title: The effects of general anesthesia on the central nervous and cardiovascular system toxicity of local anesthetics.
abstract: BACKGROUND
  Local anesthetic toxicity is often studied experimentally in acutely prepared, anesthetized laboratory animals. We determined the influence of halothane/O(2) anesthesia on cardiovascular and central nervous system (CNS) toxic responses to six amide-type local anesthetics administered i.v..
  
  
  METHODS
  Behavioral, cardiovascular, and pharmacokinetic responses were determined in previously instrumented ewes (approximately 45-50 kg, n = 18), on separate occasions when conscious and anesthetized, to bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), prilocaine (350 mg), and saline (control) infused i.v. over 3 min.
  
  
  RESULTS
  The local anesthetics caused convulsions in conscious sheep, but no overt CNS effects in anesthetized sheep. Negative inotropy and slight bradycardia without changes in arterial blood pressure occurred initially in conscious sheep, followed by positive inotropy, tachycardia, and hypertension at the abrupt onset of CNS excitotoxicity, along with widening of QRS complexes. Fatal cardiac arrhythmias occurred in, respectively, 3 of 11, 2 of 12, and 2 of 13 conscious sheep infused with bupivacaine, levobupivacaine, and ropivacaine; in 1 of 9 with prilocaine, electromechanical dissociation (followed by polymorphic ventricular tachycardia) caused death. In anesthetized sheep, cardiovascular depression, preexisting from the general anesthesia, was exacerbated by all local anesthetics, and increased QRS width was prolonged; concurrent blood local anesthetic concentrations were doubled. Nevertheless, all anesthetized animals survived.
  
  
  CONCLUSIONS
  General anesthesia produced physiological perturbations, exacerbated local anesthetic-induced cardiovascular depression, and changed the pharmacokinetics of toxic doses of local anesthetics. However, cardiovascular fatalities from local anesthetics occurred only in conscious animals.
authors.affiliation: Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, Sydney NSW 2065, Australia.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Copeland
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Ladd
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Gu
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Mather
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000577:Amides / Q000633:toxicity; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000633:toxicity; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D002490:Central Nervous System / Q000187:drug effects*; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced; D007262:Infusions, Intravenous; D000077554:Levobupivacaine; D008012:Lidocaine / Q000633:toxicity; D008619:Mepivacaine / Q000633:toxicity; D011318:Prilocaine / Q000633:toxicity; D000077212:Ropivacaine; D012640:Seizures / Q000139:chemically induced; D012756:Sheep; D013997:Time Factors
chemical_list: D000577:Amides; D018685:Anesthetics, Inhalation; D000779:Anesthetics, Local; D011318:Prilocaine; D000077212:Ropivacaine; D008012:Lidocaine; D000077554:Levobupivacaine; D008619:Mepivacaine; D006221:Halothane; D002045:Bupivacaine