Prolonged exposure to volatile anesthetic isoflurane worsens the outcome of polymicrobial abdominal sepsis

Abstract

Sepsis continues to result in high morbidity and mortality. General anesthesia is often administered to septic patients, but the impacts of general anesthesia on host defense are not well understood. General anesthesia can be given by volatile and intravenous anesthetics. Our previous in vitro study showed that volatile anesthetic isoflurane directly inhibits leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), critical adhesion molecules on leukocytes. Thus, the role of isoflurane exposure on in vivo LFA-1 and Mac-1 function was examined using polymicrobial abdominal sepsis model in mice. As a comparison, intravenous anesthetic propofol was given to a group of mice. Wild type, LFA-1, Mac-1, and adhesion molecule-1 knockout mice were used. Following the induction of polymicrobial abdominal sepsis by cecal ligation and puncture, groups of mice were exposed to isoflurane for either 2 or 6 h, or to propofol for 6 h, and their outcomes were examined. Bacterial loads in tissues and blood, neutrophil recruitment to the peritoneal cavity and phagocytosis were studied. Six hours of isoflurane exposure worsened the outcome of abdominal sepsis (P < .0001) with higher bacterial loads in tissues, but 2 h of isoflurane or 6 h of propofol exposure did not. Isoflurane impaired neutrophil recruitment to the abdominal cavity by inhibiting LFA-1 function. Isoflurane also impaired bacterial phagocytosis via complement receptors including Mac-1. In conclusion, prolonged isoflurane exposure worsened the outcome of experimental polymicrobial abdominal sepsis and was associated with impaired neutrophil recruitment and bacterial phagocytosis via reduced LFA-1 and Mac-1 function.

The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain–Fas‐associated death domain interaction

“…The better survival of isofluraneor sevoflurane‐exposed group was presumably explained by the significant reduction of proinflammatory mediator levels by these volatile anesthetics. In contrast, our model used 2‐time puncture of the cecum and was not associated with the mortality within the first 48 h in WT mice (8). Our proinflammatory cytokine levels were not as elevated as in the aforementioned study (8).…”

“…All the experimental procedures complied with institutional and federal guidelines regarding the use of animals in research. Polymicrobial abdominal sepsis was induced by CLP, as we previously performed (8). In brief, mice were anesthetized with ketamine (60 mg/kg) and xylazine (5 mg/kg) given intraperitoneally.…”

“…We and others have demonstrated that volatile anesthetics may negatively affect immune functions and surgical outcomes (1)(2)(3)(4)(5)(6)(7). Regarding sepsis, we have previously shown that isoflurane worsened the outcome of septic mice (8). Understanding the impact of existing medical treatment on sepsis outcome and optimizing it is critical, particularly because there is no targeted therapy at this point.…”

Volatile Anesthetic Isoflurane Attenuates Liver Injury in Experimental Polymicrobial Sepsis Model

“…Organ injury represents a main complication with significant morbidity and mortality, and overwhelming migration of activated neutrophils into organs and subsequent endothelial cell damage are mainly responsible [ 2 ]. Patients suffering from sepsis often undergo procedures or are sedated in intensive care unit (ICU) in Europe and Canada under volatile anesthetics [ 3 – 6 ]. A growing literature suggests that volatile anesthetics possess immunomodulatory effects [ 7 , 8 ].…”

“…LFA-1 and Mac-1 are two major β2 integrins expressed constitutively on neutrophils, and interact with several ligands including a common ligand called intercellular adhesion molecule-1 (ICAM-1), which is constitutively expressed on the endothelial cells and some other cells [ 20 ]. We previously showed that commonly used volatile anesthetic isoflurane blocked both LFA-1 and Mac-1 on neutrophils [ 3 , 21 – 24 ]. Polymicrobial abdominal sepsis model induced by cecal ligation and puncture (CLP) surgery is the model widely used to study sepsis, recapitulating human sepsis [ 25 ].…”