Intensive care unit-acquired weakness: A review from molecular mechanisms to its impact in COVID-2019

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.

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

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.