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. 2024 Apr 1;52(4):596-606.
doi: 10.1097/CCM.0000000000006119. Epub 2023 Nov 20.

Antibiotics, Sedatives, and Catecholamines Further Compromise Sepsis-Induced Immune Suppression in Peripheral Blood Mononuclear Cells

Muska Miller  1 , Miranda J Melis  1 , James R C Miller  1 , Anna Kleyman  1 , Manu Shankar-Hari  2 , Mervyn Singer  1
Affiliations

Antibiotics, Sedatives, and Catecholamines Further Compromise Sepsis-Induced Immune Suppression in Peripheral Blood Mononuclear Cells

Muska Miller et al. Crit Care Med. .

Abstract

Objectives: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals.

Design: In vitro/ex vivo investigation.

Setting: University laboratory.

Subjects: Healthy volunteers, infected (nonseptic) patients in the emergency department, and septic ICU patients.

Interventions: PBMCs were isolated from these subjects and treated with ciprofloxacin (100 µg/mL), propofol (50 µg/mL), norepinephrine (10 µg/mL), or all three drugs combined, with and without lipopolysaccharide (100 ng/mL) for 6 or 24 hours. Comparison was made between study groups and against untreated cells. Measurements were made of cell viability, cytokine production, phagocytosis, human leukocyte antigen-DR (HLA-DR) status, mitochondrial membrane potential, mitochondrial reactive oxygen species production, and oxygen consumption. Gene expression in immune and metabolic pathways was investigated in PBMCs sampled from healthy volunteers coincubated with septic serum.

Measurements and results: Coincubation with each of the drugs reduced cytokine production and phagocytosis in PBMCs isolated from septic patients, and healthy volunteers coincubated with septic serum. No effect was seen on HLA-DR surface expression. No cumulative effects were seen with the drug combination. Sepsis-induced changes in gene expression and mitochondrial functionality were not further affected by addition of any of the drugs.

Conclusion: Drugs commonly used in critical care lead to significant immune dysfunction ex vivo and enhance sepsis-associated immunosuppression. Further studies are required to identify underlying mechanisms and potential impact on patient outcomes.

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Conflict of interest statement

Dr. Melis’ institution received funding from the European Union’s Horizon 2020 research and innovation program (number 676129). Dr. Singer’s institution received funding from Biotest, Roche, and Deltex Medical; they received funding from Volition, Calbiochem, AOP Pharma, Aptarion, Matisse, NewB, Paion, Pfizer, Biomerieux, and Hemotune. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

    1. Singer M, Deutschman CS, Seymour CW, et al.: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801–810
    1. Gogos C, Kotsaki A, Pelekanou A, et al.: Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection. Crit Care 2010; 14:R96
    1. Turnbull IR, Clark AT, Stromberg PE, et al.: Effects of aging on the immunopathologic response to sepsis. Crit Care Med 2009; 37:1018–1023
    1. Shankar-Hari M, Ambler M, Mahalingasivam V, et al.: Evidence for a causal link between sepsis and long-term mortality: A systematic review of epidemiologic studies. Crit Care 2016; 20:101
    1. van der Poll T, Shankar-Hari M, Wiersinga WJ: The immunology of sepsis. Immunity 2021; 54:2450–2464