Cerebral Effects of High-dose Midazolam and Subsequent Reversal with Ro 15–1788 in Dogs

Abstract

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 .cntdot. kg-1 min-1 for 60 min for a total dose of 40 mg .cntdot. 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 .cntdot. min-1 .cntdot. 100 g-1 and 49 .+-. 3 ml .cntdot. min-1 .cntdot. 100 g-1, respectively, mean .+-. SEM). This occurred after 6-10 mg .cntdot. kg-1 of midazolam, corresponding to serum midazolam levels between 18.4 .+-. 3.8 and 31.2 .+-. 3.3 .mu.g .cntdot. ml-1. Serum midazolam levels increased throughout the midazolam infusion, reaching a mean value of 53 .+-. 5.5 .mu.g .cntdot. 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 .cntdot. kg-1 caused a return of CMRO2 and EEG activity to control levels. CBF and intracranial pressure (CP) increased markedly, to greater than control levels immediately following Ro 15-1788. After 15 min, both CBF and ICP had decreased to near levels seen immediately prior to Ro 15-1788 administration. Ro 15-1788 administration was associated with a decrease in MAP requiring treatment with intravenous fluids and a low-dose phenylephrine infusion to maintain mean arterial pressure (MAP) above 60 mmHg samples for cerebral metabolite determination taken either at the end of the midazolam infusion, or following Ro 15-1788, were essentially normal. The authors conclude that midazolam produces a limited dose-related decrease in CMRO2 which correlates with decreases in neuronal function. There were no apparent toxic effects of midazolam 40 mg .cntdot. kg-1. The combination of midazolam and Ro 15-1788 was effective in reversing the cerebral effects of high-dose midazolam, without untoward effects upon cerebral metabolite concentrations. However, Ro 15-1788 administration was associated with a significant increase in CBF and ICP, and a decrease in MAP.