Comparative cardiotoxicity of bupivacaine and lidocaine in the isolated perfused mammalian heart

This study was designed to compare the direct actions of bupivacaine and lidocaine on the isolated perfused guinea pig Langendorff heart preparation. Sixty min after mounting, either bupivacaine HCl (0.3 or 3 micrograms/ml) or lidocaine HCl (10 or 30 micrograms/ml) was added to the perfusate, and the effect (if any) was compared to untreated control values 30, 60, and 90 min later. Although the highest concentrations of both drugs invariably produced statistically significant reductions in heart rate, df/dt, coronary blood flow, and myocardial oxygen consumption (MVO2), these reductions were consistently greater after bupivacaine. Moreover, arrhythmias occurred in 6 of 12 preparations in those hearts exposed to 3 micrograms/ml of bupivacaine. Most often these arrhythmias consisted of heart block and bi- or trigeminy. Additional studies indicated that the reduction in coronary blood flow and MVO2 produced by 3 micrograms/ml of bupivacaine was a consequence of its direct negative inotropic and chronotropic action. Although the myocardial depression produced by bupivacaine and lidocaine could be reversed readily by substituting fresh perfusate, increasing the extracellular calcium concentration in stepwise increments did not augment the negative inotropic or chronotropic effect produced by 3 micrograms/ml of bupivacaine or 10 micrograms/ml of lidocaine. We conclude that 3 micrograms/ml of unbound bupivacaine is more cardiotoxic than 30 micrograms/ml of unbound lidocaine in this model.     

Functional and metabolic effects of bupivacaine and lidocaine in the perfused working rat heart

The effects of bupivacaine (2.5, 5, 10, and 12.5 mg/L) and lidocaine (12.5, 25, 40, and 50 mg/L), on spontaneous heart rate, mean pressure development, cardiac output, and coronary flow were compared after 15 minutes' exposure in the isolated perfused working rat heart preparation. In addition, myocardial oxygen consumption, glucose utilization, lactate production, tissue content of glycogen, adenine nucleotides, and creatine phosphate content were measured. The relative potency of bupivacaine to lidocaine, calculated from slopes of regression equations, as indicated by the four mechanical variables and oxygen consumption, was 4.59. When the bupivacaine concentration was "normalized" using this value, bupivacaine and lidocaine showed indistinguishable effects on glucose utilization, lactate production, and tissue glycogen. Neither of the local anesthetics had any influence on energy charge or creatine phosphate content.     

氨吡酮对离体大鼠灌注心脏布比卡因毒性作用的影响

目的　在离体大鼠灌注心脏模型中观察氨吡酮对布比卡因 (BU P)心脏毒性作用的影响。方法　选用 SD大鼠离体心脏 L angendorff灌注模型 ,随机将大鼠心脏分为三组 ,分别为对照组(组 )、输注 Bup 80μg/ min 15 min(组 )、输注 Bup 80μg/ m in 15 min后 ,输注氨吡酮 80μg/ m in 15 min(组 ) ,观察心率 (HR)、左室舒张末期压 (L VEDP)、左室发展压 (L VDP)、 dp/ dt、- dp/ dt的变化以及心肌 c AMP含量。结果　组 、组 在输注 Bup后 HR,L VDP、 dp/ dt、- dp/ dt值与基础值比较均明显降低 ,而 L VEDP则明显高于基础值 ,而组 在输注氨吡酮后上述指标均得以恢复 ,组 心肌c AMP含量也明显低于组 和组 。结论　氨吡酮逆转 Bup心脏毒性作用可能与其增加心肌组织c AMP含量和改善心肌收缩舒张功能有关。     

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 micrometer 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. CONCLUSIONS: In the isolated rabbit heart, racemic bupivacaine, levobupivacaine, and ropivacaine induce an increase in QRS duration in the respective ratio of 1:0.4:0.3, which was rate dependent in approximately the same ratio.     

Isoproterenol corrects the effects of bupivacaine on the electrophysiologic properties of the isolated rabbit heart

The purpose of this study was to test the hypothesis that isoproterenol could reverse bupivacaine toxicity. In eight isolated rabbit hearts an electrophysiologic evaluation was performed then repeated during infusion of bupivacaine (1 microgram/mL) alone and bupivacaine plus isoproterenol (1-2 micrograms/mL). Bupivacaine alone increased electrocardiographic intervals (P wave, QRS complex, PR, AV, and QTc interval) and refractory periods of the myocardium and atrioventricular junction as well as the Wenckebach cycle and pacing thresholds. The addition of isoproterenol corrected partially or completely all bupivacaine-induced abnormalities, and decreased sinus cycle length, suggesting a potential therapeutic value in the treatment of bupivacaine intoxication.     

Effects of progesterone on the cardiac electrophysiologic action of bupivacaine and lidocaine.

Pregnancy is accompanied by an increased cardiac and neural sensitivity to some local anesthetic agents such as bupivacaine. The current study was initiated to investigate the relationship between increased progesterone concentrations and the electrophysiologic effects of bupivacaine, and lidocaine in isolated Purkinje fiber (PF)-ventricular muscle (VM) preparations. Twenty-four oophorectomized female white rabbits were killed after receiving 30 mg.kg-1.day-1 of progesterone intramuscularly or peanut oil alone for 4 days. PF and VM action potentials were recorded using standard electrophysiologic procedures. Plasma progesterone concentrations were 5 +/- 2.9 ng/ml in control animals compared to 59.8 +/- 11.0 ng/ml in progesterone-treated animals (P less than 0.05). Bupivacaine (3.5-17.4 microM) depressed the maximal rate of depolarization (Vmax) of PF to a significantly greater extent in tissues from progesterone-treated animals as compared to control animals. For example, at 3.5 microM bupivacaine decreased PF Vmax 52% in progesterone-treated tissues compared to 32% in controls (P less than 0.05); the Vmax of VM was also depressed to a greater extent in tissues from progesterone-treated animals (P less than 0.001). Lidocaine did not demonstrate an enhanced depressant effect in tissues from progesterone-treated animals. These results indicate that progesterone selectively increases the cardiac membrane depressant effects of bupivacaine but not lidocaine. This may contribute to the enhanced toxicity of bupivacaine in pregnant animals.     

Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of ropivacaine, a new amide local anesthetic

Ropivacaine is a new amino-amide local anesthetic whose anesthetic profile appears similar to that of bupivacaine. Moreover, in intact animals ropivacaine was reportedly less arrhythmogenic than bupivacaine. These experiments evaluated the cardiac transmembrane electrophysiologic effects of ropivacaine compared with those of lidocaine and bupivacaine in an isolated rabbit Purkinje fiberventricular muscle preparation. Only bupivacaine (3-5 micrograms/ml, 0.92-1.5 x 10(-5) m) significantly decreased Purkinje fiber maximum diastolic potential. Action potential amplitude and maximal rate of depolarization (Vmax) were significantly decreased by all agents in the following order: bupivacaine, ropivacaine, lidocaine. High concentrations of bupivacaine and ropivacaine caused premature depolarizations during phase 3 in some preparations. In addition, bupivacaine altered the action potential configuration by producing "notching" not seen with either ropivacaine or lidocaine. This may reflect effects caused by changes in Ca2+, K+, or electrotonic effects. Ropivacaine and bupivacaine (30 micrograms/ml, 9.2 x 10(-5) m) and lidocaine (100 micrograms/ml, 3.74 x 10(-4) m) caused Purkinje fiber inexcitability and Purkinje fiber-ventricular muscle conduction block. However, the duration of PF inexcitability following exposure to ropivacaine and lidocaine was significantly shorter than in bupivacaine-treated preparation. Duration of PF-VM conduction block also tended to be shorter for ropivacaine than bupivacaine, but significantly longer than lidocaine. In general, ropivacaine is less potent than bupivacaine but more potent than lidocaine in terms of its depressant effect on cardiac excitation and conduction.     

The clinical effectiveness of epidural bupivacaine, bupivacaine with lidocaine, and bupivacaine with fentanyl for labor analgesia

STUDY OBJECTIVE: To examine the efficacy of bupivacaine alone and in combination with lidocaine or fentanyl for epidural analgesia during labor. DESIGN: Randomized, single-blind study. SETTING: Labor and delivery unit at a university medical center. PATIENTS: Forty-five primiparas requesting epidural analgesia. INTERVENTIONS: Following epidural placement at L3-4 interspace, patients received either bupivacaine 0.5% (Group 1, n = 15), bupivacaine 0.25% with lidocaine 1% (Group 2, n = 15), or bupivacaine 0.5% with fentanyl 50 micrograms in 10 ml of saline (Group 3, n = 15). Patients in Groups 1 and 2 received 6 to 10 ml of local anesthetic depending on patient height, while patients in Group 3 received 5 ml of local anesthetic plus 50 micrograms of fentanyl in 10 ml of saline. All solutions contained epinephrine 1:200,000. MEASUREMENTS AND MAIN RESULTS: Patients were assessed at regular intervals following administration of the epidural solution. Visual analog scale (VAS) scores were used to measure onset of analgesia, time to complete pain relief, duration of analgesia, and patient satisfaction with therapy. The frequency of shivering and pruritus and the extent of sensory/motor block also were evaluated. There were no intragroup differences in time to complete pain relief or patient satisfaction. However, patients in Group 3 noted the most rapid onset and longest duration of pain relief. Patients in Group 3 also experienced significantly less shivering and had the lowest degree of motor block. Two patients in Group 3 experienced mild pruritus. CONCLUSIONS: Epidurally administered fentanyl safely extended the duration of labor analgesia while reducing bupivacaine dose requirements and magnitude of motor block. In this setting, the combination of bupivacaine and lidocaine offered no clinical advantage over bupivacaine alone.     

Electrophysiologic effects of bupivacaine in the isolated rabbit heart

To assess the direct electrophysiologic effects of bupivacaine, we examined the spontaneous sinus rhythm and induced rapid and premature atrial and ventricular pacing in 11 isolated rabbit hearts perfused in the Langendorff apparatus with varying concentrations (designated by []) of bupivacaine (control, n = 2; 0.3 microgram/mL, n = 3; 1.5 micrograms/mL, n = 3; 3.0 micrograms/mL, n = 3). There was no change in sinus node automaticity or sinus node recovery time at any concentration and no evidence of abnormal automaticity. Depression of conduction was reflected by prolongation of the PR interval at the following concentrations: 1.5 micrograms/mL (65.0 ms before, 96.6 ms after) and 3.0 micrograms/mL (61.6 ms before, 103.3 ms after) and increase in atrial and ventricular pacing thresholds at 3.0 micrograms/mL (atrial: 0.86-8.6 mA, ventricular: 2.0-10.0 mA). No spontaneous tachyarrhythmias occurred; 2:1 spontaneous atrioventricular block (n = 1) and a decrease in maximal paced rate with 1:1 anterograde or retrograde atrioventricular conduction were noted at all concentrations of bupivacaine. Thus bupivacaine did not change automaticity but had a depressant effect on conduction at the atrial, ventricular, and atrioventricular levels, providing a basis for clinically occurring atrioventricular block and reentrant arrhythmias.     

Cerulein-induced pancreatitis in the ex vivo isolated perfused canine pancreas

Infusion of supramaximal doses of the cholecystokinin analog cerulein is well established as an in vivo technique for inducing experimental pancreatitis in small animals. An attempt was made to simulate this model and initiate pancreatitis in the ex vivo isolated perfused canine pancreas. Control preparations gained minimal weight (mean 8.3 +/- 5.1 gm), demonstrated no edema accumulation, and did not develop hyperamylasemia (mean 1342 +/- 790 units) after 4 hours of perfusion. Electron microscopy after 4 hours of perfusion remained normal. Intraarterial cerulein infusion produced significant weight gain (mean 27.6 +/- 12.3 gm; p less than 0.001), edema formation, and marked hyperamylasemia (mean 26,838 +/- 21,341 units; p less than 0.001) after 4 hours of perfusion. During the 4-hour perfusion, electron microscopy of cerulein preparations demonstrated depletion of zymogen granules, condensing vacuole formation, and basolateral exocytosis. Pretreatment of cerulein preparations with the free radical scavengers superoxide dismutase and catalase and the iron chelator deferoxamine did not modify the pancreatitis. Continuous infusion of the nonpeptide cholecystokinin antagonist L364,718 reduced cerulein-induced weight gain (4.3 +/- 3.4 gm; p less than 0.001) and hyperamylasemia (9392 +/- 6718 units; p less than 0.05). We conclude that cerulein pancreatitis in the ex vivo isolated perfused canine pancreatic preparation is identical physiologically, biochemically, and morphologically with that seen in intact animals.     

Amrinone preconditioning in the isolated perfused rabbit heart

BACKGROUND: Ischemic preconditioning (IPC) reduces infarct size in experimental preparations. IPC, however, is not without detrimental effects. We studied amrinone as a possible alternative to IPC. METHODS: Isolated perfused rabbit hearts were given a 5-minute infusion of 10 micromol/L amrinone followed by a 5-minute washout (n = 6). The anterior descending artery was then occluded for 1 hour and reperfused for 1 hour. Six hearts underwent IPC, with two episodes of 5-minute global ischemia followed by 5-minute reperfusion before LAD occlusion; eight control hearts received no preconditioning. Left ventricular pressure and ischemic zone epicardial monophasic action potentials were continuously monitored. RESULTS: IPC but not amrinone reduced peak pressure before anterior descending artery occlusion. Peak pressure fell significantly during ischemia and reperfusion in all hearts. End diastolic pressure rose significantly during reperfusion in control and IPC hearts but not in amrinone hearts. Action potentials shortened during ischemia in all hearts. They returned to preocclusion values in control hearts but lasted beyond preocclusion values in IPC and amrinone hearts. Both the incidences of ventricular fibrillation and infarct size were significantly reduced in amrinone hearts but not in IPC hearts. CONCLUSIONS: Amrinone is not only a useful inotropic agent but is also a superior preconditioning agent when compared to IPC.     

Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart

BACKGROUND AND OBJECTIVES: Infusion of a lipid emulsion has been advocated for treatment of severe bupivacaine cardiac toxicity. The mechanism of lipid rescue is unknown. These studies address the possibility that lipid infusion reduces cardiac bupivacaine content in the context of cardiac toxicity. METHODS: We compared the effects of a 1% lipid emulsion with standard Krebs buffer after inducing asystole in isolated rat heart with 500 micromol/L bupivacaine. We compared times to first heart beat and recovery of 90% of baseline rate pressure product (RPP = heart rate x [left ventricular systolic pressure - left ventricular diastolic pressure]) between controls and hearts receiving 1% lipid immediately after bupivacaine. We also used minibiopsies to compare control bupivacaine tissue content with hearts getting lipid immediately after an infusion of radiolabeled bupivacaine. We then compared bupivacaine efflux from hearts with and without lipid infusion started 75 seconds after radiolabeled bupivacaine was administered. RESULTS: Infusion of lipid resulted in more rapid return of spontaneous contractions and full recovery of cardiac function. Average (+/- SEM) times to first beat and to 90% recovery of rate pressure product were 44.6 +/- 3.5 versus 63.8 +/- 4.3 seconds (P < .01) and 124.7 +/- 12.4 versus 219.8 +/- 25.6 seconds (P < .01) for lipid and controls, respectively. Lipid treatment resulted in more rapid loss of bupivacaine from heart tissue (P < .0016). Late lipid infusion, 75 seconds after bupivacaine infusion ended, increased the release of bupivacaine measured in effluent for the first 15-second interval compared with controls (183 vs. 121 nmol, n = 5 for both groups, P < .008). CONCLUSIONS: Lipid emulsion speeds loss of bupivacaine from cardiac tissue while accelerating recovery from bupivacaine-induced asystole. These findings are consistent with the hypothesis that bupivacaine partitions into the emulsion and supports the concept of a "lipid sink." However, the data do not exclude other possible mechanisms of action.     

Fetal heart rate after epidural lidocaine and bupivacaine for elective cesarean section

This prospective double-blind study was designed to determine whether the fetal heart rate (FHR) changes that have been reported after epidural administration of bupivacaine and lidocaine during labor are present when larger doses of these drugs are given during elective cesarean section. Prior to inserting an epidural catheter, FHR and maternal vital signs were monitored during a control period in 60 healthy term parturients. Patients were randomly assigned to receive either 0.5% bupivacaine with 0.1 mEq sodium bicarbonate added to each 20 ml (n = 30) or 2% lidocaine with 1:300,000 epinephrine (n = 30). A 3-ml test dose of the study solution was injected via the catheter and was followed by an additional 17 ml, in increments; additional doses were administered as necessary to obtain surgical anesthesia. FHR and maternal vital signs were monitored for at least 20 min and the characteristics of the anesthetic block noted. At delivery, neonatal status was evaluated, and maternal and cord blood samples were obtained for local anesthetic assays and neonatal blood gases. The groups were similar with respect to maternal characteristics, onset of surgical anesthesia, time to delivery, and uterine incision-delivery interval. Maternal blood pressure decreased from control values in both groups (P less than 0.05), but there was no difference between the groups in either the incidence of hypotension or ephedrine requirements. Analysis of FHR tracings by a perinatologist blinded to the study group revealed no changes after anesthesia and no significant differences between the groups at any time in basal FHR, short- or long-term variability, or the incidence of accelerations or decelerations.(ABSTRACT TRUNCATED AT 250 WORDS)     

The comparative neurotoxicity of intrathecal lidocaine and bupivacaine in rats

There is a considerable difference in the number of reports of neurologic injury in the literature between lidocaine and other local anesthetics. Few in vivo animal studies have produced convincing results showing a difference in neurotoxicity among anesthetics. We investigated whether lidocaine and bupivacaine differ with respect to sensory impairment and histologic damage when equipotent doses of the two are administered intrathecally in rats. First, to determine relative anesthetic potency, rats intrathecally received 20 muL of saline, 0.625%, 1.25%, 2.5%, or 5% lidocaine, or 0.125%, 0.25%, 0.5%, or 1.0% bupivacaine, and were examined with the tail-flick test for 90 min. The potency ratio calculated was approximately 1:4.70 (95% confidence interval, 3.65-6.07) for lidocaine/bupivacaine. In the next experiment, 45 rats intrathecally received 20 muL of saline, 2.13% bupivacaine (approximately 1.5 mg/kg), or 10% lidocaine (approximately 6.9 mg/kg), and were examined for persistent functional impairment and morphologic damage. Rats given lidocaine developed significantly more prolonged tail-flick latencies than those in other groups 4 days after injection and incurred more morphologic damage than those given saline or bupivacaine. In conclusion, although the doses of anesthetics administered were larger than those used clinically, the present results suggest that bupivacaine is less neurotoxic than lidocaine when administered intrathecally at equipotent concentrations in the rat model. IMPLICATIONS: Bupivacaine induces less severe functional impairment and morphologic damage than lidocaine when the two anesthetics are intrathecally administered at equipotent concentrations in the rat.