatt D, Polimera H, Sahu N, Vunnam R, Golamari R, Kumar A, Jain R. Approach to critical illness myopathy and polyneuropathy in the older SARS- CoV-2 patients. J Clin Neurosci. 2020 Sep;79:241- 245. doi: 10.1016/j.jocn.2020.07.058. 7. Lad H, Saumur TM, Herridge MS, Dos Santos CC, Mathur S, Batt J, Gilbert PM. Intensive Care Unit- Acquired Weakness: Not just Another Muscle Atrophying Condition. Int J Mol Sci. 2020 Oct 22;21(21):7840. doi: 10.3390/ijms21217840. 8. Morley JE, Kalantar-Zadeh K, Anker SD. COVID- 19: a major cause of cachexia and sarcopenia? J Cachexia Sarcopenia Muscle. 2020 Aug;11(4):863- 865. doi: 10.1002/jcsm.12589. 9. Damian MS, Wijdicks EFM. The clinical management of neuromuscular disorders in intensive care. Neuromuscul Disord. 2019 Feb;29(2):85-96. doi: 10.1016/j.nmd.2018.12.005. 10. Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired weakness. Crit Care. 2015 Aug 5;19(1):274. doi: 10.1186/s13054-015- 0993-7. 11. Latronico N, Herridge M, Hopkins RO, Angus D, Hart N, Hermans G, Iwashyna T, Arabi Y, Citerio G, Ely EW, Hall J, Mehta S, Puntillo K, Van den Hoeven J, Wunsch H, Cook D, Dos Santos C, Rubenfeld G, Vincent JL, Van den Berghe G, Azoulay E, Needham DM. The ICM research agenda on intensive care unit-acquired weakness. Intensive Care Med. 2017 Sep;43(9):1270-1281. doi: 10.1007/s00134-017-4757-5. mailto:claudio.cabello@unab.cl mailto:a.gonzalezrojas@uandresbello.edu mailto:j.abrigoleon@uandresbello.edu mailto:oscar.achiardi@pucv.cl mailto:fsimon@unab.cl Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 11 - 12. Piva S, Fagoni N, Latronico N. Intensive care unit- acquired weakness: unanswered questions and targets for future research. F1000Res. 2019 Apr 17;8:F1000 Faculty Rev-508. doi: 10.12688/f1000research.17376.1. 13. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011 Oct;10(10):931-41. doi: 10.1016/S1474- 4422(11)70178-8. 14. Fan E, Cheek F, Chlan L, Gosselink R, Hart N, Herridge MS, Hopkins RO, Hough CL, Kress JP, Latronico N, Moss M, Needham DM, Rich MM, Stevens RD, Wilson KC, Winkelman C, Zochodne DW, Ali NA; ATS Committee on ICU-acquired Weakness in Adults; American Thoracic Society. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit Care Med. 2014 Dec 15;190(12):1437-46. doi: 10.1164/rccm.201411-2011ST. 15. Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med. 2014 Jul 17;371(3):287-8. doi: 10.1056/NEJMc1406274. 16. Yang T, Li Z, Jiang L, Wang Y, Xi X. Risk factors for intensive care unit-acquired weakness: A systematic review and meta-analysis. Acta Neurol Scand. 2018 Aug;138(2):104-114. doi: 10.1111/ ane.12964. 17. Hermans G, Wilmer A, Meersseman W, Milants I, Wouters PJ, Bobbaers H, Bruyninckx F, Van den Berghe G. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med. 2007 Mar 1;175(5):480-9. doi: 10.1164/rccm.200605-665OC. 18. Latronico N, Gosselink R. A guided approach to diagnose severe muscle weakness in the intensive care unit. Rev Bras Ter Intensiva. 2015 Jul- Sep;27(3):199-201. doi: 10.5935/0103-507X.2015 0036. 19. Wolfe KS, Patel BK, MacKenzie EL, Giovanni SP, Pohlman AS, Churpek MM, Hall JB, Kress JP. Impact of Vasoactive Medications on ICU- Acquired Weakness in Mechanically Ventilated Patients. Chest. 2018 Oct;154(4):781-787. doi: 10.1016/j.chest.2018.07.016. 20. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. 21. Bourenne J, Hraiech S, Roch A, Gainnier M, Papazian L, Forel JM. Sedation and neuromuscular blocking agents in acute respiratory distress syndrome. Ann Transl Med. 2017 Jul;5(14):291. doi: 10.21037/atm.2017.07.19. 22. deBacker J, Hart N, Fan E. Neuromuscular Blockade in the 21st Century Management of the Critically Ill Patient. Chest. 2017 Mar;151(3):697- 706. doi: 10.1016/j.chest.2016.10.040. 23. Wieske L, van Hest RM, Witteveen E, Verhamme C, Schultz MJ, van Schaik IN, Horn J. Is gentamicin affecting the neuromuscular system of critically ill patients? Intensive Care Med. 2015 Apr;41(4):727- 8. doi: 10.1007/s00134-015-3731-3. 24. Parry SM, Puthucheary ZA. The impact of extended bed rest on the musculoskeletal system in the critical care environment. Extrem Physiol Med. 2015 Oct 9;4:16. doi: 10.1186/s13728-015-0036-7. 25. De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, Raphaël JC, Outin H, Bastuji-Garin S; Groupe de Réflexion et d'Etude des Neuromyopathies en Réanimation. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002 Dec 11;288(22):2859-67. doi: 10.1001/jama.288.22.2859. 26. Chlan LL, Tracy MF, Guttormson J, Savik K. Peripheral muscle strength and correlates of muscle weakness in patients receiving mechanical ventilation. Am J Crit Care. 2015 Nov;24(6):e91-8. doi: 10.4037/ajcc2015277. 27. Kramer CL. Intensive Care Unit-Acquired Weakness. Neurol Clin. 2017 Nov;35(4):723-736. doi: 10.1016/j.ncl.2017.06.008. 28. Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. doi: 10.1056/NEJMoa 1011802. 29. Fan E, Dowdy DW, Colantuoni E, Mendez-Tellez PA, Sevransky JE, Shanholtz C, Himmelfarb CR, Desai SV, Ciesla N, Herridge MS, Pronovost PJ, Needham DM. Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. Crit Care Med. 2014 Apr;42(4):849-59. doi: 10.1097/CCM.000000000 0000040. 30. Parry SM, Berney S, Granger CL, Dunlop DL, Murphy L, El-Ansary D, Koopman R, Denehy L. A new two-tier strength assessment approach to the diagnosis of weakness in intensive care: an observational study. Crit Care. 2015 Feb 26;19(1):52. doi: 10.1186/s13054-015-0780-5. 31. Vanpee G, Hermans G, Segers J, Gosselink R. Assessment of limb muscle strength in critically ill Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 12 - patients: a systematic review. Crit Care Med. 2014 Mar;42(3):701-11. doi: 10.1097/CCM.0000000000 000030. 32. Denehy L, de Morton NA, Skinner EH, Edbrooke L, Haines K, Warrillow S, Berney S. A physical function test for use in the intensive care unit: validity, responsiveness, and predictive utility of the physical function ICU test (scored). Phys Ther. 2013 Dec;93(12):1636-45. doi: 10.2522/ptj.2012 0310. 33. Huang M, Chan KS, Zanni JM, Parry SM, Neto SG, Neto JA, da Silva VZ, Kho ME, Needham DM. Functional Status Score for the ICU: An International Clinimetric Analysis of Validity, Responsiveness, and Minimal Important Difference. Crit Care Med. 2016 Dec;44(12):e1155-e1164. doi: 10.1097/CCM. 0000000000001949. 34. Chan KS, Pfoh ER, Denehy L, Elliott D, Holland AE, Dinglas VD, Needham DM. Construct validity and minimal important difference of 6-minute walk distance in survivors of acute respiratory failure. Chest. 2015 May;147(5):1316-1326. doi: 10.1378/chest.14-1808. 35. Supinski GS, Westgate P, Callahan LA. Correlation of maximal inspiratory pressure to transdiaphragmatic twitch pressure in intensive care unit patients. Crit Care. 2016 Mar 23;20:77. doi: 10.1186/s13054-016-1247-z. 36. Doorduin J, van Hees HW, van der Hoeven JG, Heunks LM. Monitoring of the respiratory muscles in the critically ill. Am J Respir Crit Care Med. 2013 Jan 1;187(1):20-7. doi: 10.1164/rccm.201206- 1117CP. 37. Dres M, Goligher EC, Heunks LMA, Brochard LJ. Critical illness-associated diaphragm weakness. Intensive Care Med. 2017 Oct;43(10):1441-1452. doi: 10.1007/s00134-017-4928-4. 38. Qian Z, Yang M, Li L, Chen Y. Ultrasound assessment of diaphragmatic dysfunction as a predictor of weaning outcome from mechanical ventilation: a systematic review and meta-analysis. BMJ Open. 2018 Oct 4;8(9):e021189. doi: 10.1136/bmjopen-2017-021189. 39. Friedrich O, Reid MB, Van den Berghe G, Vanhorebeek I, Hermans G, Rich MM, Larsson L. The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill. Physiol Rev. 2015 Jul;95(3):1025-109. doi: 10.1152/physrev.00028.2014. 40. Kelmenson DA, Quan D, Moss M. What is the diagnostic accuracy of single nerve conduction studies and muscle ultrasound to identify critical illness polyneuromyopathy: a prospective cohort study. Crit Care. 2018 Dec 17;22(1):342. doi: 10.1186/s13054-018-2281-9. 41. Appleton RT, Kinsella J, Quasim T. The incidence of intensive care unit-acquired weakness syndromes: A systematic review. J Intensive Care Soc. 2015 May;16(2):126-136. doi: 10.1177/ 1751143714563016. 42. Formenti P, Umbrello M, Coppola S, Froio S, Chiumello D. Clinical review: peripheral muscular ultrasound in the ICU. Ann Intensive Care. 2019 May 17;9(1):57. doi: 10.1186/s13613-019-0531-x. 43. Joskova V, Patkova A, Havel E, Najpaverova S, Uramova D, Kovarik M, Zadak Z, Hronek M. Critical evaluation of muscle mass loss as a prognostic marker of morbidity in critically ill patients and methods for its determination. J Rehabil Med. 2018 Aug 22;50(8):696-704. doi: 10.2340/16501977-2368. 44. Witteveen E, Sommers J, Wieske L, Doorduin J, van Alfen N, Schultz MJ, van Schaik IN, Horn J, Verhamme C. Diagnostic accuracy of quantitative neuromuscular ultrasound for the diagnosis of intensive care unit - acquired weakness: a cross- sectional observational study. Ann Intensive Care. 2017 Dec;7(1):40. doi: 10.1186/s13613-017-0263- 8. 45. Derde S, Hermans G, Derese I, Güiza F, Hedström Y, Wouters PJ, Bruyninckx F, D'Hoore A, Larsson L, Van den Berghe G, Vanhorebeek I. Muscle atrophy and preferential loss of myosin in prolonged critically ill patients. Crit Care Med. 2012 Jan;40(1):79-89. doi: 10.1097/CCM.0b013 e31822d7c18. 46. Kackstein K, Teren A, Matsumoto Y, Mangner N, Möbius-Winkler S, Linke A, Schuler G, Punkt K, Adams V. Impact of angiotensin II on skeletal muscle metabolism and function in mice: contribution of IGF-1, Sirtuin-1 and PGC-1α. Acta Histochem. 2013 May;115(4):363-70. doi: 10.1016/j.acthis.2012.09.009. 47. Lokireddy S, Mouly V, Butler-Browne G, Gluckman PD, Sharma M, Kambadur R, McFarlane C. Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin- proteasome pathway-mediated loss of sarcomeric proteins. Am J Physiol Cell Physiol. 2011 Dec;301(6):C1316-24. doi: 10.1152/ajpcell.00114. 2011. Erratum in: Am J Physiol Cell Physiol. 2014 Dec 15;307(12):C1152. 48. van Gassel RJJ, Baggerman MR, van de Poll MCG. Metabolic aspects of muscle wasting during critical illness. Curr Opin Clin Nutr Metab Care. 2020 Mar;23(2):96-101. doi: 10.1097/MCO.000000000 0000628. 49. Sidiras G, Patsaki I, Karatzanos E, Dakoutrou M, Kouvarakos A, Mitsiou G, Routsi C, Stranjalis G, Nanas S, Gerovasili V. Long term follow-up of quality of life and functional ability in patients with ICU acquired Weakness - A post hoc analysis. J Crit Care. 2019 Oct;53:223-230. doi: 10.1016/j.jcrc. 2019.06.022. Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 13 - 50. Hermans G, Van Mechelen H, Clerckx B, Vanhullebusch T, Mesotten D, Wilmer A, Casaer MP, Meersseman P, Debaveye Y, Van Cromphaut S, Wouters PJ, Gosselink R, Van den Berghe G. Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis. Am J Respir Crit Care Med. 2014 Aug 15;190(4):410-20. doi: 10.1164/rccm.201312-2257OC. 51. Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, Hiesmayr M, Mayer K, Montejo JC, Pichard C, Preiser JC, van Zanten ARH, Oczkowski S, Szczeklik W, Bischoff SC. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019 Feb;38(1):48- 79. doi: 10.1016/j.clnu.2018.08.037. 52. Batt J, Herridge M, Dos Santos C. Mechanism of ICU-acquired weakness: skeletal muscle loss in critical illness. Intensive Care Med. 2017 Dec;43(12):1844-1846. doi: 10.1007/s00134-017- 4758-4. 53. Gandotra S, Lovato J, Case D, Bakhru RN, Gibbs K, Berry M, Files DC, Morris PE. Physical Function Trajectories in Survivors of Acute Respiratory Failure. Ann Am Thorac Soc. 2019 Apr;16(4):471-477. doi: 10.1513/AnnalsATS.2018 06-375OC. 54. Kalamgi RC, Larsson L. Mechanical Signaling in the Pathophysiology of Critical Illness Myopathy. Front Physiol. 2016 Feb 4;7:23. doi: 10.3389/fphys.2016.00023. 55. Sandri M. Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin- proteasome. Int J Biochem Cell Biol. 2013 Oct;45(10):2121-9. doi: 10.1016/j.biocel.2013.04 .023. 56. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 2013 Sep;280(17):4294-314. doi: 10.1111/febs.12253. 57. Vanhorebeek I, Gunst J, Derde S, Derese I, Boussemaere M, Güiza F, Martinet W, Timmermans JP, D'Hoore A, Wouters PJ, Van den Berghe G. Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. J Clin Endocrinol Metab. 2011 Apr;96(4):E633-45. doi: 10.1210/jc.2010-2563. 58. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, Chan DC. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010 Apr 16;141(2):280-9. doi: 10.1016/j.cell. 2010.02.026. 59. Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, Milan G, Masiero E, Del Piccolo P, Foretz M, Scorrano L, Rudolf R, Sandri M. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010 May 19;29(10):1774-85. doi: 10.1038/emboj.2010.60. 60. Latronico N, Friedrich O. Electrophysiological investigations of peripheral nerves and muscles: a method for looking at cell dysfunction in the critically ill patients. Crit Care. 2019 Jan 29;23(1):33. doi: 10.1186/s13054-019-2331-y. 61. Rudolf R, Deschenes MR, Sandri M. Neuromuscular junction degeneration in muscle wasting. Curr Opin Clin Nutr Metab Care. 2016 May;19(3):177-81. doi: 10.1097/MCO.000000000 0000267. 62. Weber-Carstens S, Deja M, Koch S, Spranger J, Bubser F, Wernecke KD, Spies CD, Spuler S, Keh D. Risk factors in critical illness myopathy during the early course of critical illness: a prospective observational study. Crit Care. 2010;14(3):R119. doi: 10.1186/cc9074. 63. Baldwin CE, Bersten AD. Myopathic characteristics in septic mechanically ventilated patients. Curr Opin Clin Nutr Metab Care. 2015 May;18(3):240-7. doi: 10.1097/MCO.0000000000 000165. 64. Tuttle CSL, Thang LAN, Maier AB. Markers of inflammation and their association with muscle strength and mass: A systematic review and meta- analysis. Ageing Res Rev. 2020 Dec;64:101185. doi: 10.1016/j.arr.2020.101185. 65. Shepherd SJ, Newman R, Brett SJ, Griffith DM; Enhancing Rehabilitation After Critical Illness Programme Study Investigators. Pharmacological Therapy for the Prevention and Treatment of Weakness After Critical Illness: A Systematic Review. Crit Care Med. 2016 Jun;44(6):1198-205. doi: 10.1097/CCM.0000000000001652. 66. Walsh TS. Pharmacologic Therapies for ICU- Acquired Weakness: A Long Road Ahead. Crit Care Med. 2016 Jun;44(6):1245-6. doi: 10.1097/CCM.0000000000001705. 67. van Zanten ARH, De Waele E, Wischmeyer PE. Nutrition therapy and critical illness: practical guidance for the ICU, post-ICU, and long-term convalescence phases. Crit Care. 2019 Nov 21;23(1):368. doi: 10.1186/s13054-019-2657-5. 68. Allingstrup MJ, Kondrup J, Wiis J, Claudius C, Pedersen UG, Hein-Rasmussen R, Bjerregaard MR, Steensen M, Jensen TH, Lange T, Madsen MB, Møller MH, Perner A. Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomised, outcome assessor-blinded EAT-ICU trial. Intensive Care Med. 2017 Nov;43(11):1637-1647. doi: 10.1007 /s00134-017-4880-3. 69. Ferrie S, Allman-Farinelli M, Daley M, Smith K. Protein Requirements in the Critically Ill: A Randomized Controlled Trial Using Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2016 Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 14 - Aug;40(6):795-805. doi: 10.1177/014860711561 8449. 70. van Zanten ARH, Petit L, De Waele J, Kieft H, de Wilde J, van Horssen P, Klebach M, Hofman Z. Very high intact-protein formula successfully provides protein intake according to nutritional recommendations in overweight critically ill patients: a double-blind randomized trial. Crit Care. 2018 Jun 12;22(1):156. doi: 10.1186/s13054-018- 2070-5. 71. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011 Aug 11;365(6):506-17. doi: 10.1056/NEJMoa1102662. 72. Hermans G, Casaer MP, Clerckx B, Güiza F, Vanhullebusch T, Derde S, Meersseman P, Derese I, Mesotten D, Wouters PJ, Van Cromphaut S, Debaveye Y, Gosselink R, Gunst J, Wilmer A, Van den Berghe G, Vanhorebeek I. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med. 2013 Oct;1(8):621-629. doi: 10.1016/S2213- 2600(13)70183-8. 73. Sundström-Rehal M, Tardif N, Rooyackers O. Can exercise and nutrition stimulate muscle protein gain in the ICU patient? Curr Opin Clin Nutr Metab Care. 2019 Mar;22(2):146-151. doi: 10.1097 /MCO.0000000000000548. 74. de Jonghe B, Lacherade JC, Sharshar T, Outin H. Intensive care unit-acquired weakness: risk factors and prevention. Crit Care Med. 2009 Oct;37(10 Suppl):S309-15. doi: 10.1097/CCM.0b013e3181b6 e64c. 75. Fan E. Critical illness neuromyopathy and the role of physical therapy and rehabilitation in critically ill patients. Respir Care. 2012 Jun;57(6):933-44; discussion 944-6. doi: 10.4187/respcare.01634. 76. Chen YW, Gregory CM, Scarborough MT, Shi R, Walter GA, Vandenborne K. Transcriptional pathways associated with skeletal muscle disuse atrophy in humans. Physiol Genomics. 2007 Nov 14;31(3):510-20. doi: 10.1152/physiolgenomics. 00115.2006. 77. Booth FW. Effect of limb immobilization on skeletal muscle. J Appl Physiol Respir Environ Exerc Physiol. 1982 May;52(5):1113-8. doi: 10.1152/jappl.1982.52.5.1113. 78. Adkins DL, Boychuk J, Remple MS, Kleim JA. Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cord. J Appl Physiol (1985). 2006 Dec;101(6):1776-82. doi: 10.1152/japplphysiol.00515.2006. 79. Folland JP, Williams AG. The adaptations to strength training : morphological and neurological contributions to increased strength. Sports Med. 2007;37(2):145-68. doi: 10.2165/00007256-2007 37020-00004. 80. Matta Mello Portugal E, Cevada T, Sobral Monteiro-Junior R, Teixeira Guimarães T, da Cruz Rubini E, Lattari E, Blois C, Camaz Deslandes A. Neuroscience of exercise: from neurobiology mechanisms to mental health. Neuropsychobiology. 2013;68(1):1-14. doi: 10.1159/000350946. 81. Rivera-Brown AM, Frontera WR. Principles of exercise physiology: responses to acute exercise and long-term adaptations to training. PM R. 2012 Nov;4(11):797-804. doi: 10.1016/j.pmrj.2012.10. 007 82. Ogasawara R, Jensen TE, Goodman CA, Hornberger TA. Resistance Exercise-Induced Hypertrophy: A Potential Role for Rapamycin- Insensitive mTOR. Exerc Sport Sci Rev. 2019 Jul;47(3):188-194. doi: 10.1249/JES.0000000000 000189. 83. Hashem MD, Nelliot A, Needham DM. Early Mobilization and Rehabilitation in the ICU: Moving Back to the Future. Respir Care. 2016 Jul;61(7):971-9. doi: 10.4187/respcare.04741. 84. Saitoh M, Ishida J, Doehner W, von Haehling S, Anker MS, Coats AJS, Anker SD, Springer J. Sarcopenia, cachexia, and muscle performance in heart failure: Review update 2016. Int J Cardiol. 2017 Jul 1;238:5-11. doi: 10.1016/j.ijcard. 2017.03.155. 85. Anekwe DE, Biswas S, Bussières A, Spahija J. Early rehabilitation reduces the likelihood of developing intensive care unit-acquired weakness: a systematic review and meta-analysis. Physiotherapy. 2020 Jun;107:1-10. doi: 10.1016/ j.physio.2019.12.004. 86. Hickmann CE, Castanares-Zapatero D, Deldicque L, Van den Bergh P, Caty G, Robert A, Roeseler J, Francaux M, Laterre PF. Impact of Very Early Physical Therapy During Septic Shock on Skeletal Muscle: A Randomized Controlled Trial. Crit Care Med. 2018 Sep;46(9):1436-1443. doi: 10.1097/CCM.0000000000003263. 87. Wageck B, Nunes GS, Silva FL, Damasceno MC, de Noronha M. Application and effects of neuromuscular electrical stimulation in critically ill patients: systematic review. Med Intensiva. 2014 Oct;38(7):444-54. doi: 10.1016/j.medin.2013.12. 003. 88. Zayed Y, Kheiri B, Barbarawi M, Chahine A, Rashdan L, Chintalapati S, Bachuwa G, Al-Sanouri I. Effects of neuromuscular electrical stimulation in critically ill patients: A systematic review and meta- analysis of randomised controlled trials. Aust Crit Care. 2020 Mar;33(2):203-210. doi: 10.1016/ j.aucc.2019.04.003. Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 15 - 89. Fuke R, Hifumi T, Kondo Y, Hatakeyama J, Takei T, Yamakawa K, Inoue S, Nishida O. Early rehabilitation to prevent postintensive care syndrome in patients with critical illness: a systematic review and meta-analysis. BMJ Open. 2018 May 5;8(5):e019998. doi: 10.1136/bmjopen- 2017-019998. 90. Fossat G, Baudin F, Courtes L, Bobet S, Dupont A, Bretagnol A, Benzekri-Lefèvre D, Kamel T, Muller G, Bercault N, Barbier F, Runge I, Nay MA, Skarzynski M, Mathonnet A, Boulain T. Effect of In-Bed Leg Cycling and Electrical Stimulation of the Quadriceps on Global Muscle Strength in Critically Ill Adults: A Randomized Clinical Trial. JAMA. 2018 Jul 24;320(4):368-378. doi: 10.1001/jama.2018.9592. 91. Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8258-63. doi: 10.1073/pnas.1432869 100. 92. Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin- converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2281-90. doi: 10.1152/ajpheart.00618.2005. 93. Iwata M, Cowling RT, Gurantz D, Moore C, Zhang S, Yuan JX, Greenberg BH. Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2356-63. doi: 10.1152/ajpheart.003 17.2005. 94. Tallant EA, Ferrario CM, Gallagher PE. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1560-6. doi: 10.1152/ajpheart.00941. 2004. 95. Acuña MJ, Pessina P, Olguin H, Cabrera D, Vio CP, Bader M, Muñoz-Canoves P, Santos RA, Cabello- Verrugio C, Brandan E. Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. Hum Mol Genet. 2014 Mar 1;23(5):1237-49. doi: 10.1093/hmg/ddt514. 96. Echeverría-Rodríguez O, Del Valle-Mondragón L, Hong E. Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo. Peptides. 2014 Jan;51:26-30. doi: 10.1016/j.peptides.2013.10.022. 97. Muñoz MC, Giani JF, Burghi V, Mayer MA, Carranza A, Taira CA, Dominici FP. The Mas receptor mediates modulation of insulin signaling by angiotensin-(1-7). Regul Pept. 2012 Aug 20;177(1-3):1-11. doi: 10.1016/j.regpep.2012.04. 001. 98. Cabello-Verrugio C, Rivera JC, Garcia D. Skeletal muscle wasting: new role of nonclassical renin- angiotensin system. Curr Opin Clin Nutr Metab Care. 2017 May;20(3):158-163. doi: 10.1097/ MCO.0000000000000361. 99. Morales MG, Abrigo J, Acuña MJ, Santos RA, Bader M, Brandan E, Simon F, Olguin H, Cabrera D, Cabello-Verrugio C. Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas. Dis Model Mech. 2016 Apr;9(4):441-9. doi: 10.1242/dmm.023390. 100. Cisternas F, Morales MG, Meneses C, Simon F, Brandan E, Abrigo J, Vazquez Y, Cabello-Verrugio C. Angiotensin-(1-7) decreases skeletal muscle atrophy induced by angiotensin II through a Mas receptor-dependent mechanism. Clin Sci (Lond). 2015 Mar;128(5):307-19. doi: 10.1042/CS2014 0215. 101. Meneses C, Morales MG, Abrigo J, Simon F, Brandan E, Cabello-Verrugio C. The angiotensin- (1-7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice. Pflugers Arch. 2015 Sep;467(9):1975-84. doi: 10.1007/s00424- 014-1617-9. 102. Organization, W. H. Coronavirus Disease (COVID- 19) Pandemic Situation Reports. accessed on April 27, 2021 (2021). 103. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056 /NEJMoa2002032. 104. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Aug 25;324(8):782-793. doi: 10.1001/jama.2020.12839. 105. Pinzon RT, Wijaya VO, Buana RB, Al Jody A, Nunsio PN. Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis. Front Neurol. 2020 May 29;11:565. doi: 10.3389/fneur.2020.00565. 106. Wang JL, Wang JT, Yu CJ, Chen YC, Hsueh PR, Hsiao CH, Kao CL, Chang SC, Yang PC. Rhabdomyolysis associated with probable SARS. Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 16 - Am J Med. 2003 Oct 1;115(5):421-2. doi: 10.1016/s0002-9343(03)00448-0. 107. Nassar MS, Bakhrebah MA, Meo SA, Alsuabeyl MS, Zaher WA. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: epidemiology, pathogenesis and clinical characteristics. Eur Rev Med Pharmacol Sci. 2018 Aug;22(15):4956-4961. doi: 10.26355/eurrev_2018 08_15635. 108. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213- 2600(20)30079-5. Epub 2020 Feb 24. Erratum in: Lancet Respir Med. 2020 Apr;8(4):e26. 109. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin- Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao- Martinez AF, Paniz-Mondolfi A, Lagos-Grisales GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan AA, Harapan H, Dhama K, Nishiura H, Kataoka H, Ahmad T, Sah R; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Electronic address: https:// www. lancovid.org. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020 Mar-Apr;34:101623. doi: 10.1016/j.tmaid. 2020.101623. 110. Candan SA, Elibol N, Abdullahi A. Consideration of prevention and management of long-term consequences of post-acute respiratory distress syndrome in patients with COVID-19. Physiother Theory Pract. 2020 Jun;36(6):663-668. doi: 10.1080/09593985.2020.1766181. 111. Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, Greninger AL, Pipavath S, Wurfel MM, Evans L, Kritek PA, West TE, Luks A, Gerbino A, Dale CR, Goldman JD, O'Mahony S, Mikacenic C. Covid-19 in Critically Ill Patients in the Seattle Region - Case Series. N Engl J Med. 2020 May 21;382(21):2012-2022. doi: 10.1056/ NEJMoa2004500. 112. Bagnato S, Boccagni C, Marino G, Prestandrea C, D'Agostino T, Rubino F. Critical illness myopathy after COVID-19. Int J Infect Dis. 2020 Oct;99:276- 278. doi: 10.1016/j.ijid.2020.07.072. 113. Madia F, Merico B, Primiano G, Cutuli SL, De Pascale G, Servidei S. Acute myopathic quadriplegia in patients with COVID-19 in the intensive care unit. Neurology. 2020 Sep 15;95(11):492-494. doi: 10.1212/WNL.00000000 00010280. 114. Versace V, Sebastianelli L, Ferrazzoli D, Saltuari L, Kofler M, Löscher W, Uncini A. Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation? Front Neurol. 2021 Jan 29;12:625144. doi: 10.3389/fneur.2021. 625144. 115. Rodriguez B, Branca M, Gutt-Will M, Roth M, Söll N, Nansoz S, Cameron DR, Tankisi H, Tan SV, Bostock H, Raabe A, Schefold JC, Jakob SM, Z'Graggen WJ. Development and early diagnosis of critical illness myopathy in COVID-19 associated acute respiratory distress syndrome. J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1883-1895. doi: 10.1002/jcsm.12989. 116. Cabañes-Martínez L, Villadóniga M, González- Rodríguez L, Araque L, Díaz-Cid A, Ruz-Caracuel I, Pian H, Sánchez-Alonso S, Fanjul S, Del Álamo M, Regidor I. Neuromuscular involvement in COVID-19 critically ill patients. Clin Neurophysiol. 2020 Dec;131(12):2809-2816. doi: 10.1016/j.clinph.2020.09.017. 117. Tankisi H, Tankisi A, Harbo T, Markvardsen LK, Andersen H, Pedersen TH. Critical illness myopathy as a consequence of Covid-19 infection. Clin Neurophysiol. 2020 Aug;131(8):1931-1932. doi: 10.1016/j.clinph.2020.06.003. 118. Van Aerde N, Van den Berghe G, Wilmer A, Gosselink R, Hermans G; COVID-19 Consortium. Intensive care unit acquired muscle weakness in COVID-19 patients. Intensive Care Med. 2020 Nov;46(11):2083-2085. doi: 10.1007/s00134-020- 06244-7. 119. Hojyo S, Uchida M, Tanaka K, Hasebe R, Tanaka Y, Murakami M, Hirano T. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen. 2020 Oct 1;40:37. doi: 10.1186/ s41232-020-00146-3. 120. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol. 2020 May;20(5):277. doi: 10.1038/s41577-020-0305-6. 121. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, Kritas SK. Induction of pro- inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020 March- April,;34(2):327-331. doi: 10.23812/CONTI-E. 122. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140- 6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. 123. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 17 - from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020 Mar 17;94(7):e00127-20. doi: 10.1128 /JVI.00127-20. 124. VanderVeen BN, Fix DK, Montalvo RN, Counts BR, Smuder AJ, Murphy EA, Koh HJ, Carson JA. The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6. Exp Physiol. 2019 Mar;104(3):385- 397. doi: 10.1113/EP087429. 125. Rudroff T, Fietsam AC, Deters JR, Bryant AD, Kamholz J. Post-COVID-19 Fatigue: Potential Contributing Factors. Brain Sci. 2020 Dec 19;10(12):1012. doi: 10.3390/brainsci10121012. 126. Chan JF, Zhang AJ, Yuan S, Poon VK, Chan CC, Lee AC, Chan WM, Fan Z, Tsoi HW, Wen L, Liang R, Cao J, Chen Y, Tang K, Luo C, Cai JP, Kok KH, Chu H, Chan KH, Sridhar S, Chen Z, Chen H, To KK, Yuen KY. Simulation of the Clinical and Pathological Manifestations of Coronavirus Disease 2019 (COVID-19) in a Golden Syrian Hamster Model: Implications for Disease Pathogenesis and Transmissibility. Clin Infect Dis. 2020 Dec 3;71(9):2428-2446. doi: 10.1093/cid/ ciaa325. 127. McNab F, Mayer-Barber K, Sher A, Wack A, O'Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015 Feb;15(2):87-103. doi: 10.1038/nri3787. 128. Gonzalez A, Orozco-Aguilar J, Achiardi O, Simon F, Cabello-Verrugio C. SARS-CoV-2/Renin- Angiotensin System: Deciphering the Clues for a Couple with Potentially Harmful Effects on Skeletal Muscle. Int J Mol Sci. 2020 Oct 24;21(21):7904. doi: 10.3390/ijms21217904. 129. Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Proinflammatory effects of glucose and anti- inflammatory effect of insulin: relevance to cardiovascular disease. Am J Cardiol. 2007 Feb 19;99(4A):15B-26B. doi: 10.1016/j.amjcard.2006. 11.003. 130. Ghazi L, Drawz P. Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy. F1000Res. 2017 Mar 21;6:F1000 Faculty Rev-297. doi: 10.12688/f1000research. 9692.1. 131. Warner FJ, Lew RA, Smith AI, Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem. 2005 Nov 25;280(47):39353-62. doi: 10.1074/jbc.M508914200. 132. Leung TW, Wong KS, Hui AC, To KF, Lai ST, Ng WF, Ng HK. Myopathic changes associated with severe acute respiratory syndrome: a postmortem case series. Arch Neurol. 2005 Jul;62(7):1113-7. doi: 10.1001/archneur.62.7.1113. 133. Finsterer J, Scorza FA. SARS-CoV-2-associated critical ill myopathy or pure toxic myopathy? Int J Infect Dis. 2020 Dec;101:56. doi: 10.1016/j.ijid.2020.09.1463. Epub 2020 Sep 28. 134. Andalib S, Biller J, Di Napoli M, Moghimi N, McCullough LD, Rubinos CA, O'Hana Nobleza C, Azarpazhooh MR, Catanese L, Elicer I, Jafari M, Liberati F, Camejo C, Torbey M, Divani AA. Peripheral Nervous System Manifestations Associated with COVID-19. Curr Neurol Neurosci Rep. 2021 Feb 14;21(3):9. doi: 10.1007/s11910- 021-01102-5. 135. Pinal-Fernandez I, Casal-Dominguez M, Mammen AL. Immune-Mediated Necrotizing Myopathy. Curr Rheumatol Rep. 2018 Mar 26;20(4):21. doi: 10.1007/s11926-018-0732-6. 136. Totsuka M, Nakaji S, Suzuki K, Sugawara K, Sato K. Break point of serum creatine kinase release after endurance exercise. J Appl Physiol (1985). 2002 Oct;93(4):1280-6. doi: 10.1152/japplphysiol. 01270.2001. 137. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun 1;77(6):683-690. doi: 10.1001/jamaneurol.2020.1127. 138. Murthy S, Gomersall CD, Fowler RA. Care for Critically Ill Patients With COVID-19. JAMA. 2020 Apr 21;323(15):1499-1500. doi: 10.1001/ jama.2020.3633. 139. Wiertz CMH, Vints WAJ, Maas GJCM, Rasquin SMC, van Horn YY, Dremmen MPM, Hemmen B, Verbunt JA. COVID-19: Patient Characteristics in the First Phase of Postintensive Care Rehabilitation. Arch Rehabil Res Clin Transl. 2021 Jun;3(2):100108. doi: 10.1016/j.arrct.2021.100108. 140. Simpson R, Robinson L. Rehabilitation After Critical Illness in People With COVID-19 Infection. Am J Phys Med Rehabil. 2020 Jun;99(6):470-474. doi: 10.1097/PHM.000000000 0001443. 141. Liu K, Nakamura K, Kudchadkar SR, Katsukawa H, Nydahl P, Ely EW, Takahashi K, Inoue S, Nishida O. Mobilization and Rehabilitation Practice in ICUs During the COVID-19 Pandemic. J Intensive Care Med. 2022 Apr 27:8850666221097644. doi: 10.1177/08850666 221097644. 142. Smith V, Devane D, Nichol A, Roche D. Care bundles for improving outcomes in patients with COVID-19 or related conditions in intensive care - a rapid scoping review. Cochrane Database Syst Rev. 2020 Dec 21;12(12):CD013819. doi: 10.1002/14651858.CD013819. Intensive care unit-acquired weakness in COVID-2019 Eur J Transl Myol 32 (3): 10511, 2022 doi: 10.4081/ejtm.2022.10511 - 18 - 143. Li J. Rehabilitation management of patients with COVID-19: lessons learned from the first experience in China. Eur J Phys Rehabil Med. 2020 Jun;56(3):335-338. doi: 10.23736/S1973- 9087.20.06292-9. 144. Pancera S, Galeri S, Porta R, Pietta I, Bianchi LNC, Carrozza MC, Villafañe JH. Feasibility and Efficacy of the Pulmonary Rehabilitation Program in a Rehabilitation Center: CASE REPORT OF A YOUNG PATIENT DEVELOPING SEVERE COVID-19 ACUTE RESPIRATORY DISTRESS SYNDROME. J Cardiopulm Rehabil Prev. 2020 Jul;40(4):205-208. doi: 10.1097/HCR.0000000000 000529. 145. Medrinal C, Prieur G, Bonnevie T, Gravier FE, Mayard D, Desmalles E, Smondack P, Lamia B, Combret Y, Fossat G. Muscle weakness, functional capacities and recovery for COVID-19 ICU survivors. BMC Anesthesiol. 2021 Mar 2;21(1):64. doi: 10.1186/s12871-021-01274-0. 146. Needham E, Newcombe V, Michell A, Thornton R, Grainger A, Anwar F, Warburton E, Menon D, Trivedi M, Sawcer S. Mononeuritis multiplex: an unexpectedly frequent feature of severe COVID-19. J Neurol. 2021 Aug;268(8):2685-2689. doi: 10.1007/s00415-020-10321-8. 147. Lobanov AA, Irina A Grishechkina, Andronov SV, Gleb N Barashkov, Andrey I Popov, Anatoliy D Fesyun, Elena P Ivanova, Maccarone MC, Stefano Masiero. Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes? Eur J Transl Myol. 2022 Jul 14. doi: 10.4081/ejtm.2022.10698. 148. López-Viñas L, Vega-Villar J, Rocío-Martín E, García-García P, De La Rosa Santiago E, Galván- Román JM, Wix-Ramos R. Diaphragm impairment in patients admitted for severe COVID-19. Eur J Transl Myol. 2022 Jun 21;32(2):10460. doi: 10.4081/ejtm.2022.10460. 149. Kouhpayeh H. Clinical features predicting COVID- 19 mortality risk. Eur J Transl Myol. 2022 Apr 12;32(2):10268. doi: 10.4081/ejtm.2022.10268. 150. Finsterer J, Scorza FA, Scorza CA, Fiorini AC. Consider differentials before diagnosing COVID- 19 associated polyradiculitis. Eur J Transl Myol. 2022 Jan 5;32(1). doi: 10.4081/ejtm.2022.10111. 151. Amato A, Messina G, Feka K, Genua D, Ragonese P, Kostrzewa-Nowak D, Fischetti F, Iovane A, Proia P. Taopatch® combined with home-based training protocol to prevent sedentary lifestyle and biochemical changes in MS patients during COVID-19 pandemic. Eur J Transl Myol. 2021 Aug 31;31(3):9877. doi: 10.4081/ejtm.2021.9877. 152. Gilmutdinova IR, Kolyshenkov VA, Lapickaya KA, Trepova AS, Vasileva VA, Prosvirnin AN, Marchenkova LA, Terentev KV, Yakovlev MY, Rachin AP, Fesyun AD, Reverchuk IV. Telemedicine platform COVIDREHAB for remote rehabilitation of patients after COVID-19. Eur J Transl Myol. 2021 May 13;31(2):9783. doi: 10.4081/ejtm.2021.9783. 153. Doro M, Ferreira Marques Y, Cantarinho de Lima HF, De Oliveira Caccalano W, De Oliveira Nessi AA, Chagas Caperuto É, De Oliveira Alonso D, Leite Portella D. Physical activity and medication in Brazilians suffering with non-communicable diseases in quarantine by COVID-19. Eur J Transl Myol. 2021 Apr 29;31(2):9772. doi: 10.4081/ejtm.2021.9772. 154. Carraro U, Albertin G, Martini A, Giuriati W, Guidolin D, Masiero S, Kern H, Hofer C, Marcante A, Ravara B. To contrast and reverse skeletal muscle weakness by Full-Body In-Bed Gym in chronic COVID-19 pandemic syndrome. Eur J Transl Myol. 2021 Mar 26;31(1):9641. doi: 10.4081 /ejtm.2021.9641. 155. Moro T, Paoli A. When COVID-19 affects muscle: effects of quarantine in older adults. Eur J Transl Myol. 2020 Jun 17;30(2):9069. doi: 10.4081 /ejtm.2019.9069. 156. Angelini C, Siciliano G. Neuromuscular diseases and Covid-19: Advices from scientific societies and early observations in Italy. Eur J Transl Myol. 2020 Jun 22;30(2):9032. doi: 10.4081/ejtm.2019.9032. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submission: April 12, 2022 Revision received: August 08, 2022 Accepted for publication: August 08, 2022 Risk factors for ICU-acquired weakness Conclusions and perspectives