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Abstract |
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The aim of the present study was to compare the effects of intrathecal tetracaine (a sodium channel blocker) with those of moderate hypothermia on glutamate concentrations of intrathecal dialysate, hindlimb motor functions, and histopathology in spinal cord ischemia. New Zealand White rabbits implanted with an intrathecal dialysis probe were assigned to one of the three groups (seven in each): control (temperature 38°C), tetracaine (tetracaine 0.5%, 0.6 mL, given intrathecally 30 min before ischemia, 38°C), or moderate hypothermia (32°C). Spinal cord ischemia (20 min) was produced by occlusion of the abdominal aorta during isoflurane (1%) anesthesia. Glutamate concentrations significantly increased during ischemia in all groups, but the levels in the moderate hypothermia group were significantly lower than those in the control and tetracaine groups. Neurologic status (24 and 48 h after reperfusion) and histopathology (48 h) in the moderate hypothermia group were significantly better than in the other two groups. There were no significant differences between the tetracaine and control groups in either glutamate concentrations, neurologic status, or histopathology. We conclude that intrathecal tetracaine does not provide any protection against ischemic spinal cord injury, whereas moderate hypothermia does.
Implications: Sodium channel blockers, including local anesthetics, have been shown to reduce glutamate release in brain ischemia and have a neuroprotective effect. However, in the present study, intrathecal tetracaine did not attenuate either glutamate release or the neurologic or histopathologic outcome in spinal cord ischemia, whereas moderate hypothermia did.
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Introduction |
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Spinal cord injury due to ischemia is a major source of disability after thoracoabdominal aortic aneurysm surgery. Neurotoxic effects of the endogenous glutamate released during ischemia have been elucidated. In transient spinal cord ischemia, extracellular glutamate increases (1–3), and N-methyl-D-aspartate (4,5) or
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (6,7) receptor antagonists protect against ischemic spinal cord injury. Therefore, interventions that attenuate an increase in the extracellular concentration of glutamate during ischemia may provide protective effects. The administration of sodium channel blockers [lidocaine (8) and lamotrigine (9)], as well as moderate hypothermia (10) reduce glutamate release in brain ischemia. The route of drug administration and its permeability across the blood-brain barrier influence the clinical applicability of pharmacological interventions. If the intrathecal administration of local anesthetics reduces glutamate release during spinal cord ischemia, it can be an attractive neuroprotective strategy in the clinical setting. Indeed, one report (11) demonstrated that the intrathecal administration of tetracaine (1%, 0.3 mL), which has a longer duration of action than lidocaine, improved neurologic function after transient spinal cord ischemia in rabbits. However, in that study, neurologic function was assessed only 6–10 h after reperfusion, and this assessment may not represent final neurologic outcome because delayed neurologic deficit has been shown to occur in this model 12–24 h after reperfusion (12). The mechanism for protection by tetracaine also has not been addressed. Therefore, we examined the effects of the intrathecal administration of tetracaine on glutamate concentrations in intrathecal dialysate and the neurologic and histopathologic outcome in transient spinal cord ischemia, extending the assessment period to 48 h after reperfusion. We also compared these effects with those of moderate hypothermia, which has been shown to provide promising protective effects against spinal cord ischemia (13). |
Methods |
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This experiment was reviewed by the our ethics committee. New Zealand White rabbits weighing 2.5–3.1 kg were used in this study.
Anesthesia was induced with halothane 4% in oxygen. An ear vein catheter was inserted, and a small dose of pentobarbital (20–40 mg) was administered to facilitate tracheal intubation. After placing a 3-mm cuffed endotracheal tube, the inspired gas mixture was changed to isoflurane 2%–3% in 40% oxygen/60% nitrogen, and PaCO2 was maintained at 35–42 mm Hg by mechanical ventilation. End-tidal concentrations of isoflurane and CO2 were continuously measured by using an infrared anesthetic analyzer (Model CX-2Sp; Nippon Colin, Komaki, Japan). Lactated Ringer's solution (4 mL · kg-1 · h-1) was administered IV. With the rabbits in the prone position, midline skin and subcutaneous fascia were incised between the third lumbar and the first sacral spinous process after infiltration with bupivacaine 0.25%. Muscles were dissected; the third to seventh processes, ligamentum flavum, and epidural fat were sequentially removed; and the underlying dura was exposed. Using an operating microscope, a small slit was made in the dura and arachnoid membrane at the L3-4 interlamina space. A loop-type microdialysis probe was then implanted. The dialysis probe with 3 cm of active dialysis site was constructed according to the method described by Marsala et al. (14). From the L4-5 interlamina space, the proper position of the tip of the probe was verified. A PE-10 catheter for the administration of saline or tetracaine was implanted intrathecally through the slit made at the L6-7 interlamina space so that the tip of the catheter was located at the level of the cauda equina.
Four to six days after the implantation, animals that showed no sign of neurologic deficit were studied. To verify the effectiveness of the drug administered via the intrathecal catheter, lidocaine (1%, 0.6 mL) was administered intrathecally 1 day before the animals were subjected to aortic occlusion. Motor block was observed in all the rabbits, lasting for 23 ± 3 (mean ± SD) min.
After an overnight fast with unrestricted access to water, the rabbits were anesthetized in the same manner as described above. Surgical preparation was the same as previously reported (13). Briefly, after infiltration with bupivacaine 0.25%, PE-60 catheters were inserted into both femoral arteries. The right-side catheter was advanced 3 cm into the abdominal aorta, whereas the other was advanced 17 cm. Before catheter insertion, IV heparin 400 U was administered. A flank skin incision (4–5 cm) parallel to the spine was made at the 12th costal level with the rabbits in the right lateral decubitus position. A PE-60 catheter was retroperitoneally placed around the aorta, immediately distal to the left renal artery. An occluder tube (16F rubber tube) was then tunneled into the skin for later occlusion of the aorta to produce spinal cord ischemia.
Animals were randomly assigned to one of the following groups (seven in each): a control group, a tetracaine group, or a moderate hypothermia group. Core temperature was monitored by using a calibrated esophageal thermistor (Model MGA-III, Type 219; Nihon Koden). To estimate spinal cord temperature, the paravertebral muscle (erector muscle of spine) temperature (15) at the level of L4-5 was monitored by a calibrated needle-type thermistor (Model PTC-201; Unique Medical, Tokyo, Japan). The paravertebral muscle temperature was maintained at 38.0–38.5°C with a heating lamp and warming pad in the control and tetracaine groups. In the moderate hypothermia group, no active warming was used during surgical preparation. After completion of surgery, the end-tidal isoflurane concentration was maintained at 1.0%. The moderate hypothermia group was slowly cooled by applying ice packs to the body surface. When the paravertebral muscle temperature reached approximately 33°C, the ice packs were removed. The temperature was then maintained at 32.0°C. PaCO2 was maintained at 35–42 mm Hg. In the moderate hypothermia group, it was controlled in stat.
Thirty minutes before the onset of ischemia, 3 mg of tetracaine (dissolved in 0.6 mL of saline) was administered intrathecally in the tetracaine group. In the control and moderate hypothermia groups, an equal volume of saline was administered. In the tetracaine group, phenylephrine (2–6 µg · kg-1 · min-1) was administered to maintain proximal mean arterial pressure (MAP) at a level comparable to that in the control group.
In a preliminary study, the action of tetracaine (0.5%, 0.6 mL) was assessed by estimation of motor block duration, which was 88 ± 4 min (n = 4).
MAP and heart rate (HR) were monitored continuously, and arterial blood was sampled for determination of PaO2, PaCO2, pH, hematocrit, and plasma glucose immediately before the onset of ischemia.
IV heparin 400 U was again administered immediately before aortic occlusion. Spinal cord ischemia was produced by occluding the aorta by pulling the PE catheter and clamping an occluder tube for 20 min. After the occlusion, distal blood pressure decreased immediately and the pulsatility disappeared. At 10 min of ischemia, all measurements except blood gas were recorded (intraischemic values). At the end of the 20-min period of ischemia, reperfusion was established by removal of the occluder tube and PE catheter with simultaneous administration of 10 mL of lactated Ringer's solution. Rewarming of the animals in the moderate hypothermia group began immediately on reperfusion with a heating lamp and warming pad.
After 60 min of reperfusion, the vascular catheters were removed, and all incisions were sutured. Isoflurane was discontinued, and the lungs were ventilated with 100% oxygen in the control and tetracaine groups. In the moderate hypothermia group, isoflurane was administered until esophageal temperature reached 37°C. Extubation of the trachea was performed when adequate spontaneous ventilation occurred. The time required from the start of reperfusion to extubation was 96 ± 14, 119 ± 22, and 142 ± 38 min in the control, tetracaine, and moderate hypothermia groups, respectively. Lactated Ringer's solution (4 mL · kg-1 · h-1) was provided IV until the animals began to drink. An antibiotic (cephazolin 30 mg/kg IM) was administered once daily, and bladder contents were expressed manually as required.
The dialysis probe was perfused with artificial cerebrospinal fluid (CSF) bubbled with 95% O2/5% CO2 to adjust the final pH to 7.2 at a rate of 10 µL/min. The artificial CSF contained (in mM) Na+ 151.1, K+ 2.6, Mg2+ 0.9, Ca2+ 1.3, Cl- 122.7, HCO3- 21.0, HPO42- 2.5, and dextrose 3.5 (16). Samples of dialysate (each 10-min duration) were collected as follows: three baseline samples before administration of tetracaine or saline, three samples before ischemia, two samples during 20 min of ischemia, and six samples during 60 min of reperfusion. Samples were collected in ice-cooled tubes and immediately frozen and stored at -80°C. All samples were analyzed for glutamate by using the phenylisothiocyanate derivatization procedure using high-performance liquid chromatography with a reverse-phase C18 column (3.9 x 250 mm, 5-µm particle) and electrochemical detector. This technique has a glutamate detection sensitivity of 5 pM. The interassay and intraassay coefficients of variation of glutamate were 5.0% and 7.4%, respectively. External standards were run daily.
At 8, 12, 24, and 48 h after reperfusion, the rabbits were neurologically assessed by an observer unaware of the treatment group using the five-point grading scale proposed by Drummond et al. (17): 4 = normal motor function; 3 = ability to draw legs under body and hop, but not normally; 2 = some lower extremity function with good antigravity strength but inability to draw legs under body; 1 = poor lower extremity motor function, weak antigravity movement only; 0 = paraplegic with no lower extremity motor function.
After completion of the neurologic deficit scoring at 48 h, the animals were reanesthetized, and transcardiac perfusion and fixation were performed with 1000 mL of heparinized saline followed by 500 mL of phosphate-buffered formalin 10%. The spinal cord was removed and refrigerated in phosphate-buffered formalin 10%, for 48 h. After dehydration in graded concentrations of ethanol and butanol, the spinal cord was embedded in paraffin. Coronal sections of the spinal cord (L5-6 level) were cut at a thickness of 8 µm and stained with hematoxylin and eosin. Neuronal injury was evaluated at x400 magnification by an observer unaware of the treatment groups. Ischemic neurons were identified by cytoplasmic eosinophilia with loss of Nissl substance and by the presence of pyknotic homogenous nuclei. In paraplegic animals, the anterior spinal cord was markedly destroyed, leaving little trace of neurons. Thus, normal neurons in the anterior spinal cord (anterior to a line drawn through the central canal perpendicular to the vertebral axis) were counted in two sections for each animal and averaged.
All data were analyzed by using a commercially available computer program (StatView 4.51.1; Abacus Concepts, Inc., Berkeley, CA). Parametric data are presented as mean ± SD. To determine differences between groups over time, repeated-measures analysis of variance (ANOVA) (groups versus time) was performed. If this analysis demonstrated a significant (P < 0.05) group effect, a repeated-measures ANOVA was performed by sequentially comparing each of the groups with the control group. Factorial analysis of variances and the Bonferroni/Dunn test were also used to determine differences in peak glutamate concentrations among the groups. A paired t-test was used to test the differences between baseline values and peak levels of glutamate concentration within one group. Changes in MAP, HR, body temperature, pH, PaO2, PaCO2, glucose, and hematocrit were compared by using repeated-measures ANOVA and Scheffé's test. The hindlimb motor function and the number of normal neurons in the anterior spinal cord were analyzed using a nonparametric method (Kruskal-Wallis test) followed by the Mann-Whitney U-test. The correlation of hindlimb motor function scores and the number of normal neurons in the anterior spinal cord was analyzed by using Spearman's rank correlation. A P value <0.05 was considered statistically significant.
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Results |
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Physiologic variables are shown in Table 1. There were no significant differences among the groups for most of the variables, except for HR, PaO2, and plasma glucose.
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All animals survived until the final neurologic scor-ing (48 h after reperfusion). The results of neurologic assessments are shown in Figure 1. The neurologic status at 24 and 48 h in the moderate hypothermia group was significantly better than that in the other two groups. There was no significant difference in neurologic status between the control and tetracaine groups throughout the assessment period.
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Figure 2 shows the glutamate concentrations of intrathecal dialysate. In all groups, the glutamate concentrations increased during ischemia compared with baseline and returned to baseline levels within 30 min after reperfusion. There were significant differences in glutamate concentrations (groups versus time) between the control and moderate hypothermia groups (P = 0.0002) and between the tetracaine and moderate hypothermia groups (P = 0.0065). There was no significant difference between the control and tetracaine groups (P = 0.267) (groups versus time). The peak glutamate concentration in the moderate hypothermia group was significantly lower than that in the control (P = 0.0004) and tetracaine groups (P = 0.0070). There was no significant difference between the control and tetracaine groups (P = 0.2016).
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Histopathology of the lumbar spinal cord was examined in 20 animals. Histopathologic data were lost from one animal in the moderate hypothermia group as a result of a technical problem during perfusion-fixation. This animal had no functional neurologic deficit. The number of normal neurons in the anterior spinal cord in the moderate hypothermia group was significantly greater than that in the control group (P = 0.003). There was no statistical difference between the control and tetracaine groups (P = 0.85) (Fig. 3). Histopathologic findings of the spinal cord from the animal in the moderate hypothermia group with normal motor function and from the animal in the tetracaine group with paraplegia are shown in Figure 4. When data from all three groups were combined, there was a significant correlation between the final neurologic status and the number of normal neurons in the anterior spinal cord (r = 0.92; P < 0.001) (Figure 5).
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Discussion |
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In the present study, we demonstrated that moderate hypothermia (32°C), but not intrathecal tetracaine, significantly attenuated the increase in glutamate concentrations of intrathecal dialysate during spinal cord ischemia produced by occlusion of the abdominal aorta and improved the neurologic and histopathologic outcome.
The rabbit spinal cord ischemia model used in the present study has been well characterized and is highly reproducible (18). In a previous study, we demonstrated that mild (35°C) and moderate (32°C) hypothermia protected against ischemic spinal cord injury in rabbits. Because a burst-suppression dose of thiopental failed to protect against spinal cord injury, we concluded that metabolic depression cannot be the sole explanation for the spinal cord protection by mild to moderate hypothermia (13). Rokkas et al. (3) demonstrated that deep hypothermia (20°C) prevented an extracellular glutamate increase in spinal cord ischemia in pigs and suggested that the mechanism of hypothermic protection may be related to the decreased release of glutamate. The current study suggests that this mechanism is applicable in moderate hypothermia. Both the concentrations of glutamate before and during ischemia were significantly lower in the moderate hypothermia group than in the other two groups. This suggests that moderate hypothermia can attenuate both basal and stimulated release of glutamate. It is unlikely that the increase in plasma glucose in the moderate hypothermia group was the cause of protection because hyperglycemia itself is known to aggravate ischemic damage (17).
The failure to demonstrate protective effects of tetracaine against ischemic spinal cord damage in this study is contrary to the results reported by Breckwoldt et al. (11). They demonstrated that the preischemic intrathecal administration of 3 mg (1%, 0.3 mL) of tetracaine in rabbits improved the neurologic function after 25 and 30 min of aortic occlusion. However, they did not measure blood pressure or body temperature at any time in the study. To verify the aortic occlusion, they only confirmed loss of pulse by palpation of the distal aorta. The neurologic function was only assessed 6–10 h after reperfusion. This early assessment may not represent the final neurologic outcome because delayed onset of paraplegia often occurs in this model. In the present study, we monitored both proximal and distal blood pressures and maintained a proximal blood pressure with phenylephrine in the tetracaine group that was comparable to that in the control group. Both paravertebral muscle and esophageal temperatures were also strictly controlled. Nevertheless, we did not observe a protective effect of tetracaine on neurologic or histopathologic outcome at either early (8–24 h) or final (48 h) testing.
Preischemic intrathecal administration of tetracaine did not attenuate an increase in the glutamate concentrations during ischemia. The administration of lidocaine through a microdialysis probe into the hippocampus has been demonstrated to attenuate an increase in extracellular glutamate concentrations during transient forebrain ischemia in gerbils (8), and intraventricular administration of lidocaine attenuated neuronal damage (8). A sodium channel blocker, lamotrigine (IV), has been demonstrated to inhibit extracellular glutamate accumulation during transient global brain ischemia in rabbits (9). Two mechanisms of glutamate release during ischemia have been suggested: one is the rapid Ca2+-dependent exocytotic release from synaptic vesicles on depolarization of the plasma membrane, the other is the slow efflux from the cytoplasmic pool in a Ca2+-independent manner (19). Sodium channel blockers may inhibit mainly the rapid release from the synaptic vesicles (8). Local anesthetics at the concentration required for spinal anesthesia also possess inhibitory potencies for L-type and N-type calcium channels (20). The blocking potency for the L-type calcium channel is greater than that for the N-type calcium channel, the potency rank sequence being dibucaine > tetracaine > bupivacaine >> procaine = lidocaine (20). Glutamate release during brief brain ischemia depends mainly on the N-type calcium channel (21), but the L-type calcium channel also seems to be involved (22). In the present study, we hypothesized that tetracaine inhibits glutamate release during transient spinal cord ischemia by affecting both sodium and calcium channels. However, our results did not support this hypothesis.
Whether the failure to demonstrate the protective effect of tetracaine on the neurologic and histopathologic outcome, as well as whether an attenuation of an increase in the glutamate concentration may represent an inadequate dose of the drug used, deserves consideration. We did not perform a dose-response study for tetracaine. However, in a preliminary study, we observed an unexplainable increase in the glutamate concentration after the administration of tetracaine (1%, 0.3 mL) in some rabbits. Therefore, to avoid the possible neurotoxic effect of a high concentration, we selected a dose of tetracaine 0.5%, 0.6 mL instead of 1%, 0.3 mL, as used by Breckwoldt et al. (11). The dose administered in this study may represent the maximal tolerable dose from a neurotoxic standpoint because concentrations of tetracaine greater than those used in the present study have been demonstrated to impair neurologic function (23). In our preliminary study, 3 mg of tetracaine (0.5%, 0.6 mL) produced motor block for 88 ± 4 min; thus, when given 30 min before ischemia, its effect should have lasted beyond the ischemic interval. Thus, it is unlikely that the failure to demonstrate any protective effect with tetracaine is due to an inadequate dose.
One may suspect that intrathecal tetracaine caused a substantial decrease in distal blood pressure, which may have affected the residual blood flow to the spinal cord during aortic occlusion and, hence, the outcome. However, the blood pressure in the tetracaine group was maintained by infusing phenylephrine at a level comparable to that in the control group. As a result, there were no differences in the proximal or distal blood pressure during ischemia among the three groups. Therefore, it is unlikely that hemodynamic state after tetracaine administration is the reason that we detected no protective effect.
Lidocaine delays the onset of anoxic depolarization after global cerebral ischemia (24). The duration of anoxic depolarization is a critical variable that ultimately defines neurologic outcome (25). There may have been a delay in the onset of anoxic depolarization during the early period of ischemia in the tetracaine group. There is also a possibility that the neuroprotective effect of tetracaine is observed during a much shorter duration of ischemia than that in the present study.
In summary, moderate hypothermia (32°C) attenuated an increase in the glutamate concentrations of intrathecal dialysate during ischemia and protected against ischemic spinal cord injury. The mechanism for protection by moderate hypothermia is related to the inhibition of glutamate release during spinal cord ischemia. In contrast, preischemic intrathecal administration of tetracaine did not attenuate ischemia-induced glutamate increase or improve neurologic or histopathologic outcome. The results suggest that an intrathecal sodium channel blocker, tetracaine, does not provide any protective effect against ischemic spinal cord injury, whereas moderate hypothermia does.
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Acknowledgments |
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Supported in part by Ministry of Education, Science, Sports, and Culture Grant 09671567 (to MM).
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