Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies
Authors:Flavia Lambertucci1, David Skurnik2,3, Damien Roux4,5, Laurence Arbibe6, Lucillia Bezu1,7,8, Isabelle Martins1 and Guido Kroemer1,7,9
1 Team “Metabolism, Cancer & Immunity”, Équipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Inserm UMRS1138, Université Paris Cité, Sorbonne Université, Paris, France. 2 Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France. 3 Service de Microbiologie Clinique, AP-HP, Hôpital Necker Enfants Malades, Paris, France. 4 AP-HP, Hôpital Louis Mourier, DMU ESPRIT, Service de Médecine Intensive Réanimation, Colombes, France. 5 Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Paris, France. 6 Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France. 7Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. 8 Intensive Care Unit, Gustave Roussy, Villejuif, France. 9Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
Keywords:
acyl-CoA binding protein, bacterial clearance, diazepam binding inhibitor, emergency medicine, infection, intensive care
Corresponding Author(s):
Conflict of interest statement:
FL, IM and GK are co-inventors of a patent application describing the therapeutic of ACBP/DBI neuralization in sepsis. IM is a co-founder of Sanvitalia and has been consulting for Osasuna Therapeutics. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, Sanvitalia and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier, and Rejuveron Life Sciences/Centenara Labs AG. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. GK’s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.
Please cite this article as:
Flavia Lambertucci, David Skurnik, Damien Roux, Laurence Arbibe, Lucillia Bezu, Isabelle Martins, Guido Kroemer (2026). Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies. Cell Stress 10: 64-73. doi: 10.15698/cst2026.08.320
© 2026 Lambertucci et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
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.