What is the pathophysiology of Intensive Care Unit (ICU) acquired weakness?

From the Guidelines

ICU-acquired weakness (ICUAW) is primarily caused by a complex interplay of muscle and nerve damage from systemic inflammation, prolonged immobility, and medications commonly used in the ICU, such as corticosteroids and neuromuscular blocking agents, as supported by recent studies 1. The pathophysiology of ICUAW involves multiple factors, including:

• Muscle proteolysis, dysfunction of the contractile elements, mitochondrial dysfunction, and oxidative stress, which are exacerbated by systemic inflammation and prolonged immobility 1
• Ventilator-induced diaphragm dysfunction (VIDD) and extra-diaphragmatic muscle weakness, which can occur even in the absence of sepsis and does not require a systemic inflammatory state 1
• Disuse atrophy, with muscle mass decreasing by up to 5% daily in critically ill patients, as reported in studies on early mobilisation in the ICU 1
• Critical illness polyneuropathy (nerve damage) and critical illness myopathy (muscle damage), which collectively manifest as diffuse, symmetrical weakness that primarily affects limb and respiratory muscles, often delaying recovery and rehabilitation 1 Key factors contributing to ICUAW include:
• Sepsis, which activates catabolic pathways and causes mitochondrial dysfunction
• Prolonged immobility, which leads to disuse atrophy and muscle mass loss
• Medications, such as corticosteroids and neuromuscular blocking agents, which can exacerbate muscle weakness
• Hyperglycemia, which damages peripheral nerves and muscles through oxidative stress and microvascular injury
• Malnutrition, which compromises muscle integrity by limiting protein availability for repair
• Multiple organ failure, which creates a catabolic state with impaired oxygen delivery to tissues.

From the Research

Pathophysiology of ICU Acquired Weakness

The pathophysiology of ICU acquired weakness (ICUAW) is complex and multifactorial, involving various mechanisms that contribute to muscle wasting, impaired contractility, and neuropathy. Some of the key mechanisms include:

• Muscle protein degradation through the ubiquitin proteasome system and dysregulated autophagy 2
• Preferential loss of myosin, a distinct feature of ICUAW 2
• Inflammation, steroid use, and paralysis, which can contribute to the development of ICUAW 2, 3
• Complex structural and functional alterations within myofibers and neurons 3
• Disuse atrophy from prolonged immobility, which can contribute to muscle weakness 4

Risk Factors

Several risk factors have been identified as contributing to the development of ICUAW, including:

• Age, weight, and comorbidities 3
• Illness severity, organ failure, and exposure to certain drugs 3
• Immobility and other intensive care-related factors 3
• Hyperglycemia, which may be an important risk factor for critical illness neuromyopathy (CINM) 4
• Corticosteroids and neuromuscular blocking agents, which have been implicated in CINM, although the evidence is inconsistent 4

Diagnostic Tools

Clinical and electrophysiological tools are used to diagnose ICUAW, each with its own advantages and limitations 3. These tools can help to separate ICUAW from other disorders and identify possible treatment strategies.

Consequences

ICUAW can have significant consequences, including:

• Increased risk of in-ICU, in-hospital, and long-term mortality 3
• Prolonged duration of mechanical ventilation and hospitalization 3
• Increased healthcare-related costs and likelihood of prolonged care in rehabilitation centers 3
• Reduced physical function and quality of life in the long term 3