Search

To study the effect of dexmedetomidine priming on convulsion reaction induced by lidocaine.The New Zealand white rabbits were applied for the mechanism study of dexmedetomidine priming for preventing convulsion reaction induced by lidocaine. The influence of dexmedetomidine priming with different doses on the time for convulsion occurrence and the duration time of convulsion induced by lidocaine, as well as contents of excitatory amino acids (aspartate [Asp], glutamate [Glu]) and inhibitory amino acids (glycine [Gly], γ-aminobutyric acid [GABA]) in the brain tissue were investigated.With 3 and 5 μg/kg dexmedetomidine priming, the occurrence times of convulsion were prolonged from 196 seconds to 349 and 414 seconds, respectively. With dexmedetomidine priming, the contents of excitatory amino acids (Asp, Glu) were much reduced at occurrence time of convulsion comparing with that without dexmedetomidine priming, while content of inhibitory amino acids Gly was much enhanced.The application of dexmedetomidine before local anesthetics can improve intoxication dose threshold of the lidocaine, delay occurrence of the convulsion, and helped for the recovery of convulsion induced by lidocaine. The positive effect of dexmedetomidine on preventing convulsion would owe to not only the inhibition of excitatory amino acids (Asp, Glu), but also the promotion of inhibitory amino acids Gly secretion., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: Epistaxis is a common problem that occurs in up to 60% of the general population, and is a common emergency department (ED) complaint. The use of lidocaine for analgesia is common when cauterization is required for bleeds that are refractory to manual compression. Although the use of lidocaine is generally thought of as a benign intervention, it is not completely without risk., Case Report: We present the case of a 19-year-old man who presented to the ED with persistent anterior epistaxis. He developed severe lidocaine toxicity resulting from topical anesthesia applied prior to intranasal cautery for the epistaxis. This toxicity, which manifested as seizures, bradycardia, hypotension, nausea, and emesis, was rapidly recognized and appropriately treated, with a good clinical outcome for the patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We present this case to increase awareness among emergency physicians of the potential complications of the intranasal use of topical lidocaine, something that is generally considered a benign intervention. We also discuss the pathophysiology and management of lidocaine toxicity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Following initial signs of dural infection, or as prophylactic postoperative therapy, three cynomologus macaques were given an intramuscular or a subcutaneous injection of ceftriaxone dissolved in a 1% lidocaine diluent (CL). Two to 15 min later, all three monkeys experienced a long-lasting generalized apnoeic clonic convulsive seizure. The injected doses of lidocaine (0.7-2 mg/kg) were as low as 7-20-fold less than the experimental intravenous dosage (14.2 +/- 3.2 mg/kg) previously reported to induce seizure in healthy rhesus monkeys. Under different clinical conditions, the same three animals were either once (1 animal) or repeatedly given CL without any resultant neurological alterations. The monkeys had a cranial device implanted and two of them were craniotomized. This first report of accidental lidocaine-induced seizure in laboratory non-human primates following CL injection strongly suggests increased susceptibility when lidocaine administration is associated with central nervous system alteration. A novel hypothesis, the possible role of cytokine in lowering the lidocaine seizure threshold, is suggested.

Background: Propranolol is a beta-adrenoceptor antagonist used clinically. Local anesthetics are used for controlling pain, whereas propranolol is concomitantly given to treat hypertension and tachycardia. However, there are few studies examining the effects of propranolol on the toxicity of local anesthetics. We investigated the effect of propranolol on lidocaine-induced convulsions in awake, spontaneously breathing rats., Methods: Male Sprague-Dawley rats were randomly divided into six groups (n = 8, each group). Rats were pretreated with intracerebroventricular saline (cerebroventricle-control: CV-C group), 10 or 30 microg/kg of (S)-(-)-propranolol (propranolol) (cerebroventricle-small dose: CV-S and cerebroventricle-large dose: CV-L groups, respectively) or i.v. saline (IV-control: IV-C group), 1 or 3 mg/kg of propranolol (IV-small dose: IV-S and IV-large dose: IV-L groups, respectively). Three minutes later, lidocaine was administered i.v. at 4 mg x kg(-1) x min(-1) until tonic-clonic convulsions occurred., Results: The convulsive dose of lidocaine in the CV-L group was significantly larger than that in the CV-C group (30.6 +/- 5.1 vs 23.5 +/- 2.2 mg/kg, respectively, P = 0.008). Plasma concentrations of total and protein-unbound lidocaine, concentrations of lidocaine in the brain at the onset of convulsions were also significantly higher in the CV-L group than those in the CV-C group (36.1 +/- 4.8 vs 26.0 +/- 3.8 microg/mL, 22.5 +/- 3.5 vs 13.7 +/- 2.6 microg/mL, 82.7 +/- 7.1 vs 57.3 +/- 5.7 microg/g, P < 0.001 for all). The convulsive dose, plasma concentrations of total and protein-unbound lidocaine, and brain lidocaine in the IV-L group were also significantly larger than those in IV-C group and comparable with those in the CV-L group. The plasma concentration of propranolol before starting an infusion of lidocaine in the IV-L group was approximately 60-fold higher than that in the CV-L group (554.7 +/- 104.6 and 9.3 +/- 6.7 ng/mL, respectively)., Conclusions: Propranolol increased the threshold for lidocaine-induced convulsions by directly acting on the brain.

Ivermectin is one of the most commonly used drugs in pharmacotherapy of parasitic diseases in domestic and wild animals caused by parasitic nematodes and arthropods. However, ivermectin and other avermectins very often produce side-effects in hosts. The most dominant clinical symptom of ivermectin toxicity in domestic and wild animals is CNS depression. In nematodes, the target site of ivermectin's action is glutamate-gated chloride-channel receptor and GABA receptor. The depressive effect of ivermectin in mammals might include more than one mechanism; therefore, the anticonvulsive effect of ivermectin against convulsions caused by lidocaine and strychnine was evaluated. Ivermectin antagonized lidocaine- and strychnine-induced convulsions in rats, although these have different mechanisms. In the present study, the anticonvulsive ED50 ofivermectin for lidocaine-induced convulsions was 2.44 mg/kg (95% CL 1.67 to 3.57 mg/kg), whereas for convulsions induced by strychnine it was higher at 4.25 mg/kg (95% CL 2.32 to 3.78 mg/kg). At the same time, both anticonvulsive doses are significantly lower then the observed LD50 of ivermectin (18.20 mg/kg). Furthermore, flumazenil (0.1 and 0.2 mg/kg), an antagonist of benzodiazepine receptors, antagonizes just one part of these anticonvulsive effects of ivermectin. Our results show the significant anticonvulsive properties of ivermectin and support the findings that ivermectin in the CNS of mammals produces multiple inhibitory effects, probably through participation in the function of GABA-sensitive and GABA-insensitive chloride channels.

Experiments were carried out on male albino rats of 200-250 g weight with bipolar electrodes implanted in neocortex, as well as in the right and the left dorsal hippocampus for the study of the effect of lidocaine and its combination with adrenaline on the electric activity of brain. On the fifth day from the implantation in the first group of animals 0,3 ml 2% lidocaine was injected intra-peritoneally and the electric activity from the above mentioned structures was registered. In the second group 0,3 ml 2% lidocaine with adrenaline was injected intra-peritoneally (1:100000). In 8-12 sec after injection in the first group of animals the encephalogram showed sharply defined clone type seizure activity, which soon obtained tonus character. Simultaneously clone-tonus type behavioural manifestation was revealed, which lasted for 20-25 minutes. In the second group of animals in 30-40 sec after injection the encephalogram revealed convulsion activity with high amplitude synchronous oscillations, which lasted for 20-25 minutes, although in this group, in distinct from the first group, no clone-tonus behavioural manifestation was detected.

Purpose: To examine whether inhibition of P-glycoprotein (P-gp) activity by quinidine affects the central nervous system toxicity of lidocaine and racemic bupivacaine (bupivacaine)., Methods: Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10). Fifteen minutes following administration of 15 mg x kg(-1) of quinidine (QL and QB groups) or saline (L and B groups), lidocaine (L and QL groups, 4 mg x kg(-1) x min(-1)) or bupivacaine (B and QB groups, 1 mg x kg(-1) x min(-1)) was infused until convulsions occurred. Concentrations of lidocaine and its primary metabolite, monoethylglycinexylidide (MEGX) and bupivacaine in plasma and in the brain at the onset of convulsions were measured by high-performance liquid chromatography., Results: There were no differences in the dose of lidocaine required to induce convulsions between the L and QL groups. There were no differences in the concentrations of total (L = 17.2 +/- 3.5, QL = 16.6 +/- 2.6 micro g x mL(-1)) or unbound lidocaine (L = 7.8 +/- 2.5, QL = 7.3 +/- 2.3 micro g x mL(-1)), total (L = 1.2 +/- 0.5, QL = 1.3 +/- 0.7 micro g x mL(-1)) or unbound MEGX (L = 0.9 +/- 0.5, QL = 0.8 +/- 0.4 micro g x mL(-1)) in plasma, total lidocaine or MEGX in the brain at the onset of convulsions between the L and QL groups. The dose of bupivacaine required to induce convulsions was comparable in the B and QB groups. At the onset of convulsions, plasma concentrations of both total (B = 4.9 +/- 1.1, QB = 4.0 +/- 0.6 micro g x mL(-1), P = 0.03) and unbound bupivacaine (B = 1.4 +/- 0.6, QB = 0.9 +/- 0.2 micro g x mL(-1), P = 0.02) were significantly lower in the QB group than in the B group. There were no differences in concentration of total bupivacaine in the brain between the B and QB groups., Conclusion: These results suggest that quinidine inhibited P-gp activity, resulting in increased brain/plasma concentration ratio of bupivacaine, but not of lidocaine, and decreased the threshold of plasma concentration for bupivacaine-induced convulsions.

The effects of N-nitro-L-arginine-methyl ester (L-NAME) a nitric oxide (NO) synthase inhibitor and L-arginine, a NO precursor, were investigated on lidocaine-induced convulsions. In the first experiment, four groups of mice received physiological saline (0.9%), L-arginine (300 mg/kg, i.p.), L-NAME (100 mg/kg, i.p.) and diazepam (2 mg/kg), respectively. Thirty minutes after these injections, all mice received lidocaine (50 mg/kg, i.p.). In the second experiment, four groups of mice received similar treatment in the first experiment, and 30 min after these injections, all mice received a higher dose of lidocaine (80 mg/kg). L-NAME (100 mg/kg, i.p.) and diazepam (2 mg/kg) significantly decreased the incidence of lidocaine (50 mg/kg)-induced convulsions. In contrast, the L-arginine treatment increased the incidence of lidocaine (80 mg/kg, i.p.)-induced convulsions significantly. These results may suggest that NO is a proconvulsant mediator in lidocaine-induced convulsions.

Lidocaine induces electroencephalographic seizures and generalized convulsions at large doses. It is possible that epileptic patients are more susceptible to the proconvulsant effect of lidocaine. Using a kindling model of epilepsy, we examined whether the seizure susceptibility to lidocaine increases in epileptic rats. Kindled epileptic rats were prepared by repeated, initially subconvulsive, electrical stimulations applied to the amygdala for 9-14 days through a chronically implanted electrode, resulting in the establishment of a long-lasting epileptic focus. Unexpectedly, kindled rats had significantly less susceptibility to the proconvulsant action of IV lidocaine. Lidocaine-induced convulsions were observed in 11%, 75%, and 77% of control rats at 7.5, 10.0, and 12.5 mg/kg, respectively, compared with 0%, 25%, and 37% of amygdala-kindled rats, respectively. We also demonstrated that small doses of lidocaine suppressed kindled seizures in a dose-dependent manner. We conclude that the critical mechanisms underlying lidocaine-induced seizures differ from the mechanisms underlying kindled epileptogenesis. Furthermore, the establishment of a kindled epileptic focus decreases susceptibility to the proconvulsant action of lidocaine.

The effects of various anticonvulsants on local anaesthetics procaine- and lidocaine-induced convulsions were investigated in rats. Pretreatment with diazepam (2.5-5 mg/kg, intraperitoneally) and clonazepam (5-10 mg/kg, intraperitoneally) completely protected the rats against both local anaesthetic-induced convulsions. Phenobarbital (12.5-50 mg/kg, subcutaneously) also significantly decreased the incidence of both convulsions and prolonged their latencies. Carbabazepine (10-40 mg/kg, intraperitoneally) did not completely repress both convulsions, but it prolonged their latencies. Phenytoin (5-20 mg/kg, intraperitoneally) and primidone (30-60 mg/kg, intraperitoneally) markedly enhanced both local anaesthetic-induced convulsions, as shown by shortening of latency and increase in mortality. Valproate (100-200 mg/kg, intraperitoneally) produced a protective effect against procaine-induced convulsions, while it strongly enhanced lidocaine-induced convulsions. These results suggest that the benzodiazepines are effective drugs to prevent neurotoxicity induced by local anaesthetics, while phenytoin and primidone potentiate them.

Seizures are common after severe cerebral ischemia. To examine the mechanisms underlying these seizures, we determined the impact of prior forebrain ischemia on the seizure thresholds of four convulsants with differing modes of action: lidocaine, pentylenetetrazol (PTZ), N-methyl-D-aspartate (NMDA), and picrotoxin. Anesthetized Sprague-Dawley rats were chronically instrumented with screw electrodes and vascular catheters, and then subjected to 10 min of forebrain ischemia, produced by carotid occlusion and hypotension (mean arterial pressure to 30 mmHg). Animals were then awakened. 6, 24 or 48 h later, groups of awake animals received intravenous infusions of the four drugs. The total dose of drug infused prior to either electrical seizures (lidocaine, PTZ, and picrotoxin) or tonic-clonic convulsions (all drugs) were noted. For each drug, a group of Sham animals (no ischemia) served as controls. There were markedly different patterns of changes in the convulsant thresholds for the drugs. For example, at 6 h post-ischemia, rats treated with lidocaine died before convulsing, while the threshold for PTZ increased by 86%. There was no change in the picrotoxin threshold at 6 h, but the dose of NMDA needed to induce tonic-clonic seizure activity was reduced by 70%. By 48 h, lidocaine and PTZ thresholds had returned to values similar to those in Shams, but the NMDA threshold had now increased to a value 62% greater than Sham. Ten minutes of cerebral ischemia is followed by a complex and changing pattern of susceptibility to chemical convulsants. Finding suggests that early post-ischemic seizures may be related to increased NMDA receptor sensitivity., (Copyright 1999 Elsevier Science B.V.)

Minor brain injury was inflicted with a small hypodermic needle at four sites from the scalp 7 days before the production of convulsion by i.p. injection of 100 mg/kg lidocaine in mice. The latency to convulsion and survival rate were significantly longer and higher, respectively, in the brain-injured group than in the sham-operated one. Thus, the results suggest that a protective mechanism develops in the injured brain against asphyxia caused by lidocaine convulsion.

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.kg-1.min-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 +/- 5 mmHg. 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 +/- 2.9 > E = 24.1 +/- 2.7, N = 27.1 +/- 2.8, P = 26.7 +/- 2.5 mg.kg-1; values are mean +/- SD, P < 0.01). In addition, plasma lidocaine concentrations (C = 11.0 +/- 0.7 > E = 7.4 +/- 0.5, N = 7.9 +/- 0.6, P = 8.1 +/- 0.8 micrograms.ml-1, P < 0.01) and brain lidocaine concentrations (C = 50.9 +/- 4.5 > E = 32.6 +/- 4.2, N = 34.5 +/- 4.8, P = 37.1 +/- 4.5 micrograms.g-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 +/- 2.9 < N + SNP = 34.8 +/- 2.8, P < 0.01) < P + SNP = 40.2 +/- 3.0 mg.kg-1, P < 0.01). The brain/plasma concentration ratios were similar for the seven groups., Conclusions: An equal degree of acute hypertension induced by these three different vasopressors may play a role in reducing the threshold (plasma and brain lidocaine concentrations) as well as the cumulative convulsant doses associated with lidocaine-induced convulsions.

Recent studies have shown that proto-oncogene c-fos mRNA is induced in the central nervous system by a variety of stimuli including generalised convulsions. In this study, the expression of c-fos protein (c-Fos) following lignocaine-induced convulsions was examined and compared with that following convulsions induced by non-anesthetic convulsants, such as pentylenetetrazol, kainic acid and electroconvulsive shocks, in rat brain. Administration of 120 mg.kg-1 lignocaine by the intraperitoneal route induced generalised convulsions in all rats examined within 10 min. C-Fos was markedly induced in the piriform cortex and amygdala, and slightly induced in the neocortex and thalamus, while no c-Fos expression was observed in the hippocampus. In contrast, c-Fos expression following generalised convulsions induced by non-anaesthetic convulsants was very marked in the hippocampal region, piriform cortex and amygdala, and extended to the thalamus and neocortex. These results contradict those of previously reported local cerebral metabolic studies using 2-deoxyglucose as a metabolic marker, and suggest that lignocaine-induced convulsions, unlike those induced by non-anaesthetic convulsants, may not cause severe sequelae (plastic changes) in the hippocampus.

We tested the hypothesis that glutamate receptor antagonists increase the dose of lidocaine required to induce seizure activity. Sprague-Dawley rats were anesthetized with halothane in 40% O2/balance N2 and mechanically ventilated. After surgical preparation, halothane was discontinued. Normocapnia, normoxia, and normothermia were maintained. The electroencephalogram (EEG) and arterial blood pressure were monitored continuously. Rats were then randomized to one of six groups (control, one of three intravenous [i.v.] bolus doses of the competitive glutamate N-methyl-D-aspartate [NMDA] receptor antagonist CGS 19755, or one of two i.v. bolus and continuous infusion regimens of the competitive glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxalline [NBQX]). Thirty minutes after onset of CGS 19755 or NBQX administration (end-tidal halothane < 0.2%), rats received a continuous i.v. infusion of 1.5% lidocaine until EEG seizures occurred. The duration of the infusion (min) and total lidocaine dose (mg/kg) administered were recorded. CGS 19755 increased the lidocaine seizure threshold in a log-linear dose-dependent fashion (P < 10(-6)). The largest dose of CGS 19755 (112.5 mg/kg) increased the time to initial EEG seizure activity more than twofold (e.g., control = 12.6 +/- 2.6 min; CGS 19755 = 28.6 +/- 6.9 min). The effect of AMPA receptor antagonism was less obvious because treatment resulted in an EEG morphology dissimilar to that observed in the CGS 19755 or control groups. Our findings indicate that competitive NMDA receptor antagonists (e.g., CGS 19755) increase the dose of lidocaine required for seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

The thresholds for pentylenetetrazol and lidocaine-induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, alpha-methyl-p-tyrosine and p-chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine-induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine-beta-hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol-induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L-dihydroxyphenylalanine (L-DOPA) caused significant increase in brain DA contents, while 5-hydroxytryptophan (5-HTP) treatment caused significant increase in brain 5-hydroxytryptamine (5-HT) contents, but the thresholds for lidocaine and pentylenetetrazol-induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine-induced convulsions.

Influences of drug-induced manipulations of central serotonergic function on lidocaine- and pentylenetetrazol (PTZ)-induced convulsions were examined in mice. Agents that suppressed serotonergic transmission increased, whereas drugs that facilitated serotonin (5-HT) function decreased the incidence of lidocaine-induced convulsions. These treatments had similar influences on the incidence of PTZ-induced convulsions. Lidocaine (10(-5)-10(-3) M) reduced the stimulation evoked [3H]5-HT release from cortical slices, followed with an increased spontaneous [3H] overflow at higher concentrations. These results may suggest that brain 5-HT neurons are causally involved as inhibitory neurons in lidocaine-induced convulsions as in the case of PTZ-induced convulsions.

Although altered effects of various anesthetics have been demonstrated during pregnancy, published studies have incompletely defined potential pregnancy-induced changes in the central nervous system toxicity of lidocaine. Accordingly, the seizure threshold for lidocaine was measured in three groups of mechanically ventilated rats breathing 70% N2O-30% O2: male (n = 21), nonpregnant female (n = 19), and pregnant female (n = 23). Lidocaine was administered intravenously at a constant rate of 2.3 mg.kg-1.min-1 while the electroencephalogram was monitored continuously. Total doses of lidocaine and the durations of lidocaine infusion necessary to induce seizure activity were similar among groups. Plasma lidocaine concentrations at the onset of electroencephalographic seizure activity were also similar among groups (male = 10.7 +/- 5.5, nonpregnant female = 12.1 +/- 4.9, pregnant female = 10.8 +/- 4.1 micrograms/mL). In a subset of each group, brain lidocaine concentrations at the onset of seizure activity were also measured, and again no differences among groups were observed (male = 17.4 +/- 6.3, nonpregnant female = 16.8 +/- 4.5, pregnant female = 16.7 +/- 4.2 micrograms/100 g wet wt). The authors conclude that there are no pregnancy-specific alterations in either plasma or brain concentration thresholds for central nervous system toxicity of lidocaine in rats.

The toxic profile of bupivacaine (1 mg/kg/minute) when administered intravenously alone or with lidocaine (1 mg/kg loading dose, then 1 mg/kg/minute) was examined in 12 2-day-old pigs anesthetized with 70% N2O/30% O2 and paralyzed with 0.15 mg/kg pancuronium. Bupivacaine doses producing arrhythmias, seizures, isoelectric EEG and asystole were about 24% lower in the lidocaine plus bupivacaine group (n = 6) than in the bupivacaine group (n = 6). However, the incidence of cardiac arrhythmias in the combination local anesthetic group (3/6) was half that in the bupivacaine group (6/6). Administration of lidocaine with bupivacaine under conditions of this study apparently reduces the risk of cardiac arrhythmias and acts along with bupivacaine to produce seizures, cerebral depression (isoelectric EEG) and asystole.

Study Hypothesis: The toxic effects of cocaine are enhanced in the presence of lidocaine., Study Population: Male Sprague-Dawley rats weighing 200 to 300 g., Methods: Animals received intraperitoneal injections of cocaine (10, 20, 35, or 50 mg/kg), lidocaine (30 or 40 mg/kg), or a combination of all doses of cocaine given simultaneously with 30 or 40 mg/kg lidocaine. The incidence and time to seizure and death were recorded in these groups and compared by chi 2 and analysis of variance analyses, respectively., Results: At doses of 30 or 40 mg/kg, lidocaine does not induce seizures or death. The effect of simultaneous injection of both cocaine and lidocaine was to dramatically increase the incidence of both seizures and death over that of cocaine alone. The incidence of seizures in animals receiving 35 mg/kg cocaine alone was 10%; this increased to 50% and 80% with the addition of 30 and 40 mg/kg lidocaine, respectively (P less than or equal to .05; P less than or equal to .01). Death did not occur in animals receiving 35 mg/kg cocaine alone; the addition of 30 and 40 mg/kg lidocaine resulted in death in 30% and 60% of animals, respectively (P less than or equal to .01 each group). Similarly, in rats receiving 50 mg/kg cocaine, the incidence of death increased from 0% to 60% and 80% with 30 and 40 mg/kg lidocaine, respectively (P less than or equal to .01)., Conclusion: In the rat, overall toxicity of cocaine is significantly increased with simultaneous exposure to lidocaine.

The influence of hyperkalemia on the central nervous system and cardiac toxicity of bupivacaine and lidocaine was studied in open-chested mechanically ventilated dogs. The seizure and cardiotoxic doses of intravenously administered lidocaine and bupivacaine were determined in two separate groups of normokalemic (2.7 +/- 0.05 SEM mEq/1) dogs. In the case of both anesthetics, the cardiotoxic dose was found to be approximately four times the seizure dose. Under conditions of hyperkalemia (5.4 +/- 0.08 SEM mEq/1), however, the cardiotoxic doses of both anesthetics were decreased significantly to approximately two times the seizure dose. Hyperkalemia did not change the seizure dose for either anesthetic. The cardiac to seizure dose ratio was decreased significantly for bupivacaine but not for lidocaine. The results of this study suggest that hyperkalemia enhances the cardiotoxic effects of both lidocaine and bupivacaine, with this enhancement being more pronounced in the case of bupivacaine.

The effect of 50% convulsant (CD50) and 50% lethal (LD50) doses of lidocaine, bupivacaine and pentylenetetrazol were determined in mice stressed by paradoxical sleep deprivation (PSD). The results showed a reduced mortality after high doses of local anesthetics and decreased seizure susceptibility induced by bupivacaine after 48 h and 72 h of PSD. On the other hand this stressful manipulation increased the susceptibility to pentylenetetrazol-induced convulsions. These data may suggest a different mechanism of action for these drugs. Possible alterations in drug metabolism or on aminergic transmission after PSD may be involved in the protection to the toxic effect of the local anesthetics.

Oral lidocaine analogues, such as tocainide, recently have been introduced to treat cardiac arrhythmias. The side effects of tocainide are similar to those of lidocaine, but possible interactions with lidocaine have not been examined thoroughly. With the increased use of these agents, emergency physicians must decide the safety of concurrent administration of lidocaine for local anesthesia or arrhythmia management. Twelve dogs were assigned randomly to either a lidocaine (L) or a tocainide/lidocaine (TL) group. The L group received lidocaine at a dosage of 0.5 mg/kg/min until the animals seized. The TL group received both loading and maintenance doses of tocainide to obtain therapeutic steady-state tocainide levels prior to receiving lidocaine at a dosage of 0.5 mg/kg/min. Venous blood samples to measure drug levels were obtained at 20-minute intervals and at the time of seizures. The average duration of lidocaine administration required to induce seizures in the L group was 70.0 +/- 7.5 minutes, and in the TL group 29.0 +/- 7.0 minutes (P less than .05). In addition, the average serum lidocaine level at the time of seizures was 11.2 +/- 1.0 micrograms/mL in the L group and 6.2 +/- 1.7 micrograms/mL in the TL group (P less than .05). Our results show that in animals the presence of a therapeutic serum level of tocainide lowers the seizure threshold following the administration of lidocaine. These findings may have important implications for clinical care because they suggest that lidocaine should be used cautiously and in reduced dosage in patients already taking tocainide.

Lidocaine hydrochloride (HCl) (80-320 mg), bupivacaine HCl (20-80 mg), and ropivacaine HCl (30-120 mg) were administered as intravenous bolus doses to conscious sheep (n = 18; average body weight 45 kg) that had previously placed intravascular cannulae for hemodynamic monitoring and for obtaining blood samples. The mean convulsive doses and arterial blood concentrations were approximately 110 mg and 40 mg/L, respectively, for lidocaine HCl, 45 mg and 14 mg/L for bupivacaine HCl, and 60 mg and 20 mg/L for ropivacaine HCl. After subconvulsive doses of each agent, there were minimal cardiovascular effects. After convulsive doses, there were marked increases in heart rate, mean arterial pressure, pulmonary artery pressure, cardiac output, systemic vascular resistance, left ventricular end diastolic pressure, and myocardial contractility. Ventricular fibrillation caused death in two sheep after bupivacaine (80 mg) and in two sheep after ropivacaine (90 and 120 mg) administration. With sublethal doses, the hemodynamic responses to these agents were qualitatively and quantitatively similar when compared with their local anesthetic potencies.

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.

The central-nervous-system toxicities of local anesthetic mixtures consisting of lidocaine and etidocaine or lidocaine and tetracaine, administered intravenously to four healthy, non-medicated rhesus monkeys, were evaluated. Toxicities were compared by determining seizure dosages for each drug alone and then in a lidocaine-etidocaine-tetracaine mixture. Arterial plasma levels of lidocaine and etidocaine at which electrical seizure activity occurred also were measured when the drugs were administered alone and in combination. The seizure dosages and arterial plasma levels for the drug mixtures studied were equal to the sums of the dosages and thresholds for individual constituents of the mixtures. Under the conditions of this investigation local anesthetic toxicity was additive. (Key words: Anesthetics, local, lidocaine; Anesthetics, local, etidocaine; Anesthetics, local, tetracaine; Brain, seizure thresholds; Toxicity, convulsions.)

The central nervous system toxicities of etidocaine, bupivacaine, and lidocaine were studied during constant-rate intravenous infusions in rhesus monkeys. Comparison of drug effects was achieved by determining the drug dosages and arterial plasma concentrations that induced electrical seizure activity. The central nervous system toxicity of etidocaine was similar to that of bupivacaine. The toxicity of each was four times greater than that of lidocaine. Since the drug infusion rates were proportional to anesthetic potencies in clinical usage, the therapeutic-toxic ratios of these three drugs are similar.

Controversy persists surrounding the relative safety of bupivacaine compared with lidocaine especially with regard to its cardiovascular toxicity and the ability to resuscitate following such occurrences. The margin of safety between seizure onset and cardiovascular collapse was compared in lightly anesthetized and ventilated cats given an equipotent infusion of either lidocaine or bupivacaine (N = 10 for each group). The infusion rates were 4 mg X kg-1 X min-1 bupivacaine or 16 mg X kg-1 X min-1 lidocaine. Onset of electrical seizure activity occurred at about the same time in both groups and was defined as the central nervous system (CNS) toxic end point. The infusion continued until the mean arterial pressure reached 10 mmHg (cardiotoxic end point). Despite the early occurrence of electrocardiographic changes in the bupivacaine group, mean arterial pressure was greater and sustained significantly longer (4.9 +/- 1.3 min; mean +/- SD) with this drug compared with lidocaine (3.0 +/- 0.6 min) (P less than 0.005). Using the blood pressure criterion for defining cardiovascular (CV) collapse, the CV/CNS toxicity ratio for drug dosage was 4.0 with lidocaine and 4.8 with bupivacaine. The use of a standardized resuscitation protocol made it possible to compare the ability to resuscitate animals in each group. Despite very high plasma local anesthetic concentrations, all lidocaine-infused animals were quickly resuscitated (4.4 +/- 3.0 min; mean +/- SD). The resuscitation time for the bupivacaine group (5.4 +/- 2.4 min) was similar. Two cats in the bupivacaine group could not be brought to resuscitation criterion, a difference, however, that was not statistically significant.

The present study determined whether oral flunitrazepam was effective reducing CNS toxicity of lidocaine and bupivacaine. Pretreatment of mice with flunitrazepam, 0.065-0.25 mg X kg-1, significantly reduced or prevented convulsions and mortality induced by lidocaine 106 and 209 mg X kg-1 or bupivacaine 58 and 90 mg X kg-1 injected intraperitoneally. The doses of flunitrazepam used did not cause measurable sedation in mice. The efficacy of oral flunitrazepam in preventing local anaesthetic-induced convulsions is similar to that previously reported by intraperitoneal or intramuscular injections in mice. Flunitrazepam could be useful for oral premedication of patients before regional anaesthesia.

Median convulsant (CD50) and median lethal (LD50) doses of three representative local anesthetics were determined in adult mice to evaluate the threat to life of local anesthetic-induced convulsions. The CD50 and LD50, respectively, were 57.7 and 58.7 mg/kg for bupivacaine, 111.0 and 133.1 mg/kg for lidocaine, and 243.4 and 266.5 mg/kg for chloroprocaine. When given intraperitoneally, bupivacaine thus was only about twice as toxic as lidocaine and four times as toxic as chloroprocaine. Convulsions always preceded death, except after precipitous cardiopulmonary arrest from extreme doses. A CD50 dose of local anesthetic (causing convulsions in 50% of mice) was fatal in 90% of bupivacaine-induced seizures, in 57% of the chloroprocaine group, and in 6% of the lidocaine group. The narrow gap between convulsant and lethal doses of local anesthetics indicates that untreated convulsions present much more of a threat to life than heretofore appreciated.

Diazepam 0.05-0.25 mg/kg increased the dose of lignocaine required to cause seizures in Rhesus monkeys by 24-34%. Spontaneous ventilation was maintained adequately during lignocaine administration following diazepam treatment and no adverse cardiovascular effects occurred. Before the onset of lignocaine-induced seizures in non-treated animals, the animals appeared to be drowsy. However, prior to administration of diazepam masked this effect. Convulsions were controlled by smaller doses of diazepam in non-treated animals than in diazepam-treated animals. Also, the animals that were pretreated with diazepam had a greater duration of depression after seizure.