Neurosurgical Anesthesia: Research Report
Midazolam has been used for general anesthesia and sedation during local anesthesia or artificial ventilation. Midazolam acts on the γ-aminobutyric acid (GABA) receptor in the brain and spinal cord (1). There are many studies investigating the effects of midazolam on cerebral circulation (2–6). Most studies showed that IV midazolam decreased cerebral blood flow (2–5).
It has become clear that midazolam has an analgesic property mediated by GABA receptors in the spinal cord (1). Therefore, it is important to know the effects of midazolam on spinal cord blood flow. However, there are no studies about the effects of midazolam on spinal cord circulation. During general anesthesia, midazolam is usually co-administered with other anesthetics. Therefore, the present study was performed to explore the effects of midazolam administered IV during isoflurane anesthesia.
After obtaining institutional approval, 32 cats (male; 2.5–3.5 kg; Nippon Biosupply, Tokyo, Japan) were fasted for 12 h. Anesthesia was induced with isoflurane (4%) anesthesia in 100% oxygen, and tracheostomies were made. Anesthesia was maintained with 1.5% isoflurane in 40% oxygen mixed with air. Artificial ventilation was adjusted to maintain end-tidal carbon dioxide tension (ETco2) between 35 and 40 mm Hg. The femoral vein was cannulated to infuse lactated Ringer's solution at a rate of 30 mL · kg−1 · h−1. The femoral artery was cannulated to monitor arterial blood pressure. Heart rate was monitored by electrocardiogram. Arterial blood gas analysis was performed before study drug treatment (ABL 505; Radiometer CO Ltd, Copenhagen, Denmark). Rectal temperature was monitored and maintained within 37.0°C ± 0.5°C by a heating blanket and a heating lamp.
The cats were fixed in a stereotaxic apparatus in the supine position. Via a midline skin incision, the laminas of L1-5 were removed, and the spinal cord was exposed. A platinum electrode (100 μM in diameter, UHE-100; Unique Medical, Tokyo, Japan) was inserted stereotaxically into the spinal cord to a depth of 1 mm at 2 mm lateral to the midline at L2. Spinal cord blood flow was measured with the hydrogen clearance method (7). Hydrogen was added to the anesthetic gas mixture at a concentration of 15% for 2 min. Hydrogen was then eliminated from the inspired gas, and the washout curve was recorded. Local spinal cord blood flow during the 2 min after the first 30 s of the washout curve was calculated (MHG-D1; Unique Medical) based on the blood-tissue exchange theory of Kety and Schmidt (8).
Arterial blood pressure, heart rate, and spinal cord blood flow were measured before and at 5, 15, 30, 60, 90, and 120 min after IV bolus administration of midazolam 0, 1, 2, or 4 mg/kg in saline 5 mL (n = 8 cats per dose).
Data are expressed as mean ± sd or mean and range. Spinal cord blood flow was converted to percent change against the control value before drug administration. Statistical analysis was performed with repeated-measures analysis of variance followed by the Student-Newman-Keuls test when indicated by a significant F ratio. A P value <0.05 was considered statistically significant.
Arterial blood gas values before the study drug treatment were a pH value of 7.38 (range, 7.34–7.40), oxygen tension (Pao2) was 221 mm Hg (201–242 mm Hg), and carbon dioxide tension (Paco2) was 37.8 mm Hg (36.3–39.5 mm Hg) without any differences detected among the groups. Arterial blood pressure decreased during the first 30 min after midazolam 2 and 4 mg/kg but did not change with midazolam 0 or 1 mg/kg. Heart rate did not change after any dose (Fig. 1). Spinal cord blood flow before drug administration was 55 ± 15 mL · 100 g−1 · min−1, 50 ± 16 mL · 100 g−1 · min−1, 46 ± 15 mL · 100 g−1 · min−1, and 52 ± 14 mL · 100 g−1 · min−1 in the 0, 1, 2, and 4 mg/kg of midazolam groups, respectively. These values were not significantly different. Spinal cord blood flow increased significantly for 90 min after midazolam 1 mg/kg and for 15 min after midazolam 2 mg/kg (Fig. 2).
Spinal cord blood flow was increased by the smallest dose of IV midazolam used (1 mg/kg) without any changes in arterial blood pressure, whereas the largest dose (4 mg/kg) did not induce any changes in spinal cord blood flow but decreased arterial blood pressure.
Spinal cord blood flow in cats was reported by Landau et al. (9) to be 14 mL · 100 g−1 · min−1 in the white matter and 63 mL · 100 g−1 · min−1 in the gray matter. Griffiths (10) reported a spinal cord blood flow of 16 mL · 100 g−1 · min−1 in the white matter and 48 mL · 100 g−1 · min−1 in the gray matter in the dog. In the present study, the platinum electrode was inserted 1 mm below the spinal cord surface. Therefore, blood flow in the gray matter could be measured. Baseline values in the present study are consistent with reports using different methods of measurement (9,10). The hydrogen clearance method was used in the present study because it is still considered to be a standard (11), and complicated apparatus such as magnetic resonance imaging or radiation detector are not required. In addition, a good correlation was obtained between the hydrogen clearance method and other techniques (11,12). Mean baseline spinal cord blood flow (time 0) was 20% different between the 0 mg/kg and 2 mg/kg groups. Although the difference was not statistically significant, to avoid the effects of the variation on the comparison, percent changes were used to analyze data.
There are many factors affecting spinal cord blood flow. Spinal cord blood flow increased as ETco2 increased (13), but it did not change with mean arterial blood pressure between 50 and 135 mm Hg (14) or with Pao2 more than 40 mm Hg (15). In the present study, ETco2 was kept between 35 and 40 mm Hg with the initial Paco2 values ranging from 35 to 40 mm Hg, arterial blood pressure was in the range of autoregulation, and the Pao2 was more than 40 mm Hg. Therefore, spinal cord blood flow measured in the present study was likely to have been free from the influence of Paco2, Pao2, and arterial blood pressure changes.
Spinal cord blood flow might change similarly to cerebral blood flow. In awake volunteers, bolus midazolam (0.15 mg/kg) decreased cerebral blood flow, but mean arterial blood pressure also decreased (3). During fentanyl-nitrous oxide anesthesia, bolus midazolam 0.2 mg/kg decreased cerebral blood flow for 15 minutes without any changes in arterial blood pressure (4). However, Cold et al. (6) observed no change in cerebral blood flow by a bolus plus continuous infusion of midazolam supplemented with nitrous oxide and fentanyl, and they did not show a change in arterial blood pressure. Therefore, IV bolus midazolam does not increase cerebral blood flow.
The effects of other IV anesthetics on spinal cord blood flow have been investigated. Pentobarbital did not change spinal cord blood flow when arterial blood pressure and arterial oxygen tension were controlled in conscious sheep (16), whereas a large dose of thiopental decreased spinal cord blood flow during morphine and nitrous oxide anesthesia without control of arterial blood pressure (17). IV morphine decreased spinal cord blood flow during halothane (1%–1.5%) anesthesia that was antagonized by naloxone (18). IV butorphanol had no effects on spinal cord blood flow during halothane (0.8%) anesthesia (19). All of these studies should be considered as an interaction between the studied drug, other anesthetics coadministered, arterial blood pressure, Pao2, and Paco2. However, no IV anesthetics increased spinal cord blood flow as did midazolam in the present study. The mechanism of the increase is not known. The present study was performed during isoflurane anesthesia. Isoflurane increased spinal cord blood flow within the arterial blood pressure range of 90–130 mm Hg (20). In addition, isoflurane may have impaired autoregulation, even in a range of arterial blood pressure usually considered to be within the autoregulatory range (20). Therefore, the decrease in arterial blood pressure in the midazolam 2 and 4 mg/kg groups may have decreased spinal cord blood flow during isoflurane anesthesia that masked the increase otherwise caused by midazolam. To know the effects of midazolam, isoflurane should be discontinued. However, anesthesia was required because of the invasiveness of the surgical procedure. However, in patients, midazolam is often coadministered with other anesthetics. Therefore, this study may present information relevant to clinical scenarios.
In conclusion, a smaller dose of midazolam (1 mg/kg) increased spinal cord blood flow without changes in arterial blood pressure, but a larger dose (4 mg/kg) did not change spinal cord blood flow, but this was associated with a substantial arterial blood pressure decrease during isoflurane anesthesia.
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© 2005 International Anesthesia Research Society
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