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© 2001 International Anesthesia Research Society
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Abstract |
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We have reported that large concentrations of intrathecal tetracaine increase glutamate concentrations in the cerebrospinal fluid (CSF) and cause neuronal injury in the spinal cord. In this study, we investigated whether the addition of epinephrine to tetracaine modulates these events. New Zealand white rabbits were assigned into five groups (six rabbits in each group) and intrathecally received 0.3 mL of epinephrine 0.1 mg/mL in NaCl solution (control), 1% tetracaine dissolved in saline (1%T), 1% tetracaine with epinephrine (1%TE), 2% tetracaine (2%T), or 2% tetracaine with epinephrine (2%TE). Glutamate concentrations in the lumbar CSF were monitored by microdialysis. Neurologic and histopathologic assessments were performed 1 wk after the administration. Glutamate concentrations significantly increased in all four groups that received tetracaine, whereas no change was observed in the Control group. The addition of epinephrine to tetracaine sustained large concentrations of glutamate. Sensory and motor dysfunction was observed in the 1%TE, 2%T, and 2%TE groups, and the dysfunction tended to be progressively exacerbated in this order. Characteristic histologic changes in animals with sensory and motor dysfunction were vacuolation in the dorsal funiculus and chromatolytic damage of motor neurons. The vacuolation of the dorsal funiculus in the 1%TE group was significantly worse than in the 1%T group. These results suggest that the addition of epinephrine to tetracaine may increase its neurotoxicity, which may possibly be related to a sustained increase of glutamate concentrations in the CSF.
IMPLICATIONS: Sustained increase of glutamate concentrations produced by the addition of epinephrine to intrathecal tetracaine can cause neuronal injury.
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Introduction |
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Epinephrine has often been used to prolong spinal anesthesia. However, an editorial has questioned the continued use of epinephrine for that purpose (1). Epinephrine is thought to decrease uptake of local anesthetics because of a vasoconstrictive effect and, therefore, to increase the duration of exposure of neurons to local anesthetics. An increased exposure to local anesthetics might cause neuronal injury because local anesthetics are potentially neurotoxic (2,3).
However, there has been no study that demonstrates definite evidence of epinephrine-induced neurotoxicity. In the study of Horlocker et al. (4), persistent paresthesia after spinal anesthesia occurred in none of 790 patients with epinephrine but in 6 of 3977 patients without epinephrine. Pollock et al. (5) reported no difference in the incidence of transient radicular irritation after spinal anesthesia between the patients with epinephrine and those without epinephrine (16% vs 16%). In the study of Horlocker et al. (4), however, the frequency of minor transient neurologic complications might have been underestimated, because their study was retrospective. The Pollock (5) study was a prospective one that examined transient radicular symptoms in detail, but unfortunately, the local anesthetic solution with epinephrine (5% hyperbaric lidocaine) was not identical to that without epinephrine (2% isobaric lidocaine).
The clinical study has some limitations in regard to exploring the details of the modulation of local anesthetic-induced neurotoxicity by epinephrine. Recently, we have reported that in rabbits intrathecal administration of tetracaine (1%, 2%, and 4%) increased glutamate concentrations in cerebrospinal fluid (CSF) microdialysate and worsened hind-limb motor function in a dose-dependent manner (6). Histopathologic examination revealed vacuolation of the dorsal funiculus and central chromatolysis of the motor neuron in the lumbar spinal cord, possibly suggesting dorsal and ventral root injuries (6). The precise mechanisms of the increase in glutamate concentrations are still unknown. The membrane depolarization occurs with large concentrations of lidocaine (7). Therefore, excessive synaptic releases of glutamate may have occurred because of membrane depolarization with tetracaine. Activation of glutamate receptors of the neurons might lead to central sensitization at the dorsal horn (8), neuronal injuries (9), or both.
This study was designed to investigate whether the addition of epinephrine to tetracaine modulates neurologic and histopathologic outcome after the intrathecal injection and whether the effect is related to the response in glutamate concentrations in CSF microdialysate.
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Methods |
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The protocol of this experiment was reviewed and approved by the Committee of the Ethics on Animal Experiments in the Yamaguchi University School of Medicine. We used 30 New Zealand white rabbits weighing 2.9 ± 0.2 kg (mean ± SD).
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 (6,10). Briefly, under general anesthesia with isoflurane, the fourth to sixth lumbar spinous processes, ligamentum flavum, and epidural fat were sequentially removed, and the underlying dura was exposed with the rabbit in the prone position. By 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 (11). 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 NaCl solution 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. Two to three days after implantation, the animals that showed no sign of neurologic deficit were studied.
After an overnight fast with unrestricted access to water, the rabbits were anesthetized, and an ear vein catheter was inserted for the administration of drugs and lactated Ringer’s solution. After placement of a 3-mm cuffed endotracheal tube (Mallinckrodt, St. Louis, MO), 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. Core temperature was monitored with a calibrated esophageal thermistor (Model MGA-III, Type 219; Nihon Koden, Tokyo, Japan).
The implanted dialysis probe was perfused with artificial CSF bubbled with 95% oxygen and 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, HCO-3 21.0, HPO42- 2.5, and dextrose 3.5 (12). The probe was perfused for at least 1 h before baseline samples were collected. Samples of dialysate (each of 10 min duration) were collected as follows: three baseline samples before the administration of tetracaine, tetracaine with epinephrine, or NaCl with epinephrine solution; and nine 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 o-phthalaldehyde procedure by using Eicom high-performance liquid chromatography (Eicom, Kyoto, Japan) 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.
Animals were randomly assigned to one of the following groups: a Control group (n = 6), a 1% Tetracaine group (1%T group, n = 6), a 1% Tetracaine with Epinephrine (0.1 mg/mL) group (1%TE group, n = 6), a 2% Tetracaine group (2%T group, n = 6), or a 2% Tetracaine with Epinephrine (0.1 mg/mL) group (2%TE group, n = 6). The Control group received 0.3 mL of 330 mOsm NaCl solution with 0.1 mg/mL of epinephrine. The 1%T and 2%T groups received 0.3 mL of 1% or 2% tetracaine (dissolved in saline) intrathecally, respectively. The 1%TE and 2%TE groups received 0.3 mL of 1% or 2% tetracaine (dissolved in saline with 0.1 mg/mL of epinephrine) intrathecally, respectively. The osmolarity of 1% or 2% of tetracaine was 327–340 mOsm/L (Osmostat OM-6040; Arkray, Shiga, Japan). Mean arterial pressure was maintained at >60 mm Hg by infusion of phenylephrine after the intrathecal administration of tetracaine.
After collecting the last sample (90 min after intrathecal administration of tetracaine or NaCl solution), the vascular catheters were removed, and all incisions were sutured. Isoflurane was discontinued, and the lungs were ventilated with 100% oxygen. Extubation of the trachea was performed when adequate spontaneous ventilation occurred. 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.
The rabbits were neurologically assessed daily until 1 wk after tetracaine administration 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 sacral to thoracic dermatomes. The score of the sensory function was assessed by the following three-point grading scale: 2 = normal; 1 = the region with diminished response is present; 0 = the region with no response is present. The hind-limb motor function was assessed with the five-point grading scale proposed by Drummond and Moore (13): 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 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. The coronal sections of the spinal cord at L3, L4, and L5 levels were cut at a thickness of 8 µm and stained with hematoxylin and eosin. Morphologic 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 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 neuron. 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 is vacuolated; 2 = 10%–50% area of the dorsal funiculus is vacuolated; 3 = >50% area of the dorsal funiculus is 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.
Parametric data are presented as mean ± SD. To determine differences in glutamate concentrations between groups over time, a repeated-measures analysis of variance (ANOVA) (groups versus time) was performed. If this analysis demonstrated a significant (P < 0.05) group effect, factorial ANOVA and Fisher’s protected least significant difference test were used to determine differences in glutamate concentrations among the groups. A paired t-test was used to test the differences between baseline values and peak levels of glutamate concentration in each group. Changes in mean arterial pressure, heart rate, esophageal temperature, pH, PaO2, PaCO2, glucose, and hematocrit were also compared with repeated-measures ANOVA followed by factorial ANOVA and Fisher’s protected least significant difference test. The cutaneous sensation, hind-limb motor function, and morphologic 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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Physiologic variables are shown in Table 1. There were no significant differences among the groups for most of the physiologic variables, except for plasma glucose, which was larger in the groups that received epinephrine. Total doses of phenylephrine used to maintain mean arterial blood pressure >60 mm Hg after tetracaine administration in the 1%T, 1%TE, 2%T, and 2%TE groups were 0.40 ± 0.11, 0.66 ± 0.37, 0.35 ± 0.15, and 0.47 ± 0.10 mg, respectively (mean ± SD). There were no significant differences among the four groups.
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Glutamate concentrations in CSF microdialysate are shown in Figure 1. Intrathecal administration of tetracaine significantly increased glutamate concentrations in CSF microdialysate, but there was no significant change in glutamate concentrations after intrathecal injection of epinephrine in NaCl solution. A repeated-measures ANOVA (groups versus time) revealed a significant difference among the four groups (1%T, 1%TE, 2%T, and 2%TE) (F3,200 = 3.229). There were no significant differences in the peak glutamate concentrations between the 1%T group and the 1%TE group or between the 2%T group and the 2%TE group. However, glutamate concentrations in CSF microdialysate in the 2%TE group at 20, 30, and 40 min were larger than those in the 2%T group. In the 1%TE group, the glutamate concentrations in CSF microdialysate tended to remain at higher levels than in the 1%T group, but the difference did not reach statistical significance except for the values at 50 min after the injection.
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significant difference from the 1%T group. T = tetracaine dissolved in saline; TE = tetracaine with epinephrine.All animals in the Control and 1%T groups showed normal cutaneous sensation 1 wk after tetracaine injection (score 2). In the 1%TE group, three of six animals showed normal cutaneous sensation (score 2), whereas the other three animals showed the region with diminished cutaneous sensation (score 1). In the 2%T and 2%TE groups, five of six animals and three of six animals showed the region with diminished cutaneous sensation (score 1), whereas one and three animals showed loss of cutaneous sensation (score 0), respectively. Sensory function scores in the 2%T and 2%TE groups were significantly worse than in the Control and 1%T groups. The regions of disturbance in sensation were mainly buttocks, thighs, and tail. No substantial differences in the regions were noted among the groups.
Motor function was normal in all animals in the Control and 1%T groups 1 wk after tetracaine injection (score 4). Mild motor dysfunction (score 3) was observed in one of six animals in the 1%TE group, two of six animals in the 2%T group, and three of six animals in the 2%TE group. Other animals in the 1%TE, 2%T, and 2%TE groups showed normal motor function.
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 motor neurons with round-shaped cytoplasm and laterally placed nuclei, predominantly in the ventral horn (Fig. 2A). The vacuolation in the white matter was confined within the dorsal funiculus. Histopathologic scores of the vacuolation in the dorsal funiculus in the 1%TE group were significantly worse than in the 1%T group at L4- and L5-level sections (Table 2). 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 strong correlation between the histopathologic score and sensory function score (Fig. 3, r = 0.811, P < 0.0001). No animals in the 1%T group, two animals in the 1%TE group, and four animals in the 2%T and 2%TE groups showed chromatolytic appearance of motor neurons, but there was no significant difference in the number of chromatolytic neurons between the 1%T and 1%TE group or between the 2%T and 2%TE group (Table 3). All sections in the Control group showed normal appearance (Fig. 2B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we demonstrated that the addition of epinephrine (0.1 mg/mL) to tetracaine injected intrathecally sustained large concentrations of glutamate in CSF microdialysate and worsened histologic injuries of the lumbar spinal cord. Epinephrine (0.1 mg/mL) itself neither increased glutamate concentrations nor exhibited neurotoxicity.
There have been many reports showing neurotoxic potentials of local anesthetics injected intrathecally (2,3). It is important to elucidate whether epinephrine, which is often used to prolong spinal anesthesia, exacerbates the neurotoxicity of local anesthetics after intrathecal administration. Epinephrine does not decrease spinal cord blood flow, but it decreases epidural blood flow (14); this may reduce intravascular uptake of local anesthetics. Therefore, the addition of epinephrine to local anesthetics may increase the duration of exposure of neurons to local anesthetics, leading to neuronal injuries. However, there is no definite evidence of epinephrine-induced spinal neuronal toxicity in the literature. Sakura et al. (15) reported that the addition of phenylephrine to tetracaine increased the potential for transient neurologic symptoms after spinal anesthesia with tetracaine. They speculated that phenylephrine increased the effective exposure of neurons to anesthetics because of decreased uptake of tetracaine (15).
In our previous study, we demonstrated that intrathecal administration of tetracaine (1%, 2%, and 4%) increased glutamate concentrations in CSF microdialysate and caused neuronal injury in a dose-dependent manner (6). Histopathologic damage was characterized by vacuolation in the dorsal funiculus and central chromatolysis of the motor neurons in the lumbar spinal cord (6). Because central chromatolysis often occurs after axonal injury of motor neurons, axons of the motor neurons in the spinal cord appear to be injured by tetracaine. Similarly, it is feasible that tetracaine injures primary afferent fibers at the dorsal root segment. We speculate that the axonal injuries of 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. In this study, we tested the effect of addition of epinephrine to 1% and 2% tetracaine, omitting 4% tetracaine because the damage was expected to be too severe with 4% tetracaine alone.
The peak concentrations of glutamate after intrathecal administration of 1% and 2% tetracaine were 4-fold and 12-fold larger than the baseline values, respectively. The results are essentially consistent with our previous results (6). The addition of epinephrine to tetracaine did not augment the peak concentrations of glutamate, but it sustained larger glutamate concentrations after the injection of tetracaine. It is likely that the addition of epinephrine decreases uptake of tetracaine into the systemic circulation and that the dorsal roots are continuously exposed to large concentrations of tetracaine. These events may result in stimulating A
or C fibers, or both, and releasing glutamate from their terminals. Alternatively, epinephrine itself might decrease uptake of glutamate. Large concentrations of glutamate at the synapse of the dorsal horn might activate glutamate receptors of the secondary neurons. The persistent activation of glutamate receptors might cause central sensitization (8), neuronal injury (9), or both. To determine whether large concentrations of glutamate in the CSF are the cause of neuronal injury, an antagonizing study with antagonists of glutamate receptors is warranted.
The vacuolation in the dorsal funiculus in the 1%TE group was significantly worse than in the 1%T group at L4 and L5 levels. All animals with decreased cutaneous sensation showed vacuolation in the dorsal funiculus, and the damage was exacerbated by the addition of epinephrine. In contrast, no significant worsening in the vacuolation in the dorsal funiculus was observed by adding epinephrine to 2% tetracaine. This is probably because the damage by 2% tetracaine per se was already severe, and additional deterioration by epinephrine was difficult to detect. The results suggest that the use of epinephrine in spinal anesthesia might cause sensory dysfunction.
The addition of epinephrine to 1% tetracaine tended to worsen cutaneous sensation, but the difference was not significant. This does not preclude the possibility of the adverse effects of the addition of epinephrine to local anesthetics, but it suggests a limitation in sensory assessments in the animals. The concentrations of tetracaine examined in this study are larger than those used clinically. However, the results may indicate that the exacerbation of local anesthetic-induced neuronal toxicity by epinephrine can occur in critical situations, such as repeated intrathecal injection or a maldistribution of local anesthetics in the subarachnoid space because of anatomic changes, both of which may cause unexpectedly large concentrations of local anesthetics.
In summary, we demonstrated that the intrathecal administration of tetracaine with epinephrine sustained large concentrations of glutamate in CSF microdialysate and that histologic damage of the lumbar spinal cord was exacerbated by the addition of epinephrine. Large concentrations of glutamate might cause central sensitization, neuronal injury, or both. These results suggest that the addition of epinephrine to tetracaine may increase its neurotoxicity, which may possibly be related to the sustained increase of glutamate concentrations in the CSF.
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Acknowledgments |
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Supported, in part, by the Ministry of Education, Science, Sports, and Culture Grant 11671500 (to 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.
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References |
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- Drasner K. Lidocaine spinal anesthesia [editorial]. Anesthesiology 1997; 87: 469–72.[Web of Science][Medline]
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Hodgson PS, Neal JM, Pollock JE, et al. 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.
- Horlocker TT, McGregor DG, Matsushige DK, et al. A retrospective review of 4767 consecutive spinal anesthetics: central nervous system complications. Anesth Analg 1997; 84: 578–84.[Abstract]
- Pollock JE, Neal JM, Stephenson CA, et al. Prospective study of the incidence of transient radicular irritation in patients undergoing spinal anesthesia. Anesthesiology 1996; 84: 1361–7.[Web of Science][Medline]
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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.
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Hudspith MJ. Glutamate: a role in normal brain function, anaesthesia, analgesia and CNS injury. Br J Anaesth 1997; 78: 731–47.
[Free Full Text] - Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 1986; 19: 105–11.[Web of Science][Medline]
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Wakamatsu H, Matsumoto M, Nakakimura K, et al. 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]
- Kozody R, Palahniuk RJ, Wade JG, et al. The effect of subarachnoid epinephrine and phenylephrine on spinal cord blood flow. Can Anaesth Soc J 1984; 31: 503–8.[Web of Science][Medline]
- Sakura S, Sumi M, Sakaguchi Y, et al. The addition of phenylephrine contributes to the development of transient neurologic symptoms after spinal anesthesia with 0.5% tetracaine. Anesthesiology 1997; 87: 771–8.[Web of Science][Medline]
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