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Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison to diazepam
Abstract:
The effects of midazolam maleate and diazepam on cerebral metabolism and circulation were examined for each drug in six dogs maintained on N2O 70 per cent and halothane less than 0.1 per cent. Midazolam maleate at 0.2 mg/kg and diazepam at 0.3 mg/kg (the ED 100 per cent for induction of anesthesia for each drug in humans) did not decrease metabolic rate for oxygen (CMRO2) but did decrease cerebral blood flow (CBF) to about 55 per cent of control. Additional drug administrations (2.0, 5.0, and 10.0 mg/kg midazolam maleate, and 3.0 and 7.5 mg/kg diazepam) resulted in dose-related decreases in CMRO2 to a maximum of 55 per cent of control after 10.0 mg/kg midazolam maleate. Concomitant with the initial decreases in CMRO2, there was a change in the EEG as reflected by a decrease in frequency and an increase in amplitude. This EEG change suggests that 2.0 mg/kg midazolam maleate and 3.0 mg/kg diazepam represent a comparable canine anesthetic dose. Each additional dose of midazolam maleate decreased CBF to a greater extent than did the added doses of diazepam. Brain biopsies taken at the end of the midazolam maleate studies revealed a normal cerebral energy state (phosphocreatine, ATP, ADP, and AMP) and normal glucose, lactate, and pyruvate concentrations. In a hypoxic mouse model (FIO2 = 0.05), midazolam maleate provided greater protection from hypoxia (2.8 x control survival time) than diazepam (1.6 x control survival time). By comparison barbiturates in this model provide a survival time which is 4.0 x control.
Insights
Midazolam maleate and diazepam reduced cerebral blood flow in dogs. Midazolam maleate offered greater protection against hypoxia in mice compared to diazepam.
Area of Science:
- Neuroscience
- Anesthesiology
- Pharmacology
Background:
- Midazolam maleate and diazepam are commonly used anesthetic agents.
- Understanding their effects on cerebral metabolism and circulation is crucial for safe clinical application.
Purpose of the Study:
- To compare the effects of midazolam maleate and diazepam on cerebral metabolism and circulation in dogs.
- To evaluate the neuroprotective effects of these agents in a hypoxic mouse model.
Main Methods:
- Dogs were anesthetized with nitrous oxide and halothane.
- Midazolam maleate and diazepam were administered in increasing doses.
- Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were measured.
- Electroencephalogram (EEG) changes were monitored.
- Brain biopsies were analyzed for energy metabolites and glucose.
- Mice were exposed to hypoxia (FIO2 = 0.05) to assess survival time.
Main Results:
- Both drugs decreased CBF without affecting CMRO2 at lower doses.
- Higher doses of midazolam maleate and diazepam dose-dependently decreased CMRO2.
- EEG showed decreased frequency and increased amplitude, indicating anesthetic effects.
- Midazolam maleate caused a more pronounced decrease in CBF than diazepam at higher doses.
- Brain biopsies revealed normal cerebral energy state and metabolites.
- Midazolam maleate significantly increased survival time in hypoxic mice compared to diazepam.
Conclusions:
- Midazolam maleate and diazepam affect cerebral circulation and metabolism differently.
- Midazolam maleate demonstrates superior neuroprotection in a hypoxic mouse model.
- These findings have implications for anesthetic management and neuroprotection strategies.