Cerebral effects of high-dose midazolam and subsequent reversal with Ro 15-1788 in dogs

The effects of a continuous high-dose infusion of midazolam on cerebral function, metabolism, and hemodynamics were studied in nine dogs receiving a spinal anesthetic and breathing 65% nitrogen/35% oxygen. In five dogs, the effects of 65% nitrous oxide (N2O) inspired and the benzodiazepine antagonist Ro 15-1788 were also examined. Midazolam was infused at a rate of 0.66 mg.kg-1.min-1 for 60 min for a total dose of 40 mg.kg-1. Cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) (measured by venous outflow technique) both decreased until a plateau level was reached at approximately 75% of control values (4.0 +/- 0.2 ml.min-1.100 g-1 and 49 +/- 3 ml.min-1.100 g-1, respectively, mean +/- SEM). This occurred after 6-10 mg.kg-1 of midazolam, corresponding to serum midazolam levels between 18.4 +/- 3.8 and 31.2 +/- 3.3 micrograms.ml-1. Serum midazolam levels increased throughout the midazolam infusion, reaching a mean value of 53 +/- 5.5 micrograms.ml-1 by the end of the midazolam infusion. A similar plateau was seen for changes in the electroencephalogram (EEG), which never developed burst suppression. Five dogs inspired 65% nitrous oxide/35% oxygen during minutes 30-45 of the midazolam infusion, rather than 65% nitrogen/35% oxygen. Nitrous oxide had no effect upon CMRO2, but significantly increased CBF when compared to dogs receiving nitrogen. Ro 15-1788, 1.0 mg.kg-1 caused a return of CMRO2 and EEG activity to control levels. CBF and intracranial pressure (ICP) increased markedly, to greater than control levels immediately following Ro 15-1788.