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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Acute Phase Histopathological Study of Spinally Administered Midazolam in Cats

Tomoki Nishiyama, MD, PhD^*, Takashi Matsukawa, MD, PhD, and Kazuo Hanaoka, MD, PhD^*

*Department of Anesthesiology, The University of Tokyo, Faculty of Medicine, Tokyo, Japan; and Department of Anesthesia, Yamanashi Medical University, Yamanashi, Japan

Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332-0015, Japan.

	Abstract

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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.

	Introduction

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The –amino butyric acid (GABA)_A receptors in the spinal cord are involved in nociceptive mechanisms (1). Midazolam has analgesic properties via the benzodiazepine-GABA_A receptor complex in the spinal cord (2,3). In human studies, Serrao et al. (4) administered midazolam intrathecally to relieve back pain. In our previous studies, the epidural administration of midazolam was effective on postoperative wound pain (5–7).

Despite its favorable profiles, midazolam is not often used spinally for pain management because there is still controversy regarding its possible neurotoxicity to the spinal cord. Many animal studies have shown no neurotoxicity of spinally administered midazolam (8–10); however, large doses have induced some histological changes (11,12). All studies investigated only the chronic phase of the histological changes. Acute-phase toxicity and inflammatory changes have not been examined. Furthermore, in previous studies, only small animals were used. In addition, a catheter was inserted into the intrathecal space, which made it difficult to distinguish the damages induced by midazolam from those induced by the catheter. The purpose of the present study was to investigate the acute-phase histological and inflammatory reactions of the spinal cord to directly administered midazolam in cats.

	Methods

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After the approval of our animal care committee, 40 male cats (2.5–3.5 kg) were anesthetized with IM ketamine 30 mg/kg, followed by inhalation of 2% sevoflurane in 100% oxygen 4 L/min. Tracheostomy was performed. The femoral vein and artery were cannulated for the administration of lactated Ringer's solution with 5% glucose and for the measurement of blood pressure. Ventilation was controlled to maintain PETCO₂ (measured by using Ultima^TM; Datex, Helsinki, Finland) at 30–35 mm Hg. Four cats that showed a >20% decrease in blood pressure compared with the control value were not included because hypotension might damage the spinal cord.

Cats were fixed onto a stereotaxic apparatus. After the midline skin incision at the lumbar area, muscles were bluntly dissected from the vertebrae. Laminectomy was performed in all animals in the lumbar area, and the dura was cut at the midline and fixed to the muscles using pins to expose a 5-cm segment of spinal cord. The dura became a wall to keep solution around the spinal cord. For 20 cats, midazolam 10 mg (10 mg/2 mL, Dormicum^TM; Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan) was administered directly to the spinal cord. For 20 cats, isotonic sodium chloride solution 2 mL was administered. The spinal cords were left exposed, but a clear vinyl sheet covered it at the skin level. At 1, 2, 4, or 6 h after drug administration, five cats in each group were killed with IV thiopental 70 mg/kg. Cats were then perfused with 10% formalin through the ascending aorta, and the 5 cm of exposed lumbar spinal cord was removed with the ventral and dorsal roots. The removed spinal cord was fixed in 10% formalin, then embedded in paraffin. Five-micrometer slices were examined by using light microscopy with hematoxylin and eosin staining by an animal pathologist who was blinded to the time course and the treatment. The evidence of abnormalities or damage was classified as shown in Table 1 and was scored by the pathologist as follows: 0 = no abnormal changes, 1 = very slight changes, 2 = slight changes, 3 = moderate changes, and 4 = marked changes.

	Results

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Cerebrospinal fluid (CSF) was clouded by midazolam but not by saline. There were no time-dependent differences in histopathological findings up to 6 h (Table 1). Both groups showed some slight to moderate changes in the spinal cord, but no severe damage was observed. Inflammatory reactions were only seen in one cat with slight neutrophil infiltration in the saline-treated group. These changes were not different between the midazolam-treated group and the saline-treated group.

	Discussion

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Directly administering midazolam to the spinal cord caused only slight to moderate histological changes up to six hours after treatment. However, these changes were also observed in cats treated with saline. No inflammatory reactions were seen in the midazolam-treated group. Histological changes were not statistically different between the midazolam- and saline-treated groups.

We planned to examine the histology for at least 24 hours after the administration of midazolam. However, we limited the study to six hours to maintain optimal hemodynamics and to keep the exposed spinal cord moist, in normal temperature, and free from nonspecific inflammatory reactions. Six hours might not be long enough to see acute histological changes that would result in chronic changes. In our previous in vitro study (13) and in the present study, however, midazolam clouded CSF just after administration, which would induce an inflammatory reaction that could be detected within six hours. Therefore, even only six hours' observation is useful to detect acute changes. We cannot extrapolate the present results, with its limited time course and single administration of midazolam, to the safety of chronic administration. Therefore, it is possible that the chronic administration of midazolam may cause neurotoxicity.

A light microscopic study in the rat demonstrated no spinal cord toxicity after 15 days of daily doses of intrathecally administered midazolam (10). Serrao et al. (8) also reported no damage to the spinal cord after the intrathecal administration of midazolam. In the acute phase up to six hours, no histological damage was observed in our study. In contrast, Malinovsky et al. (12) reported necrosis, hemorrhage, and other histopathological changes in three of nine spinal cords of rabbits that had received a single intrathecal injection of midazolam 300 µg. After 21 days of daily injections of midazolam 100 µg, Svensson et al. (11) observed that the number of nerve cells decreased and the mean cell volume increased. Degenerated nerve cell somata, fibers, and terminals were also observed in most of the rats treated with intrathecal midazolam by electromicroscopic examination (11). In the neonatal rabbit, single-dose epidural midazolam 250 µg/kg also induced neurotoxic effects, such as degeneration of vacuoles, cytoplasma, and neurofilaments; disruption of myelin sheaths; lysis of cell membranes; perivascular edema; and pyknosis of nuclei (14). Our results showed that no histological damage occurred in the first six hours and that no inflammation ensued to trigger such damage in adult cats receiving 10 mg of midazolam applied topically.

Ketamine and sevoflurane might have some effects on inflammatory reactions. However, both the midazolam-treated group and the saline-treated group were anesthetized similarly. Therefore, both groups were comparable, and midazolam did not induce an more inflammatory reaction than saline.

The studies that showed neurotoxicity used doses much larger than the analgesic dose. Regarding the analgesic dose, Yanez et al. (15) reported that intrathecally administered midazolam 20–60 µg produced dose-dependent antinociception on thermally induced pain. In a study using rats (unpublished data), we found that the 50% effective dose of intrathecal midazolam was 1.57 µg, and doses >30 µg induced motor dysfunction. Bahar et al. (16) showed that the intrathecal administration of 75 µg of midazolam induced sleep in rats. Clearly, the delayed neurotoxicity of the analgesic dose should be investigated. The present study shows that an acute reaction is unlikely at any reasonable dose.

One of the concerns when applying midazolam to the spinal cord is that the drug is acidified (pH approximately 3.5) and causes clouding of the CSF. Other studies do not mention the characteristic changes in CSF by midazolam. Because of their low pH, local anesthetics, especially chloroprocaine, may be neurotoxic (17). Another concern is that midazolam preparations contain 1% benzyl alcohol as a preservative. However, adding analgesic doses of midazolam to human CSF does not cause clouding or a decrease in pH to <7.0, although larger doses do (13).

In conclusion, up to six hours after the direct administration of midazolam 10 mg to the spinal cord, no histological damage or inflammatory reaction of the spinal cord was seen in cats.

	Acknowledgments

 
We thank Professor C. Lee, Department of Anesthesiology, UCLA School of Medicine, for his comments.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999