Benzodiazepine poisoning causes
coma and
respiratory depression. Our objective was to determine whether, and to what extent, arterial blood gas disturbances correlated with blood or cerebral kinetics of
midazolam. A 160 mgkg(-1) single dose of
midazolam was infused intravenously over 20 min in catheterized male Sprague-Dawley rats.
Midazolam kinetics was simultaneously determined in plasma and brain using striatal microdialysis.
Midazolam concentrations were measured using a high-performance liquid chromatographic assay with ultraviolet detection.
Midazolam (160 mgkg(-1)) reproducibly induced deep
coma with
respiratory acidosis. Plasma
midazolam kinetics was well described by a bi-exponential model, with an elimination half-life of 6.4+/-1.8 h. The striatal
dialysate concentration peaked at 50.0+/-8.9 min after the end of infusion, with a significant delay to peak concentration compared to plasma.
Respiratory depression, assessed by the elevation in PaCO2, was more closely correlated with
midazolam striatal
dialysate rather than plasma kinetics. These results suggest a central mechanism for
midazolam respiratory effects at toxic doses in rats. In conclusion, our study showed a delayed onset in peak PaCO2 and pH effects after the slow infusion of a toxic dose of
midazolam in rats. The effects on arterial blood
gases were better correlated with
midazolam striatal concentrations than with plasma concentrations. This study may contribute to better understanding of
benzodiazepine-induced
respiratory depression in
poisonings.