CONTEXT: Opioids remain a standard supportive therapy in patients admitted to the ICU with sepsis. However, as preclinical models indicate an association between opioid exposure and immunosuppression, the use of this class of drugs warrants investigation. The objective of this study was to investigate whether opioid exposure causes immunosuppression in patients with sepsis, and to use a murine sepsis model to determine the effects of opioid exposure on secondary infection. HYPOTHESIS: We hypothesized opioid exposure would be associated with immunosuppression in patients with sepsis and secondary infection in a murine sepsis model. METHODS AND MODELS: This was a two-phase preclinical and clinical study. The clinical phase included a subgroup of patients with sepsis from an existing randomized controlled trial while the preclinical phase used a murine model of sepsis with C57BL/6 mice. In the clinical phase, a post hoc analysis was performed in subjects receiving fentanyl versus no opioid receipt. In the preclinical phase, a murine cecal slurry-induced sepsis model followed by secondary infection was used. Mice were randomized to fentanyl versus no fentanyl concomitantly. RESULTS: In clinical sepsis, a significant decrease in interleukin-23 (IL-23) level in patients with fentanyl exposure was observed and lower IL-23 was associated with mortality (p < 0.001). Other measured cytokines showed no significant differences. Concomitant fentanyl exposure during murine sepsis was associated with a significantly higher bacterial burden (p < 0.001) after secondary infection; however, immune cell counts and plasma cytokine levels were largely unaffected by fentanyl. INTERPRETATION AND CONCLUSIONS: Minimal alterations in cytokines were seen with opioid exposure during clinical sepsis. In a preclinical model, opioid exposure during sepsis was associated with ineffective bacterial clearance upon secondary infection. Further studies are warranted to evaluate the immunomodulatory role of opioids and their implications, especially in the post-sepsis period.
|Critical Care Explorations
|Published - Jan 17 2023
Bibliographical noteFunding Information:
Funding for this study was provided by the University of Kentucky Igniting Research Collaborations Program and National Institutes of Health R01 grant GM129532 awarded to Dr. Starr. We gratefully acknowledge Mrs. Donna Gilbreath of the Markey Cancer Center Research Communications Office for illustrative expertise as well as the University of Kentucky Biostatistics, Epidemiology & Research Design Core for statistical support.
Funding for this study was provided by the University of Kentucky Igniting Research Collaborations Program and National Institutes of Health R01 grant GM129532 awarded to Dr. Starr.
© 2023 the Author(s). Published by Wolters Kluwer Health, Inc.
- critical illness
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine