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Anesth Analg 2005;101:541-547 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000155960.61157.12
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Abstract |
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There is a considerable difference in the number of reports of neurologic injury in the literature between lidocaine and other local anesthetics. Few in vivo animal studies have produced convincing results showing a difference in neurotoxicity among anesthetics. We investigated whether lidocaine and bupivacaine differ with respect to sensory impairment and histologic damage when equipotent doses of the two are administered intrathecally in rats. First, to determine relative anesthetic potency, rats intrathecally received 20 µL of saline, 0.625%, 1.25%, 2.5%, or 5% lidocaine, or 0.125%, 0.25%, 0.5%, or 1.0% bupivacaine, and were examined with the tail-flick test for 90 min. The potency ratio calculated was approximately 1:4.70 (95% confidence interval, 3.65–6.07) for lidocaine/bupivacaine. In the next experiment, 45 rats intrathecally received 20 µL of saline, 2.13% bupivacaine (approximately 1.5 mg/kg), or 10% lidocaine (approximately 6.9 mg/kg), and were examined for persistent functional impairment and morphologic damage. Rats given lidocaine developed significantly more prolonged tail-flick latencies than those in other groups 4 days after injection and incurred more morphologic damage than those given saline or bupivacaine. In conclusion, although the doses of anesthetics administered were larger than those used clinically, the present results suggest that bupivacaine is less neurotoxic than lidocaine when administered intrathecally at equipotent concentrations in the rat model.
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Introduction |
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Increasing laboratory evidence suggests that local anesthetics are potentially neurotoxic and that neurologic impairment after spinal anesthesia may result from a direct neurotoxic effect of local anesthetics (1–4). Thus, because reported permanent neurologic injury, including cauda equina syndrome, has been associated with lidocaine in most cases (5–8), this anesthetic may be more neurotoxic than other local anesthetics. However, few in vivo animal studies have produced convincing results showing this to be the case. Drasner et al. (1) intrathecally administered lidocaine, bupivacaine, and tetracaine into rats to induce sensory impairment and found that animals given lidocaine incurred more sensory deficit. However, the three drugs were continuously infused as commercially available solutions but not in equipotent concentrations and, as a result, the lidocaine solution administered was much more potent than the others. Other animal studies (3,9) using equipotent solutions from the same laboratory have revealed no significant difference in functional impairment or morphologic damage among lidocaine and bupivacaine or prilocaine.
Recently we (10) developed a rat model in which lidocaine was intrathecally administered as a bolus injection to produce persistent sacral sensory deficit and morphologic damage. Although animal models used in Drasner et al.’s laboratory and ours both received large dose local anesthetics, differences in the method of catheterization and/or drug administration, i.e., continuous or bolus, may have induced injury differently. Accordingly, in the present experiments, we investigated whether the difference in nerve injury can be observed between intrathecal lidocaine and bupivacaine when the two are administered as equipotent solutions in doses larger than used clinically in our rat model.
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Methods |
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The protocol was approved by the Animal Research and Use Committee of Shimane University (Permission No. 03-44). Male Sprague-Dawley rats weighing 289 ± 19 (mean ± sd) g were housed in groups of 4 in metal cages on a 12-h light-dark cycle. After catheterization, they were moved individually to a plastic cage within wood chips. Food and water were provided ad libitum. To reduce the influence of handling on behavioral reactions, all rats were trained in the test situation at least 3 times before experiments.
After administration of sodium pentobarbital (Dainippon Pharmaceutical, Osaka, Japan) (30 mg/kg intraperitoneally) with 1.5% halothane anesthesia, a heat-connected catheter of stretched polyethylene tubing PE-10 (1.1 cm), PE-10 (10 cm), and PE-20 (6 cm) was introduced into the subarachnoid space using an aseptic technique. Catheters were passed through the L4–5 intervertebral space and advanced 1.1 cm in the caudal direction. Before starting experiments, rats were allowed 4 days to rest for recovery from the operation. Rats having any problem with tail movements or motor dysfunction in the hindlimbs were not used in the ensuing experiments.
Neurologic function was measured by an investigator who was blinded to the solution administered to each animal. To measure the response of the tail to noxious heat stimulus, tail-flick (TF) test was performed using TF equipment (model DS20; Ugo Basile, Comerio-Varese, Italy). A 100-W projector lamp was focused on a distal segment of the tail approximately 5 cm from the tip. The time at which rats withdrew the tail was defined as the TF latency. A cutoff time of 10 s was used to avoid damage to the tail.
To measure the response of the legs to noxious mechanical stimulus, a paw pressure (PP) test was applied to the dorsal surface of both hindpaws using a device (Type 7200; Ugo Basile) capable of progressively increasing the pressure at a rate of 15 g/s. The pressure at which rats withdrew the paw from the device was defined as the PP threshold, and the mean value of both paws was used for analysis. A cutoff pressure of 400 g was used to prevent damage to the paws.
Motor function (MF) in lower limbs was also assessed. The grading of the motor block was as follows: 0 = none, 1 = partially blocked, and 2 = completely blocked. The normal baseline score was 0, and the score with bilateral complete block was 2 + 2 = 4. TF, PP, and MF tests were performed sequentially at the same time point with a 15-s interval.
In Experiment 1, to determine relative anesthetic potency for lidocaine and bupivacaine, groups of 5 rats each received an injection of 20 µL of 0 (saline), 0.625%, 1.25%, 2.5%, or 5% lidocaine or 0 (saline), 0.125%, 0.25%, 0.5%, or 1.0% bupivacaine into the intrathecal space. Ten microliters of saline was then injected to flush the catheter. The TF test was performed at 5, 10, 15, 20, 30, 45, 60, and 90 min after the drug administration. Some rats were tested on multiple days (not more than three), but never received the same or smaller concentration of anesthetic for the following injections. The intervals between injections were at least 24 h, and only those rats that recovered completely were used.
In Experiment 2, after the measurement of baseline TF latency and PP threshold, 45 rats with an intrathecal catheter were randomly divided into 3 groups to receive normal saline (group S, n = 14), 10% lidocaine (group L, n = 16), or 2.13% bupivacaine (group B, n = 15). Each solution was given in a volume of 20 µL intrathecally followed by 10 µL of saline to flush the catheter; the total doses of lidocaine and bupivacaine were approximately 6.9 and 1.5 mg/kg, respectively. Measurements of the TF, PP, and MF tests were repeated at 10, 20, 30, 60, 120, 180, and 240 min after drug administration and continued daily for 4 days. Rats in groups L and B that did not show any increase in the TF latency were excluded from the data analysis.
Anesthetic solutions were prepared by dissolving crystalline lidocaine and bupivacaine hydrochloride (Sigma Chemical, Steinheim, Germany) in sterile distilled water (Otsuka Pharmaceutical, Tokyo, Japan). All solutions were administered manually by a single bolus injection using a microsyringe at a rate of approximately 10 µL/15 s. The osmolarity and pH of all the solutions were measured (Auto & Stat, OM-6030, Arkray, Kyoto, Japan; and pH meter, F-22, Horiba, Kyoto, Japan).
After the last measurements in Experiments 2, rats were euthanized by injection of an overdose of pentobarbital and then perfused intracardially with a phosphate-buffered 2.0% paraformaldehyde-2.5% glutaraldehyde fixative. Methyl green solution was injected to confirm the location of the catheter after the perfusion. The spinal cord and nerve roots were dissected out and immersed in the same fixative for 4 h. Two specimens (10 mm rostral and caudal to the conus medullaris) from each rat were postfixed with cacodylate-buffered 1% osmium tetroxide, dehydrated in a series of graded alcohol solutions, and embedded in epoxy resin. From the embedded tissue, 1-µm transverse sections were obtained using the microtome (MT6000; RMC, Tucson, AZ) and stained with toluidine blue dyes. Neuropathologic examination was conducted using light microscopy by a pathologist who was masked to the group assignment and the results of functional assessments. Sections obtained from 10 mm rostral to the conus (caudal spinal cord) were used for qualitative evaluation. Quantitative analysis of nerve injury was performed using the sections obtained from 10 mm caudal to the conus (cauda equina). Each fascicle present in the cross-section was assigned an injury score of 0–3 (where 0 = normal, 1 = mild, 2 = moderate, and 3 = severe). The details of the nerve injury scoring system have been published previously (11). The injury score for each cross-section was then calculated as the average score of all the fascicles present in the cross-section. In addition, ultrathin sections were obtained using the same microtome described above and double-stained with uranyl acetate and lead citrate for electron microscopy (EM-002B; Topcon, Tokyo, Japan).
Sample size for Experiment 2 was determined by a power analysis based on the variability observed in our previous study (sd 0.6) and an expected difference of 0.8 in nerve injury score with ß set at 0.2 and 
set at 0.05. A minimal sample of 39 rats (13 in each group) met these criteria. Data were presented as means ± sem unless otherwise stated. TF latencies and PP thresholds were converted to the percent of the maximal possible effect, calculated as (postdrug value – baseline value)/(cutoff value – baseline value) x 100%. The area under the time-effect curve (AUC) was calculated by accumulating the effect measured at the discrete time intervals using the trapezoidal integration method. The dose-effect relationship for anesthesia was determined by using AUC values, and the potency ratio was calculated and tested for significance with a computer-based program (GraphPad Prism; GraphPad Software, Inc., San Diego, CA). The results of the TF and PP tests were analyzed by ANOVA with repeated measures followed by the Scheffé and Dunnett tests. The injury score for each solution was compared using one-way ANOVA followed by the Scheffé test. MF was analyzed by the Kruskal-Wallis test followed by Mann-Whitney U-test. The frequency (i.e., the number of rats with lesions) in each group was analyzed by 
2 test. A P value < 0.05 was considered to be statistically significant.
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Results |
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Experiment 1
In the course of Experiment 1, 2 rats were excluded from the study as a result of catheter failure. The two local anesthetics produced parallel dose-effect curves that significantly differed from each other (Fig. 1). The potency ratio calculated was approximately 1:4.70 (95% confidence interval, 3.65–6.07) for lidocaine/bupivacaine.
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Experiment 2
The osmolarities (mean ± sd) of the saline, 10% lidocaine, and 2.13% bupivacaine solutions were 292 ± 1, 629 ± 8, and 111 ± 2 mOsm/L, respectively, and the pH 6.31 ± 0.24, 4.97 ± 0.08, and 5.25 ± 0.11. Two animals each in groups L and B failed to develop anesthesia and were excluded from the study. One additional animal in group S was excluded because the catheter was located in the epidural space after the perfusion. Baseline TF latencies and PP thresholds did not differ among groups. TF latency and PP threshold did not change in rats in group S during the experiment. TF latencies in group B returned to the baseline values after 60 min, whereas rats in group L showed a persistent increase in TF latency for 4 days (Fig. 2). In addition, TF latencies in 4 of the 14 rats in group L continued to show cutoff values until 4 days after injection. The difference in TF latency between groups L and B was significant from 120 min to 4 days.
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PP threshold increased temporarily in rats given lidocaine and bupivacaine, but did not show any persistent increase after injection. The difference in PP threshold between groups L and B was significant at 30 min.
No rats given saline developed motor block during the experiment (Table 1). Rats in group L showed significantly higher motor block scores compared with those in group B at 30 min. However, the decrease in MF was observed only temporarily in any rats given local anesthetics.
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Nerve injury score with lidocaine was significantly greater than with saline and bupivacaine (Fig. 3). Representative sections from animals in each group are presented in Figure 4. Histologic changes in nerve roots were characterized by edema and axonal degeneration including appearance of myelin ovoid, and swelling, atrophy, and loss of axons with macrophage infiltration.
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Histologic examination of the spinal cord revealed axonal degeneration in the white matter and vacuolar degeneration of neurocytes in the gray matter in addition to the infiltration of macrophage in rats given local anesthetics. However, although the former changes were observed in both groups L and B, the latter changes in the gray matter were present only in rats in group L (Table 2).
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Typical electron microscopic findings are shown in Figure 5. In the specimen from a rat in group S, axons and myelin lamellae of myelinated fibers were almost intact. Unmyelinated fibers were also almost intact with clear neurofilaments, neurotubules, and mitochondria. In contrast, the specimen from a rat given lidocaine included axonal degeneration, disintegrated myelin lamellae, and myelin ovoid. Unmyelinated fibers were swollen, and unclear neurofilaments and neurotubules, and degenerated mitochondria were present. In addition, Schwann sheaths appeared to be degenerated. Similar pathologic changes were also observed in specimens from rats in group B.
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Discussion |
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Two experiments were performed. In the first, the dose-effect relationship for sensory anesthesia of the tail was determined and the potency ratio for the two local anesthetics was calculated. Anesthetic potencies have usually been determined by using a peak value or a value at a certain time after drug administration. However, because intrathecal lidocaine and bupivacaine differ in pharmacology and pharmacokinetic and, thus, onset and peak times, duration, and so forth, a single value at one point may not reflect the net effects of drugs administered. Therefore, we calculated AUC to compare the anesthetic effects of the two. The potency ratio calculated was approximately 1:4.7 for lidocaine/bupivacaine. Although equivalent relative potency would not necessarily be expected in different models, our findings agree closely with previously reported values. For example, in a study conducted in Drasner et al.’s (3) laboratory using continuous infusion, the relative potency was 1:4.3 for lidocaine/bupivacaine.
The neurotoxic effects of equipotent lidocaine and bupivacaine were compared functionally and morphologically in the second experiment. We decided to use 10% lidocaine, because the solution had produced nerve injury in our previous study (10). The data indicate that lidocaine produces more functional impairment and morphologic damage than bupivacaine. The results of electron microscopic examination are also worthy of note, showing that intrathecal local anesthetic can induce morphologic damage in both myelinated and nonmyelinated nerve fibers.
Previously, many in vitro studies have been conducted to compare the neurotoxicity of different local anesthetics. For example, Lambert et al. (12) assessed recovery from conduction blockade of desheathed frog sciatic nerve after exposure to some of the local anesthetic solutions frequently used for spinal anesthesia. Kasaba et al. (13) used cultured neurons from the freshwater snail Lymnaea stagnalis to observe morphologic changes in the growth cones and neuritis induced by local anesthetics. However, the results obtained from in vitro studies do not necessarily explain the clinical phenomenon because of a lack of blood supply and a difference in relative potency.
Various animal models have been developed for in vivo studies of neurotoxicity. Kalichman et al. (14) assessed relative neurotoxicity of etidocaine, lidocaine, chloroprocaine, and procaine using rat sciatic nerve and found that the order of potency for causing nerve injury was comparable to that for producing motor nerve conduction block, suggesting that local anesthetic neural toxicity parallels potency for producing local anesthesia. However, their results obtained with sciatic nerves do not necessarily apply to clinical injury after spinal anesthesia. Li et al. (15) intrathecally infused 0.5% bupivacaine, 1.5% lidocaine, and 2% 2-chloroprocaine into rats and found that residual paralysis of hindlimbs was similar for the 3 anesthetics and that perineuronal vacuolation in the gray matter was more common in the lidocaine and 2-chloroprocaine groups than in the bupivacaine group. In their model, however, the local anesthetics were not compared as equipotent solutions, and, because abnormal histology was also present in control rats, the difference in histology was not definitive evidence for different neurotoxicity among anesthetics. Yamashita et al. (16) used rabbits to observe functional and histologic changes after intrathecal local anesthetics and found that sensory and MFs and vacuolation in the dorsal funiculus were worse after lidocaine than tetracaine, bupivacaine, and ropivacaine. Unfortunately, they did not analyze the histology of nerve roots, which are preferentially injured with local anesthetics, and the functions observed were in lumbar segments area. In addition, despite adopting a fivefold difference in dosage between lidocaine and other anesthetics including tetracaine, bupivacaine, and ropivacaine, the equipotency was not confirmed.
The neurotoxic effects of equipotent lidocaine and bupivacaine were previously compared only once in a study (3), in which, despite a trend toward greater toxicity with lidocaine than with bupivacaine, a significant difference between the two anesthetics was not detected. The reason for the difference in conclusion between the previous and the present studies is highly speculative. Because a relatively small number of animals was used in the previous study, a type II error might have been involved. However, it should be noted that both studies differed in the method of injection and the amount of anesthetics injected. Although much larger concentrations of anesthetics were compared in this study, the doses of anesthetics administered as a bolus in the present study were smaller than those continuously infused in the previous study, in which drugs with less toxicity might have induced injury.
One of the possible criticisms against the protocol of the present study may be that the technique used to determine relative potency only reflects the specific index, which was TF latency and does not necessarily reflect the drug existence in the cerebrospinal fluid in the sacral region. In fact, both anesthetics were different in motor blockade in Experiment 2; at 30 minutes, rats given lidocaine developed higher motor block score than those given bupivacaine. Thus, if the relative potency had been determined based on the results of MF, the potency of bupivacaine would have been less than it was, and a larger concentration of bupivacaine would have been injected in Experiment 2, causing different results; neurotoxic effects of bupivacaine had been more apparent than they were.
Another criticism of the study may be the dose and concentration of local anesthetic used. Because local anesthetic solutions clinically administered rarely induce neurologic injury, the observation of neurotoxic effects would require larger dosage of drugs. To produce injury, Drasner et al. (1) have been using a rat model in which local anesthetics are continuously infused. In the present study, by contrast, we increased the concentration of local anesthetic. As a result, the concentrations of lidocaine and bupivacaine that induced neurologic damage in the present study exceed by far that used clinically. Thus, the functional impairment and morphologic damage observed may not be clinically relevant. However, the fact that rats given 2.13% bupivacaine incurred only minimal morphologic damage without functional impairment indicates that bupivacaine is far less neurotoxic than lidocaine.
In conclusion, the present experiments demonstrate that bupivacaine is less neurotoxic than lidocaine when administered intrathecally as equipotent solutions in doses larger than used clinically in the rat model.
The authors thank Dr. Toshiko Tsumori (Assistant Professor, Department of Morphological Neuroscience, Shimane University) for neuropathologic assessment and Mr. Tsunao Yoneyama (Technician, Center for Integrated Research in Science, Shimane University) for technical assistance.
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Footnotes |
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Supported by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (No. 15591630).
Presented in part at the Annual Meeting of the American Society of Anesthesiologists, Las Vegas, NV, October 23–27, 2004.
Accepted for publication December 29, 2004.
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References |
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- 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]
- Sakura S, Chan VWS, Ciriales R, Drasner K. The addition of 7.5% glucose does not alter the neurotoxicity of 5% lidocaine administered intrathecally in the rat. Anesthesiology 1995;82:236–40.[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]
- 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] - Schell RM, Brauer FS, Cole DJ, Applegate RL II. Persistent sacral nerve root deficits after continuous spinal anaesthesia. Can J Anaesth 1991;38:908–11.[Web of Science][Medline]
- Auroy Y, Narchi P, Messiah A, et al. Serious complications related to regional anesthesia: results of a prospective survey in France. Anesthesiology 1997;87:479–86.[Web of Science][Medline]
- Gerancher JC. Cauda equina syndrome following a single spinal administration of 5% hyperbaric lidocaine through a 25-gauge Whitacre needle. Anesthesiology 1997;87:687–9.[Web of Science][Medline]
- Kishimoto T, Bollen AW, Drasner K. Comparative spinal neurotoxicity of prilocaine and lidocaine. Anesthesiology 2002;97:1250–3.[Web of Science][Medline]
- Kirihara Y, Saito Y, Sakura S, et al. Comparative neurotoxicity of intrathecal and epidural lidocaine in rats. Anesthesiology 2003;99:961–8.[Web of Science][Medline]
- Sakura S, Hashimoto K, Bollen AW, et al. Intrathecal catheterization in the rat: an improved technique for morphologic analysis of drug-induced injury. Anesthesiology 1996;85:1184–9.[Web of Science][Medline]
- Lambert LA, Lambert DH, Strichartz GR. Irreversible conduction block in isolated nerve by high concentrations of local anesthetics. Anesthesiology 1994;80:1082–93.[Web of Science][Medline]
- Kasaba T, Onizuka S, Takasaki M. Procaine and mepivacaine have less toxicity in vitro than other clinically used local anesthetics. Anesth Analg 2003;97:85–90.
[Abstract/Free Full Text] - Kalichman MW, Moorhouse DF, Powell HC, Myers RR. Relative neural toxicity of local anesthetics. J Neuropathol Exp Neurol 1993;52:234–40.[Web of Science][Medline]
- Li DF, Bahar M, Cole G, Rosen M. Neurological toxicity of the subarachnoid infusion of bupivacaine, lignocaine, or 2-chloroprocaine in the rat. Br J Anaesth 1985;57:424–9.
[Abstract/Free Full Text] - Yamashita A, Matsumoto M, Matsumoto S, et al. A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits. Anesth Analg 2003;97:512–9.
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