Local Myotoxicity from Sustained Release of Bupivacaine from Microparticles

Background: Sustained release of local anesthetics is frequently associated with myotoxicity. The authors investigated the role of particulate delivery systems and of the pattern of drug release in causing myotoxicity.

Methods: Rats were given sciatic nerve blocks with bupivacaine solutions, two types of bupivacaine-containing microparticles (polymeric microspheres and lipid-protein-sugar particles), or blank particles with or without bupivacaine in the carrier fluid. Myotoxicity was scored in histologic sections of the injection sites. Bupivacaine release kinetics from the particles were measured. Myotoxicity of a range of bupivacaine concentrations from exposures up to 3 weeks was assessed in C2C12 myotubes, with or without microparticles.

Results: Both types of bupivacaine-loaded microparticles, but not blank particles, were associated with myotoxicity. Whereas 0.5% bupivacaine solution caused little myotoxicity, a concentration of bupivacaine that mimicked the amount of bupivacaine released initially from particles caused myotoxicity. Local anesthetics showed both concentration and time-dependent myotoxicity in C2C12s. Importantly, even very low concentrations that were nontoxic over brief exposures became highly toxic after days or weeks of exposure. The presence of particles did not increase bupivacaine myotoxicity in vitro but did in vivo. Findings applied to both particle types.     

Comparative Ventricular Electrophysiologic Effect of Racemic Bupivacaine, Levobupivacaine, and Ropivacaine on the Isolated Rabbit Heart

Background: Numerous local anesthetics have an asymmetric tetrahedron carbon, which confers stereoselective differences between the isomers. The authors attempted to quantify the depressant effect of racemic bupivacaine, levobupivacaine, and ropivacaine on myocardial ventricular conduction and on myocardial contractility.

Methods: The authors studied the pharmacokinetics (outflow concentration) and pharmacodynamics (QRS widening) of the three drugs infused in an isolated rabbit heart preparation. All data were fitted simultaneously with use of mixed-effect modeling, thus allowing precise statistical comparison between the three drug parameters. The rate dependence of QRS widening was fitted separately.

Results: Racemic bupivacaine, levobupivacaine, and ropivacaine induced a calculated maximum increase in QRS duration in the ratio 1:0.4:0.3. Css50, the dose which caused half the maximum increase in QRS duration at steady state, was similar for all three drugs (22 [mu]m free concentration). A rate dependence of QRS widening was observed, which was in the ratio 1:0.5:0.25 for racemic bupivacaine, levobupivacaine, and ropivacaine, respectively.     

Comparative study between Levobupivacaine and Bupivacaine for hernia surgery in the elderly

Background

The inguinal hernia is one of the most common diseases in the elderly. Treatment of this type of pathology is exclusively surgical and relies almost always on the use of local anesthesia. While in the past hernia surgery was carried out mainly by general anesthesia, in recent years there has been growing emphasis on the role of local anesthesia.

Methods

The aim of our study was to compare intra-and postoperative analgesia obtained by the use of levobupivacaine compared with that of bupivacaine. Bupivacaine is one of the main local anesthetics used in the intervention of inguinal hernioplasty. Levobupivacaine is an enantiomer of racemic bupivacaine with less cardiotoxicity and neurotoxicity. The study was conducted from April 2010 to May 2012. We collected data of forty male patients, aged between 73 and 85 years, who underwent inguinal hernioplasty with local anesthesia for the first time.

Results

Minimal pain is the same in both groups. Mild pain was more frequent in the group who used bupivacaine, moderate pain was slightly more frequent in the group who used levobupivacaine, and the same for intense pain. It is therefore evident how Bupivacaine is slightly less preferred after four and twenty four hours, while the two drugs seem to have the same effect at a distance of twelve and forty-eight hours. Bupivacaine shows a significantly higher number of complications, as already demonstrated by previous studies. The request for an analgesic was slightly higher in patients receiving levobupivacaine.

Conclusions

After considering all these elements, we can conclude that the clinical efficacy of levobupivacaine and racemic bupivacaine are essentially similar, when used under local intervention of inguinal hernioplasty.

     

Comparative study between Levobupivacaine and Bupivacaine for hernia surgery in the elderly

Background

The inguinal hernia is one of the most common diseases in the elderly. Treatment of this type of pathology is exclusively surgical and relies almost always on the use of local anesthesia. While in the past hernia surgery was carried out mainly by general anesthesia, in recent years there has been growing emphasis on the role of local anesthesia.

Methods

The aim of our study was to compare intra-and postoperative analgesia obtained by the use of levobupivacaine compared with that of bupivacaine. Bupivacaine is one of the main local anesthetics used in the intervention of inguinal hernioplasty. Levobupivacaine is an enantiomer of racemic bupivacaine with less cardiotoxicity and neurotoxicity. The study was conducted from April 2010 to May 2012. We collected data of forty male patients, aged between 73 and 85 years, who underwent inguinal hernioplasty with local anesthesia for the first time.

Results

Minimal pain is the same in both groups. Mild pain was more frequent in the group who used bupivacaine, moderate pain was slightly more frequent in the group who used levobupivacaine, and the same for intense pain. It is therefore evident how Bupivacaine is slightly less preferred after four and twenty four hours, while the two drugs seem to have the same effect at a distance of twelve and forty-eight hours. Bupivacaine shows a significantly higher number of complications, as already demonstrated by previous studies. The request for an analgesic was slightly higher in patients receiving levobupivacaine.

Conclusions

After considering all these elements, we can conclude that the clinical efficacy of levobupivacaine and racemic bupivacaine are essentially similar, when used under local intervention of inguinal hernioplasty.

     

Effects of Intermittent Femoral Nerve Injections of Bupivacaine, Levobupivacaine, and Ropivacaine on Mitochondrial Energy Metabolism and Intracellular Calcium Homeostasis in Rat Psoas Muscle

Background: Long-acting local anesthetics cause muscle damage. Moreover, long-acting local anesthetics act as uncoupler of oxidative phosphorylation in isolated mitochondria and enhance sarcoplasmic reticulum Ca2+ release. The aim of the study was to evaluate effects of perineural injections of local anesthetics on mitochondrial energetic metabolism and intracellular calcium homeostasis in vivo.

Methods: Femoral nerve block catheters were inserted in adult male Wistar rats. Rats were randomized and received seven injections (1 ml/kg) of bupivacaine, levobupivacaine, ropivacaine, or isotonic saline at 8-h intervals. Rats were killed 8 h after the last injection. Psoas muscle was quickly dissected from next to the femoral nerve. Local anesthetic concentrations in muscle were determined. Oxidative capacity was measured in saponin-skinned fibers. Oxygen consumption rates were measured, and mitochondrial adenosine triphosphate synthesis rate was determined. Enzymatic activities of mitochondrial respiratory chain complexes were evaluated. Local calcium release events (calcium sparks) were analyzed as well as sarcoplasmic reticulum calcium content in saponin-skinned fibers.

Results: Eight hours after the last injection, psoas muscle concentration of local anesthetics was less than 0.3 [mu]g/g tissue. Adenosine triphosphate synthesis and adenosine triphosphate-to-oxygen ratio were significantly decreased in the muscle of rats treated with local anesthetics. A global decrease (around 50%) in all of the enzyme activities of the respiratory chain was observed. Levobupivacaine increased the amplitude and frequency of the calcium sparks, whereas lower sarcoplasmic reticulum calcium content was shown.     

The Placental Transfer and Fetal Effects of Levobupivacaine, Racemic Bupivacaine, and Ropivacaine

Background: The purposes of this study were to assess the effects of levobupivacaine on uterine blood flow and fetal well-being and to compare its placental transfer with that of bupivacaine and ropivacaine.

Methods: After a control period, pregnant ewes that were fitted with instruments for long-term monitoring were randomized to receive a two-step intravenous infusion of levobupivacaine, bupivacaine, or ropivacaine, in a blinded manner, for 1 h. Maternal and fetal hemodynamics were monitored during the study. Arterial blood samples were drawn at 30 and 60 min of infusion from the mother and fetus to determine the acid-base status (60 min only) and serum drug concentrations. The fetal brain, heart, liver, lungs, adrenal glands, and kidneys were obtained to measure tissue drug levels.

Results: Maternal blood pressure, central venous and intraamniotic pressures, acid-base status and uterine blood flow were unaffected by any drug infusion. In contrast to the other two local anesthetics, the infusion of bupivacaine was associated with a small but significant decrease in the ewe's heart rate. At the end of the study, the heart rate in the bupivacaine-treated animals was significantly less than in the animals treated with the other two drugs. All fetuses were in good condition at the start of study, and none of the local anesthetics affected fetal well-being. No significant differences were found among the three drugs in the maternal serum, fetal serum, fetal tissue concentrations, and tissue:serum concentration ratios.     

Minimum Local Analgesic Doses of Ropivacaine, Levobupivacaine, and Bupivacaine for Intrathecal Labor Analgesia

Background: Doses for intrathecal opioid-local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up-down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic.

Methods: Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal-epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey.

Results: The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33-3.96 mg) for ropivacaine, 2.94 (2.73-3.16) mg for levobupivacaine, and 2.37 (2.17-2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 (0.56-0.76) for ropivacaine:bupivacaine, 0.80 (0.70-0.92) for ropivacaine:levobupivacaine, and 0.81 (0.69-0.94) for levobupivacaine:bupivacaine. There were significant trends (P <= 0.021) for greater motor block with bupivacaine and levobupivacaine.     

Spermatogenesis of Rat: Effect of Central Norepinephrine Synthesis Inhibition by Diethyldithiocarbamate

Spermatogenesis and steroidogenesis of male Wistar rats under the influence of a decreased central NE level was studied. Inhibition of NE synthesis was produced by chronic injection (7 days) of DDC, a Dopamine hydroxylase blocker, which decreased brain NE, increased brain DA without significantly affecting brain 5-HT. Rats were sacrificed on the day after cessation of treatment (8th day) and after an interval of 13 days following the cessation of treatment (21st day). The time interval of 13 days is equivalent to one cycle of the seminiferous epithelium in Wistar strain rats. A degenerative change (reduced spermatid count) in the spermatogenic pattern at stage-VII of the cycle of the seminiferous epithelium was observed in the rats sacrificed on the 8th day, the degeneration being much greater in the rats sacrificed on the 21st day. Rats sacrificed on the day after cessation of DDC treatment revealed an inhibition of plasma testosterone level. Such change was not observed in the rats sacrificed after the interval of 13 days following DDC treatment. Human chorionic gonadotropin supplementation in the rats sacrificed on the 21st day partially restored the spermatogenesis towards the vehicle treated control. The inhibition of spermatogenesis and steroidogenesis reflects a decrease in the pituitary gonadotropin secretion under the influence of a decreased NE synthesis in brain, following chronic treatment of DDC.     

Comparative Somatic and Visceral Antinociception and Neurotoxicity of Intrathecal Bupivacaine, Levobupivacaine, and Dextrobupivacaine in Rats

Background: The current study investigated whether racemic bupivacaine and its S(-)- and R(+)-enantiomers, levobupivacaine and dextrobupivacaine, differ in somatic and visceral antinociception and neurotoxicity when administered intrathecally in rats.

Methods: In experiment 1, rats intrathecally received 15 [mu]l saline or 0.125, 0.25, 0.5, or 1% bupivacaine, levobupivacaine, or dextrobupivacaine. The tail-flick and colorectal distension tests were performed to assess somatic and visceral antinociceptive effects, respectively, for 180 min after injection. In experiment 2, rats given 0.25% anesthetic solutions were evaluated with colorectal distension-induced response in blood pressure and heart rate. In experiment 3, four groups of rats received a 1-h infusion of saline or 2.5% bupivacaine, levobupivacaine, or dextrobupivacaine. Additional rats received either 1.25% bupivacaine or levobupivacaine for 1 h. Four days after infusion, animals were assessed for persistent sensory impairment using the tail-flick test. Spinal cords and nerve roots were obtained for histologic analysis.

Results: In experiment 1, the three drugs produced similar time course effects and dose-effect relations in tail-flick latency. Colorectal distension thresholds and motor paralysis were slightly lower and less apparent, respectively, at some concentrations in rats given levobupivacaine than in those given the other agents. In experiment 2, colorectal distension-induced response in heart rate was less depressed in rats given levobupivacaine than in those given the other anesthetics. In experiment 3, three groups of rats given 2.5% anesthetic solutions developed similar significant increases in tail-flick latency and incurred similar morphologic damage. Two groups of rats receiving 1.25% anesthetic solutions were similar in functional impairment and nerve injury scores.     

Glucocorticoids Prolong Rat Sciatic Nerve Blockade In Vivo from Bupivacaine Microspheres

Background: Previous work showed that incorporation of dexamethasone (0.05 weight/weight percentage) into bupivacaine microspheres prolonged blockade by eight to 13 times compared with that produced by bupivacaine microspheres alone. The determinants of dexamethasone's block-prolonging effect were examined and reported here.

Methods: Polylactic-co-glycolic acid polymer microspheres (65/35) with 75 weight/weight percentage bupivacaine were prepared. Microspheres were injected adjacent to the rat sciatic nerve, and sensory and motor blockade were assessed. A procedure was developed to test drugs for block-prolonging ability in vivo by placing test drugs in the injection fluid along with a suspension of bupivacaine microspheres.

Results: Dexamethasone alone in suspension did not produce blockade, nor did it prolong blockade induced by aqueous bupivacaine. Bupivacaine microspheres (150 mg drug/kg rat weight) produced blockade for 6 to 10 h. Dexamethasone in the suspending solution of microspheres prolonged block by up to five times. Glucocorticoids prolonged block in proportion to glucocorticoid/antiinflammatory potency. The corticosteroid antagonist cortexolone inhibited dexamethasone's blockade-prolonging action. Durations of blockade with or without dexamethasone were unaltered by hydroxyurea-induced neutrophil depletion. Microspheres were extracted from rats at time points ranging from 7 h to 7 days, and residual microsphere dry weight and bupivacaine content were similar in groups of rats injected with either bupivacaine microspheres or bupivacaine microspheres containing dexamethasone, respectively.     

Effects of CNS Site-directed Carotid Arterial Infusions of Bupivacaine, Levobupivacaine, and Ropivacaine in Sheep

Background: Previous preclinical safety studies in ewes have found intravenous levobupivacaine and ropivacaine to be less potent toward causing central nervous system (CNS) and cardiac toxicity than bupivacaine. Analogous cardiotoxicity has been demonstrated directly in various cardiac preparations ex vivo. Moreover, drug-related arrhythmogenicity has been demonstrated from direct CNS injection of local anesthetic agents in vivo, suggesting CNS-related cardiotoxicity. This study investigated whether CNS site-directed blood-borne drug administration (with minimal systemic recirculation) would demonstrate drug-related cardiotoxicity.

Methods: Direct CNS effects and indirect cardiotoxic sequelae were determined after bilateral carotid arterial infusions of levobupivacaine, bupivacaine, or ropivacaine in ewes. After pilot studies to validate the procedures, equimolar doses (24-96 [mu]mol, [almost equal to]7.5-30 mg) were infused over 3 min using a crossover design. Behavioral CNS signs, quantitative electroencephalographic (EEG), cardiovascular, and electrocardiographic effects were recorded. Drug blood concentrations in superior sagittal sinus and aorta were measured serially.

Results: Blood drug concentrations in the superior sagittal sinus were 5-10 times those concurrently in the aorta, confirming highly selective CNS delivery with minimal systemic recirculation. Dose-dependent CNS excitatory behavior and EEG changes, with increased mean arterial blood pressure, heart rate, cardiac output, and myocardial contractility, were found, consistent with sympathetic nervous system stimulation. The overall rank order of potency for these effects was ropivacaine < levobupivacaine < bupivacaine. Nonfatal cardiac arrhythmias were observed, but the type or frequency did not differ between drugs.     

Nicotinic Acetylcholine Receptor Regulation of Spinal Norepinephrine Release

Background: Neuronal nicotinic acetylcholine receptor (nAChR) agonists produce antinociception in animals. nAChRs exist almost exclusively on presynaptic terminals in the central nervous system and stimulate neurotransmitter release. This study tested whether nAChR agonists stimulate spinal release of the neurotransmitter norepinephrine either by direct actions on noradrenergic terminals or indirectly by stimulating release of other neurotransmitters to induce norepinephrine release.

Methods: Adult male rats were anesthetized and microdialysis probes inserted in the L2-L4 dermatomes of the spinal cord. Probes were perfused with artificial cerebrospinal fluid containing nicotine, the specific [alpha]4[beta]2* nAChR agonist metanicotine, or nicotine plus nAChR antagonists and norepinephrine measured in the microdialysates. The effects of specific glutamate receptor antagonists and nitric oxide synthase inhibitors were also examined. To determine direct effects on noradrenergic terminals, synaptosomes were prepared from spinal cord and incubated with nAChR agonists and antagonists.

Results: Both nicotine and metanicotine induced norepinephrine release in spinal microdialsyates, an effect reduced by nicotinic antagonists but not glutamate antagonists or nitric oxide synthase inhibitors. Both of the nicotinic agonists stimulated norepinephrine release in synaptosomes, and the effect of metanicotine was blocked at lower concentrations of [alpha]4[beta]2*- than [alpha]7*-preferring nAChR antagonists.     

Systemic Toxicity of Levobupivacaine, Bupivacaine, and Ropivacaine during Continuous Intravenous Infusion to Nonpregnant and Pregnant Ewes

Background : Levobupivacaine, the single levorotatory isomer of bupivacaine, is now available for clinical use. This study was undertaken to determine whether pregnancy affects the systemic toxicity of levobupivacaine and to compare the systemic toxicity of levobupivacaine with that of bupivacaine and ropivacaine.

Methods : Chronically prepared nonpregnant and pregnant sheep were randomized to receive an intravenous infusion of 0.52% levobupivacaine, 0.52% bupivacaine, or 0.50% ropivacaine at a constant rate of 0.1 ml [middle dot] kg-1 [middle dot] min-1 until circulatory collapse. The investigators were blinded to the identity of the local anesthetic. Physiologic parameters, including cardiac rhythm, were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations. These were analyzed for total and free serum drug concentrations as well as arterial blood p H and gas tensions.

Results : The doses of all three drugs required to produce convulsions were lower in pregnant than nonpregnant animals. However, as the infusion continued, there were no significant differences between pregnant and nonpregnant ewes in the dose of drug required to produce more advanced manifestations of toxicity: hypotension, apnea, and circulatory collapse. The mean cumulative dose and serum concentration at each toxic manifestation was lowest for bupivacaine, intermediate for levobupivacaine, and highest for ropivacaine in both pregnant and nonpregnant animals. For all three local anesthetics, there were no significant differences between pregnant and nonpregnant ewes in total and free serum drug concentrations, except that at circulatory collapse, these were higher in pregnant animals.     

Clinical Effects and Maternal and Fetal Plasma Concentrations of 0.5% Epidural Levobupivacaine versus Bupivacaine for Cesarean Delivery

Background: Bupivacaine exists as a mixture of two enantiomers, levobupivacaine and dexbupivacaine. Data suggest that levobupivacaine has equal local anesthetic potency, with reduced potential for central nervous system and cardiovascular toxicity. The present study compares the efficacy of 0.5% levobupivacaine with 0.5% bupivacaine for epidural anesthesia in parturients undergoing elective cesarean delivery.

Methods: Sixty healthy obstetric patients undergoing elective cesarean delivery with epidural anesthesia completed the study. Patients were randomized to receive 30 ml of either 0.5% levobupivacaine or 0.5% bupivacaine in a double-blind fashion. The efficacy endpoint measures included onset, offset, and quality of anesthesia. Neonatal blood gas analyses, Apgar score determinations, and neurobehavioral examinations were performed. Venous samples for pharmacokinetic studies and serial electrocardiograms were obtained in 10 patients in each group.

Results: Levels of sensory block, motor block, muscle relaxation, and overall quality of anesthesia did not differ between groups. The frequency of hypotension was 84.4% in the levobupivacaine group and 100% for the bupivacaine group (P 相似文献   

Comparison of Effects of Levobupivacaine and Ropivacaine Infiltration on Cutaneous Wound Healing in a Rat Model

ABSTRACT

Purpose: To compare the effects of fluid resuscitation with lactated Ringer's solution (LR) and saline-based 6% hydroxyethyl starch 130/0.4 (HES) on the inflammatory response and oxidative stress in the small intestine as well as on bacterial translocation to the liver. Methods: Sprague–Dawley rats were subjected to blood pressure-controlled hemorrhagic shock and then resuscitated with LR or HES. At 1, 3, 6, 12, and 24 hr after resuscitation, liver tissues were collected to count the bacterial colonies, and small intestines were harvested to analyze the levels of inflammatory (TNF-α and HO-1) and oxidative stress (MPO) mediators as well as the intestinal injury by immunohistochemistry, colorimetry and hematoxylin &; eosin staining, respectively. Results: The expression level of TNF-α in the LR group was stable from 1 to 6 hr but decreased at 12 hr and then abruptly increased at 24 hr. The expression level of TNF-α in the LR group was significantly lower than that in the HES group, especially during the first 12 hr post-fluid infusion. MPO activity decreased to its lowest level at 3 hr but increased from 6 to 12 hr, with no difference at 24 hr between the two groups. Although a decreasing tendency was observed from 6 hr, HO-1 expression levels remained higher in the LR group than in the HES group at 12 and 24 hr, particularly at 12 hr. During the initial 12 hr, the LR group exhibited significantly lower colony-forming units in the liver tissues than the HES group. Chiu's score in the intestine decreased regardless of which resuscitative fluids were used. Conclusions: During early resuscitation (within 12 hr), LR may be superior to HES in reducing intestinal injuries by suppressing inflammatory and oxidative mediators.     

Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate-sensitive Potassium Channels in the Cardiovascular System

Background: Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits.

Methods: The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs.

Results: Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 [mu]m) stereoselectively (levobupivacaine, IC50 = 168 [mu]m; ropivacaine, IC50 = 249 [mu]m). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2[DELTA]C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit.     

Comparison of the Effects of Racemic Bupivacaine, Levobupivacaine, and Ropivacaine on Ventricular Conduction, Refractoriness, and Wavelength: An Epicardial Mapping Study

Background: The study was designed to compare the effects of equimolar concentrations of racemic bupivacaine, levobupivacaine, and ropivacaine on ventricular conduction, anisotropy, duration and homogeneity of refractoriness, and wavelengths, and to provide a potency ratio for effects on conduction velocity.

Methods: Isolated frozen rabbit hearts (which leave a thin layer of surviving epicardial muscle) were treated with 0.1, 1, and 10 [mu]m racemic bupivacaine, levobupivacaine, or ropivacaine. Left ventricular longitudinal and transverse conduction velocities, anisotropic ratio, minimum pacing cycle length, use dependency, duration and dispersion of ventricular effective refractory period, and wavelengths were studied. A high-resolution mapping system was used for data acquisition. In addition to two-way analysis of variance for repeated measures, data for conduction velocities were fitted simultaneously using a nonlinear mixed-effect modeling program to allow intergroup comparison.

Results: Each agent induced a concentration- and use-dependent slowing of conduction velocities, with no change of the anisotropic ratio. The use-dependent effect of levobupivacaine is similar to that of racemic bupivacaine concerning longitudinal conduction velocity. Fitting of conduction velocities provided a racemic bupivacaine to levobupivacaine and to ropivacaine ratio of 1:1.38 for concentration effect at 1,000-ms pacing cycle length, and 1:0.74 for use-dependent effect at 600-ms pacing cycle length. Racemic bupivacaine and levobupivacaine prolonged the ventricular effective refractory period, whereas ropivacaine did not. No dispersion in ventricular effective refractory period values occurred. All three agents induced significant decreases in wavelengths. This effect was not different among groups.