Muscle weakness after critical illness: unravelling biological mechanisms and clinical hurdles

Abstract

Survivors of intensive care unit (ICU) are increasingly numerous because of better hospital care. However, several consequences of an ICU stay, known as post-intensive care syndrome, worsen long-term prognoses. A predominant feature in survivors is reduced muscle strength, mass, and physical function. This leads to lower exercise capacity, long-lasting physical disability, higher mortality risk, and subsequent health costs. While ICU-acquired muscle weakness has been extensively studied these past decades, underlying mechanisms of post-ICU muscle weakness remain poorly understood, and there is still no evidence-based treatment for improving long-term physical outcomes. One hypothesis, among others, could be that the pathophysiology is dynamic over time, differing between the acute ICU and post-ICU recovery periods. This narrative review aims to address the clinical, physiological and biological determinants of persistent muscle dysfunction in ICU survivors, with particular attention to the molecular, cellular and systemic mechanisms involved. Specifically, pre-ICU health factors such as obesity and sarcopenia, ICU-related complications and treatments, and post-ICU management all influence recovery. Dysfunctions in the neuroendocrine, vascular, neurological, and muscle systems contribute as physiological determinants of the muscle weakness. Complex and multifaceted biological mechanisms drive the post-ICU muscle dysfunction with mitochondrial and autophagy dysfunction, epigenetic modifications, cellular senescence, muscle inflammation with altered cell-cell communication, including dysfunction of immune cells, stem cell exhaustion and extracellular matrix remodelling. The review also sheds light on new and innovative therapeutic approaches and discusses future research directions. Emphasis is placed on the potential for multi-approach treatments that integrate nutritional, physical, and biological interventions. Addressing these aspects in a holistic and dynamic manner, from ICU to post-ICU phases, may provide avenues for mitigating the long-term burden of muscle weakness and physical disability in ICU survivors.

Keywords: ICU survivors; Long-term outcome; Muscle weakness; Post-ICU syndrome; Translational research.

Fig. 1

Clinical factors influencing the post-ICU physical recovery. ARDS: acute respiratory distress syndrome, ICU: Intensive Care Unit, ICUAW: ICU acquired weakness, NMBA: neuromuscular blocking agents, QOF: quality of life

Fig. 2

Putative and established post-ICU clinical factors influencing physical recovery. Factors related to physical health are shown in red (left), mental health in blue (upper right), and other factors in yellow (lower right). PICS: post-intensive care syndrome

Fig. 3

Physiological determinants of the post-ICU muscle weakness at the system level. Further research directions are highlighted in italics. T3: triiodothyronine, rT3: inactive reverse T3, CNS: Central nervous system, PNS: peripheral nervous system, NMJ: neuromuscular junction, RCT: randomized controlled trial

Fig. 4

Biological mechanisms underlying post-ICU muscle weakness at the cellular and molecular levels: nuclear and organelle dysfunction. Further research directions are highlighted in italics. ICU: intensive care unit, UPS: ubiquitin proteasome system

Fig. 5

Biological mechanisms underlying post-ICU muscle weakness at the cellular and molecular levels: alteration of intercellular communication. Further research directions are highlighted in italics. DAMPs: damage-associated molecular patterns, NK cells: natural killer cells, miRNA: micro-RNA