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Anesth Analg 2001;93:1598-1605
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA

The Comparative Electrophysiologic and Hemodynamic Effects of a Large Dose of Ropivacaine and Bupivacaine in Anesthetized and Ventilated Piglets

Jean-Yves Lefrant, MD PhD*, Jean E. de La Coussaye, MD PhD*, Jacques Ripart, MD PhD*, Laurent Muller, MD MSc*, Laurent Lalourcey, MD MSc*, Pascale A. Peray, MD PhD{dagger}, X. Mazoit, MD PhD{ddagger}, Antoine Sassine, MD§, and Jean-Jacques Eledjam, MD*

Departments of *Anesthesiology, Critical Care, and Emergency, and the {dagger}Department of Epidemiology and Biostatistics, University-Hospital of Nîmes, France; {ddagger}Laboratoire d’Anesthésie, UPRES EA 392, Faculté de Médecine, Université Paris Sud, Kremlin Bicêtre, Bicêtre, France; and §the Laboratory of Anesthesiology and Cardiovascular Physiology, Medical School of Montpellier-Nîmes, France

Address correspondence and reprint requests to Professeur Jean E. de La Coussaye, Département d’Urgences-Réanimation, CHU Nîmes, 5 Rue Hoche, 30029 Nîmes, Cedex 4, France.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Ropivacaine is less potent and less toxic than bupivacaine. We administered these two local anesthetics in a cardiac electrophysiologic model of sodium thiopental-anesthetized and ventilated piglets. After assessing the stability of the model, bupivacaine (4 mg/kg) and ropivacaine (6 mg/kg) were given IV in two groups (n = 7) of piglets. No alteration in biological variables was reported throughout the study. Bupivacaine and ropivacaine similarly decreased mean aortic pressure from 99 ± 22 to 49 ± 31 mm Hg and from 87 ± 17 to 58 ± 28 mm Hg, respectively, and decreased the peak of the first derivative of left ventricular pressure from 1979 ± 95 to 689 ± 482 mm Hg/s and from 1963 ± 92 to 744 ± 403 mm Hg/s, respectively. Left ventricular end-diastolic pressure was similarly increased from 6 ± 5 to 9 ± 5 mm Hg and from 6 ± 4 to 12 ± 4 mm Hg, respectively. Bupivacaine and ropivacaine similarly lengthened the cardiac cycle length (R-R; from 479 ± 139 to 706 ± 228 ms and from 451 ± 87 to 666 ± 194 ms, respectively), atria His (from 71 ± 15 to 113 ± 53 ms and from 64 ± 6 to 86 ± 10 ms, respectively), and QTc (QTc = QT x R-R-0.5, Bazett formula; from 380 ± 71 to 502 ± 86 ms and from 361 ± 33 to 440 ± 56 ms, respectively) intervals. Bupivacaine altered to a greater extent the PQ (the onset of the P wave to the Q wave of the QRS complex) (from 97 ± 20 to 211 ± 60 ms versus from 91 ± 8 to 145 ± 38 ms, P < 0.05), QRS (from 58 ± 3 to 149 ± 34 ms versus from 60 ± 5 to 101 ± 17 ms, P < 0.05), and His ventricle interval (from 25 ± 4 to 105 ± 30 ms vs from 25 ± 4 to 60 ± 30 ms, P < 0.05) than ropivacaine. A 6 mg/kg ropivacaine dose induced similar hemodynamic alterations as 4 mg/kg bupivacaine. However, bupivacaine altered the variables of ventricular conduction (QRS and His ventricle) to a greater extent.

IMPLICATIONS: A 6 mg/kg ropivacaine dose induced similar hemodynamic alterations as 4 mg/kg bupivacaine. However, bupivacaine altered the variables of ventricular conduction (QRS and His ventricle) to a greater extent.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The mechanisms of cardiac arrest, cardiovascular collapse, and lethal and nonlethal ventricular arrhythmias induced by a toxic dose of bupivacaine have been well documented (1). A large dose of bupivacaine induces a marked decrease in myocardial contractility and dramatically impairs cardiac electrophysiology, mainly ventricular conduction (2–10). Clarkson and Hondeghem (11) demonstrated on guinea pig ventricular myocardium that bupivacaine markedly decreases the maximum upstroke velocity of fast action potential in a dose- and use-dependent manner. Using left ventricular epicardial mapping in rabbit heart, we demonstrated that the occurrence of ventricular conduction block, and therefore of reentrant ventricular arrhythmias, is facilitated by a large concentration of bupivacaine (dose dependence) and by rapid pacing (use dependence) (12). We also demonstrated in anesthetized dogs given a large dose of bupivacaine (i.e., 4 mg/kg) that the increase in heart rate enhances the His ventricle interval (HV) lengthening and the QRS widening and therefore facilitates the occurrence of ventricular arrhythmias (9).

These adverse effects have led to introduction of new local anesthetics such as ropivacaine. By using a microelectrode technique on Purkinje fibers and ventricular muscle cells of rabbit heart, Moller and Covino (13) demonstrated that maximum upstroke velocity is decreased to a lesser extent with ropivacaine than with bupivacaine. Reiz et al. (14) demonstrated, in an experimental in vivo study, that ropivacaine was less cardiotoxic than bupivacaine when these two drugs were used at nearly the same dose (4–5 mg/kg). However, some studies tended to support that ropivacaine is less potent than bupivacaine. The depressant effect of bupivacaine was shown to be 16% greater than that of ropivacaine on motor fiber in the rabbit vagus nerve (15). More recently, Polley et al. (16) showed, in parturients, that epidural ropivacaine was 40% less potent than epidural bupivacaine. This difference in potency could have accounted for differences in cardiotoxicity. Therefore, the aim of this study was to compare the electrophysiologic and hemodynamic effects of a large dose of bupivacaine (4 mg/kg) versus 50% of a larger dose of ropivacaine (6 mg/kg) in an in vivo model of anesthetized and ventilated piglets.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The principles for the care and treatment of experimental animals complied with the national guidelines of the French Ministry of Agriculture. The study was performed in an in vivo model of anesthetized and ventilated piglets.

Piglets weighing 10 to 25 kg were premedicated with ketamine (250 mg IM), midazolam (15 mg IM), and atropine (1 mg IM). Within 15 min, an ear vein was catheterized. Piglets were anesthetized with sodium thiopental (10 mg/kg IV). Tracheostomy was quickly performed. The trachea was intubated and the lungs were mechanically ventilated with room air; the tidal volume was 10 mL/kg, and the respiratory rate was 15 breaths/min (Bennett MA 1-B; Puritan Bennett, Los Angeles, CA). Body temperature was maintained at 38°C ± 0.5°C with a rewarming humidifier device. Piglets were paralyzed with vecuronium bromide (0.1 mg/kg IV) as required, and anesthesia was maintained with an IV infusion of sodium thiopental (15 mg · kg-1 · h-1). During the preparation and experiment (90 to 120 min), 500 to 750 mL of 0.9% sodium chloride was infused.

The instrumentation of piglets was as previously described in dogs (8). Electrocardiogram recordings were taken from standard lead II. The left carotid artery was cannulated with a 6F double-high-fidelity micromanometer (Millar Instruments, Houston, TX) that was advanced into the left ventricle to measure left ventricular and aortic pressures. A 6F bipolar electrode catheter (USCI; C. R. Bard, Inc., Billerica, MA) was introduced via the femoral vein into the right ventricle to record the His-bundle electrical activity (17). Another 6F bipolar electrode catheter was introduced via the left jugular vein into the right atria for atrial pacing. A 5F Teflon catheter (Plastimed, Saint-Leu La Forêt, France) was inserted via the femoral artery into the descending aorta to withdraw arterial blood samples. After this preparation, a 15-min stability period was observed.

The first aim of the study was to assess the stability of the model. For this purpose, hemodynamic, electrophysiologic, and biological variables were measured every 30 min for 2 h in a group of 10 piglets (Control group).

The second and main aim of the study was to compare bupivacaine (bupivacaine HCl 0.5%, Astra, Nanterre, France) with ropivacaine (ropivacaine HCl 0.75%, Astra, France) in two groups of piglets. Four milligrams per kilogram body weight bupivacaine (Group B, n = 10) or 6 mg/kg ropivacaine (Group R, n = 8) was given via the peripheral ear vein over a 30-s period. The local anesthetic was administered in randomized order but not in blinded fashion. Hemodynamic, electrophysiologic, and biological variables were measured for a 30-min period.

The following electrophysiologic variables (ms) were measured (8): cardiac cycle length (R-R), PQ interval (measured from the onset of the P wave to the Q wave of the QRS complex), atria His interval (AH) (measured from the onset of the atrial depolarization to the His bundle electrogram of the endocavitary lead), HV interval (measured from the His bundle electrogram of the endocavitary lead to the Q wave of electrocardiogram lead II), QRS duration, QT interval, QT interval corrected by heart rate (QTc = QT x R-R-0.5, Bazett formula), and JTc interval [JTc = (QT - QRS) x R-R-0.5]. The following hemodynamic variables were measured: mean aortic pressure (MAoP, mm Hg), left ventricle end-diastolic pressure (LVEDP, mm Hg), and LVdP/dtmax (mm Hg/s), derived with a Gould differentiator. All these variables were si-multaneously recorded on an ES 1000 polygraph (100 mm/s) (Gould, Inc., Oxnard, CA). Moreover, because local anesthetics slow the ventricular conduction in a dose- and frequency-dependent manner (9), the ventricular conduction variables represented by HV interval and QRS duration were measured after 10 atrial stimuli given at pacing cycle length 20% more than the spontaneous sinusal cycle length measured at baseline (Stimulator CSO; Savita, Paris, France).

Blood samples were obtained to measure the following serum concentrations: sodium (mmol/L), potassium (mmol/L), total and ionized calcium (mmol/L), protein (g/L), albumin (g/L), and arterial lactate (mmol/L) (Astra 4 Beckman analyzer). Hematocrit was determined by using a micromethod. Arterial blood gas analysis (PaO2 [mm Hg], PaCO2 [mm Hg], pH, arterial oxygen saturation, and HCO3- [mmol/L]) was performed with a 1306 pH/blood gas analyzer (Instrument Laboratory, Lexington, MA).

In both groups, the plasma concentrations of bupivacaine and ropivacaine were measured with gas chromatography (18). Briefly, 100 µL internal standard solution (mepivacaine 10 µg/mL), 100 µL NaOH 2 N, and 200 µL pentane were added to 0.5 mL plasma. After rapid vortex agitation for 45 s and centrifugation at 3500g, 2 µL of the supernatant was injected on column. The chromatograph (Varian model 3400; Varian; Les Ulis, France) equipped with a nitrogen/phosphorus detector was fitted with a megabore J&W DB-1701 column (30 m x 0.53 mm, film thickness 1 µm). Helium was used as carrier gas at 30 mL/min, and air and hydrogen were set at 150 and 4.5 mL/min, respectively. The temperatures were as follows: injector 250°C, detector 290°C, and oven 230°C. The standard curve was linear in the range 0.01–8 µg/mL. The limit of detection at four times the basal noise was <0.01 µg/mL for the two drugs. The intra- and interday coefficients of variation were 6% and 8% at 200 µg/mL. Finally, the mortality rate between groups was compared.

In the Control group, electrophysiologic, hemodynamic, and biological variables were measured at baseline (T0) and after 15 (T15, except for biological variables), 30 (T30), 60 (T60), 90 (T90), and 120 (T120) min. In the Bupivacaine and Ropivacaine groups, electrophysiologic and hemodynamic variables were measured at T0, T1, T2, T3, T4, T5, T10, T15, and T30 after the administration of the local anesthetic. Biological variables were measured at T0 and T30. The plasma concentrations of bupivacaine and ropivacaine were measured at T0, at the end of the IV bolus of local anesthetic (T0.5), and at T3, T15, and T30.

Results are expressed as mean ± SD. In the Control group, the time effect was analyzed by using one-way analysis of variance with repeated measures followed by contrast study and was completed by Bonferroni’s correction. The effects of ropivacaine and bupivacaine were tested with one-way analysis of variance with repeated measures followed by contrast study and were completed by Bonferroni’s correction. Comparisons between groups were performed using the area under the curve (trapeze method). One-way analysis of variance was then performed for each variable, followed by the Newman-Keuls test. The comparison of mortality between groups was performed by using Fisher’s exact test. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Three of 10 piglets died during the preparation procedure before control measurements and were not included in the statistical analysis. The model stability was assessed in seven piglets. The electrophysiologic, hemodynamic, and biological variables did not change during this 2-h period (Tables 1 and 2).


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  		Table 1. Biological variables of the Control Group (n = 7)
 

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  		Table 2. Hemodynamic and Electrophysiologic Variables of the Control Group (n = 7)
 
In the Bupivacaine group (n = 10), two piglets died from ventricular fibrillation at 4 and 15 min after bupivacaine administration, respectively. A third piglet experienced a junctional tachycardia from T3 to T10 and was excluded. In the Ropivacaine group (n = 8), one piglet died from ventricular fibrillation 3 min after ropivacaine administration. Mortality was not statistically different between groups. Comparisons of hemodynamic, electrophysiologic, and biological variables were performed in seven piglets in each group. The comparison of biological variables is reported in Table 3. Biological variables were not significantly altered within and between groups. The comparison of hemodynamic variables is reported in Figure 1. MAoP decreased from T1 to T5. LVEDP increased from T1 to T3. LVdP/dtmax decreased from T1 to T30. Hemodynamic alterations were similar in both groups. The comparison of electrophysiologic variables is reported in Figure 2. In both groups, R-R, AH, QT, and QTc values were increased from T1 to T30, with no difference between the groups. In contrast, PQ, QRS, and HV intervals were altered to a greater extent by bupivacaine than ropivacaine from T1 to T30. JTc was never altered in either group. No atrial pacing could be efficiently achieved in either group, and no data concerning HV interval and QRS duration were available.


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  		Table 3. Biological Variables of the Bupivacaine and Ropivacaine Groups
 


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  		Figure 1. The effects of 4 mg/kg bupivacaine and 6 mg/kg ropivacaine on the hemodynamic variables (MAoP = mean aortic pressure; LVEDP = left ventricular end diastolic pressure; dP/dtmax = first derivative of LV pressure). *P < 0.05 versus T0 in the Bupivacaine group; #P < 0.05 versus T0 in the Ropivacaine group. There was no difference between the two groups.

 


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  		Figure 2. The effects of 4 mg/kg bupivacaine and 6 mg/kg ropivacaine on the electrophysiologic (R-R, atria His interval [AH], QTc, JTc, PQ, His ventricle interval [HV], and QRS) variables. *P < 0.05 versus T0 in the Bupivacaine group; #P < 0.05 versus T0 in the Ropivacaine group; §P < 0.05 between the two groups.

 
The plasma concentrations of bupivacaine and ropivacaine are reported in Figure 3. They decreased from T0.5 to T30. No difference was observed between the groups.



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  		Figure 3. Plasma concentrations of bupivacaine and ropivacaine. *P < 0.05 versus T0.5 in the Bupivacaine group; #P < 0.05 versus T0.5 in the Ropivacaine group. There was no difference between the two groups.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study shows that 4 mg/kg bupivacaine and 6 mg/kg ropivacaine similarly altered the measured hemodynamic variables, heart rate, AH, and QTc intervals. Despite larger dose of ropivacaine, bupivacaine impairs to a greater extent the PR interval and the variables of ventricular conduction (HV and QRS). In contrast, plasma concentrations of ropivacaine and bupivacaine were similar throughout the study period. Finally, the Control group and the analysis of biological variables confirm the stability of the model in piglets as previously reported in dogs (7).

In the Control group, hemodynamic, electrophysiologic, and biological variables were not altered throughout the two-hour period. Although anesthetic drugs were used, this in vivo model of piglets could be considered stable.

In the Bupivacaine group, the hemodynamic and electrophysiologic alterations were similar to those reported in a previous model of anesthetized and ventilated dogs given 4 mg/kg of bupivacaine (8–10). In previous studies (8–10), we demonstrated that an IV bolus of 4 mg/kg bupivacaine induces large plasma bupivacaine levels and reproducible electrophysiologic and hemodynamic impairments without causing immediate death by cardiovascular collapse or ventricular arrhythmias. As previously described, some animals died during the protocol (10). Two piglets and one piglet died in the Bupivacaine and Ropivacaine groups, respectively. Concerning ropivacaine, the electrophysiologic effects seen in this study were in accordance with those reported by Reiz et al. (14). Therefore, it could be assumed that this in vivo model is adequate to study the cardiotoxicity of local anesthetics.

MAoP and LVdP/dtmax were decreased and LVEDP was increased in both groups. This confirms the decrease in myocardial contractility after being given a large dose of these local anesthetics (4–6,14). Although LVdP/dtmax is a poor index of contractility, the negative inotropic action of bupivacaine and ropivacaine was shown on frog atrial fiber and in guinea pig ventricular muscle (6,19,20).

Bupivacaine and ropivacaine induced alterations of R-R, AH, QTc, PQ, HV, and QRS intervals. The alterations of PQ, QRS, and QTc intervals were also reported in animal and human studies (14,21). The blockade of calcium-mediated slow action potentials could explain the lengthening of R-R and AH intervals. The widening of QTc was caused by the widening of QRS, because JTc was not altered in either group. The lengthening of QRS and HV intervals is in accordance with studies showing that local anesthetics slowed ventricular conduction velocities (7,8,12,14).

In this study, bupivacaine and ropivacaine induced similar alterations in hemodynamic variables. This is in accordance with the study performed by Reiz et al. (14), showing no difference when 4 mg/kg bupivacaine or 5.33 mg/kg ropivacaine was administered into the left anterior descending coronary artery of pentobarbital-anesthetized pigs.

Bupivacaine and ropivacaine induced the same effects on R-R, AH, and JTc intervals. In contrast, PQ, QRS, and HV were more lengthened with bupivacaine than with ropivacaine. Reiz et al. (14) previously showed that the QRS interval was less lengthened with ropivacaine than with bupivacaine. However, no widening in PQ was reported. This PQ enlargement was caused by an enlargement in HV lengthening, because AH alteration was similar in both groups. Thus, bupivacaine slowed ventricular conduction velocities to a greater extent than ropivacaine. By using ventricular mapping in anesthetized dogs given incremental doses of lidocaine, Anderson et al. (22) reported that activation patterns obtained just before the onset of ventricular tachycardias simultaneously showed a marked slowing of ventricular conduction velocities and QRS widening. The same results were reported in rabbit heart with bupivacaine (12). In this study, two ventricular fibrillations (inducing animal death) and one junctional tachycardia were noted with bupivacaine, whereas there was only one ventricular fibrillation with ropivacaine (inducing animal death). The difference in QRS and HV is not caused by a difference in heart rate between the two groups. It could be induced by a different stereoselective block of sodium channels (23). Other mechanisms could be expected. Because ropivacaine is an L enantiomer and bupivacaine is a racemic mixture, the reported difference in electrophysiologic impairment could be induced by different binding protein of different stereoselective inhibition of cardiac sodium channels (24). Whatever the mechanism involved, this study showed that a 50% larger dose of ropivacaine was less cardiotoxic than bupivacaine, because ventricular conduction variables were dramatically less altered. Although the effect on mortality between the Bupivacaine and Ropivacaine groups was not statistically different, it could be speculated that ropivacaine induces less ventricular arrhythmias than bupivacaine.

Despite a 50% larger dose of ropivacaine, the plasma concentration levels of bupivacaine and ropivacaine were similar. Even if the protein bindings of bupivacaine and ropivacaine are similar in humans (95% versus 94%, respectively) (25), the free portions of bupivacaine and ropivacaine were not measured in this study. However, bupivacaine exhibits a marked nonspecific binding in the lungs during the first two or three minutes after injection (26). The same phenomenon could occur with ropivacaine, but to a greater extent, leading, after caudal injection of ropivacaine in children, to marked flip-flop kinetics and delayed absorption as compared with bupivacaine (27). A greater first-pass binding with ropivacaine may partly explain the results, but this remains to be shown. In contrast, ropivacaine and bupivacaine similarly decrease cardiac contractility. A similar effect on cardiac output could be expected. The difference in the kinetics of ropivacaine and bupivacaine could not be explained by differences in their respective effects on cardiac output. All these hypotheses are still speculation and remain to be shown. However, whatever the involved mechanism, this study in anesthetized piglets shows that 6 mg/kg ropivacaine leads to similar plasma concentrations and decreased alterations of ventricular conduction variables than 4 mg/kg bupivacaine. However, ropivacaine was as toxic as bupivacaine on the other electrophysiologic and hemodynamic variables measured.

This study shows that 6 mg/kg ropivacaine is less cardiotoxic than 4 mg/kg bupivacaine in terms of ventricular conduction. Because it has been demonstrated that the severity of a toxic accident is mainly caused by the slowing of ventricular conduction, facilitating the occurrence of reentrant ventricular arrhythmias (9–14,22), it could be postulated that a 50% larger dose of ropivacaine than bupivacaine is safer in the case of accidental intravascular administration. Nevertheless, care must be taken before extrapolating these results to the clinical setting. First, the effects of anesthesia have to be taken into account. The hemodynamic effects of sodium thiopental could precipitate those induced by local anesthetics (28). However, this model was stable during a two-hour period. In addition to sodium thiopental, ketamine and atropine were given as premedication. Ketamine was shown to slow ventricular conduction velocity and to lengthen the ventricular effective refractory period in the rabbit isolated heart (29). Concerning midazolam, the dose given had a slight effect on cardiac electrophysiologic variables (30).

Even if hemodynamic and electrophysiologic alterations reported in this study could be partly explained by the effect of premedication or anesthesia, the differences observed between the two groups were caused only by a difference in direct cardiac effect of the local anesthetics. Second, the frequency dependence of bupivacaine and ropivacaine was not studied; no atrial pacing could be efficiently achieved because of the Class 1 antiarrhythmic effects of local anesthetics. However, the alterations in R-R interval were similar. Third, the hemodynamic and cardiac electrophysiologic alterations we reported were induced at similar plasma concentrations of bupivacaine and ropivacaine. Therefore, at the same large plasma concentrations, ropivacaine is less toxic than bupivacaine on ventricular electrophysiologic variables. Therefore, further comparisons between local anesthetics should take into account the mode of administration, the range of the administered dose, the plasma concentrations, and the organ for which the variables are compared. It would be interesting to compare the cardiotoxicity of bupivacaine (4 mg/kg) versus incremental doses of ropivacaine.

In conclusion, this study showed that ventricular electrophysiologic variables were less altered with ropivacaine (6 mg/kg) than with bupivacaine (4 mg/kg). However, hemodynamic alterations were similar with both drugs. Therefore, bupivacaine and ropivacaine should both be used with the same caution in clinical practice.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 6, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press