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Anesth Analg 2003;97:512-519 © 2003 International Anesthesia Research Society
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Abstract |
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We have reported that increased glutamate concentrations in microdialysate of the cerebrospinal fluid (CSF) may be clue phenomena to elucidate mechanisms of neurotoxicity of intrathecal tetracaine. However, little is known about whether this is true for other local anesthetics. In this study, we compared the effects of local anesthetics on glutamate concentrations in CSF microdialysate and neurologic and histopathologic outcome. Rabbits were assigned into 5 groups (n = 6 in each) and intrathecally received 0.3 mL of NaCl solution (control), 2% tetracaine, 10% lidocaine, 2% bupivacaine, or 2% ropivacaine. Neurologic and histopathologic assessments were performed 1 wk after the administration. Intrathecal local anesthetics significantly increased glutamate concentrations with no significant differences among the four local anesthetics. The sensory and motor functions in the lidocaine group were significantly worse than in the other groups. Characteristic histopathologic changes were vacuolation in the dorsal funiculus and chromatolytic damage of motor neurons. The extent of vacuolation of the dorsal funiculus was in the order of lidocaine = tetracaine > bupivacaine > ropivacaine. Although the differences among the local anesthetics cannot be explained by glutamate concentrations, the results suggest that the margin of safety may be smallest with lidocaine.
IMPLICATIONS: Large concentrations of local anesthetics administered intrathecally increased glutamate concentrations in the cerebrospinal fluid. The margin of safety may be smallest with lidocaine.
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Introduction |
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A rare but feared complication after spinal anesthesia is persistent neurologic injury. Four cases of cauda equina syndrome after continuous spinal anesthesia with 5% lidocaine or 1% tetracaine were reported in 1991 and generated concern about the neurotoxic potential of local anesthetics administered intrathecally (1). In 1993, Schneider et al. (2) first reported transient neurologic symptoms (TNS) after bolus injection of 5% lidocaine into the lumbar subarachnoid space. TNS is characterized by pain, dysesthesia, or both in the buttocks, thighs, or lower limbs occurring after recovery from anesthesia. Although a relation between the persistent neurologic injury and TNS remains to be clarified, it is possible that TNS represents the lower end of a spectrum of toxicity (3). Many prospective clinical studies have investigated the effects of various local anesthetics, including lidocaine, bupivacaine, and tetracaine, on TNS (4,5). In general, the results of those studies suggest that lidocaine is associated with a more frequent incidence of TNS (4,5).
Ready et al. (6) investigated the neurotoxicity of local anesthetics, including lidocaine, bupivacaine, and tetracaine, after bolus injection into the subarachnoid space of the spinal cord in rabbits. They observed that persistent neurologic deficits were not seen with clinically used concentrations of lidocaine, bupivacaine, and tetracaine but that such deficits were seen with larger concentrations of lidocaine and tetracaine. However, there appeared to be no difference in neurologic deficiencies in those three local anesthetics, given that the potency ratios they reported (1:5:5 for lidocaine/bupivacaine/tetracaine) were taken into consideration.
We have reported in rabbits that intrathecal administration of tetracaine (1%, 2%, and 4%) increased glutamate concentrations in cerebrospinal fluid (CSF) microdialysate and worsened the hind-limb motor function in a dose-dependent manner (7). Histopathologic examination revealed vacuolation of the dorsal funiculus and central chromatolysis of the motor neurons in the lumbar spinal cord, possibly suggesting dorsal and ventral root injuries. A positive correlation was observed between glutamate concentration and tetracaine concentration (and neural injury). In the subsequent study, we demonstrated that there was a strong correlation between the degree of vacuolation of the dorsal funiculus and the sensory impairment (8). Although the precise mechanisms and roles of the increase in glutamate concentrations are still unknown, we speculate that large concentrations of glutamate are associated with the neurotoxicity of intrathecally administered local anesthetics (7,8).
This study was designed to compare the effects of tetracaine, lidocaine, bupivacaine, and ropivacaine on glutamate concentrations in CSF microdialysate and to discover the neurologic and histopathologic outcome. Ropivacaine has been newly introduced for clinical anesthesia, but the neurotoxicity of intrathecally administered ropivacaine has not been investigated.
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Methods |
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The protocol of this experiment was reviewed and approved by the Ethics Committee on Animal Experiments in Yamaguchi University School of Medicine. We used 46 New Zealand White rabbits weighing 2.9 ± 0.3 kg (mean ± SD).
Experiment 1
The methods for implantation of an intrathecal microdialysis probe and a catheter for drug administration, monitoring, microdialysis, and neurologic and histopathologic evaluations were almost the same as in our previous studies (7–9). Briefly, under general anesthesia with isoflurane, a loop-type microdialysis probe was implanted intrathecally from the L3-4 interlaminar space (10). From the L4-5 interlaminar space, the proper position of the tip of the probe was verified. A PE-10 catheter for drug administration was also implanted intrathecally (directed caudad) through the L5-6 interlaminar space so that the tip of the catheter was located at the level of the cauda equina. Two to three days after implantation, the animals that showed no sign of neurologic deficit were studied.
The rabbits were anesthetized, and an ear vein catheter was inserted for the administration of drugs and lactated Ringer’s solution. After placement of an endotracheal tube, mechanical ventilation was adjusted to maintain PaCO2 at 35–42 mm Hg (fraction of inspired oxygen, 0.4; isoflurane 1%). A PE-60 catheter was inserted into the left femoral artery for measurement of arterial blood pressure and arterial blood gases. Esophageal temperature was monitored.
The implanted dialysis probe was perfused with artificial CSF (11). The probe was perfused for at least 1 h before baseline samples were collected. Samples of dialysate (each 10 min in duration) were collected as follows: three baseline samples before the administration of NaCl solution, tetracaine, lidocaine, bupivacaine, or ropivacaine; and 9 samples during 90 min after intrathecal injection of the drugs. Samples were collected in ice-cooled tubes and immediately frozen and stored at -80°C. All samples were analyzed for glutamate by high-performance liquid chromatography.
Animals were randomly assigned to one of the following groups (six in each): a control group, a tetracaine group, a lidocaine group, a bupivacaine group, or a ropivacaine group. The control group received 0.3 mL of 330-mOsm NaCl solution. The tetracaine, lidocaine, bupivacaine, and ropivacaine groups received 0.3 mL of 2% tetracaine (crystalline tetracaine hydrochloride dissolved in saline; Kyorin Pharmaceutical, Tokyo, Japan), 10% lidocaine (10% lidocaine solution; AstraZeneca Japan, Osaka, Japan), 2% bupivacaine (crystalline bupivacaine hydrochloride dissolved in saline; AstraZeneca Japan), and 2% ropivacaine (crystalline ropivacaine hydrochloride monohydrate dissolved in saline; AstraZeneca Japan), respectively. The osmolarity and pH of 2% tetracaine, 10% lidocaine, 2% bupivacaine, and 2% ropivacaine were 
330, 650, 410, and 400 mOsm/L (Osmostat OM-6040; Arkray, Shiga, Japan) and 5.30, 5.90, 4.95, and 5.00, respectively. Each local anesthetic was administered intrathecally over 1 min. Mean arterial blood pressure (MAP) was maintained at more than 60 mm Hg by infusing phenylephrine after intrathecal administration of local anesthetic.
After the last sample was collected (90 min after intrathecal administration of NaCl solution or local anesthetics), the vascular catheter was removed, and all incisions were sutured. Extubation of the trachea was performed when adequate spontaneous ventilation occurred. An antibiotic (cephazolin 30 mg/kg IM) was administered once daily.
The rabbits were neurologically assessed daily until 1 wk after the administration of a local anesthetic by an observer unaware of the treatment group. Sensory function was evaluated by seeking an aversive response to pinprick stimulation with a 23-gauge needle progressing from the sacral to thoracic dermatomes (8). The score of the sensory function was assessed by a 3-point grading scale: 2, normal; 1, diminished response present; 0, no response present. The hind-limb motor function was assessed with the 5-point grading scale proposed by Drummond and Moore (12): 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 function scoring at 1 wk, the animals were reanesthetized, and transcardiac perfusion and fixation were performed. The coronal sections of the spinal cord (8 µm) at the L5 level were stained with hematoxylin and eosin. Morphological changes of the spinal cord were assessed at a magnification of 100–400x by an observer unaware of the treatment groups. As described in Results, the characteristic histologic changes were vacuolation in the dorsal funiculus and the chromatolytic appearance of the motor neurons. Accordingly, the degree of the spinal cord damage was assessed individually for the vacuolation in the dorsal funiculus and the chromatolytic change of the motor neurons. The degree of the vacuolation of the dorsal funiculus was assessed with a four-point grading scale: 0, no vacuolation; 1, <10% area of the dorsal funiculus vacuolated; 2, 10%–50% area of the dorsal funiculus vacuolated; 3, more than 50% area of the dorsal funiculus vacuolated. The neurons with chromatolytic appearance were identified by round-shaped cytoplasm with loss of Nissl substance from the central part of the cell and eccentric nuclei. The motor neurons with chromatolytic appearance were counted in two sections for each animal and averaged.
Experiment 2
To compare the anesthetic effects of tetracaine, lidocaine, bupivacaine, and ropivacaine in our model, we administered 0.3 mL of 0.5% tetracaine (dissolved in saline), 2.5% lidocaine (diluted with saline), 0.5% bupivacaine (dissolved in saline), or 0.5% ropivacaine (dissolved in saline) into the lumbar subarachnoid space in awake rabbits implanted with an intrathecal catheter (four in each). The method for implantation of the intrathecal catheter was the same as described in Experiment 1, except that the microdialysis probe was not implanted. We measured the time from the injection of a local anesthetic to the time point when the analgesia level regressed to half of the maximum level by repeating an assessment every 5 min. An analgesia level was evaluated by seeking an aversive response to pinprick stimulation with a 23-gauge needle.
Parametric data are presented as mean ± SD. To determine differences in glutamate concentrations among groups over time, a repeated-measures analysis of variance (ANOVA) (groups versus time) was performed. To quantify the CSF concentrations of glutamate over time, the glutamate exposure index was calculated for each of the treatment groups by multiplying the glutamate concentration by the duration (in minutes) over which a given dialysate was collected. The values were summed from t = 10 through t = 60 for each of the treatment groups. Between-group comparison for the glutamate exposure index was made using one-way ANOVA. Changes in physiological variables were also compared by using repeated-measures ANOVA followed by factorial ANOVA and Fisher’s protected least significant difference test. The cutaneous sensation, hind-limb motor function, and morphological changes of the spinal cord were analyzed with a nonparametric method (Kruskal-Wallis test) followed by the Mann-Whitney U-test. A Spearman’s rank correlation test was applied to analyze the correlation of the extent of vacuolation of the dorsal funiculus with sensory disturbance. P < 0.05 was considered statistically significant.
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Results |
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There were no significant differences among the groups for most of the physiological variables, except for MAP and heart rate, which were less at the same time point in the groups given local anesthetics compared with those in the control group (Table 1). The dose of phenylephrine infusion given to maintain MAP more than 60 mm Hg was not different among the four groups given local anesthetics.
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Intrathecal administration of tetracaine, lidocaine, bupivacaine, and ropivacaine significantly increased glutamate concentrations in CSF microdialysate, whereas there was no significant change in glutamate concentrations after intrathecal injection of NaCl solution (control) (Fig. 1). There were no significant differences in glutamate concentrations among the four local anesthetic groups (tetracaine, lidocaine, bupivacaine, and ropivacaine), with a tendency of minimum increase for ropivacaine, by a repeated-measures ANOVA (groups versus time). Comparison of the glutamate exposure index (from t = 10 through t = 60) revealed no significant difference among the four groups.
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All animals in the control and ropivacaine groups showed normal cutaneous sensation 1 wk after the injection of NaCl solution or ropivacaine (Table 2). The sensory function score in the lidocaine group was significantly worse than in the other four groups. The sensory function score in the tetracaine group was significantly worse than in the bupivacaine, ropivacaine, or control groups but was better than in the lidocaine group. Sensory function at 2 days after injection was similar to that at 7 days after injection.
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The motor function score was normal in all animals in the control, bupivacaine, and ropivacaine groups 1 wk after the injection of NaCl solution, bupivacaine, or ropivacaine (Table 3). Motor function slightly improved in five animals and slightly deteriorated in one animal over the 7-day observation period. The motor function score in the tetracaine and lidocaine group was significantly worse than in the other three groups.
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Characteristic findings in the histopathology of the spinal cord in animals with decreased cutaneous sensation and motor dysfunction were vacuolation in the white matter and central chromatolytic damage of the motor neurons, with round-shaped cytoplasm and laterally placed nuclei predominantly in the ventral horn (Fig. 2). The vacuolation in the white matter was confined within the dorsal funiculus. The histopathologic scores of vacuolation in the dorsal funiculus in the tetracaine and lidocaine groups were significantly worse than in the bupivacaine and ropivacaine groups (Table 4). Between the bupivacaine group and the ropivacaine group, the histopathologic score was significantly better in the ropivacaine group than in the bupivacaine group. All animals with decreased cutaneous sensation showed vacuolation of the dorsal funiculus of the lumbar spinal cord. When data from all five groups were combined, there was a significant correlation between the histopathologic score and the sensory function score (Fig. 3; rs = 0.795; P < 0.0001), but there was no significant correlation between the histopathologic score and peak glutamate concentrations (Fig. 4; P = 0.453) or the glutamate exposure index. In the tetracaine group, three animals exhibited chromatolytic motor neurons (2, 2, and 19 neurons). These three animals all showed mild sensory impairment (score = 1) and slight motor dysfunction (score = 3). Also, in the lidocaine group, two animals exhibited chromatolytic motor neurons (5 and 12 neurons). The sensory function of these two animals had a score of 0, and motor function was scored 3 and 1. In the other animals, no motor neuron with chromatolytic appearance was observed.
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In Experiment 2, the time from the injection of a local anesthetic to the time point when the analgesia level regressed to half of the maximum level was 71 ± 9 min, 25 ± 7 min, 51 ± 5 min, and 48 ± 7 min (mean ± SD) in the 0.5% tetracaine, 2.5% lidocaine, 0.5% bupivacaine, and 0.5% ropivacaine groups. The maximum rostral analgesic levels were around the 10th thoracic vertebra. All animals showed no sensory or motor dysfunction at 1 wk after recovery of local anesthetic effects.
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Discussion |
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In this study, we demonstrated that the neurotoxicity of lidocaine was the greatest among the local anesthetics tested and that the least neurotoxic potential was with ropivacaine. The large concentrations of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally all increased glutamate concentrations in CSF microdialysate, but the extent of increase did not achieve a statistically significant difference among the local anesthetics.
Ready et al. (6) investigated the neurotoxicity of local anesthetics administered intrathecally at the cauda equina level both neurologically and histopathologically in rabbits. The large concentrations of local anesthetics were demonstrated to have neurotoxic potential. They observed histopathological damage to the cauda equina, with axonal degeneration, areas of central necrosis within the spinal cord, and subpial vacuolation. However, they observed no correlation between lesions in the cauda equina and the extent or type of functional loss. In this study, the degree of vacuolation of the dorsal funiculus was scored, and there was a significant correlation between the histopathologic score and the sensory function score. The correlation was consistent with the results in our previous study (8). Therefore, the histopathologic scoring system used in this study is believed to be reliable for the study of local anesthetic-induced neurotoxicity. We speculate that the axonal injuries of the primary afferent fibers result in Wallerian degeneration, which is observed as vacuolation in the dorsal funiculus because the dorsal funiculus is constituted of primary afferent fibers without synapsing in the dorsal horn. The preferential damage to nerve roots after intrathecal administration of local anesthetics demonstrated in other studies would support this speculation (13,14).
The anesthetic potency ratios calculated from the estimated values of the minimum reversible concentration in rabbits are approximately 1:5:5 for lidocaine, tetracaine, and bupivacaine, respectively (6). Regarding ropivacaine, the studies in animals, including rabbits, demonstrated that ropivacaine and bupivacaine were equipotent (15,16). In our previous study in rabbits, we investigated the dose-dependent neurotoxic effects of tetracaine and reported that 0.3 mL of 1%, 2%, and 4% tetracaine caused slight neuronal injury at 1%, mild to moderate neuronal injury at 2%, and severe neuronal injury at 4% (7). On the basis of our previous results, we believed that in this study it was appropriate to choose the concentrations of local anesthetics 2 to 4 times as large as those used clinically to evaluate toxicity. Therefore, we chose 2% tetracaine, 10% lidocaine, 2% bupivacaine, and 2% ropivacaine. In Experiment 2, these local anesthetics were administered intrathecally in awake rabbits. The administration volume was the same as in Experiment 1, but the concentration was one-fourth of the concentration used in Experiment 1. The results of analgesia levels and duration suggest that the sensitivity of rabbits to these local anesthetics is not far from that of humans.
The neurotoxicity of lidocaine was the greatest among the local anesthetics tested in this study. This result is consistent with the previous study by Drasner et al. (17), who examined lidocaine, tetracaine, and bupivacaine. They established a rat model in which local anesthetics were administered continuously into the lumbar subarachnoid space (13,17). They reported in rats that 5% lidocaine had a greater sensory disturbance compared with 0.5% tetracaine or 0.75% bupivacaine, although the distribution of local anesthetics in their model was restricted in the cauda equina. There was no difference between tetracaine and bupivacaine (17). The histopathological evaluation was not performed in their study. In this study, we compared 2% tetracaine, 10% lidocaine, and 2% bupivacaine and demonstrated that lidocaine had greater neurotoxicity than tetracaine or bupivacaine. In addition, bupivacaine was demonstrated to be less neurotoxic than tetracaine.
Ropivacaine has been newly introduced for clinical anesthesia (18) and is usually administered epidurally. There is no study regarding the neurotoxicity of ropivacaine administered intrathecally. The results suggest that 2% ropivacaine has the least neurotoxicity of the local anesthetics in this study.
In our previous studies, we demonstrated that tetracaine (1%, 2%, and 4%) administered intrathecally consistently increased glutamate concentrations in a dose-dependent manner in CSF microdialysate (7). In this study, we found that lidocaine, bupivacaine, and ropivacaine, when given at large concentrations, also increased glutamate concentrations in CSF microdialysate. These results suggest that glutamate release is the phenomenon common to large concentrations of local anesthetics administered intrathecally. No apparent neuronal necrosis in the gray matter of the lumbar spinal cord was demonstrated in this study. This finding is consistent with our previous observations and suggests that large increases in glutamate concentration are caused by synaptic release by depolarization of nerve terminals by local anesthetics (19). A large concentration of glutamate is well known for its neurotoxicity. Although a positive correlation was observed between glutamate concentration and neuronal injury in our previous studies (7), there was no significant difference in the concentrations of glutamate among the groups given different local anesthetics in this study, despite the existence of different potentials of neurotoxicity. Large variability of glutamate concentrations may have affected the results. To explore the role of glutamate released into CSF after the administration of local anesthetics, further studies, including the use of glutamate receptor antagonists, may be warranted.
There are some limitations to this study. First, it examined the effects of local anesthetics at concentrations exceeding those clinically used. However, in our previous studies, 1% tetracaine sometimes caused vacuolation in the dorsal funiculus. If the TNS observed in patients represented the lower end of a spectrum of toxicity, the present results have substantial clinical relevance. Second, we did not analyze the histopathology of nerve roots that have been known to be preferentially injured with local anesthetics. Third, 2% ropivacaine and 2% bupivacaine may not be equipotent, because several studies in humans demonstrated that ropivacaine was less potent in both sensory and motor blockade (20,21). Taking these limitations into consideration, the possibility of overestimation for the safety of ropivacaine cannot be completely excluded.
In summary, large concentrations of local anesthetics administered intrathecally increased glutamate concentrations in CSF and revealed neurotoxicity. The concentration of lidocaine tested in this study was two times as large as the clinically used concentration, whereas those of tetracaine, bupivacaine, and ropivacaine were four times as large as clinically used concentrations. Nevertheless, the toxicity was the greatest for lidocaine. Therefore, it is suggested that the margin of safety may be smallest with lidocaine.
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Acknowledgments |
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Supported in part by the Ministry of Education, Science, Sports, and Culture (Grant 13671585) (MM).
The authors thank Dr. Tokuhiro Ishihara (First Department of Pathology) and Dr. Mutsuo Takahashi (Department of Surgical Pathology) for their advice in the assessment of histopathology and AstraZenaca Japan Ltd. for the supply of bupivacaine and ropivacaine.
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References |
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- Rigler ML, Drasner K, Krejcie TC, et al. Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg 1991; 72: 275–81.
[Abstract/Free Full Text] - Schneider M, Ettlin T, Kaufmann M, et al. Transient neurologic toxicity after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth Analg 1993; 76: 1154–7.
[Free Full Text] - Hampl KF, Heinzmann-Wiedmer S, Luginbuehl I, et al. Transient neurologic symptoms after spinal anesthesia. Anesthesiology 1998; 88: 629–33.[Web of Science][Medline]
- Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg 1999; 88: 797–809.
[Free Full Text] - Hampl KF, Schneider MC, Drasner K. Toxicity of spinal local anesthetics. Curr Opin Anaesthesiol 1999; 12: 559–64.
- Ready LB, Plumer MH, Haschke RH, et al. Neurotoxicity of intrathecal local anesthetics in rabbits. Anesthesiology 1985; 63: 364–70.[Web of Science][Medline]
- Ohtake K, Matsumoto M, Wakamatsu H, et al. Glutamate release and neuronal injury after intrathecal injection of local anesthetics. Neuroreport 2000; 11: 1105–9.[Web of Science][Medline]
- Oka S, Matsumoto M, Ohtake K, et al. The addition of epinephrine to tetracaine injected intrathecally sustains an increase in glutamate concentrations in the cerebrospinal fluid and worsens neuronal injury. Anesth Analg 2001; 93: 1050–7.
[Abstract/Free Full Text] - Wakamatsu H, Matsumoto M, Nakakimura K, Sakabe T. The effects of moderate hypothermia and intrathecal tetracaine on glutamate concentrations of intrathecal dialysate and neurologic and histopathologic outcome in transient spinal cord ischemia in rabbits. Anesth Analg 1999; 88: 56–62.
[Abstract/Free Full Text] - Marsala M, Malmberg AB, Yaksh TL. The spinal loop dialysis catheter: characterization of use in the unanesthetized rat. J Neurosci Methods 1995; 62: 43–53.[Web of Science][Medline]
- Yamamoto K, Ishikawa T, Sakabe T, et al. The hydroxyl radical scavenger Nicaraven inhibits glutamate release after spinal injury in rats. Neuroreport 1998; 9: 1655–9.[Web of Science][Medline]
- Drummond JC, Moore SS. The influence of dextrose administration on neurologic outcome after temporary spinal cord ischemia in the rabbit. Anesthesiology 1989; 70: 64–70.[Web of Science][Medline]
- Sakura S, Bollen AW, Ciriales R, Drasner K. Local anesthetic neurotoxicity does not result from blockade of voltage-gated sodium channels. Anesth Analg 1995; 81: 338–46.[Abstract]
- Hashimoto K, Sakura S, Bollen AW, et al. Comparative toxicity of glucose and lidocaine administered intrathecally in the rat. Reg Anesth Pain Med 1998; 23: 444–50.[Web of Science][Medline]
- Akerman B, Hellberg IB, Trossvik C. Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesiol Scand 1988; 32: 571–8.[Web of Science][Medline]
- Bader AM, Datta S, Flanagan H, Covino BG. Comparison of bupivacaine- and ropivacaine-induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 1989; 68: 724–7.
[Abstract/Free Full Text] - Drasner K, Sakura S, Chan VWS, et al. Persistent sacral sensory deficit induced by intrathecal local anesthetic infusion in the rat. Anesthesiology 1994; 80: 847–52.[Web of Science][Medline]
- Brown DL, Carpenter RL, Thompson GE. Comparison of 0.5% ropivacaine and 0.5% bupivacaine for epidural anesthesia in patients undergoing lower-extremity surgery. Anesthesiology 1990; 72: 633–6.[Web of Science][Medline]
- Gold MS, Reichling DB, Hampl KF, et al. Lidocaine toxicity in primary afferent neurons from the rat. J Pharmacol Exp Ther 1998; 285: 413–21.
[Abstract/Free Full Text] - Polley LS, Columb MO, Naughton NN, et al. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor. Anesthesiology 1999; 90: 944–50.[Web of Science][Medline]
- McDonald SB, Liu SS, Kopacz DJ, Stephenson CA. Hyperbaric spinal ropivacaine. Anesthesiology 1999; 90: 971–7.[Web of Science][Medline]
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Y. Koizumi, M. Matsumoto, A. Yamashita, S. Tsuruta, T. Ohtake, and T. Sakabe The effects of an AMPA receptor antagonist on the neurotoxicity of tetracaine intrathecally administered in rabbits. Anesth. Analg., March 1, 2006; 102(3): 930 - 936. [Abstract] [Full Text] [PDF]
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N. C. Voermans, B. J. Crul, B. de Bondt, M. J. Zwarts, and B. G. M. van Engelen Permanent Loss of Cervical Spinal Cord Function Associated with the Posterior Approach Anesth. Analg., January 1, 2006; 102(1): 330 - 331. [Full Text] [PDF]
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S. Sakura, Y. Kirihara, T. Muguruma, T. Kishimoto, and Y. Saito The Comparative Neurotoxicity of Intrathecal Lidocaine and Bupivacaine in Rats Anesth. Analg., August 1, 2005; 101(2): 541 - 547. [Abstract] [Full Text] [PDF]
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S. Kaneko, M. Matsumoto, S. Tsuruta, T. Hirata, T. Gondo, and T. Sakabe The Nerve Root Entry Zone Is Highly Vulnerable to Intrathecal Tetracaine in Rabbits Anesth. Analg., July 1, 2005; 101(1): 107 - 114. [Abstract] [Full Text] [PDF]
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H. Kokki, P. Ylonen, M. Laisalmi, M. Heikkinen, and M. Reinikainen Isobaric Ropivacaine 5 mg/mL for Spinal Anesthesia in Children Anesth. Analg., January 1, 2005; 100(1): 66 - 70. [Abstract] [Full Text] [PDF]
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H. Saeki, M. Matsumoto, S. Kaneko, S. Tsuruta, Y. Jun Cui, K. Ohtake, K. Ishida, and T. Sakabe Is Intrathecal Magnesium Sulfate Safe and Protective Against Ischemic Spinal Cord Injury in Rabbits? Anesth. Analg., December 1, 2004; 99(6): 1805 - 1812. [Abstract] [Full Text] [PDF]
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