The Commonly Used Anesthetic Propofol Dramatically Increases Host Susceptibility to Microbial Infection
thesisposted on 2013-06-28, 00:00 authored by Lavanya Visvabharathy
Hospital peri-operative infections remain a major health concern, with surgery representing a leading cause of nosocomial infections. Anesthetics modulate host immune responses, but it has been difficult to separate the variable of surgery from anesthesia administration when analyzing infection rates. Here, the well-studied bacterial pathogen Listeria monocytogenes (LM) was used to assess the impact of a surgical anesthetic on host infection susceptibility. Brief sedation with propofol was sufficient to increase the bacterial burdens of LM in mouse target organs by 10,000-fold following both oral and intravenous routes of infection. Increased host susceptibility to oral infection with LM was dependent on heightened bacterial translocation across the intestinal barrier, but not through intestinal epithelial cells. This indicated that propofol increases LM translocation through alternate portals of entry. Propofol treatment did not alter LM invasion or replication within host cells in culture, disrupt tight junction integrity in Caco-2 intestinal epithelial cells, or decrease the efficacy of LM killing in primary murine macrophages. Though sedation with propofol is brief due to its short half-life, animals remained highly susceptible to infection even 96 hours after recovery from sedation. Though the alternate anesthetics sodium pentobarbital and ketamine increased the susceptibility of mice to oral infection with LM, they did not affect susceptibility to intravenous systemic infection with LM, unlike propofol. Additionally, anesthetized animals infected with LM displayed more severe organ pathology in livers, spleens, and intestines. Propofol treatment altered serum cytokine and chemokine levels throughout infection, with particularly striking effects on IFN-γ, MCP-1, IL-10 and TNF-α. Concurrently, fewer differentiated macrophages and TNF and iNOS producing dendritic cells, both important in clearing LM, were evident in animals treated with propofol. Finally, animals sedated with propofol showed heightened susceptibility to 2 methicillin-resistant Staphylococcus aureus, Salmonella enterica serovar Typhimurium, and Streptococcus pyogenes as evidenced by increased bacterial burdens in target organs. These data indicate that anesthetization with propofol severely compromises host resistance to infection, an observation that has potentially profound implications for surgical outcomes and, ultimately, patient survival.