Lidocaine increases the granule cell excitability in hippocampal dentate area instead of affecting GABAergic inhibition]

Lidocaine is well known to have toxic effects on the central nervous system including the induction of electroencepharographic seizures and convulsions at high doses. Although lidocaine was reported to induce electroencepharographic seizures and behavioral convulsions by decreasing the strength of GABAergic synaptic inhibition, detailed mechanisms underlying the lidocaine-induced seizures remain unclear. To determine whether lidocaine decreases GABAergic inhibition or increases the cellular excitability instead of reducing GABAergic inhibition, in the present study, we examined effects of lidocaine on monosynaptic field potentials in the hippocampal dentate gyrus of urethane-anesthetized rats. Lidocaine (10-15 mg.kg-1, i.v.) decreased significantly the threshold for action potential generation instead of producing a significant decrease in GABAergic paired-pulse inhibition. The results suggest that lidocaine first produces the hyperexcitability of hippocampal neurons, which then decreases the hippocampal GABAergic inhibition by the so-called inhibition failure leading to the induction of seizures.     

Clonidine does not affect lidocaine seizure threshold in rats

We investigated the effect of clonidine on intravenous (iv) lidocaine-induced haemodynamic changes and convulsions in awake rats. Wistar rats (200–250 g) were divided into three groups of eight and were pretreated with iv clonidine or normal saline 15 min before lidocaine infusion. Group 1 received normal saline; Group 2, 1 μg · kg^?1 clonidine; and Group 3, 10 μg · kg^?1 clonidine. After surgical preparation and recovery from anaesthesia, all groups received a continuous iv infusion of lidocaine (15 mg · ml^?1) at a rate of 4 mg · kg^?1 · min^?1 until generalized convulsions occurred. Oxygenation was well maintained in all groups. Pretreatment with clonidine changed neither cumulative convulsant doses (Group 1: 41.8 ± 2.2, Group 2: 43.8 ± 2.6, Group 3: 42.3 ± 2.0 mg · kg^?1, respectively) nor plasma concentrations of lidocaine at the onset of convulsions (Group 1: 10.5 ± 0.3, Group 2: 10.8 ± 0.3, Group 3: 10.6 ± 0.3 μg · ml^?1, respectively). The mean arterial blood pressures in Groups 2 and 3 were decreased after clonidine pretreatment (Group 2: 93 ± 1, P < 0.01, Group 3: 90 ± 1%, P < 0.01, respectively) and they gradually increased during lidocaine infusion. The heart rates decreased after clonidine pretreatment (Group 2: 94 ± 2, P < 0.05, Group 3: 86 ± 2%, P < 0.01, respectively) and the combination of clonidine and lidocaine potentiated the bradycardic effect of lidocaine at a subconvulsant dose. Our results indicate that clonidine has neither anticonvulsant nor proconvulsant effects on lidocaineinduced convulsions. However, the interactions of clonidine and lidocaine on blood pressure and heart rate should be investigated further.     

The effect of neuroleptics and neuroleptic/analgesic combinations on the sensitivity to seizures in mice

Combinations of neuroleptic and morphine-like analgesic drugs are used alone for minor surgery or as anesthetic premedication. While morphine-like analgesics given in the therapeutic dose range show anticonvulsant properties, there is evidence indicating that neuroleptics are rather proconvulsant. This study was performed to investigate the influence of the most widely used combinations pethidine/promethazine and fentanyl/droperidol on seizure susceptibility. METHODS: Thresholds for convulsions induced by electroshock and pentetrazole infusion were used as models for seizure susceptibility. The drugs tested were injected s.c. 20-30 min before determination of the seizure threshold. RESULTS: Pethidine/promethazine and fentanyl/droperidol reduced the susceptibility to seizures induced by electroshock. Promethazine and droperidol alone elevated the threshold only at the highest doses used (2 mg/kg and 2.5 mg/kg respectively). Promethazine, whether given alone or in combination with pethidine, showed no effect on the threshold for pentetrazole-induced convulsions. Droperidol alone lowered the threshold for pentetrazole-induced clonic convulsions only at the lowest dose used (0.625 mg/kg), but lowered that for tonic convulsions at all doses studied (0.625, 1.25 and 2.5 mg/kg). The combination of fentanyl and droperidol lowered the threshold for both clonic and tonic convulsions at the two lower doses (12.5 micrograms/kg fentanyl + 0.625 mg/kg droperidol and 25 micrograms/kg fentanyl + 1.25 mg/kg droperidol). Only the highest dose studied (50 micrograms/kg fentanyl + 2.5 mg/kg droperidol) showed no significant effect. CONCLUSION: Pethidine and fentanyl show anticonvulsant properties in mice, but it is evident from our results that there is some interaction between their combinations with neuroleptics and seizure susceptibility. This is more pronounced with the combination fentanyl/droperidol in the model of pentetrazole-induced convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pro- and anticonvulsant effects of anesthetics (Part II)

Perioperative seizures have numerous potential etiologies. In general, when seizures occur during surgery, their onset often coincides with the introduction of a specific anesthetic or analgesic drug. Conversely, postoperative seizures are more commonly due to nonanesthetic causes. However, there have been reports of postoperative convulsions that appeared to be caused by anesthetic or analgesic drugs administered intraoperatively via inhalation or injection (e.g., intravenous, epidural, or peripheral nerve block). Some anesthetics appear to possess both proconvulsant and anticonvulsant properties. One possible factor is an inherent pharmacodynamic variability in the responsiveness of inhibitory and excitatory target tissues in the CNS. This is well illustrated by the anticonvulsant and proconvulsant effects of progressively higher doses of local anesthetic drugs. This variability in neuronal responsiveness could also explain the conflicting findings for low versus high doses of fentanyl and etomidate. Furthermore, biological variation in the individual patient's responsiveness to certain anesthetic drugs could be an additional contributory factor. Differing structure-activity relationships might also explain why some anesthetic agents possess both proconvulsant and anticonvulsant properties. Relatively minor modifications in a drug's structure can influence its affinity for a specific receptor site and its intrinsic pharmacologic activity. For example, when methohexital was first introduced, convulsions were commonly encountered in patients with and without a history of epilepsy. Subsequent fractionation of the original compound into its two isomeric forms resulted in the identification of the isomer primarily responsible for this convulsive activity. In its present formulation (Brevital; Eli Lilly, Indianapolis, Ind.), the epileptogenic properties of methohexital are limited to patients with psychomotor epilepsy. However, compared with thiopental, excitatory effects are still more common with methohexital. The excitatory effects of methohexital are presumably due to its methylated structure. The inhaled anesthetic flurothyl (hexaflurodiethyl) ether and the intravenous anesthetic ketamine also illustrate how subtle changes in stereoisomerism can result in significant changes in structure-activity relationships. Flurothyl, a fluorinated ether analogue, reliably produces convulsions in nonepileptic patients, whereas its structural isomer isoindoklon has not been associated with seizure activity. Other examples of isomer or structural analogue relationships that produce differential effects on neuronal hyperexcitability include enflurane-isoflurane and meperidine-normeperidine. In conclusion, the patient population (epileptic or nonepileptic), the method of documentation (EEG study or clinical observation), and the method of EEG analysis (cortical or depth electrodes) must be considered to properly analyze the proconvulsant and/or anticonvulsant properties of an anesthetic or analgesic drug.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of flumazenil on intravenous lidocaine-induced convulsions and anticonvulsant property of diazepam in rats.

We investigated the effect of flumazenil on intravenous (IV) lidocaine-induced convulsions with and without diazepam pretreatment in rats. Wistar rats (200-250 g) were divided into four groups of seven each and were pretreated with IV diazepam or normal saline solution at 6 min and flumazenil or normal saline solution at 3 min before lidocaine infusion. The control group received normal saline solution; the diazepam group received 0.2 mg/kg of diazepam and normal saline solution; the diazepam+flumazenil group received 0.2 mg/kg of diazepam and 0.1 mg/kg of flumazenil; and the flumazenil group received normal saline solution and 0.1 mg/kg of flumazenil. After surgical preparation and recovery from anesthesia, all groups received a continuous IV infusion of lidocaine (15 mg/mL) at a rate of 4 mg.kg-1.min-1 until tonic/clonic convulsions occurred. The values of pH and blood gases were maintained within physiologic ranges. Heart rate was significantly decreased after 5 min of lidocaine infusion, but arterial blood pressure did not change until convulsions occurred in all groups. Pretreatment with diazepam alone increased both cumulative convulsant doses and plasma concentrations of lidocaine at the onset of convulsions. Flumazenil reversed these effects of diazepam. Pretreatment with flumazenil alone changed neither cumulative convulsant doses nor plasma concentrations of lidocaine at the onset of convulsions. Our data show that IV flumazenil reverses the anticonvulsant property of IV diazepam against lidocaine-induced convulsions and that flumazenil itself has no effect on lidocaine-induced convulsions in rats.     

Diazepam prophylaxis for lignocaine induced convulsions.

The effectiveness of intraperitoneal phenobarbitone (4 mg/kg), pentobarbitone (6 mg/kg) and diazepam (2.5, 5 and 7.5 mg/kg) in preventing lignocaine-induced seizures was studied in rats. Although the barbiturates exerted a marked depressant action on wakefulness and gait of the rats, they were still associated with a very high incidence of convulsions and deaths following 100 mg/kg intraperitoneal lignocaine hydrochloride. Diazepam, however, even in doses (2.5 and 5 mg/kg) which did not produce marked sedation was able to completely prevent convulsions. Mortality was not completely prevented as one animal in each of the groups receiving these doses died without convulsing. Diazepam in the dose of 7.5 mg/kg completely prevented the seizures as well as the mortality but exerted a more profound effect on wakefulness and gait of the animals. The effectiveness of diazepam pretreatment in preventing lignocaine-induced seizures in rats is confirmed.     

Alterations in the pharmacokinetic properties of amide local anaesthetics following local anaesthetic induced convulsions

The comparative pharmacokinetic properties of lidocaine, bupivacaine, etidocaine and mepivacaine were investigated in convulsing and non-convulsing dogs. The same dose of a given local anaesthetic was administered as either a 30-s intravenous (IV) bolus to produce convulsions or as a 15-min IV infusion producing no convulsions. Derived pharmacokinetic data were found to be different in convulsing and non-convulsing animals. Total body clearance was found to be significantly reduced for lidocaine (29%, P less than 0.05), bupivacaine (31%, P less than 0.05), etidocaine (60%, P less than 0.01) and mepivacaine (68%, P less than 0.01) in convulsing animals. Increases in elimination half-life only achieved statistical significance in mepivacaine-treated animals (non-convulsing 45.2 min, convulsing 105.4 min, P less than 0.01). Overall, the most profound effects of convulsions on pharmacokinetic data were seen with mepivacaine. Convulsions were associated with increases in heart rate ranging from 117% (lidocaine, P less than 0.05) to 129% (mepivacaine, P less than 0.05), increases in cardiac output ranging from 78% (mepivacaine) to 232% (bupivacaine, P less than 0.05) and increases in mean arterial pressure ranging from 45% (lidocaine, P less than 0.05) to 80% (bupivacaine, P less than 0.05). The results suggest that when local anaesthetic-induced seizures occur in man, it cannot be assumed that these drugs will be distributed and eliminated as predicted by intravenous infusion of non-toxic doses.     

Effect of midazolam pretreatment on the intravenous toxicity of lidocaine with and without epinephrine in rats

The effect of the benzodiazepine midazolam on the intravenous toxicity of lidocaine with and without epinephrine was studied in male Sprague-Dawley rats. Test rats with and control rats without midazolam premedication (2.5 mg/kg intraperitoneally, 10% of the median dose that caused loss of the righting reflex in a third group of rats) were given 2% lidocaine with and without 10 micrograms/ml epinephrine intravenously in doses sufficient to construct log-dose response curves for both convulsant and lethal responses. In control rats the median convulsant dose (CD50) of lidocaine was 15.2 mg/kg given alone and 10.9 mg/kg with epinephrine (a statistically significant difference); respective values for the median lethal dose (LD50) were 26.4 and 18.5 mg/kg (also statistically significant). While epinephrine enhanced lidocaine seizure activity and lethality by approximately 50%, midazolam almost completely prevented lidocaine-induced convulsions but had no significant effect on mortality.     

Anticonvulsant actions of enflurane on epilepsy models in cats

The effects of enflurane on three epilepsy models were studied in cats. The models used were seizures in amygdaloid kindled cats and those induced by bicuculline and penicillin. The authors found that not only a subconvulsive (1.5%) but a convulsive (3.5%) dose of enflurane suppressed the seizures in all models. There was no sign of activation by enflurane of the epileptic focal activities in the dose range studied: the penicillin-induced cortical seizure was suppressed completely, and the threshold dose of bicuculline required to induce seizure in normal cats and the threshold current required to induce seizure in amygdaloid-kindled cats were both increased by both the subconvulsive and convulsive dose of enflurane. The pattern of suppression was, however, dissimilar in each model. It was dose dependent in the case of penicillin-induced seizure, while it was biphasic in several aspects in the seizures of bicuculline-induced and amygdaloid kindled models. For the subconvulsive dose the degrees of increase in the thresholds required to induce seizure in bicuculline-induced and amygdaloid-kindled models were both greater than those for the convulsive dose of enflurane. In spite of such a definite suppression of the excitability of focus, the propagation of amygdaloid after-discharge was facilitated by the convulsive dose. The intensity of convulsion induced by suprathreshold dose of bicuculline was depressed in a dose-related manner. The intensity of the convulsion in the amygdaloid-kindled model was also suppressed when it was estimated by visual inspection of behavior and the degree of activation of the brain electrical activities. The authors conclude that there is little, if any, exacerbation by enflurane of preexisting epileptic foci, the only exception possibly being the case of certain myoclonic type epilepsies such as progressive myoclonic epilepsy and photosensitive epilepsy. This anesthetic probably can be used with a considerable degree of safety for epileptic patients.     

Central nervous system toxicity of local anesthetic mixtures in the rat.

Local anesthetics are often administered as mixtures during regional anesthesia. This study investigated whether a synergistic or antagonistic interaction between amide/amide or amide/ester local anesthetic combinations is present with respect to central nervous system toxicity. For surgical preparation, rats were anesthetized with 0.8% halothane in 30% O2/balance N2O and mechanically ventilated. Mean arterial blood pressure and the electroencephalogram were continuously monitored. After surgery, the halothane was discontinued for 15 min. An intravenous infusion of solutions containing lidocaine alone, bupivacaine alone, or any of three mixtures of the two drugs was then begun and continued at a fixed rate until seizure activity was observed on the electroencephalogram. Total administered doses of both drugs were compared by isobolographic analysis. After a similar protocol, a second experiment was performed evaluating lidocaine, tetracaine, or any of three mixtures of those two drugs. In both experiments, normocapnia, normoxia, and normothermia were maintained for all rats. For mixtures of lidocaine/bupivacaine (P = 0.40) and lidocaine/tetracaine (P = 0.24), there was no evidence that a significant degree of either synergism or antagonism was present. At the onset of seizures, mean arterial pressure was lowest in the lidocaine-alone groups in both experiments. Increasing doses of either bupivacaine or tetracaine (with correspondingly decreasing doses of lidocaine) were associated with greater mean arterial pressure values at onset of seizures. We conclude that central nervous system toxic effects of amide/amide or amide/ester anesthetic combinations, such as might occur during accidental intravascular injection, are no more than when the drugs are administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anesthetic management of a patient with West syndrome

A 21-year-old female with West syndrome was scheduled for resection of hordeolum. She had an episode of convulsion at three months of age, and was diagnosed as having West syndrome at one year of age. She had epileptic seizures twice a week in spite of administration of phenytoin, clonazepam and sodium valproate. These drugs had been administered till the morning of the surgery. After premedication with atropine 0.25 mg, anesthesia was induced with propofol (12-->10-->8 mg.kg-1.h-1). The tracheal intubation was performed with vecuronium 0.1 mg.kg-1 and anesthesia was maintained with continuous infusion of propofol 6-8 mg.kg-1.h-1 and local infiltration with 1.0% lidocaine 5 ml. We administered phenytoin to prevent epileptic seizures during the surgery. No epileptic seizures occurred perioperatively. We conclude that propofol may be useful for a patient with West syndrome, and we should be careful not to lower the threshold for convulsion during the perioperative period.     

Modification of intravenous lidocaine-induced convulsions by epinephrine in rats

We studied intravenous lidocaine-induced convulsions in rats to determine whether added epinephrine influences the provocation of lidocaine toxicity. Wistar rats (200–250 g) were divided into three groups of ten, depending on the concentration of epinephrine added to lidocaine. Group 1: plain 1.5% lidocaine; Group 2: 1.5% lidocaine with 1∶200,000 epinephrine; Group 3: 1.5% lidocaine with 1∶100,000 epinephrine. After surgical preparation and recovery from anaesthesia, all rats received a continuous iv infusion of lidocaine (15 mg·ml^?1) at a rate of 4.0 mg·kg^?1·min^?1 until generalized convulsions occurred. The epinephrine-treated animals developed acute hypertension after one minute of lidocaine infusion (105±2 to 141±2 mmHg in Group 2 and 103±2 to 151±2 mmHg in Group 3). The PaO₂ values in the epinephrine groups at the onset of convulsions were decreased significantly (88.3±1.0 to 84.0 ±1.5 mmHg in Group 2 P < 0.05 and 86.9±1.2 to 78.1±2.4 mmHg in Group 3 P<0.01). However, these values were still within physiological ranges. Serum potassium concentrations in all groups were decreased P<0.05, (4.24±0.09 to 3.52±0.12 mEq·L^?1 in Group 1, 4.02±0.09 to 3.63±0.17 mEq·L^?1 in Group 2, and 4.15±0.10 to 3.69 ±0.17 mEq·L^?1 in Group 3). Blood sugar concentrations in all groups were increased at the onset of convulsions, and the levels in the epinephrine groups were higher than in Group 1 P<0.01 (119±4 to 149±7 mg·dl^?1 in Group 1: 120±4 to 195±10 mg·dl^?1 in Group 2, and 127±3 to 190±6 mg·dl^?1 in Group 3). There were differences in the cumulative convulsant doses of lidocaine among the groups, as follows: Group 1=41.9±1.3 > Group 2=30.0±0.7 > Group 3=24.2±0.9 mg·kg^?1; P<0.01. At the onset of convulsions, not only the plasma lidocaine concentrations (Group 1=10.7±0.3 > Group 2=8.3±0.2 (P<0.01) > Group 3=7.5±0.2 μg·ml^?1 (P<0.01 vs Group 1, P < 0.05 vs Group 2), but also the brain lidocaine concentrations which were extracted from the whole brain homogenates: Group 1=48.7±1.9 > Group 2=38.2±1.1 (P<0.01) > Group 3=33.0±1.3 μg·g^?1 (P <0.01 vs Group 1, P<0.05 vs Group 2) showed differences. The brain/plasma lidocaine concentration ratios were, however, similar in the three groups (Group 1=4.5±0.1; Group 2=4.6±0.1; Group 3=4.4±0.2). Our data show that added epinephrine decreases the threshold of lidocaine-induced convulsions dose-dependently; however, the added ephinephrine does not cause a greater proportion of the infused lidocaine to enter the CNS.     

Sturge-Weber disease without facial nevus

A rare case of Sturge-Weber syndrome without facial nevus and epileptic seizures is reported. The other cases of incomplete form of the disease reported in the literature showed occipital calcification and epileptic seizures without facial nevus, while in the present case also the convulsions were absent. The possible pathogenic mechanism is discussed. The CT findings of these incomplete forms include unilateral or often bilateral occipital calcifications with no evidence of contrast enhancement. The Authors conclude that the radiologic finding of bilateral gyriform calcifications in the occipital region must suggest the diagnosis of Sturge-Weber disease even in the absence of facial nevus and epileptic seizures.     

Fetal heart rate decelerations during ECT‐induced seizures: is it important?

Electroconvulsive therapy (ECT) is sometimes indicated during pregnancy and may offer advantages over pharmacotherapy for the patient and the fetus (1,2). However, very little data is available on the impact of epileptic or ECT-induced seizures on the fetus. We report a case of brief fetal heart rate decelerations in a fetus associated with maternal ECT-induced convulsions.     

Effect of Vasoconstrictive Agents Added to Lidocaine on Intravenous Lidocaine-induced Convulsions in Rats

Background: Epinephrine is reported to decrease the threshold of intravenous lidocaine-induced convulsions. However, the mechanism underlying this effect is not clear. Therefore, we carried out a study to examine the role of vasopressor-induced hypertension.

Methods: Fifty-six awake Wistar rats were assigned to seven groups of eight. All groups received a continuous intravenous infusion of lidocaine at a rate of 4 mg *symbol* kg sup -1 *symbol* min sup -1 until generalized convulsions occurred. The control group (group C) received plain lidocaine. The acute hypertensive groups received lidocaine with epinephrine (group E), norepinephrine (group N), or phenylephrine (group P) to increase mean arterial blood pressure (MAP) to 150 plus/minus 5 mm Hg. Sodium nitroprusside (SNP) was added to prevent an increase in mean arterial pressure in the remaining three groups (vasopressor-SNP groups).

Results: The acute hypertensive groups required significantly smaller cumulative doses of lidocaine to produce convulsions compared with control (C - 41.5 plus/minus 2.9 > E - 24.1 plus/minus 2.7, N = 27.1 plus/minus 2.8, P = 26.7 plus/minus 2.5 mg *symbol* kg sup -1; values are mean plus/minus SD, P < 0.01) In addition, plasma lidocaine concentrations (C = 11.0 plus/minus 0.7 > E = 7.4 plus/minus 0.5, N = 7.9 plus/minus 0.6, P = 8.1 plus/minus 0.8 micro gram *symbol* ml sup -1, P < 0.01) and brain lidocaine concentrations (C = 50.9 plus/minus 4.5 > E = 32.6 plus/minus 4.2, N - 34.5 plus/minus 4.8, P - 37.1 plus/minus 4.5 micro gram *symbol* g sup -1, P < 0.01) were less in the acute hypertensive groups at the onset of convulsions. In the vasopressor-SNP groups, the plasma and brain lidocaine concentrations at the onset of convulsions returned to the control values, although epinephrine and norepinephrine, but not phenylephrine, still decreased cumulative convulsant doses of lidocaine significantly (P < 0.01) compared with control (E + SNP = 30.8 plus/minus 2.9 < N + SNP = 34.8 plus/minus 2.8, P < 0.01) < P + SNP = 40.2 plus/minus 3.0 mg *symbol* kg sup -1, P < 0.01). The brain/plasma concentration ratios were similar for the seven groups.     

An anesthetic experience of epileptic focus resection in a nine month-old girl under monitoring by electrocorticography

We report a successful electrocorticography (ECoG) monitoring for a epileptic cortical focus resection in a 9-month-old girl with uncontrollable epileptic seizures. Anesthesia was induced and maintained with nitrous oxide, oxygen, and sevoflurane with vecuronium. After the craniotomy, ECoG monitoring was used to locate the epileptic cortical lesion. During the procedure of subpial resection and gyrectomy, ECoG was repeatedly recorded. It was necessary to maintain adequate depth of anesthesia throughout the procedure to clarify the epileptic waves. For this purpose, sevoflurane (2.5%) with and oxygen (97.5%) under controlled-hyperventilation (PaCO2 30 mmHg), was useful for monitoring the epileptic seizure wave from cortical focuses properly.     

LACK OF CORRELATION BETWEEN THE ANAESTHETIC AND ANTI-CONVULSANT POTENCIES OF ALTHESIN, KETAMINE AND METHOHEXITONE

Using Sprague-Dawley rats, the anti-convulsant potencies ofAlthesin, ketamine and methohexitone were determined for bicuculline-and strychnine-induced seizures and compared with their effectson hyperbaric seizures. All three anaesthetics protected againstboth types of chemical convulsants; the degree of protectionvaried from 34 to 151 %, with Althesin being the most effective.However, there was no correlation between their anti-convulsantand anaesthetic potencies, and no relationship between the effectson chemical convulsions and the interactions of the same agentswith hyperbaric convulsions. These data suggest that the orderof anti-convulsant potencies at equivalent anaesthetic concentrationis Althesin >> ketamine = methohexitone, and that neitherbicuculline- nor strychnine-induced seizures are a good modelfor hyperbaric convulsions.     

Use of a charged lidocaine derivative, tonicaine, for prolonged infiltration anesthesia

BACKGROUND AND OBJECTIVES: We tested the hypothesis that the duration of cutaneous anesthesia elicited by the permanently charged compound N-phenylethyl lidocaine (tonicaine) would be longer than that elicited by its parent structure, lidocaine, and that it would be less affected by epinephrine (epi), after subcutaneous injection in rats, as a model for infiltration anesthesia. METHODS: Subcutaneous injections were performed on the shaved dorsal skin of rats with either tonicaine or lidocaine (0.1% or 0.5%, n = 8 in each group) with and without epi (1:200,000). Inhibition of the cutaneous trunci muscle reflex was quantitatively evaluated by a blinded observer by the number of times pinpricks failed to elicit the nocifensive motor response out of a total of 6 pinpricks applied to the injected area. RESULTS: Duration of complete nociceptive blockade in the 0.5% tonicaine and lidocaine groups was 619 +/- 47 and 58 +/- 2 minutes, respectively; duration of full recovery in these groups was 1,106 +/- 19 and 86 +/- 3 minutes, respectively. Epi increased the duration of complete block in the 0.5% tonicaine and lidocaine groups to 750 +/- 13 and 97 +/- 11 minutes, respectively, and the duration of full recovery to 1,185 +/- 13 and 172 +/- 6 minutes, respectively. Skin toxicity was seen only in the 0.5% tonicaine with epi group (3 of 8 rats). CONCLUSIONS: Tonicaine is a substantially longer lasting local anesthetic with a delayed onset of action compared with lidocaine and may be useful in situations where long duration of infiltration block is desirable.     

Vigabatrin directed against kindled seizures following cortical insult: impact on epileptogenesis and somatosensory recovery.

The anticonvulsant drug vigabatrin has not been found to be detrimental to the recovery process when administered following focal cortical insult. This finding is in contrast to the negative postinjury consequences of other anticonvulsant drugs (e.g., phenobarbital and diazepam) with more direct activation of the GABA/benzodiazepine receptor complex. Moreover, phenobarbital directed against kindled seizures affects functional recovery more adversely than either the drug or subconvulsive seizures alone. The purpose of the present study was to determine whether vigabatrin (150, 200, and 250 mg/kg) directed against kindled seizures would impact recovery from lesion-induced somatosensory deficits. Vigabatrin was coupled with daily electrical kindling of the amygdala during the first week after a unilateral anteromedial cortex (AMC) lesion. Somatosensory recovery was assessed using bilateral tactile stimulation tests. Animals receiving the highest dose of vigabatrin prior to electrical kindling (250 mg/kg vigabatrin/kindled) remained significantly impaired even after two months of testing relative to vehicle/kindled, kindled/250 mg/kg vigabatrin, which received vigabatrin after electrical kindling, and the 150, 200, and 250 mg/kg vigabatrin/nonkindled groups (p < 0.0001). In contrast, neither vigabatrin (at any of the doses tested) nor subconvulsive kindled seizures impacted the recovery process (p > 0.05) when administered alone (i.e., without the drug + seizure interaction). These data add to the accumulating experimental and clinical evidence suggesting that the neurobehavioral consequences of the interaction between anticonvulsant drugs and subclinical seizures after brain insult are detrimental to functional recovery.     

The comparative neurotoxicity of intrathecal lidocaine and bupivacaine in rats

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 muL 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 muL 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. IMPLICATIONS: Bupivacaine induces less severe functional impairment and morphologic damage than lidocaine when the two anesthetics are intrathecally administered at equipotent concentrations in the rat.