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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toxic systemic reactions to bupivacaine usually involve a number of factors, including hypoxia and acidosis. The objective of this study was to test the hypothesis that cardiovascular and central nervous system responses to bupivacaine overdose are proportional to the severity of hypoxia. The central nervous system and cardiovascular toxicity of bupivacaine was examined in three groups of pigs breathing 30%, 15%, or 10% O2, 70% N2O, and He (FIO2 = 0.15 and 0.1 groups). The 18 2-week-old pigs (6 animals per treatment) were paralyzed with pancuronium and their lungs ventilated mechanically. During the intravenous infusion of bupivacaine 2 mg.kg-1.min-1, four readily identified toxic endpoints (seizures, arrhythmias, isoelectric electroencephalogram, asystole) were observed in all animals, with the exception that 1 pig in the FIO2 = 0.3 group and 1 in the FIO2 = 0.15 group had no arrhythmias. Bupivacaine doses producing seizures, isoelectric EEG, and asystole were significantly less in the FIO2 = 0.1 groups as compared to the other groups. Arrhythmias occurred before seizures in all animals in the FIO2 = 0.1 group but in only 1 of 5 and 2 of 5 animals in the FIO2 = 0.15 and 0.3 groups, respectively. There was no significant difference between the arrhythmic dose of bupivacaine in the FIO2 = 0.3 versus 0.1 animals (8.4 +/- 2.4 vs. 4.0 +/- 1.4 mg.kg-1), but the dose was significantly less in the FIO2 = 0.1 animals than in the FIO2 = 0.15 animals (12.5 +/- 5.6 mg.kg-1). Arterial pH was stable in all three groups during bupivacaine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Severe hypoxia enhances central nervous system and cardiovascular toxicity of bupivacaine in lightly anesthetized pigs. 160 87

An animal model with four well defined endpoints for studying the cardiotoxicity and neurotoxicity of bupivacaine is described. Five male Wistar rats (264-324 g) were anesthetized, tracheostomized and ventilated, and ECG and EEG leads were placed. Femoral arteries and veins were then cannulated. Twenty minutes before bupivacaine infusion, 0.1 mg/kg pancuronium was given intravenously, and anesthesia was adjusted to halothane 0.5%, 30% O2 and 70% N2O. Bupivacaine infusion was then begun at 2 mg/kg/minute. Bupivacaine doses producing the following endpoints were then determined: (1) first ventricular arrhythmia (ARR), (2) seizures (SZ), (3) isoelectric EEG (ISO EEG), and (4) asystole (ASYS). The doses of bupivacaine (in mg/kg +/- SD) precipitating AAR, SZ, ISO EEG and ASYS were 4.22 +/- 1.87, 7.08 +/- 1.55, 11.05 +/- 5.15 and 20.4 +/- 6.49 mg/kg, respectively. These endpoints were present and readily determined in all animals. The doses of bupivacaine producing ARR and SZ were not significantly different (p greater than 0.05). The doses producing SZ, ISO EEG and ASYS were significantly different from each other (p greater than 0.05, ANOVA and the Duncan test). These results indicate that it is possible to study, in the anesthetized and paralyzed rat that is intensely monitored, many of the variables associated with local anesthetic toxicity currently of clinical interest. The use of a constant local anesthetic infusion allows ready observation of the progression of toxic signs.
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PMID:A rodent model for studying four well defined toxic endpoints during bupivacaine infusion. 191 99

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.
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PMID:Cardiovascular and central nervous system effects of co-administered lidocaine and bupivacaine in piglets. 204 32

The influence of age and volatile anesthetic agents on plasma concentrations and toxic effects of bupivacaine were studied in 2-day-old, 2-week-old, and 2-month-old pigs. Bupivacaine was infused at a constant rate while the pigs' ECGs and EEGs were recorded. Six pigs in each age group were lightly anesthetized with 70% N2O/30% O2 during the bupivacaine infusion, and twelve 2-day-old pigs were anesthetized with 70% N2O/30% O2 plus either 0.5 X MAC halothane or isoflurane. Two-day-old pigs were more resistant than older pigs to the toxic effects of bupivacaine despite higher plasma concentrations at all sample times. All pigs given N2O alone or N2O plus halothane had ventricular dysrhythmias, but only one pig in the N2O plus isoflurane group had a ventricular dysrhythmia. Threshold doses of bupivacaine for dysrhythmias in the N2O alone and N2O plus halothane groups did not differ. Seizures occurred in all pigs in the N2O alone group, in none of the N2O plus halothane group, and in two of the N2O plus isoflurane group. The doses required to depress cardiac index and cause asystole were less in the groups receiving halothane and isoflurane. It was concluded that N2O plus halothane and N2O plus isoflurane increase the lethality of bupivacaine while preventing early warning signs of toxicity.
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PMID:Bupivacaine toxicity in young pigs is age-dependent and is affected by volatile anesthetics. 238 52

To determine what effect the addition of epinephrine has on bupivacaine toxicity, toxic doses of bupivacaine were administered to awake spontaneously breathing pigs. Twenty animals were randomized to one of two groups. One group received an infusion of bupivacaine with epinephrine (5 micrograms/ml) at a rate of 2 mg.kg-1.min-1; the other received an infusion of plain bupivacaine at the same rate. Bupivacaine infusion was continued until cardiovascular collapse. Following cardiovascular collapse we attempted to resuscitate the animals via open chest cardiac massage and a standardized resuscitation protocol. The addition of epinephrine to bupivacaine significantly increased blood pressure and systemic vascular resistance but not heart rate or cardiac output early in the bupivacaine infusion. Epinephrine had no effect on the dose of bupivacaine that caused cardiovascular collapse (P = 0.1), on the plasma concentration of bupivacaine at collapse (P = 0.9), or on the ability to resuscitate animals following cardiovascular collapse. The addition of epinephrine decreased the dose of bupivacaine required to initiate cardiac dysrhythmias (P = 0.003). The first dysrhythmia experienced by the epinephrine group was second degree heart block, which contrasts with the premature ventricular and atrial dysrhythmias experienced by the plain group. The dose of bupivacaine that produced seizures was also reduced by the addition of epinephrine (P = 0.006). The addition of epinephrine to bupivacaine did not alter the dose of bupivacaine that caused cardiovascular collapse in awake spontaneously breathing pigs but did decrease the dose of bupivacaine that caused seizures and dysrhythmias.
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PMID:Effect of epinephrine on central nervous system and cardiovascular system toxicity of bupivacaine in pigs. 281 65

The effects of alpha- and beta-adrenergic blockade on the systemic and pulmonary circulation during i.v. bolus injection of sub-seizure doses of lidocaine and bupivacaine were studied in dogs anesthetized with nitrous oxide. Pretreatment with hexamethonium or propranolol produced a marked decrease in cardiac output (CO), although pretreatment with phenoxybenzamine inhibited the decrease in CO during i.v. administration of lidocaine. Pretreatment with hexamethonium or phenoxybenzamine attenuated the increase in total peripheral resistance (TPR) following lidocaine 10 mg/kg i.v. In contrast, the propranolol-treated dogs developed a marked increase in TPR. The increases in mean pulmonary arterial pressure and pulmonary vascular resistance (PVR) following lidocaine 10 mg/kg i.v. were blocked by pretreatment with hexamethonium. Furthermore, PVR increased markedly with pretreatment with propranolol, although pretreatment with phenoxybenzamine prevented the large increase in PVR. These findings indicate that lidocaine has both a direct depressant effect and an indirect beta adrenergic stimulant effect on the heart. Systemic or pulmonary vasoconstriction following intravenous administration of lidocaine 10 mg/kg is associated primarily with an indirect stimulant effect mediated by alpha-adrenergic mechanisms. Bupivacaine, as well as lidocaine, has an indirect stimulant effect mediated by the autonomic nervous system.
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PMID:Influence of alpha- and beta-adrenergic blockade on systemic and pulmonary hemodynamics during intravenous administration of local anesthetics. 614 36

Thirty Sprague-Dawley rats were paralysed with pancuronium and their lungs ventilated mechanically with 70% nitrous oxide and 0.5% halothane in oxygen. Bupivacaine 2 mg kg-1 min-1 was infused continuously i.v. until the animals died. At the onset of seizures, animals were given an i.v. bolus of propofol 1 mg kg-1 (n = 10), thiopentone 2 mg kg-1 (n = 10) or lipid vehicle (n = 10). Administration of propofol or thiopentone was repeated each time seizures restarted and lipid vehicle administrations were repeated at 2-min intervals until the electroencephalogram became isoelectric. All animals developed seizures, arrhythmias, isoelectric EEG and asystole. Administration of lipid vehicle induced no obvious changes in ongoing epileptiform activity. The initial doses of thiopentone and of propofol stopped epileptiform activity in all animals, usually within 6 s after administration. The seizure-free period after the initial administration of thiopentone and of propofol lasted, on average, 0.98 min and 1.72 min, respectively. We conclude that propofol may have value in treating seizures induced by bupivacaine.
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PMID:Comparison of propofol with thiopentone for treatment of bupivacaine-induced seizures in rats. 825 Dec 86

We have previously shown that pretreatment of rats with a nonselective nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), enhances the cardiovascular system (CVS) toxicity and reduces the central nervous system (CNS) toxicity of local anesthetics. This study was performed to differentiate the neuronal from the endothelial effects of L-NAME on the CNS and CVS toxicity of bupivacaine by comparing the effects of L-NAME with a neuronal selective NOS inhibitor, 7-nitroindazole (7-NI). Lightly anesthetized rats were premedicated for 30 min with L-NAME (2 mg kg(-1) x min(-1) intravenously [I.V.]), 7-NI (30 mg/kg intraperitoneally), or saline (control) then bupivacaine (2 mg x kg(-1) x min(-1)) was infused I.V. until asystole occurred. Bupivacaine doses required to produce seizures were the same among groups (saline = 10.1 +/- 2.6 mg/kg; L-NAME = 9.0 +/- 1.2 mg/kg; 7-NI = 10.2 +/- 1.0 mg/kg). However, plasma bupivacaine concentration (microg/mL) at seizure onset was significantly higher in animals pretreated with L-NAME (16.4 +/- 2.1) and, to a lesser degree, 7-NI (11.6 +/- 1.3) than that of control (9.7 +/- 1.6). Seizure duration and the number of epileptiform bursts were significantly reduced in L-NAME versus the other two groups. Doses for arrhythmias and asystole as well as plasma bupivacaine concentrations at arrhythmia onset were dramatically smaller in L-NAME-pretreated rats than in the other two groups. In summary, endothelial NOS inhibition dramatically alters both the CVS and CNS toxicity of bupivacaine with neuronal NOS inhibition playing a minor role.
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PMID:Modification of bupivacaine toxicity by nonselective versus neuronal nitric oxide synthesis inhibition. 908 62

Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravascular injection. Small children are more prone than adults to methaemoglobinaemia, and the combination of sulfonamides and prilocaine, even when correctly administered, should be avoided in this age group. The incidence of true allergy to local anaesthetics is rare. All local anaesthetics can cause CNS toxicity and cardiovascular toxicity if their plasma concentrations are increased by accidental intravenous injection or an absolute overdose. Excitation of the CNS may be manifested by numbness of the tongue and perioral area, and restlessness, which may progress to seizures, respiratory failure and coma. Bupivacaine is the local anaesthetic most frequently associated with seizures. Treatment of CNS toxicity includes maintaining adequate ventilation and oxygenation, and controlling seizures with the administration of thiopental sodium or benzodiazepines. Cardiovascular toxicity generally begins after signs of CNS toxicity have occurred. Bupivacaine and etidocaine appear to be more cardiotoxic than most other commonly used local anaesthetics. Sudden onset of profound bradycardia and asystole during neuraxial blockade is of great concern and the mechanism(s) remains largely unknown. Treatment of cardiovascular toxicity depends on the severity of effects. Cardiac arrest caused by local anaesthetics should be treated with cardiopulmonary resuscitation procedures, but bupivacaine-induced dysrhythmias may be refractory to treatment. Many recent reports of permanent neurological complications involved patients who had received continuous spinal anaesthesia through a microcatheter. Injection of local anaesthetic through microcatheters and possibly small-gauge spinal needles results in poor CSF mixing and accumulation of high concentrations of local anaesthetic in the areas of the lumbosacral nerve roots. In contrast to bupivacaine, the hyperbaric lidocaine (lignocaine) formulation carries a substantial risk of neurotoxicity when given intrathecally. Drugs altering plasma cholinesterase activity have the potential to decrease hydrolysis of ester-type local anaesthetics. Drugs inhibiting hepatic microsomal enzymes, such as cimetidine, may allow the accumulation of unexpectedly high (possibly toxic) blood concentrations of lidocaine. Reduction of hepatic blood flow by drugs or hypotension will decrease the hepatic clearance of amide local anaesthetics. Special caution must be exercised in patients taking digoxin, calcium antagonists and/or beta-blockers.
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PMID:Adverse effects and drug interactions associated with local and regional anaesthesia. 956 36

We have previously demonstrated that inhibition of nitric oxide synthase (NOS) alters the toxicity of local anesthetics including bupivacaine. Because significant changes in blood distribution are associated with the use of nonselective NOS inhibitors, the purpose of this study was to determine whether modification of bupivacaine toxicity by nonselective NOS inhibition is due to alteration in tissue disposition of bupivacaine. Rats were anesthetized with halothane and pretreated with either: 1) a nonselective NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME, 2 mg/kg/min, IV for 30 min); 2) a neuronal NOS inhibitor, 7-nitroindazole (7-NI, 30 mg/kg, IP); or 3) vehicle (control). Thirty minutes later, bupivacaine 2 mg/kg/min IV was infused until onset of seizures, arrhythmias, or asystole. L-NAME caused a rapid increase in plasma bupivacaine concentrations (3-4 times faster than in the other groups), which was associated with markedly lower bupivacaine doses (mg/kg) required to produce arrhythmias in L-NAME (4.2 +/- 0.5) vs. control (26 +/- 3, p < 0.01) and 7-NI groups (17 +/- 3, p < 0.01). Myocardial bupivacaine concentrations at arrhythmia onset were slightly lower in the L-NAME group. Bupivacaine seizure doses in 7-NI and L-NAME pretreated animals were similar to control but significantly different from each other. Brain bupivacaine concentrations at seizure onset were similar among the groups. There were no significant differences between 7-NI and control groups in any parameter observed. We conclude that enhanced cardiotoxicity of bupivacaine by nonselective NOS inhibition is primarily due to rapid increases in plasma and myocardial distribution of bupivacaine.
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PMID:Nitric oxide modulation affects the tissue distribution and toxicity of bupivacaine. 1089 80


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