Serum and cerebrospinal fluid concentrations of midazolam after epidural administration in dogs.

UNLABELLED: The epidural administration of midazolam has analgesic effects that might be mediated by gamma-aminobutyric acid type A receptors in the spinal cord. In this study, we examined both serum and cerebrospinal fluid (CSF) concentrations of midazolam after epidural administration to investigate the possibility of midazolam entering CSF directly from the epidural space. Five male mongrel dogs had catheters inserted in a femoral artery, the epidural space at L3-4, and the intrathecal space at the atlanto-occipital region under general anesthesia. Midazolam 1 mg/kg was epidurally administered, and arterial blood and CSF samples were collected until 240 min after the midazolam administration to measure midazolam concentration. Serum midazolam concentration increased and reached a peak at 30 min after the administration (224.8 +/- 30.5 ng/mL) and then decreased to 25.8 +/- 6.0 ng/mL at 240 min. Midazolam concentration in the CSF was less than the detection limit at 5 min, reached a peak at 30 min after the administration (7.2 +/- 4.7 ng/mL), and decreased to 3.6 +/- 3.3 ng/mL at 240 min. In conclusion, epidurally administered midazolam enters CSF, but CSF concentrations are only 3% of those in the systemic circulation. IMPLICATIONS: Midazolam, which has spinally mediated analgesic potency, was epidurally administered in dogs, and serum and cerebrospinal fluid concentrations were measured. Epidurally administered midazolam enters the cerebrospinal fluid, but concentrations are only 3% of those in the systemic circulation.

Acute phase histopathological study of spinally administered midazolam in cats.

UNLABELLED: Midazolam may be a useful analgesic when administered intrathecally. However, neurotoxicity must be excluded. The purpose of this study was to investigate whether spinally administered midazolam induces acute-phase histopathological or inflammatory reactions of the spinal cord. A lumbar laminectomy was performed on 40 cats, and their spinal cords were exposed. Midazolam 10 mg (2 mL, n = 20 cats) or saline 2 mL (20 cats) was administered directly to the spinal cord. At 1, 2, 4, or 6 h after the administration, cats were killed, and the lumbar spinal cord was removed and fixed in 10% formalin. Histology was examined using light microscopy with hematoxylin and eosin staining. Both groups showed slight to moderate changes in the spinal cord, but no severe damage was observed. Inflammatory reactions were seen in only one cat in the saline group with slight neutrophil infiltration. These changes were not different between the midazolam group and the saline group. In conclusion, up to 6 h after direct exposure to midazolam, no acute histological damage or inflammatory reaction of the spinal cord was seen in cats. IMPLICATIONS: Spinally administered midazolam, even in large doses, does not cause acute neurotoxicity or inflammation of the spinal cord.

A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration.

PURPOSE: The purpose of this investigation was to compare the pharmacokinetics of midazolam following intravenous, intranasal drop, and nasal-atomizer administration in beagle dogs. METHODS: Six animals weighing 9-13 kg were used in a repeated-measure design, group assignment based on route of drug administration. Midazolam (1.5 mg/kg) was administered with the delivery route based on group assignment. Blood samples were obtained at baseline and at 1, 3, 5, 7, 10, 15, 20, 30, and 45 min after administration. Cerebrospinal fluid samples (CSF) were obtained at 5 and 10 min after administration. Plasma and CSF concentrations of midazolam were determined by electron-capture gas-liquid chromatography. RESULTS: Comparison between groups and over time demonstrated that both nasal routes resulted in significantly higher CSF concentrations relative to corresponding plasma levels, and that nasal-atomizer administration produced significantly higher CSF concentrations compared to the drop approach.

In vitro changes in the transparency and pH of cerebrospinal fluid caused by adding midazolam.

The effects of adding midazolam and bupivacaine to human cerebrospinal fluid in glass test tubes were examined by looking for changes in pH and a reduction in the transparency of the solution. Midazolam (n = 6), 0.25% bupivacaine (n = 6), 5 mg of midazolam in 6 mL of 0.25% bupivacaine (n = 6) and 5 mg of midazolam in 10 mL of saline (n = 6) were added to 1.5-mL samples (n = 24) of cerebrospinal fluid taken at the time spinal anaesthesia was begun. Transparency and pH were checked after each increment. Cerebrospinal pH was decreased to below 7.0 by adding more than 3 mg of midazolam, more than 1.9 mL of 0.25% bupivacaine or 1.3 mL of the mixture. Cerebrospinal transparency was decreased by adding more than 0.7 mg of midazolam, 1.1 mL of 0.25% bupivacaine or 0.6 mL of the mixture. Midazolam in saline neither decreased the pH below 7.0 nor reduced transparency. These results do not suggest that clinically useful doses of intrathecal or epidural midazolam are neurotoxic.