Mice Treated With a Benzodiazepine Had an Improved Survival Rate Following Pseudomonas aeruginosa Infection

Abstract

Psychological stress has a high incidence after burn injury, therefore, anxiolytic drugs are often prescribed. Unfortunately, to date, no burn study has investigated the effects of anxiolytic drugs on the ability to fight infection. This study was undertaken to determine if psychological stress, anxiety-modulating drugs, or both, alter survival following an infection. On day 0, 7-week-old male C57Bl/6 mice either received a 15% full-thickness flame burn or were sham treated (anesthesia and shaved), whereas controls received no treatment. Mice received midazolam (1 mg/kg intraperitoneally) or saline daily and were stressed by exposure to rat in a guinea pig cage or placed in an empty cage for 1 hour a day, beginning on postburn day 1. For the survival experiments, mice either received bacteria after 2 or 8 consecutive days of predator exposure and drug treatment, which continued daily for 7 days after inoculation. In a separate set of experiments, after eight daily injections of midazolam, mice were given lipopolysaccharide, bacteria, or saline and were killed 12 hours later. Mice that received midazolam had improved survival rates when compared with their saline-treated counterparts, and the protective effect was more significant the more days they received the drug. For most of the cytokines, the bacteria-induced increase was significantly attenuated by midazolam as was the amount of bacteria in the liver. The protective effect seems to be independent of the drug's anxiolytic activity as there were no significant differences in survival between the predator-stressed and the nonstressed mice. The mechanisms responsible for the protective effect remain to be elucidated.

The Burn Wound Inflammatory Response Is Influenced by Midazolam

“…1). Our previous work in non-burn mice showed no impact of midazolam, in the absence of bacteria or LPS, on serum cytokines/chemokines with the exception of a significant drug-induced increase in KC on day 8 [8]. Interestingly, in the current study the only serum chemokine to be influenced by midazolam following the burn was KC which was increased on PBD 7 (Fig.…”

“…Interestingly, this survival benefit was shown to be independent of the drug's anxiolytic effect. The reason for the finding of significantly attenuated cytokine levels in the drug-treated group after the bacteria inoculation, but no effect on the LPS-induced cytokine increases or survival rate was not elucidated [8].…”

“…Therefore, in the current study we set out to uncover the mechanism(s) responsible for the protective effect of midazolam observed in our previous study [8] focusing on whether the drug has any impact on the burn injury-induced immune alterations. Since burn injury solely elicits an immune response, we ascertained the impact of midazolam on the burn injury-induced inflammatory response on the days post-burn that we injected mice with bacteria or LPS in our previous study.…”

“…Nitrate/nitrite is a metabolite of NO, and in our previous study in nonburn mice, we found that midazolam significantly attenuated the LPS-induced increase in serum nitrate [8]. Therefore, we measured serum nitrate levels in the current study.…”

“…In a previous study, we found that mice that received midazolam daily had improved survival rates following Pseudomonas aeruginosa infection when compared to their saline-treated counterparts and the protective effect became more significant when the number of days of drug treatment before inoculation increased. The protective effect appears to be independent of the drug's anxiolytic activity as there were no significant differences in survival between the predator-stressed and the non-stressed mice [8].…”