Functional and muscle recovery after critical illness: current and future nutritional, physical and metabolic strategies

Despite gains in survival, recovery from the physical consequences of critical illness has not improved. ICU-acquired weakness (ICUAW) develops in roughly half of mechanically ventilated patients and causes durable muscle dysfunction, reduced exercise capacity and curtailed autonomy that persist for years, with impact on quality of life and healthcare utilization. The diagnostic framework remains limited: the Medical Research Council sum score is informative at ICU discharge but loses sensitivity during convalescence, and capturing the full deficit requires multidimensional assessment of muscle function, physical function and quality of life, in line with the PRACTICE core outcome set and the conceptual continuum from acute ICUAW to post-ICU sarcopenia. Two pillars structure current therapy — nutritional support and physical rehabilitation. Nutritional support: avoidance of severe hyperglycaemia is established, but large RCTs consistently show that escalating acute-phase calorie or protein delivery does not improve, and may worsen, outcomes, particularly in vulnerable subgroups such as those with acute kidney injury. This paradox is explained by the concept of feeding responsiveness: anabolic resistance blunts muscle protein synthesis in a way that cannot be overcome by dose escalation; as inflammation and metabolism recover, a catabolic-to-anabolic transition restores nutrient utilization, and dynamic biomarkers (urea trajectory, phosphate kinetics, insulin resistance index) may identify the catabolic-to-anabolic transition at the bedside. These insights translate into a four-phase individualized strategy spanning permissive underfeeding with conditional escalation, standard targets, protocol-guided individualized support during early (in-hospital) convalescence, and enriched nutrition with structured dietitian-led follow-up after discharge. Physical rehabilitation: early mobilization improves short-term outcomes — muscle strength at ICU discharge, duration of mechanical ventilation and length of stay — but recent trials, notably TEAM, show that augmented-dose mobilization does not translate into long-term functional benefit and may harm identifiable subgroups, mirroring the nutritional paradox. The concept of exercise responsiveness — captured by clinical signatures of non-response (diabetes, low achievable ICU Mobility Scale, illness severity) and molecular determinants (persistent inflammation, mitochondrial and proteostatic dysfunction) — supports a four-phase physiology-informed prescription, from safety-first early mobilization to home-based adapted physical activity sustaining a continuous training stimulus. Beyond these two pillars, emerging metabolic support offers complementary, biology-targeted interventions still under preclinical and translational development. These include alternative oxidative substrates, autophagy and mitochondrial modulators, and anabolic agents — forcing anabolism acutely may be harmful, as growth hormone showed, but androgens, oestrogens and amino acid metabolites may merit testing in convalescence — alongside senolytics and cell-based approaches targeting impaired muscle regeneration. The convergent

Results: of dose-based interventions can be operationalized through the concepts of feeding and exercise responsiveness, which point to biology-guided individualization. Composite ready-to-feed and ready-to-train indicators integrating bedside biomarkers, muscle microbiopsy readouts and biological signatures, validated through adaptive platform trials, represent the next frontier toward synchronized restoration of muscle and functional recovery after critical illness.