JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Groban, L.
Right arrow Articles by Butterworth, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Groban, L.
Right arrow Articles by Butterworth, J.
Anesth Analg 2000;91:1103-1111
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Ventricular Arrhythmias With or Without Programmed Electrical Stimulation After Incremental Overdosage with Lidocaine, Bupivacaine, Levobupivacaine, and Ropivacaine

Leanne Groban, MD, Dwight D. Deal, BS, Jason C. Vernon, BS, Robert L. James, MS, and John Butterworth, MD

Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence and reprint requests to Leanne Groban, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009. Address e-mail to lgroban{at}wfubmc.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
It is unclear whether the mechanism of death from local anesthetic (LA) intoxication is primarily a consequence of cardiac arrhythmias or myocardial contractile depression, and whether LAs might differ in this susceptibility to these two mechanisms. By using programmable electrical stimulation (PES) protocols in anesthetized, ventilated dogs, we compared the arrhythmogenic potential of bupivacaine (BUP), ropivacaine (ROP), levobupivacaine (LBUP), and lidocaine (LIDO). Open-chest dogs were randomized to receive escalating incremental infusions of the four local anesthetics until cardiovascular collapse. We assumed a concentration relationship of 4:1 for LIDO/BUP, LBUP, and ROP. The effective refractory period did not change significantly until the dose increment corresponding to target concentrations of 8 and 32 µg/mL for BUP, LBUP, ROP, and LIDO, respectively. Thirty percent to 50% increases in effective refractory period oc-curred in surviving dogs at this dose. The incidence ofspontaneous or PES-induced ventricular tachycardia and ventricular fibrillation did not differ among groups. Compared with LIDO, the incidence of PES-induced extrasystoles was more frequent for BUP- and LBUP-treated dogs (P < 0.05). ROP-treated dogs did not differ from LIDO-treated dogs with respect to PES-induced extrasystoles. At the dose increment preceding cardiovascular collapse, all LAs produced significant increases in heart rate and reductions in blood pressure compared with their respective baseline values. The incidence of programmable electrical stimulation-induced ventricular tachycardia and fibrillation with BUP does not differ from the incidence that occurs with the single S(-) enantiomers LBUP and ROP, providing further evidence against stereoselective arrhythmogenesis as a primary component of local anesthetic-induced cardiotoxicity.

Implications: Progressive bupivacaine intoxication in anesthetized, ventilated dogs does not produce early arrhythmogenic events. The incidence of programmable electrical stimulation-induced ventricular tachycardia and fibrillation with bupivacaine does not differ from the incidence that occurs with the single S(-) enantiomers levobupivacaine and ropivacaine, providing further evidence against stereoselective arrhythmogenesis as a primary component of local anesthetic-induced cardiotoxicity.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The cardiovascular effects of an accidental intravascular injection of bupivacaine (BUP) can be catastrophic. Electrophysiologic and hemodynamic disturbances, including conduction blocks, ventricular arrhythmias, and fatal cardiovascular collapse have been reported in patients (1,2) and observed experimentally (3–5). However, it is unclear whether the mechanism of death from BUP intoxication is primarily a consequence of cardiac arrhythmias or of myocardial contractile depression, or some combination of the two. Some groups suggest that cardiotoxic BUP concentrations produce a direct myocardial depression that precedes the onset of lethal arrhythmias (4–6). Others propose that death from BUP toxicity results from ventricular tachyarrhythmias, or severe bradycardia, with or without electromechanical dissociation, ultimately leading to cardiovascular collapse (7–9).

One reason for this continuing uncertainty is that the study of BUP intoxication in conscious, spontaneously breathing animals, has been confounded by sympathetic nervous system activation, hypoxemia, hypercarbia, and other metabolic consequences of seizures (7,8,10). Also, only a limited amount of quantitative cardiovascular information can be obtained by using experimental models using bolus local anesthetic (LA) administration. Selective hemodynamic and electrophysiologic measures are often unobtainable in such a model because of the minimal separation between blood concentrations of LA leading to central nervous system (CNS) and cardiovasculartoxicity (11,12). Additionally, LA tolerance decreases with the speed of infusion (13). Finally, there are minimal data about LA toxicity resulting from gradual IV overdosage, such as might occur during continuous regional infusions for pain management.

Therefore, by using an incrementally escalating LA dosing regimen in anesthetized, ventilated dogs, our goal was to test the hypotheses that: 1) there is a stereoselective relationship among the amino amide pipecoloxylidide (PPX)-type LAs such that racemic BUP, or R,S-1-butyl-2',6'-PPX, has a greater arrhythmogenic potential than its S(-) enantiomer, levobupivacaine (LBUP), or S-(-)-1-butyl-2',6'-PPX, and the single enantiomer ropivacaine (ROP) or S-(-)-1-propyl-2',6'-PPX, and 2) there is a structure-activity relationship among LAs such that longer-acting compounds (BUP, LBUP, and ROP) are more arrhythmogenic than less potent, shorter-acting LAs (lidocaine [LIDO]). Standard, programmable electrical stimulation (PES) protocols were used to determine the arrhythmogenic potential of each LA. The purpose of PES was to elicit arrhythmias at a smaller BUP plasma concentration than would be required to spontaneously produce arrhythmias, to minimize the effects of BUP-induced CNS toxicity upon electrophysiologic responses.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This investigation was reviewed and approved by our animal care and use committee. All experimental procedures and protocols complied with the Guiding Principles in the Care and Use of Animals, approved by the Council of the American Physiological Society.

Forty heartworm-free, nonpregnant, purebred hounds (Harlan Sprague Dawley, Inc., Indianapolis, IN), weighing between 18 and 23 kg, were used. Anesthesia was induced with 20 mg/kg IV sodium thiopental and maintained with a continuous infusion of fentanyl (0.3 µg · kg-1 · min-1) and midazolam (0.005 µg · kg-1 · min-1). The tracheas were intubated, and mechanical ventilation was instituted with an oxygen-enriched room air mixture. Both femoral arteries and veins were cannulated for arterial pressure monitoring and sampling, and for drug and fluid infusion, respectively. Body temperature was measured rectally, and maintained between 37° to 38°C during the experiment by using a heating blanket. Minute ventilation was adjusted, or sodium bicarbonate solution (8.4%) was administered, to maintain pHa, 7.35–7.45; PaCO2, 30–40 mm Hg; and PaO2, 150–300 mm Hg. A continuous infusion of 0.9% of NaCl at 3 mL · kg-1 · h-1 was given throughout the experiment. The urinary bladder was catheterized.

A left thoracotomy was performed and the heart was exposed and supported by a pericardial cradle. Two insulated silver-coated wires were inserted 1-cm apart into the epicardial surface of the left ventricle to allow for pacing and programmed stimulation. A surface lead II electrocardiogram and arterial blood pressure were continuously monitored on an oscilloscope and recorded on a polygraph interfaced with a computer (486 Optiplex; Dell Computer Corp., Austin, TX) for data retrieval.

The dogs were randomized to receive incremental infusions of vehicle (saline; n = 3) or one of four LAs until cardiovascular collapse: 0.5% methylparaben-free BUP HCl (AstraZeneca, Philadelphia, PA) (n = 10), 0.5% methylparaben-free ROP HCl (AstraZeneca) (n = 10), 0.5% LBUP HCl (n = 10) (AstraZeneca R&D, Södertälje, Sweden), or 2.0% methylparaben-free LIDO (AstraZeneca) (n = 7). The principal investigator, who gathered the data, remained blinded to the LA until all of the experiments had been completed. The dosing regimens for BUP, LBUP, and ROP were based on drug clearance rates in dogs provided by AstraZeneca R&D, and the desired plasma target concentrations were 2, 4, 8, 16, and 19 mg/L. A clearance rate of 0.9 l · h-1 · kg-1 was assumed for BUP and LBUP, and a clearance rate of 1.16 l · h-1 · kg-1 was assumed for ROP. The clearance rate assumed for LIDO was 1.71 l · h-1 · kg-1, and the desired plasma concentrations to be achieved were 8, 16, 32, and 64 mg/L, assuming a BUP-to-LIDO potency ratio of 4:1. Drug infusions consisted of a 12-min initial infusion (defined as three times the calculated maintenance rate) followed by a 12-min maintenance infusion (defined as: clearance rate (L/h/kg) x desired target concentration (mg/L) = mg/h/kg). From previous pharmacokinetic data (AstraZeneca R&D), it was assumed that 88% of the desired plasma concentration would be achieved after the initial, 12-min initial infusion, and that 92% of the desired target concentration would be achieved after the maintenance infusion. The data collection periods began after the 12-min maintenance infusions and ended after completion of the PES protocols for each dose increment.

The PES of the ventricle was performed by using a Medtronic Model 5325 programmable stimulator (Medtronic Inc., Minneapolis, MN) (Fig. 1). The heart was paced for eight beats (S1) at an intrastimulus interval of 500 ms (and 400 ms) and a pulse duration of 1.5 ms at 3 times the diastolic threshold of approximately 12 mA. The intrastimulation interval was progressively shortened between the last paced beat and a single extrastimulus (S2) until ventricular refractoriness was reached. The effective refractory period (ERP) represented the shortest interval between the paced ventricular stimulus (S1) and the premature ventricular stimulus (S2) that failed to generate a cardiac response (as determined visually by a mechanical contraction or an arterial pressure waveform). After the ERP was determined, PES of the ventricle was performed as follows: the heart was paced for eight beats (S1), followed by two additional paced beats (S2 and S3) that occurred progressively earlier in diastole. The premature extrastimulus S2 was introduced 20 ms beyond the predetermined ERP and the second extrastimulus (S3) was introduced at decreasing coupling intervals (10 ms) until ventricular tachyarrhythmias were elicited or no cardiac response resulted. Four seconds was allowed to elapse between periods of pacing. ERP determination and PES protocols were performed when each target plasma concentration was reached. A premature ventricular complex or extrasystole was defined as a single ventricular response that was reproducibly initiated during the PES protocol. Ventricular tachycardia (VT) was defined as a run of at least four uniform, repetitive extrasystoles. Ventricular fibrillation (VF) was defined as a ventricular arrhythmia with a persisting nonuniform morphology. Cardiovascular collapse was defined as severe hypotension (mean arterial blood pressure [MAP] <= 45 mm Hg) or VF or sustained VT with concomitant hypotension to a degree <= 50 mm Hg.



View larger version (29K):
[in this window]
[in a new window]
  		Figure 1. Schematic diagram of programmable electrical stimulation (PES) protocol at an intrastimulus (S1) pacing interval of 500 ms. S2 and S3 = premature extra stimuli; V1, V2, and V3 = ventricular responses corresponding to paced stimuli S1, S2, and S3. ECG = electrocardiogram.

 
At baseline (control), and at each target concentration, heart rate (HR), MAP, and ERP were obtained and PES protocols were performed. Arterial blood samples for free and total plasma LA concentrations were taken at the beginning and at the end of each data collection period. The plasma concentrations were determined at AstraZeneca R&D Laboratories by using high-pressure liquid chromatography.

Data for hemodynamics and ERP were returned to baseline values of 100%. Data were analyzed using SAS version 6.1 (SAS Institute, Cary, NC). Analysis of variance was used to analyze ERP, HR, MAP, and LA plasma concentrations. The mean free and total LA concentration for each dose measurement was determined from the plasma sample taken at the beginning and end of each data collection period. The data were log-transformed before analysis. The exact {chi}2 test was used to compare the drugs at 8 µg/mL for the presence/absence of premature ventricular contractions (PVCs). For each drug, paired McNemar tests were used to test whether the presence/absence of PVCs changed with dose. The primary comparisons were between the 0- and 8-µg/mL doses with P values <0.0125 considered significant (Bonferroni corrections for four multiple comparisons). When the primary comparisons between the 0- and 8-µg/mL doses for a drug were significant, additional pair-wise comparisons were made among all the dose levels with the {alpha}-level remaining at 0.0125. If, however, the primary 0- versus 8-µg/mL comparison for a drug was not significant, then additional pair-wise comparisons among all drug levels were made, but with full Bonferroni corrections for all the multiple comparisons. Exact {chi}2 tests were used to examine differences among groups with respect to PES-induced VF and VT. Post tests were corrected for multiple comparisons when the overall effects or interactions were not significant (Fisher’s protected least significant difference). P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Forty-one dogs were used to provide 40 successful experiments. One BUP dog was excluded from analysis because of IV catheter problems that resulted in a failure of drug delivery. Data from the protocol control dogs were not included in statistical analyses. No dog exhibited clinical signs of convulsive activity during the study. Because fatality occurred after differing drug doses during the protocol, not all animals of each group received the same number of dose increments of LA. Outcomes for HR, MAP, and ERP were, therefore, analyzed from subsets in which drug-paired analyses were available (i.e., in which no more than one dog died in a group).

Groups did not differ with respect to weight, baseline hemodynamics, and arterial blood gas measurements (Table 1). Doses (mg), plasma concentrations of the LAs (free and total), and the duration of the infusion periods associated with hemodynamic and electrophysiologic measurements at each dose increment are shown in Table 2. Total plasma concentrations were similar among BUP and ROP dogs throughout the dosing regimen; however, concentrations were slightly less for LBUP at the first two dosing levels (P < 0.001). As planned and anticipated, the total and free plasma concentrations measured in the LIDO-treated dogs were 4-to-5 times greater than the respective plasma concentrations observed in the dogs treated with BUP, LBUP, and ROP. The free plasma concentrations were similar among BUP and LBUP dogs throughout the protocol; however, concentrations were significantly greater for ROP at each dose (P < 0.001).


View this table:
[in this window]
[in a new window]
  		Table 1. Group Characteristics at Baseline
 

View this table:
[in this window]
[in a new window]
  		Table 2. Drug Doses, Plasma Local Anesthetic Concentrations, and Elapsed Time at Each Target Dose Increment
 
Hemodynamic responses in the groups were similar (Fig. 2). All LAs provoked a concentration-dependent increase in HR and MAP. At the dose preceding cardiovascular collapse, the predominant effect was tachycardia (HR >120 bpm) with an associated decline in MAP.



View larger version (34K):
[in this window]
[in a new window]
  		Figure 2. A, The effect on heart rate of increasing concentrations of free plasma local anesthetic concentrations after incremental overdosing. The individual dogs in each group are presented. The data point to the far right represents the heart rate and plasma concentrations corresponding to the last dose increment preceding cardiovascular collapse. B, The effect on mean arterial pressure (MAP) of increasing free plasma local anesthetic concentrations after incremental overdosing. The individual dogs in each group are presented. The data point to the far right represents the MAP and plasma concentrations corresponding to the last dose increment preceding cardiovascular collapse.

 
At an intrastimulus pacing interval of 400 ms (HR 150 bpm), the baseline ERP ranged between 111 and 232 ms among dogs (Fig. 3). The ERP did not change significantly from control with any LA except at the dose increment corresponding to the target plasma concentrations of 8 and 32 µg/mL for BUP, LBUP, ROP, and LIDO, respectively. At this dose increment, 30%–50% increases in ERP occurred in surviving dogs. A similar response occurred at a pacing interval of 500 ms. The threshold current (current necessary to pace the ventricles) was not significantly altered by any of the LAs.



View larger version (29K):
[in this window]
[in a new window]
  		Figure 3. The effect of incremental increases in free local anesthetic concentrations on effective refractory period. The intrastimulus (S1) interval is at 400 ms. The individual dogs in each group are presented. The data point to the far right represents the effective refractory period (ERP) and plasma concentrations corresponding to the last dose increment preceding cardiovascular collapse.

 
One animal exhibited sustained spontaneous VF in response to the initial infusion of BUP to the target (an actual) concentration of 16 µg/mL. Asystole occurred in one animal during the initial infusion of ROP to the target concentration of 19 µg/mL, corresponding to an actual concentration of 35 µg/mL. No other LA-treated animal exhibited sustained spontaneous lethal arrhythmias. The effects of the LAs on PES-induced arrhythmias are shown in Table 3. With increasing LA concentrations, the overall incidences of PES-induced VF and sustained VT were 11% (4 of 37) and 3% (1 of 37), respectively, without a significant difference among groups. Curiously, one BUP dog and one LIDO dog experienced PES-induced VF after the first and second dose, respectively, of LA. No protocol-control dog had spontaneous or PES-induced ventricular arrhythmias at any dosing level.


View this table:
[in this window]
[in a new window]
  		Table 3. Effect of Local Anesthetic on Spontaneous and PES-Induced Arrhythmias
 
The incidence of PES-induced extrasystoles increased with increasing plasma concentrations of LA. At the dose increment corresponding to a target concentration of 8 µg/mL for BUP, LBUP, ROP, and 32 µg/mL for LIDO, there was a differential effect in extrasystoles between the longer-acting LAs and LIDO (Table 3). There was a more frequent occurrence of PES-induced extrasystoles in the BUP- and LBUP-treated dogs than in the LIDO-treated dogs at this concentration (P <0.05). There was no difference in extrasystoles between ROP- and LIDO-treated dogs (P = 0.23).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our main findings in anesthetized, ventilated dogs showed that progressive BUP intoxication from incremental increases in plasma concentration (mimicking enhanced absorption and/or accidental intravascular infusion) did not result in lethal arrhythmias. The incidence of spontaneous or PES-induced VT and VF among the S(-) enantiomers, LBUP and ROP, were not different than racemic BUP. There was an increased incidence of PES-induced extrasystoles in dogs that received the longer-acting amide LAs, BUP, LBUP, than in dogs that received LIDO. Interestingly, no difference in extrasystoles was observed between ROP- and LIDO-treated dogs.

Minimal changes in ERP and arrhythmogenicity were observed at free and total BUP concentrations of <0.4 µg/mL and <3 µg/mL, respectively. This agrees with the findings of Hotvedt et al. (14), who showed that BUP, at plasma concentrations <=2 µg/mL, had no effect on the ventricular ERP or action potential duration in pentobarbital-anesthetized dogs. Similarly, Eledjam et al. (15) failed to observe significant changes in QRS or QT duration until plasma concentrations exceeded 2 µg/mL in thiopental-anesthetized dogs. No serious ventricular arrhythmias were observed in either of these studies. Correspondingly, in the present study, at a total plasma BUP concentration of 2 µg/mL, VF was induced by PES in only 1 of 10 dogs. Although the induction of VF was not associated with any metabolic, respiratory, or hemodynamic disturbance, we suspect that this was a random event rather than a result of BUP. Wetstein et al. (16), who studied 10 open-chest dogs that did not receive LAs with normal pH and arterial blood gas measurements, found that VF could be initiated by two premature stimuli in 4 of 10 dogs. Taken together, these data suggest a possible antiarrhythmic effect of BUP at small, clinically relevant plasma concentrations.

At the free and total concentrations of BUP >=1 µg/mL and >= 5µg/mL, respectively, increases in ventricular refractoriness were observed. Despite the prolongation in ERP, only one animal exhibited spontaneous VF and only one animal demonstrated PES-induced VF. The relationship between the magnitude of ventricular repolarization and the threshold for ventricular arrhythmias is well known (17). Electrical induction of VF appears to depend on increasing the dispersion of refractoriness to a critical level (17). Accordingly, in BUP-intoxicated hearts (7 µg/mL), Kasten (18) reported that a lengthening of the ERP temporal dispersion to 200% more than control led to ventricular arrhythmias, whereas an increase of 100% was well tolerated. Perhaps the low vulnerability to VF observed in the present study can be attributed to this lack of a "critical" increase in ERP.

The basal anesthetic we used could have influenced the arrhythmogenic effects of BUP. Thiopental, although it was used only for induction of anesthesia, protects the heart from VF (19). Also, thiopental might have had a role in the suppression of seizure activity, another factor capable of altering the arrhythmogenic potential of BUP. Similarly, fentanyl might increase the VF threshold through its central vagal actions, or its attenuation of sympathetic effects (20). The influence of benzodiazepines (midazolam) on ventricular arrhythmias, and specifically LA-induced arrhythmias, is uncertain. Benzodiazepine premedication with diazepam delayed the onset of ventricular arrhythmias in pigs that were subjected to BUP cardiac toxicity; however, it had no effect on the threshold for cardiovascular collapse (8). As a whole, the background fentanyl-midazolam IV anesthetic may attenuate the arrhythmogenic response to PES in the setting of BUP toxicity.

Another explanation for the absence of ventricu-lar arrhythmias in the present study is that arrhythmias associated with BUP toxicity might result from mechanisms other than those tested by PES testing. PES-induced extrasystoles reflect inhomogeneities in repolarization, activating reentrant pathways (21). The arrhythmias responsible for BUP-induced death reported by others may result from triggered extrasystoles arising from calcium overload secondary to myocardial depression (22) or from exogenous epinephrine administration (23). Nevertheless, in the current study, circulatory collapse from BUP toxicity was not preceded by malignant ventricular arrhythmias.

The two enantiomers of BUP have differing effects on cardiac electrophysiology. BUP HCl is prepared as a racemic mixture of both R(+) and S(-) isomers. Experimental studies suggest that R(+) BUP is more cardiotoxic than S(-) BUP and its racemate (24–27). R(+) BUP has a higher affinity for the inactivated state of cardiac Na+ channel, favoring use-dependent block (26), and for the cardiac K+ channel (28) than the S(-) isomer. In isolated cardiac tissue preparations, the R(+) BUP isomer significantly prolonged AV conduction (29), slowed {image}max and increased action potential duration (30), and caused more pronounced QRS widening and severe arrhythmias (27) than equivalent anesthetic doses of S(-) BUP or its racemic mixture. Our results, however, challenge extrapolation of these observations to the in vivo animal model because we found no difference in the incidence of VT and VF among animals exposed to LBUP, ROP (the –n-propyl homologue of LBUP) or BUP. This arrhythmogenic similarity among BUP, LBUP, and ROP contradicts findings reported in conscious dogs and sheep (4,24). Differences in the state of consciousness and the mode of LA administration (infusion versus bolus) may, in part, explain the discrepancies. Nevertheless, this study is the first to quantitatively evaluate the arrhythmogenic potential of the two S(-) enantiomers against racemic BUP in an intact animal.

There are structure-activity relationships among families of LAs that may underlie their differing cardiotoxic potency. The more potent (at nerve block), longer-acting LA, BUP, has been shown in in vitro (31,32) and in vivo (3,11,33) models to be more arrhythmogenic than the shorter-acting LA, LIDO. In concert with this, the longer-acting amide LAs, BUP, and LBUP demonstrated a concentration-dependent increased incidence in PES-induced extrasystoles, whereas a similar effect was not observed with LIDO at equivalent nerve-blocking concentrations. In fact, no PVCs were elicited at any time during the PES protocol in the LIDO-treated dogs. Ventricular fibrillation did, however, occur in one dog at a plasma concentration of 16 µg/mL. Whether this was a direct effect of LIDO or an isolated, random event, is unclear. Nevertheless, the arrhythmogenic differences in extrasystoles between LIDO and BUP have been attributed to differences between LAs in the state-dependent kinetics of their binding to the Na+ channel (32). Unbinding of BUP from the Na+ channel is slow, whereas unbinding of LIDO is relatively rapid. Whether the increased incidence in extrasystoles that were observed with LBUP, compared with the short-acting LA, LIDO, is also attributable to differing drug-binding behavior involving the cardiac sodium channel, will require further study. Correspondingly, whether the lack of a significant difference in extrasystoles between the ROP- and LIDO-treated dogs is attributable to similar state-dependent kinetics, among these LAs, is unknown.

When interpreting the present study, several factors need to be considered. First, our incrementally, escalating dosing regimen consistently yielded total plasma concentrations less than the expected target level for each drug. Whether this was because of an alteration in drug metabolism, binding, or an underestimation of LA clearance rates, is unknown. However, total plasma concentrations within and among BUP-like isomers were comparable for each dose increment, suggesting an invariable experiment protocol and dosing regimen among the 40 dogs. Second, the dosing in this study was designed to span the plasma concentrations that might be expected from enhanced systemic absorption after the administration of large volumes of LAs for various regional anesthetic techniques. This allowed for a longer data acquisition time, enabling the use of PES. By eliciting tachyarrhythmias with PES, smaller doses of LAs were required than to induce these arrhythmias spontaneously (without PES). Clearly, the clinical situation that requires the widest safety margin is when a large and rapid intravascular dose of LA is inadvertently injected. However, it would be extremely difficult to use PES protocols in such a rapidly changing environment. Third, although broadening of the QRS complex of the electrocardiogram is a unique characteristic of LA toxicity and a possible explanation for BUP-induced reentrant arrhythmias, this cardiac conduction abnormality was not specifically addressed in this study. However, the differential effect of BUP, LBUP, and ROP toxicities on the QRS complex has been reported recently by others. A significantly greater QRS interval prolongation occurred in conscious rats intoxicated with racemic BUP and S(-) BUP than with ROP (34). Similarly, in anesthetized swine (35), intracoronary administration of ROP induced the least degree of QRS and QTc interval lengthening than did equivalent doses of BUP and LBUP. Whether these differing electrocardiographic effects explain the decreased occurrence of PES-induced extrasystoles with ROP and LIDO compared with the other amide LAs is speculative. Finally, acute increases in the incidence of premature ventricular beats are often thought to be the harbinger of more malignant arrhythmias (36).

Assuming this is true, then the differential effect of PES-induced extrasystoles between BUP, LBUP versus LIDO and ROP versus LIDO may have important clinical implications. Specifically, ROP’s arrhythmogenesis safety profile with respect to the occurrence of extrasystoles may be wider than BUP and LBUP in the setting of enhanced systemic absorption or accidental intravascular infusion during regional anesthesia for pain management. The clinical importance of these differences among LAs is unknown, but likely depends on the setting in which LA overdosage occurs. Increased propensity for arrhythmias would present a greater likelihood of progression from PVCs to VT or VF. Such a situation might arise with excessive sedation and hypercarbia or from migration of a central venous catheter tip into the right ventricle. Clearly, further work is necessary to define the clinical application of our findings.

In summary, our study shows that progressive BUP intoxication, in anesthetized, ventilated dogs does not produce early arrhythmogenic events. This is not consistent with an arrhythmia explanation for clinical BUP toxicity. Additionally, the incidence of PES-induced VT and VF with racemic BUP does not differ from that of the single (-) enantiomers LBUP and ROP, providing evidence against stereoselective arrhythmogenesis as a primary component of LA-induced cardiotoxicity. The increased incidence in PES-induced extrasystoles observed in dogs that received BUP and LBUP compared with LIDO suggests a structure/activity relationship among the amide LAs, such that the longer-acting, lipid soluble LAs are more prone to increase the incidence of PES-induced arrhythmias. Whether the absence of a differing effect in PES-induced extrasystoles between ROP and LIDO is attributable to similar drug binding characteristics or an intrinsic pharmacodynamic property specific to ROP will require additional study.


   Acknowledgments
 
This work was supported by a grant from AstraZeneca, Södertälje, Sweden.


   Footnotes
 
Presented in part at the American Society of Anesthesiologists annual meeting, Dallas, TX, October 11, 1999. Published in part as an abstract in Anesthesiology 1999;91(3A):A886.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Long BW, Rosenblum S, Grady IP. Successful resuscitations of bupivacaine-induced cardiac arrest using cardiopulmonary bypass. Anesth Analg 1989; 69: 403–6.[Free Full Text]
  2. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine [editorial]. Anesthesiology 1979; 51: 285–7.[Web of Science][Medline]
  3. Kotelko DM, Shnider SM, Dailey PA, et al. Bupivacaine-induced cardiac arrhythmias in sheep. Anesthesiology 1984; 60: 10–8.[Web of Science][Medline]
  4. Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog. Anesth Analg 1989; 69: 794–801.[Abstract/Free Full Text]
  5. Kasten GW, Martin ST. Comparison of resuscitation of sheep and dogs after bupivacaine-induced cardiovascular collapse. Anesth Analg 1986; 65: 1029–32.[Abstract/Free Full Text]
  6. Coyle DE, Porembka DT, Sehlhorst CS, et al. Echocardiographic evaluation of bupivacaine cardiotoxicity. Anesth Analg 1994; 79: 335–9.[Abstract/Free Full Text]
  7. Heavner JE, Dryden CF Jr, Sanghani V, et al. Severe hypoxia enhances central nervous system and cardiovascular toxicity of bupivacaine in lightly anesthetized pigs. Anesthesiology 1992; 77: 142–7.[Web of Science][Medline]
  8. Bernards CM, Carpenter RL, Rupp SM, et al. Effect of midazolam and diazepam premedication on central nervous system and cardiovascular toxicity of bupivacaine in pigs. Anesthesiology 1989; 70: 318–23.[Web of Science][Medline]
  9. Solomon D, Bunegin L, Albin M. The effect of magnesium sulfate administration on cerebral and cardiac toxicity of bupivacaine in dogs. Anesthesiology 1990; 72: 341–6.[Web of Science][Medline]
  10. Rosen MA, Thigpen JW, Shnider SM, et al. Bupivacaine-induced cardiotoxicity in hypoxia and acidotic sheep. Anesth Analg 1985; 64: 1089–96.[Abstract/Free Full Text]
  11. de Jong RH, Bonin JD. Deaths from local anesthetic-induced convulsions in mice. Anesth Analg 1980; 59: 401–5.[Abstract/Free Full Text]
  12. Liu PL, Feldman HS, Giasi R, et al. Comparative CNS toxicity of lidocaine, etidocaine, bupivacaine, and tetracaine in awake dogs following rapid intravenous administration. Anesth Analg 1983; 62: 375–9.[Abstract/Free Full Text]
  13. Scott DB. Evaluation of the toxicity of local anaesthetic agents in man. Br J Anaesth 1975; 47: 56–61.[Abstract/Free Full Text]
  14. Hotvedt R, Refsum H, Helgesen KG. Cardiac electrophysiologic and hemodynamic effects related to plasma levels of bupivacaine in the dog. Anesth Analg 1985; 64: 388–94.[Abstract/Free Full Text]
  15. Eledjam JJ, de la Coussaye JE, Brugada J, et al. Cardiac electrophysiological effects of bupivacaine in the anesthetized dog: relation with plasma concentration. Arch Int Pharmacodyn Ther 1988; 295: 147–56.[Web of Science][Medline]
  16. Wetstein L, Michelson EL, Simson MB, et al. Initiation of ventricular tachyarrhythmia with programmed stimulation: sensitivity and specificity in an experimental canine model. Surgery 1982; 92: 206–11.[Web of Science][Medline]
  17. Moore EN, Spear JF. Ventricular fibrillation threshold: its physiological and pharmacological importance. Arch Intern Med 1975; 135: 446–53.[Abstract/Free Full Text]
  18. Kasten GW. Amide local anesthetic alterations of effective refractory period temporal dispersion: relationship to ventricular arrhythmias. Anesthesiology 1986; 65: 61–6.[Web of Science][Medline]
  19. Dawson AK, Leon AS, Taylor HL. Effect of pentobarbital anesthesia on vulnerability to ventricular fibrillation. Am J Physiol 1980; 239: H427–31.
  20. Daskalopoulos NT, Laubie M, Schmitt H. Localization of the central sympatho-inhibitory effect of a narcotic analgesic agent, fentanyl, in cats. Eur J Pharmacol 1975; 33: 91–7.[Web of Science][Medline]
  21. Wit AL, Janse MJ. The ventricular arrhythmias of ischemia and infarctions: electrophysiological mechanisms. Mount Kisco, NY: Futura Publishing, 1993.
  22. Billman GE. The antiarrhythmic and antifibrillatory effects of calcium antagonists. J Cardiovasc Pharmacol 1991; 18 (Suppl 10): S107–17.
  23. Igarashi T, Hirabayashi Y, Saitoh K, et al. Dose-related cardiovascular effects of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression. Acta Anaesthesiol Scand 1998; 42: 698–706.[Web of Science][Medline]
  24. Huang YF, Pryor ME, Mather LE, Veering BT. Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesth Analg 1998; 86: 797–804.[Abstract]
  25. Lee-Son S, Wang GK, Concus A, et al. Stereoselective inhibition of neuronal sodium channels by local anesthetics: evidence for two sites of action? Anesthesiology 1992; 77: 324–35.[Web of Science][Medline]
  26. Valenzuela C, Snyders DJ, Bennett PB, et al. Stereoselective block of cardiac sodium channels by bupivacaine in guinea pig ventricular myocytes. Circulation 1995; 92: 3014–24.[Abstract/Free Full Text]
  27. Mazoit JX, Boico O, Samii K. Myocardial uptake of bupivacaine. II. Pharmacokinetics and pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart. Anesth Analg 1993; 77: 477–82.[Abstract/Free Full Text]
  28. Valenzuela C, Delpon E, Tamkun MM, et al. Stereoselective block of a human cardiac potassium channel (Kv1.5) by bupivacaine enantiomers. Biophys J 1995; 69: 418–27.[Web of Science][Medline]
  29. Graf BM, Martin E, Bosnjak ZJ, Stowe DF. Stereospecific effect of bupivacaine isomers on atrioventricular conduction in the isolated perfused guinea pig heart. Anesthesiology 1997; 86: 410–9.[Web of Science][Medline]
  30. Vanhoutte F, Vereecke J, Verbeke N, Carmeliet E. Stereoselective effects of the enantiomers of bupivacaine on the electrophysiological properties of the guinea-pig papillary muscle. Br J Pharmacol 1991; 103: 1275–81.[Web of Science][Medline]
  31. Wheeler DM, Bradley EL, Woods WT Jr. The electrophysiologic actions of lidocaine and bupivacaine in the isolated, perfused canine heart. Anesthesiology 1988; 68: 201–12.[Web of Science][Medline]
  32. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985; 62: 396–405.[Web of Science][Medline]
  33. Liu P, Feldman HS, Covino BM, et al. Acute cardiovascular toxicity of intravenous amide local anesthetics in anesthetized ventilated dogs. Anesth Analg 1982; 61: 317–22.[Abstract/Free Full Text]
  34. Ericson A-C, Avesson M. Effects of ropivacaine, bupivacaine and S(-)-bupivacaine on the ECG after rapid IV injections to conscious rats. Int Monit Reg Anesth 1996; 8: 51.
  35. Morrison SG, Dominguez JJ, Frascarolo P, Reiz S. A comparison of the electrocardiographic cardiotoxic effects of racemic bupivacaine, levobupivacaine, and ropivacaine in anesthetized swine. Anesth Analg 2000; 90: 1308–14.[Abstract/Free Full Text]
  36. El-Sherif N, Myerburg RJ, Scherlag BJ, et al. Electrocardiographic antecedents of primary ventricular fibrillation: value of the R-on-T phenomenon in myocardial infarction. Br Heart J 1976; 38: 415–22.[Abstract/Free Full Text]
Accepted for publication July 11, 2000.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
S. E. Copeland, L. A. Ladd, X.-Q. Gu, and L. E. Mather
The Effects of General Anesthesia on the Central Nervous and Cardiovascular System Toxicity of Local Anesthetics
Anesth. Analg., May 1, 2008; 106(5): 1429 - 1439.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
C. F. Royse and A. G. Royse
The Myocardial and Vascular Effects of Bupivacaine, Levobupivacaine, and Ropivacaine Using Pressure Volume Loops
Anesth. Analg., September 1, 2005; 101(3): 679 - 687.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
L. Simon, N. Kariya, E. Pelle-Lancien, and J.-X. Mazoit
Bupivacaine-Induced QRS Prolongation is Enhanced by Lidocaine and by Phenytoin in Rabbit Hearts
Anesth. Analg., January 1, 2002; 94(1): 203 - 207.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. Ohmura, M. Kawada, T. Ohta, K. Yamamoto, and T. Kobayashi
Systemic Toxicity and Resuscitation in Bupivacaine-, Levobupivacaine-, or Ropivacaine-Infused Rats
Anesth. Analg., September 1, 2001; 93(3): 743 - 748.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
L. Groban, D. D. Deal, J. C. Vernon, R. L. James, and J. Butterworth
Cardiac Resuscitation After Incremental Overdosage with Lidocaine, Bupivacaine, Levobupivacaine, and Ropivacaine in Anesthetized Dogs
Anesth. Analg., January 1, 2001; 92(1): 37 - 43.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Groban, L.
Right arrow Articles by Butterworth, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Groban, L.
Right arrow Articles by Butterworth, J.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press