Bupivacaine (1-butyl-2′,6′-pipecoloxylidide), an aminoamide local anesthetic, was first synthesized in the laboratories of Bofors Nobel-Pharma, Sweden and first described by Af Ekenstam et al. in 1957 (1). The molecular structure of this highly lipid-soluble and protein-bound compound contains a chiral center on the piperidine ring, resulting in two optically active stereoisomers [i.e., levorotatory (S−) and dextrorotatory (R+) configurations] (Fig. 1). However, since its introduction into clinical practice in the early 1960s, bupivacaine has been marketed as a 50:50 racemic mixture of the two enantiomers.
In the 1980s, concerns regarding this compound’s adverse cardiac effects motivated researchers to investigate the mechanisms underlying local anesthetic-induced toxicity and to develop new, safer compounds. As a result of these efforts, ropivacaine (1-propyl-2′,6′-pipcoloxylidide) has now entered clinical practice (Fig. 2). Although also optically active, it is the first local anesthetic to be marketed as a pure (S−) stereoisomer.
For more than 28 yr, (S−) bupivacaine (levobupivacaine) has been recognized as the lesser toxic of this compound’s two enantiomers (2,3). More recently, the toxicity of levobupivacaine has been reassessed to determine its potential benefits for clinical use (4). In this study, levobupivacaine has undergone further evaluation by comparing its cardiotoxicity with that of ropivacaine and racemic bupivacaine. We used a previously validated porcine model in which bolus doses of the local anesthetics were injected into the coronary circulation (5,6). This model thus allows examination of the direct in vivo cardiac effects of the test anesthetics, without interference from central nervous system mechanisms (7). The aims of this study were twofold: (a) to determine the lethal intracoronary dose for each of the test anesthetics and (b) to determine the relative effects of the local anesthetics on the electrocardiograph (EKG).
Animals used in this study were cared for in accordance with the American Physiologic Society’s Guiding Principles in the Care and Use of Animals. The experimental protocol was approved by our cantonal ethics committee on animal experimentation.
Twenty-eight female swine (45.3 ± 5.6 kg, mean ± sd) were premedicated with intramuscular ketamine hydrochloride (30–40 mg/kg ketaminol; Veterinaria SA, Zurich, Switzerland) and anesthetized with IV sodium pentobarbital (bolus of 12–15 mg/kg, then continuous infusion of 10–12 mg · kg−1 · h−1). Fluid balance was maintained by using Ringer’s lactate solution at 5 mL · kg−1 · h−1 (20–30 mL · kg−1 · h−1 during surgery). The airway was secured via a tracheostomy and the lungs mechanically ventilated (Servo 900B; Siemens-Elma, Solna, Sweden) by using oxygen-enriched air (Fio2 = 0.35–0.45). Expiratory end-tidal CO2 was maintained at 35–40 mm Hg (Ohmeda 4700 OxiCap®, Louisville, CO). Hematocrit, arterial blood gas tensions, and acid/base status were monitored during the preparation and stabilization phases (AVL 945; AVL Medical Instruments AG, Schaffhouse, Switzerland). Rectal temperature was monitored with a mercury thermometer, and the animals were kept warm with blankets and a heating lamp.
Intravascular catheters were inserted by direct cut-down on the vessels and their position confirmed by fluoroscopy. A triple lumen central venous catheter (Arrow International, Inc., PA) was inserted in the left external jugular vein and used for administering pentobarbital and fluids. Sheath introducers (8.5F) (Arrow International, Inc.) were placed in the left carotid and right femoral arteries. After an IV bolus of heparin (5000 IU), a 5F coronary angiography catheter (Cordis®) was passed via the carotid introducer into the left anterior descending (LAD) coronary artery. Coronary angiography was performed by using contrast solution (lopamiro 370; Sintetica, Mendrisio, Switzerland) and the tip of the catheter manipulated to lie in the proximal LAD artery. The position was monitored intermittently and adjusted to avoid spillover of contrast into the circumflex artery. An arterial catheter (Intramedic PE-160; Becton Dickinson, Sparks, MD) was passed via the femoral introducer to lie in the lower abdominal aorta. This was used for arterial blood sampling and to monitor systemic arterial pressures.
A 12-lead surface EKG was recorded using cutaneous electrodes (Ag/AgCl, Red Dot DM; 3M Health Care, Germany). To ensure satisfactory contact, the skin was shaved and then rubbed with acetone. Precordial electrodes were positioned with V1 lying at the lower right sternum, V2 at the lower left sternum, and the subsequent V3–V6 electrodes positioned equidistantly across the lateral left hemithorax.
A 12-lead EKG was monitored continuously throughout the experiment (Biomedix; Biotronik, Germany) and recorded during the experimental protocol on optical discs (DC-502A; Pioneer Electronic Corporation, Japan). Data were collected in epochs of 30 s starting just before each intracoronary injection and continued for 5 min. EKGs were analyzed post-hoc by using an electrophysiological analysis program (EPLab Electrophysiology Management System, Version 7.03; Quinton Electrophysiology Corporation, Canada). EKG intervals (PQ, QRS, QT, and R-R) were read by a blinded single observer using leads V1 and V2, a constant gain, and an EKG speed of 100 mm/s. Intervals were measured by the manual application of screen calipers and the mean value of three measurements within 10% variation determined every 30 s. Data were treated and exclusions made before breaking the randomization code. The QTc interval (QT corrected for heart rate) was calculated according to Bazett’s formula (8) as follows:MATH
Stock solutions of racemic bupivacaine hydrochloride (Marcain, 5 mg/mL; Sintetica SA, Mendrisio, Switzerland), levobupivacaine hydrochloride (7.5 mg/mL; Chiroscience R & D Ltd., Cambridge, UK) and ropivacaine hydrochloride (Naropin, 10 mg/mL; Astra Pharmaceuticals, Södertälje, Sweden) were prepared by dilution in NaCl 0.9%. The prepared concentrations adjusted for the 1.2-mL dead space of the coronary catheter plus stop-cock, such that each dose could be delivered in an injectate volume of 3 mL. Syringes containing 4.2 mL of the stock solutions were incubated in a water bath at 38°C before injection.
The protocol followed a randomized, observer-blinded design in which animals received only one study drug (racemic bupivacaine, Group B, n = 8; levobupivacaine, Group L, n = 9; and ropivacaine, Group R, n = 10). The experiments were started after a stabilization period of 30–45 min, and when the position of the coronary catheter had been reconfirmed. Dead space volume was carefully aspirated before injecting each dose at a constant rate during 10 s. The protocol was initiated with a placebo injection (3 mL NaCl 0.9%, incubated at body temperature). Increasing doses of each drug were then administered until either ventricular fibrillation or hemodynamic collapse was attained (0.375 mg, 0.75 mg, 1.5 mg, 3 mg, and 4 mg, with further doses increasing in increments of 1 mg). Injections were made at 5- to 10-min intervals, but only after hemodynamic stabilization and return of the EKG to baseline.
EKG intervals were presented as the means ± sd. Between-group comparisons were made by using a one-way analysis of variance (ANOVA) to test for differences in the EKG data after intracoronary injection of sublethal doses. Post hoc pairwise comparisons were made by using the Tukey test. Within-group comparisons were tested by using a one-way repeated-measures ANOVA with a post-hoc Dunnett’s test. Lethal doses are given as median values with their corresponding ranges and were compared by using Kruskal-Wallis ANOVA on ranks with a post hoc Dunn’s test. Correlation of QTc with QRS was tested by determining the Pearson Product Moment Correlation coefficient (R) and comparisons of the regression slopes made by using unpaired Student’s t-tests. Statistical analysis was performed by using the SigmaStat (Version 2.03) software package (SPSS, Chicago, IL) with P < 0.05.
Twenty-eight pentobarbital-anesthetized swine were used in the study. One animal died from a probable coronary embolus after placement of the intracoronary catheter. A further six animals were excluded from the principal analysis because of right coronary artery catheterization, resulting from mistaken interpretation of the fluoroscopic image. Thus, 21 animals were included in the final analysis: Group B (n = 7), Group L (n = 7), and Group R (n = 7).
Hematocrit, rectal temperature, and arterial pH, Po2, and Pco2 were similar for the three study groups after the stabilization period (Table 1).
All animals receiving injections into the LAD coronary artery died in ventricular fibrillation. QRS and QTc intervals widened within the precordial leads and progressed to a terminal fibrillation pattern within 40 s of starting the injection. Lower, nonlethal doses produced widening of the QRS and QTc intervals with polymorphic ventricular extrasystoles and short self-terminating runs of ventricular tachycardia. These EKG changes recovered spontaneously to a normal stable sinus rhythm. All six animals identified as receiving RCA injections died as a result of hemodynamic collapse after atrioventricular dissociation (Group B, n = 1; Group L, n = 2; Group R, n = 3).
Effects on EKG
Baseline values for QRS, PQ, R-R, and QTc intervals did not differ among the groups. Neither EKG morphology nor heart rate was altered by the placebo injections. In those animals receiving LAD artery injections, PQ and R-R intervals remained stable throughout the experiments.
The mean maximum QRS intervals for each dose are summarized in Table 2. The QRS was maximally prolonged within 1 min of starting the injection in all animals. Group L, in which animals survived to receive larger doses, produced the greatest QRS prolongation. This was significant with respect to control on injection of 4 mg (0.014 mmol). Similarly, ropivacaine widened the QRS interval on injection of 4 mg (0.013 mmol), but in contrast, failed to prolong the interval by more than approximately 100%. Group B produced an earlier prolongation of the depolarization interval, at the 3-mg (0.009 mmol) dose. Mean maximum QRS intervals for the seven animals, at their sublethal dose (median/range), were—Group B: 115.9 ± 32.0 ms (0.012 mmol/0.009–0.015 mmol); Group L: 159.7 ± 25.8 ms (0.024 mmol/0.021–0.028 mmol); and Group R: 122.9 ± 32.7 ms (0.029 mmol/0.010–0.029 mmol). Pairwise comparisons showed wider QRS intervals in Group L with respect to Group B (P = 0.037), but no differences either between Groups R and L, or Groups R and B.
The mean maximum QTc intervals for each dose, along with comparisons versus control, are summarized in Table 3. Mean maximum QTc intervals for the seven animals, at their sublethal dose (median/range), were—Group B: 462 ± 48 ms (0.012 mmol/0.009–0.015 mmol); Group L: 517 ± 21 ms (0.024 mmol/0.021–0.028 mmol); and Group R: 513 ± 13 ms (0.029 mmol/0.010–0.029 mmol). Groups L and R produced similar prolongation of the QTc interval. However, these anesthetics were associated with longer QTc intervals than Group B (P = 0.03 and P = 0.047, respectively).
To assess whether the QTc interval increased solely as a function of the QRS or whether other effects might be operating (e.g., ST-T wave changes), linear regression of QTc against QRS was performed. The linear regression equations were as follows—Group B: QTc = 0.72 QRS + 392, R = 0.559, see = 30.2 ms, P < 0.001; Group L: QTc = 0.80 QRS + 404, R = 0.807, see = 21.4 ms, P < 0.001; and Group R: QTc = 0.83 QRS + 406, R = 0.764, see = 21.8 ms, P < 0.001. The regression line slopes did not differ among the groups.
Lethal doses in mmoles (median/range) for the three anesthetics differed among the groups (P = 0.005): Group B (0.015/0.012–0.019), Group L (0.028/0.024–0.032), and Group R (0.032/0.013–0.032). Lethal doses for levobupivacaine and ropivacaine did not differ, but were both significantly greater than for bupivacaine (P < 0.05).
We studied the effects of left coronary artery injections of levobupivacaine, racemic bupivacaine, and ropivacaine in a porcine model with controlled ventilation. The principal findings were as follows:
- 1. The lethal dose for bupivacaine was significantly smaller than for both ropivacaine and levobupivacaine.
- 2. There was no significant difference in the lethal doses for ropivacaine and levobupivacaine.
- 3. Ropivacaine induced the least degree of QRS and QTc prolongation.
Systemically administered local anesthetics influence the EKG by direct and central nervous system mechanisms. Neurogenically mediated cardiac dysrhythmias have been observed with intracerebroventricular infusion of local anesthetics in chronically instrumented, conscious cats (7) and anesthetized rabbits (9), as well as after the direct application of local anesthetics to the medulla oblongata of rats (10). We excluded these mechanisms by using a coronary angiography catheter to deliver the test drugs directly to the myocardium. The LAD coronary artery was chosen as the injection site to expose a large mass of the left ventricle to local anesthetics, whereas simultaneously excluding the sinoatrial node, atrioventricular node, and atrial tissues. Sinus rhythm could thus be maintained, allowing assessment of QRS intervals and detection of a clear end point (i.e., death by ventricular fibrillation [VF]). Although this model does not represent the physiological events during a systemic toxic reaction, therapy-resistant VF has frequently been described in case reports of bupivacaine toxicity (11). We believe, therefore, that injection into the LAD artery is the most appropriate route for these experiments. Furthermore, use of this previously validated model has allowed comparison with earlier results, which were very similar for racemic bupivacaine and ropivacaine.
Outcome in toxicity studies is usually expressed in terms of LD50 (i.e., the lethal dose for 50% of animals treated). The numbers of animals in this study are small, however, and do not warrant such presentation. Nevertheless, the differences in lethal dose among the groups were very significant and showed a high degree of statistical power (ANOVA, power = 0.964, α = 0.05). However, for paired comparisons between Groups L and R, a power analysis of the measured lethal doses indicates that 37 animals would need to be included per group to detect a significant difference of 0.002 mmol (power > 0.8, α = 0.05). This implies that if there is a difference in lethal dose between levobupivacaine and ropivacaine, it is very small.
The doses injected were selected on the basis of previous data concerning the fibrillation thresholds for B and R (5,6). Our aim was to select a sufficient number of doses to allow construction of a log10 dose/response curve for QRS prolongation (Fig. 3). Millimole doses were derived using the respective molecular weights of each compound, as used to calculate the injectate concentrations (324.9 for racemic bupivacaine hydrochloride, 288.4 for levobupivacaine hydrochloride, and 310.9 for ropivacaine hydrochloride). Interpolation of the data on curves B and L at the maximum QRS observed in Group R allowed determination of the following cardiotoxic potency ratios—B:L:R = 2.1:1.4:1. Thus, the B:L ratio is in close agreement with previously published data for systemic administration in sheep (4). For lethal doses in millimoles, the potency ratios were B:L:R = 2.1:1.2:1.
These ratios concur with previous experiments, where the racemic form of ropivacaine (AL381) was compared with racemic bupivacaine and lidocaine (potency ratio for doubling of QRS, B:R = 2.3:1) (6). It therefore seems that stereospecificity does not play an important role in ropivacaine cardiotoxicity.
The sequence of EKG changes after LAD artery injections was similar for all animals (i.e., a progressive widening of the QRS and QTc intervals and onset of polymorphic VF within 40 s of starting the local anesthetic injection). Timing of these events indicates a direct effect of the test anesthetics on the myocardium, and it is unlikely that secondary effects, such as ischemia, were important in initiating VF.
Cardiac dysrhythmias may arise through disturbances of impulse generation, conduction, or both (12). In vitro studies have elucidated the electrophysiological effects of bupivacaine, ropivacaine and lidocaine on the action potential of rabbit Purkinje fibers and ventricular myocytes (13,14). Such changes favor the conditions necessary for reentry phenomena (i.e., slowed myocardial conduction and unidirectional block) (15). These drug effects, along with the inhomogeneity of action potential duration and conduction blockade in our model, would predispose to reentry circuits and explain the onset of terminal VF.
Racemic bupivacaine produced wider QRS complexes at smaller doses, but overall, levobupivacaine resulted in the greatest degree of sublethal QRS prolongation (Fig. 3). This is partly explained by the greater number of animals surviving to receive larger doses of levobupivacaine compared with bupivacaine. Because ropivacaine failed to more than double the QRS interval, the threshold QRS for induction of VF differed among groups. The mechanisms for this phenomenon are unclear and have not been addressed by our study. However, differences among the local anesthetics in terms of their drug-receptor binding kinetics, effects on transmembrane currents, or preferential binding sites within the conducting system may be important. Further study is warranted.
These experiments confirm the lower in vivo electrophysiological cardiotoxicity of levobupivacaine, compared with the racemate. Bupivacaine and ropivacaine have similar physicochemical properties (pka = 8.1;N-heptane:buffer partition coefficients ∼10 and ∼2.9, respectively) and are highly protein-bound (94%–95%) (16). Also, myocardial uptake of R(+) and S(−) bupivacaine is similar in isolated perfused rabbit hearts (17). A pharmacokinetic explanation for our observations therefore seems unlikely. Instead, the differing EKG effects may be related to differences in time-, voltage-, and state-dependent interactions of the local anesthetics with cardiac ion channels. All of the local anesthetics we investigated are known to bind with cardiac membrane-bound sodium (18,19), potassium (20,21), and calcium (22,23) channels. Association with receptor sites on these specific voltage-dependent gates results in inhibition of the transmembrane ion fluxes responsible for myocardial action potentials. Stereospecific drug-receptor interactions have been demonstrated for R(+) and S(−) bupivacaine in guinea pig ventricular myocytes, with the R(+) enantiomer showing greater affinity and faster binding kinetics for inactive sodium channels (19). Also, the S(−) enantiomer decreases V max and action potential duration to a lesser extent than its antipode (24).
The S(−) ropivacaine enantiomer binds with lower affinity to the human hKv1.5 potassium channel than both R(+) and S(−) bupivacaine, indicating a lower potential for QTc dispersion and ventricular dysrhythmias (20). No studies have been conducted to examine the importance of stereospecificity per se in the interaction of ropivacaine enantiomers with cardiac sodium and potassium channels. However, no stereoselectivity has been observed between R(+) and S(−) ropivacaine for L-type calcium channels in rat cerebrocortical membranes (25).
Our model used pentobarbital anesthesia. Although widely used in animal research protocols, pentobarbital can decrease myocardial automaticity and conduction (26). Furthermore, the related barbiturates thiopental and methohexital have recently been demonstrated to have opposing effects on the cardiac action potential duration (27). Nevertheless, our pig model is associated with stable pentobarbital concentrations (6), and even if this influenced membrane electrophysiology, this was a constant factor in our experiments and is unlikely to have influenced the conclusions.
Regression of QTc with QRS intervals demonstrated a direct correlation, implying that QTc increased as a function of QRS. Because the slopes of these linear relations were less than unity, broadening of the ST segment did not play a role in QTc prolongation. Also, larger doses were required to significantly prolong the QTc compared with QRS intervals. Electrophysiologically, dispersion of QTc intervals has been associated with potassium channel blockade and cardiac action potential prolongation. Because myocardial sodium channels have a higher affinity for bupivacaine than potassium channels (20), and a biphasic response on action potential duration has been observed with increasing doses of bupivacaine in vitro (14), the QTc prolongation observed at larger doses may reflect inhibition of potassium conductance.
Care must be exercised in extrapolating our results to the clinical environment, because a true perspective on the cardiotoxicity of our test drugs demands knowledge of their clinical analgesic potency. We have no data on the relative analgesic potencies of these drugs in the pig. Moreover, clinical potency data are incomplete, because local anesthetics are usually administered in relative overdose to ensure adequate anesthesia for surgery, or to ensure muscle relaxation. The concept of minimum local analgesic concentration has been introduced in obstetric analgesia to determine the minimum effective analgesic concentration of a local anesthetic (28). By using this technique, the molar analgesic potency ratio for levobupivacaine versus bupivacaine was 0.87 (29). In a similar study, the molar analgesic potency ratio for ropivacaine, compared with bupivacaine, was 0.57 (30). For lumbar epidural administration in humans, we have recently demonstrated B:R sensory and motor-blocking ratios of 1.5 (31). Therefore, the apparent advantages of ropivacaine in terms of lower cardiotoxicity may be offset by a lower analgesic potency.
In clinical practice, the principal factors reducing the incidence of systemic toxic reactions are a meticulous technique and vigilance during the practice of regional anesthesia, although the development of new compounds with improved therapeutic ratios may also play a role. Our study indicates that levobupivacaine is approximately 33%–44% less toxic than bupivacaine, but is no different from ropivacaine for lethality. Considering similar analgesic potencies, the lower cardiotoxicity of levobupivacaine might prove clinically beneficial, in the event of accidental intravascular injection.
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