ICU-Acquired Weakness: From Neuro-Metabolic Injury to Long-Term Cognitive-Motor Deficits A Neurocritical Perspective

Abstract

Background: Intensive Care Unit–acquired weakness (ICU-AW), encompassing Critical Illness Polyneuropathy (CIP) and Critical Illness Myopathy (CIM), is a debilitating neuromuscular syndrome resulting from systemic inflammation and metabolic dysregulation. From a neurocritical standpoint, ICU-AW is one component of Post-Intensive Care Syndrome (PICS), strongly correlated with persistent cognitive and psychiatric dysfunction. Despite decades of investigation, the lack of validated, actionable diagnostic criteria and targeted neuroprotective therapies represents a major failure in critical care.

Objective: To critically synthesise and evaluate the progress (2014–2025) in understanding the brain-nerve-muscle axis injury in ICU-AW, assessing the clinical translational potential of molecular diagnostics, and outlining the intractable challenges in resolving the long-term cognitive-motor deficits from a neurocritical perspective.

Methods: This is a definitive narrative review integrating high-impact systematic reviews, consensus statements, and prospective observational cohorts that focused on the neurophysiological, molecular, and long-term functional outcomes of ICU-AW. The selection prioritized literature that defined paradigm shifts in diagnostics, mechanisms, and the link between CIP/CIM and global PICS outcomes.

Results: Neurocritical advances confirm that systemic inflammation (driven by cytokines like IL-6) and acute metabolic stress induce profound mitochondrial dysfunction in both peripheral nerves and myofibres. Novel biomarkers, particularly Growth Differentiation Factor-15 (GDF-15), have emerged as highly sensitive predictors of both muscle atrophy and poor survival, suggesting a role in risk stratification. Furthermore, electrophysiological differentiation of CIP from CIM remains the cornerstone of peripheral prognostication. Critically, the long-term literature unambiguously demonstrates that ICU-AW significantly contributes to the chronic cognitive and psychiatric morbidity of PICS, yet rehabilitation models remain largely physical-centric, failing to integrate the neurocognitive deficits.

Conclusion: ICU-AW represents a complex neuro-metabolic failure that acts as a powerful predictor for the global burden of PICS. The immediate clinical imperative is the validation and integration of biomarker panels and advanced neurophysiological techniques to facilitate precision neuro-rehabilitation that simultaneously targets both the peripheral neuromuscular deficit and the persistent central cognitive impairment.