Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies.

Critical care involves the management of organismal stress by sedation. Benzodiazepines remain widely used for anxiolysis and sedation in critical care, including in septic shock. Yet converging mechanistic, preclinical and clinical evidence suggests that benzodiazepines and the endogenous ligand of benzodiazepine-binding sites, the "endozepine" acyl-CoA binding protein/diazepam binding inhibitor (ACBP/DBI), may impair host immune defenses, exacerbate organ dysfunction and contribute to long-term morbidity after intensive care. A unifying framework is that benzodiazepines may accelerate "iatrogenic aging" by antagonizing adaptive stress responses (notably autophagy) and favoring cellular senescence, chronic inflammation, immunosuppression and neurocognitive perturbations. Here, we synthesize evidence supporting benzodiazepine avoidance in sepsis-heavy intensive care populations. We propose that replacing benzodiazepines with alternative sedative strategies may improve both short-term outcomes and long-term trajectories of post-sepsis disability. We hypothesize that post-intensive-care syndrome (PICS), including -as a specific case- post-sepsis syndrome (PSS), is caused by premature aging of the organism and that PICS/PSS might be attenuated by the avoidance of benzodiazepine administration during and after critical care.