The metabolic response to stress in critical illness: updated review on the pathophysiological mechanisms, consequences, and therapeutic implications.

The understanding of the response to stress in critical illness has significantly improved in recent years. These adaptations unfold across acute, subacute, and chronic phases, with an early adaptive catabolic state, marked anabolic resistance, and a later transition toward recovery. The aim of this updated review is to summarize recent advancements focusing on pathophysiological changes in endocrine, immune, gut, and mitochondrial functions and their effects on the metabolic shift in energy production, using glycolysis and the utilization of lactate and ketones as alternative pathways to meet cellular energy demands. Advances in understanding key elements such as energy expenditure and autophagy have expanded our knowledge. Furthermore, there is increased interest in the consequences of an intense and prolonged stress response, which can lead to ICU-acquired weakness (ICU AW) and post-intensive care syndrome. Recent evidence indicates that higher protein strategies generally do not improve survival or functional recovery and may signal harm in patients with renal dysfunction, supporting cautious, phase-appropriate protein dosing rather than routine high targets. New concepts, such as chronic critical illness (CCI) and persistent inflammation, immunosuppression, and catabolism syndrome (PICS), have also emerged to characterize prolonged stress responses. For glycaemic management, intensive control offers no outcome benefit and increases hypoglycaemia risk; moderate targets are preferred. Parallel advancements in monitoring techniques, such as indirect calorimetry and body composition analysis, have improved the assessment of the consequences of the metabolic changes. Metabolomics has offered deeper characterisation of the metabolic response to stress and nutrition, highlighting key metabolic pathways and potential therapeutic targets. Integrating biomarkers and metabolomics to define clinical endotypes may help time the transition from catabolic to anabolic strategies and personalize nutrition and pharmacologic support at the bedside. New therapeutic avenues have emerged or are under investigation, including glycaemic control, nutritional strategies, and some specific interventions targeting key components of the metabolic response. In this context, we present a narrative review of the literature with a focus on the clinical consequences of the pathophysiological and metabolic response to stress, alongside therapeutic implications and future perspectives.