Advances in intensive care have improved survival from acute critical illness, leading to a growing population of patients with chronic critical illness (CCI), many of whom require prolonged organ support. This condition is associated with persistent catabolism, inflammation, and poor long-term outcomes. Understanding the metabolic alterations underlying this failure to recover may help identify targets for monitoring and intervention. This review synthesizes current clinical and translational evidence on metabolic dysregulation in CCI and discusses its implications for monitoring, nutritional strategies, and therapeutic interventions. We performed a narrative review informed by a structured search of PubMed/MEDLINE followed by manual reference screening. Preclinical, translational and clinical studies addressing energy metabolism, mitochondrial function, autophagy, ketone metabolism, inflammation and recovery trajectories in critical illness were qualitatively synthesized. Available evidence suggests that patients with CCI exhibit persistent metabolic inflexibility, impaired transition from catabolism to anabolism, mitochondrial dysfunction, altered autophagy, and disturbances in substrate utilization, including reduced ketogenesis. These alterations, together with epigenetic and immunometabolic reprogramming, may contribute to muscle wasting, immune dysfunction, and delayed functional recovery, features consistent with the persistent inflammation, immunosuppression and catabolism syndrome (PICS). Much of the mechanistic evidence, however, derives from preclinical or acute-phase studies, and validation of these findings in patients with CCI remains limited. CCI may represent a state of impaired metabolic and cellular adaptation associated with persistent inflammation, organ dysfunction, and failed recovery from acute critical illness. Improved understanding of these mechanisms may support more individualized metabolic monitoring, nutritional support, and therapeutic strategies. Further prospective and translational studies are required to determine clinical relevance and guide targeted interventions.
