Anesthetic Toxicity Research Articles

Modification of bupivacaine toxicity by nonselective versus neuronal nitric oxide synthesis inhibition.

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.

The Plasma Concentrations of Lidocaine After Slow Versus Rapid Administration of an Initial Dose of Epidural Anesthesia

We measured venous blood concentrations of lidocaine in 15 patients undergoing lower abdominal or extremity surgery after epidural injection of lidocaine. Patients were divided into either an infusion group (Group I, n = 6) or a bolus injection group (Group II, n = 9). We administered 15 ml of 2% lidocaine into the epidural space at 1 mL/min in Group I and at 1 mL/3 in Group II. Venous blood was drawn at 3, 6, 9, 12, 15, 18, 21, 30, 60, and 90 min after injection for measurement of plasma lidocaine concentrations. The peak plasma concentration (Cmax) of lidocaine in Group I was significantly less than that in Group II (P < 0.0005). We conclude that slow epidural infusion can produce a lower Cmax of lidocaine compared with that of a bolus administration and thereby decrease the potential for systemic toxicity of the local anesthetic.

The effects of bupivacaine and ropivacaine on baroreflex sensitivity with or without respiratory acidosis and alkalosis in rats.

Systemic toxicity of local anesthetics causes cardiac and central nervous system (CNS) depression that could be enhanced in the presence of respiratory acidosis. We examined a potential suppression of baroreflex function with bupivacaine and ropivacaine during hypercapnic acidosis or hypocapnic alkalosis. Baroreflex sensitivity (BRS) was randomly tested in rats with one of 13 conditions during intravenous administration of saline (control), bupivacaine 1, 2, or 3 mg/kg, or ropivacaine 2, 4, or 6 mg/kg. The effects of bupivacaine (3 mg/kg) or ropivacaine (6 mg/kg) on BRS were also examined during hypercapnic acidosis or hypocapnic alkalosis. The BRS was assessed using a value of delta heart rate/ delta mean arterial pressure after infusion of phenylephrine (3 micrograms/kg). Both bupivacaine and ropivacaine (at the largest dose) significantly suppressed BRS. Acute respiratory acidosis (pHa 7.24 +/- 0.04, Paco2 63 +/- 4 mm Hg) enhanced BRS. The BRS enhanced during acidosis was also suppressed with bupivacaine and ropivacaine, but less so than in the absence of acidosis. The presence of hypocapnic alkalosis (pHa 7.55 +/- 0.03, Paco2 25 +/- 2 mm Hg) did not affect BRS and reversed BRS suppression caused by both drugs. Thus, bupivacaine and ropivacaine affect neuronal control mechanisms for maintaining cardiovascular stability, and acute changes of respiration could significantly modify such suppression.

Local anaesthesia for major general surgical procedures. A review of 116 cases over 12 years.

Between 1980 and 1992, 116 patients had either a simple mastectomy (32) or intra-abdominal procedures (84) under local anaesthesia (0.5-1% lignocaine with 1:200 000 adrenaline). A wide variety of general surgical procedures were feasible using only supplementary intravenous sedation (54%). Complications were uncommon and related to surgical procedure (three incorrect diagnoses, three procedures impossible) rather than the anaesthetic technique. There were no anaesthetic toxicity or postoperative problems. Local anaesthesia is extremely safe and facilitates larger surgical procedures than is generally appreciated.

Pharmacology and Toxicity of Local Anesthetics

Pharmacology and Toxicity of Local Anesthetics

Biotransformation of sevoflurane.

Several characteristics of sevoflurane biotransformation are apparent from the preceding investigations. Metabolism is rapid, with fluoride and HFIP appearing in plasma within minutes after the start of sevoflurane administration (38-40,51). Peak plasma fluoride concentrations generally occur within approximately 1 h after the termination of sevoflurane administration in most patients, regardless of the dose or duration of exposure (ranging from 0.35-9.5 MAC-h) (39,48). Peak plasma inorganic fluoride concentrations are proportional to sevoflurane dose, measured in MAC-h (42-44). Inorganic fluoride concentrations decline rapidly after termination of sevoflurane administration, with concentrations well below peak levels by the first postoperative day. HFIP is rapidly conjugated, with more than 85% circulating in plasma as the glucuronide. Plasma HFIP concentrations peak later than fluoride concentrations, but both metabolites are eliminated at similar rates (52). Metabolism of sevoflurane does not contribute to the termination of clinical drug effect (52), unlike more extensively metabolized drugs such as halothane (55). Sevoflurane is metabolized by P-450 2E1, so pathophysiologic factors and drug interactions altering P-450 2E1 activity will also influence sevoflurane metabolism (52). The extent of metabolism of sevoflurane, 2% to 5%, is less than that of all other volatile anesthetics except isoflurane and desflurane. It has been proposed that the ideal anesthetic should resist biotransformation because anesthetic toxicity is related to anesthetic metabolism (67,68). Experience to date suggests that biotransformation of sevoflurane has not been causally related to either hepatic or renal toxicity. Sevoflurane does not result in formation of fluoroacetylated liver neoantigens or other reactive metabolites. Although both sevoflurane and methoxyflurane may produce plasma fluoride concentrations in excess of 50 microM, they have not produced the same nephrotoxic effects. Clearly, anesthetic metabolism and anesthetic toxicity can no longer be considered synonymous. The introduction of sevoflurane into clinical practice will hopefully stimulate new investigations into biochemical mechanisms of anesthetic toxicity and continued clinical investigations regarding the relationship between anesthetic metabolism and organ toxicity.

Sevoflurane, Flouride Ion, and Renal Toxicity

Professor Emeritus, Department of Anesthesiology, University of Arizona, College of Medicine, Tucson, Arizona 85724.In Reply:--My editorial [1]was focused only on my thoughts concerning the article by Kharasch et al. [2]in the same issue. The toxicity of compound A, hexafluoroisopropanol toxicity, and other aspects of sevoflurane, both political and scientific, were not discussed. The editorial was strictly confined to commentaries of the novel concept that local renal production and hence high local renal concentrations of fluoride ion may be of greater importance in renal toxicity from fluorinated inhalation anesthetics than is hepatic fluoride production as measured by the plasma fluoride concentration. Contrary to Tinker and Baker's contention, neither my editorial (nor Kharasch et al.'s original paper [2]) discounted the nephrotoxic potential of fluoride ions. The issue was whether renal or hepatic production of fluoride was the more important vector of nephrotoxicity with inhalation anesthetics. The fact remains that several publications have documented plasma fluoride concentrations well in excess of 50 micro Meter, whether from sevoflurane, enflurane, isoflurane, or fluoride ion intoxication, [3]without evidence of renal toxicity.Tinker and Baker refer repeatedly to "heavy biotransformation." Let me supply the facts. Eight percent of the enflurane dose and 3-5% of the sevoflurane dose [4,5]are metabolized. Tinker and Baker are correct that some anesthetic toxicity is due to biotransformation. I am not convinced of their contrapositive argument that all biotransformation results in toxicity. No clinical pharmacologist believes this either. It is unfortunate that Tinker and Baker are prepared to pontificate with the statement that sevoflurane "is a step backward," a statement obviously made without access to the facts established with the clinical development of sevoflurane.I again propose that the major hypothesis that nephrotoxicity is agent-specific, occurs primarily because of intrarenal fluoride ion production, and is not primarily dependent on fluoride ion plasma concentration is impressive. [6]It underscores the rule that medicine can never rest on its laurels [1]: minds should remain open, vigilance should be maintained, and new data should be continually sought.Burnell R. Brown, Jr., M.D., Ph.D., F.R.C.A., Professor Emeritus, Department of Anesthesiology, University of Arizona, College of Medicine, Tucson, Arizona 85724.(Accepted for publication April 29, 1995.)

Book Review: Anesthetic Toxicity

Book Review: Anesthetic Toxicity

Bupivacaine toxicity in lightly anesthetized pigs with respiratory imbalances plus or minus halothane.

Changes in acid base balance within the body, oxygen delivery to tissue, and carbon dioxide elimination, as well as general anesthetics, influence the toxicity of local anesthetics. The objective of this study was to test the hypothesis that light halothane anesthesia, hypercapnia, and hypoxia act together to alter the central nervous system and cardiovascular toxicity of bupivacaine. Three groups of 2-week-old pigs were lightly anesthetized with N2O in O2 and paralyzed with pancuronium. One group (n = 6) was made hypercapnic (group A; PaCO2 > or = 60 mg Hg), another group (n = 6) was made hypercapnic and hypoxic (group B; F1O2 = 0.1, PaCO2 = 66.8 +/- 9.91 mm Hg, PaO2 = 29.2 +/- 3.53 mm Hg), and another group (group C; n = 5) was made hypercapnic and hypoxic and given 0.5% halothane (PaCO2 = 68.54 +/- 4.18, PaO2 = 31.06 +/- 1.96). Bupivacaine was infused intravenously at 1 mg.kg-1.min-1 until the animals developed cardiac asystole. Arrhythmias, seizures, isoelectric electroencephalogram (isoEEG), and asystole were readily identified in groups A and B. None of the animals given halothane had seizures, but they did exhibit the other three toxic endpoints. The doses of bupivacaine producing asystole were significantly less in group C than in group A (7.9 +/- 1.8 versus 17.7 +/- 2.2 mg.kg-1). The doses of bupivacaine that produced isoEEG were significantly lower in groups B and C than in group A (8.9 +/- 6.2, 5.0 +/- 1.1, 14.6 +/- 3.2 mg/kg, respectively). Doses of bupivacaine producing all toxic endpoints except seizures were lower in group B animals than in group A, but only the isoEEG doses were statistically different (arrhythmias 2.3 +/- 1.1 versus 3.7 +/- 1.1; isoEEG 8.9 +/- 6.2 versus 14.6 +/- 3.2; asystole 12.1 +/- 7.5 versus 17.7 +/- 2.2 mg.kg-1). No differences in seizure pattern or type of arrhythmia were detected. Mean arterial pressure decreased during bupivacaine infusion, the rate of decrease was fastest (P < .05) in the animals receiving halothane and slowest in the hypercapnic animals. Mean arterial pressure in group A increased significantly compared to control (to 135.5 +/- 14.4% of control; P < .01) before decreasing. Heart rate decreased and the differences over time among groups differed significantly. Bupivacaine is significantly more lethal, as judged by the doses producing asystole, in young pigs that are hypercapnic, hypoxic, and receiving halothane than in young pigs that are hypercapnic.

Role of tissue glutathione in prevention of surgical trauma.

1. Surgical trauma has been associated with pre-anaesthesia fasting, anaesthetic toxicity, haemorrhage, hypovolaemic shock, and other pathological phenomena. Tissue glutathione (GSH), thiobarbituric acid-reacting substances (TBAR), and radical-trapping activity (RTA) have been determined at various time intervals after fasting, anaesthesia, and also after hepatic ischaemia and reperfusion as a model for haemorrhage and hypovolaemic shock. 2. Light ether anaesthesia of rats resulted in an immediate (5 min) and progressive decrease in liver and kidney total glutathione (GSH and GSSG), which was much greater in animals that had been fasted for 20 h. TBARs, a measure of lipid peroxidation, in rat liver and kidney increased as total GSH decreased. Fasting (20 h) alone decreased tissue GSH by 50%, and increased TBAR 100%; fasting plus 30 min of ether anaesthesia decreased tissue glutathione by 80 to 85%, and increased TBAR by some 600%. 3. Liver ischaemia alone decreased total liver GSH by 20% in the fed rat, and 50% in the fasted rat. Ischaemia, followed by reperfusion, decreased liver total GSH by 70% in the fed rat, and 90% in the fasted rat. The ratio of GSH/GSSG decreased from 16 in control animals to 7 in the fasted ischaemic rat, then to 1 in the fasted, ischaemic rat reperfused for 90 min. RTA of liver closely paralleled liver total GSH levels. TBAR was increased by ischaemia alone (50-100%), but more (400%) by 90 min reperfusion. 4. A complex series of molecular mechanisms including: (1) GSH depletion; (2) induction of CYP2E1 activity; (3) generation of reactive oxygen species; (4) lipid peroxidation; (5) cytokine release; and (6) leucocyte activation, are advanced to account for the toxic phenomena of surgical trauma and multiple system organ failure.

The pharmacology and toxicity of local anaesthetics

The pharmacology and toxicity of local anaesthetics

Effects of an intravenously administered arrhythmogenic dose of bupivacaine at the nucleus tractus solitarius in the conscious rat.

This study was designed to further investigate the CNS-mediated cardiovascular toxicity of local anesthetics and to determine any effect of anesthesia on the firing rate of cells in the nucleus tractus solitarius (NTS) of conscious animals. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. A femoral artery and vein were cannulated. A 3-mm hole was then drilled for placement of a unidirectional microdrive. The animal was removed from the stereotactic instrument, and EKG electrodes, pressure transducer and the microdrive containing a 1-micron tungsten electrode were attached. Animals were then placed in a canvas sling for recovery from the anesthetic. Cells of the NTS were located and cell firing rate (CFR) was continuously recorded. None of the animals exhibited any sign of discomfort upon recovery from anesthesia. CFRs decreased from 19 +/- 13 to 4 +/- 4 impulses/second at 20 +/- 16 seconds after the IV injection of bupivacaine (p less than 0.01). Maximum decreases in blood pressures were 26 +/- 15% of control and occurred at 32 +/- 14 seconds after the injection of bupivacaine. The maximum decrease in heart rate was 38 +/- 16% and occurred at 13 +/- 10 seconds after the injection of bupivacaine. Maximum heart rate changes occurred significantly earlier than maximum decreases in CFR (p less than 0.01). On the other hand, maximum blood pressure changes occurred significantly later than maximum decreases in CFR (p less than 0.01). The data reported here demonstrate that conscious animals respond similarly to animals anesthetized with chloral hydrate with respect to the medullary effect of local anesthetics.

Does Pregnancy Alter the Systemic Toxicity of Local Anesthetics?

Does Pregnancy Alter the Systemic Toxicity of Local Anesthetics?

Preparation and properties of 2-(dialkylaminomethyl)cyclohexyl and 2-(dialkylaminomethyl)phenyl carbanilates

A series of 2-(dialkylaminomethyl)cyclohexyl and 2-(dialkylaminomethyl)phenyl esters of substituted carbanilic acid have been prepared and their identity verified by elemental analysis and evaluation of IR and 13C NMR spectra. The spectral results have been used also for determination of isomerism of the starting 2-dialkylaminomethylcyclohexanols and final carbanilates. Local anaesthetic activity and acute toxicity have been tested with some of the substances.

Effects of Cimetidine and Ranitidine on Local Anesthetic Central Nervous System Toxicity in Mice

The effects of cimetidine (5-200 mg/kg), ranitidine (1-100 mg/kg), or saline on local anesthetic central nervous system toxicity was studied when administered 20 min before the administration of lidocaine (30-80 mg/kg) or 2-chloroprocaine (50-250 mg/kg) to female white CD-1 mice. All drugs were administered intraperitoneally. The 50% convulsive dose (CD50) was determined for each drug and dose combination. Pretreatment with cimetidine resulted in a significant, dose-dependent decrease in the CD50 of lidocaine, whereas ranitidine pretreatment did not significantly alter the lidocaine CD50. A dose of cimetidine (15 mg/kg) that caused a significant decrease in 2-chloroprocaine CD50 (from 180 to 110 mg/kg) caused only an insignificant decrease in lidocaine CD50 (from 59 to 54 mg/kg). If these results can be applied to clinical doses in humans, ranitidine may be a safer premedicant than cimetidine with regard to interactions with local anesthetics.

TOXICITY OF SEVOFLURANE IN RATS

Sevoflurane, an experimental potent volatile anesthetic with a low blood/gas partition coefficient, degrades in the presence of soda lime to products the toxicity of which is unknown. We tested whether toxic products were produced by the passage of sevoflurane through soda lime, and a comparison was made of the toxicity of sevoflurane passed through soda lime with the toxicity of other potent volatile anesthetics in current clinical use. Halothane, isoflurane, sevoflurane (all in 1-MAC concentrations), or no anesthetic (control) were passed through soda lime for 4 hr with 12, 14, or 100% oxygen to groups of rats with hepatic microsomal enzyme induction. Separate groups of 12-13 rats were given 1 MAC of sevoflurane that had not passed through soda lime and either 14 or 100% oxygen. Sevoflurane was no more toxic than isoflurane and both of these anesthetics were less toxic than halothane. Soda lime was not a factor in any toxicity produced. Hepatic injury with all agents varied inversely with the oxygen concentration administered during anesthesia.

The Effect of Cimetidine on Anesthetic Metabolism and Toxicity

Because the H2-receptor antagonist cimetidine has been shown to inhibit drug metabolism, the effects of cimetidine on anesthetic metabolism and toxicity were investigated in a rat model. Cimetidine decreased inorganic plasma fluoride production after methoxyflurane administration both in 21% oxygen (P less than 0.001) and in 100% oxygen (P less than 0.001). Phenobarbital produces an increased fluoride formation after methoxyflurane anesthesia, and this fluoride formation is also reduced by cimetidine (P less than 0.005). There was no significant difference between the plasma fluoride levels in rats anesthetized with halothane or enflurane. Although cimetidine inhibited the in vivo defluorination of methoxyflurane, fluoride levels were still within the nephrotoxic range, and cimetidine is not likely to play a role as part of a preanesthetic regimen that would permit the increased clinical use of methoxyflurane. Cimetidine also inhibited the oxidative metabolism of halothane; cimetidine decreased (P less than 0.05) trifluoroacetic acid concentrations after halothane anesthesia in 21% oxygen and in 100% oxygen and decreased (P less than 0.05) bromide concentrations after halothane anesthesia in 100% oxygen. Trifluoroacetic acid levels were less (P less than 0.02) after halothane anesthesia in 14% oxygen as compared with 100% oxygen, indicating a reduction in oxidative metabolism under hypoxic conditions. However, bromide concentrations were maximal after halothane anesthesia in 21% oxygen, and significantly (P less than 0.001) less after halothane anesthesia in 14% and 100% oxygen. Bromide production, therefore, seems to be inhibited by both hypoxia and hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of Cimetidine on Anesthetic Metabolism and Toxicity

The Effect of Cimetidine on Anesthetic Metabolism and Toxicity

Toxicity of Local Anaesthetics in Obstetrics III: Overview

Toxicity of Local Anaesthetics in Obstetrics III: Overview

Toxicity of Local Anaesthetics in Obstetrics IV: Management

Toxicity of Local Anaesthetics in Obstetrics IV: Management