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Cell Stress, Vol. 10, No. 1, pp. 64 - 73; doi: 10.15698/cst2026.08.320
Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies
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
Received originally: 04/07/2026 Received in revised form: 23/07/2026
Accepted: 27/07/2026
Published: 07/08/2026
Correspondence:
Guido Kroemer, Centre de Recherche des Cordeliers, 15 rue de l’école de médecine, 75006, Paris, France; kroemer@orange.fr
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
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.
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AUTHOR CONTRIBUTIONS
G.K. wrote the main manuscript with the input of all other authors. F.L. prepared the figures with the help of I.M. All authors reviewed the manuscript.
ACKNOWLEDGMENTS
GK is supported by the Ligue contre le Cancer (équipes labellisées); Agence Nationale de la Recherche (ANR) under the France 2030 programme (reference number 21-ESRE- 0028, ESR/Equipex+ Onco-Pheno-Screen; program RHU ANR-21-RHUS-0017 IMMUNOLIFE and ANR-23-RHUS-0010 LUCA-pi; ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC, ANR-23-R4HC-0006 Ener-LIGHT), an European Research Council Advanced Investigator Award (ERC-2021- ADG, Grant No. 101052444; project acronym: ICD-Cancer); Hevolution Network on Senescence in Aging (reference HF-E Einstein Network); European Union Horizon 2020 research and innovation programmes Oncobiome (grant agreement number: 825410), Prevalung (grant agreement number 101095604), Institut National du Cancer (INCa), Institut Universitaire de France; PAIR-Obésité INCa_18713, Seerave Foundation, SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). This study (Immuno-Onco) contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001.
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© 2026
Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies by Lambertucci et al. is licensed under a Creative Commons Attribution 4.0 International License.
