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*Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, Pennsylvania; and
Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, Texas
Address correspondence and reprint requests to Elisabet Nyström, MD, Department of Anesthesiology, The Western Pennsylvania Hospital, 4800 Friendship Ave., West Pen Hospital, Pittsburgh, PA 15224.
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Abstract |
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Implications: The increase in vascular resistance that accompanies acute bupivacaine overdose maintains blood pressure but masks severe myocardial depression.
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Introduction |
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Methods |
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A Millar catheter was inserted into the proximal aorta via the right carotid artery to measure systemic blood pressure. Heart rate was derived from the arterial pressure signal with a cardiotachometer. A balloon-tipped pulmonary artery catheter was inserted via the right external jugular vein for measurement of pulmonary artery wedge pressure.
A catheter was inserted into the left carotid artery and advanced into the arch of the aorta to provide blood samples for determination of arterial bupivacaine concentrations and blood gases. A triple-lumen catheter was inserted into the right atrium via the left external jugular vein for the infusion of isotonic sodium chloride solution (5 mL · kg-1 · h-1) and for the infusion of bupivacaine through separate ports. The heart was exposed through a midline sternotomy, and the pericardium was opened. An appropriately sized flow probe with a snug fit was placed around the proximal aorta for measurement of aortic flow with an electromagnetic flowmeter, which was calibrated by the timed collection of blood after the experiment. The electrocardiogram (ECG) was recorded from subcutaneous needle electrodes inserted into the extremities using an amplifier with a low-frequency cutoff at 0.3 Hz and a high-frequency cutoff at 50 Hz. Metocurine was used for muscle relaxation. Body temperature was maintained at approximately 39°C by using a heating pad. These preparations lasted approximately 2 h after the induction of anesthesia.
In the experimental protocol, bupivacaine 3.75 mg/mL was continuously infused via the central venous line at 5.73 mL/min (approximately 1 mg · kg-1 · min-1) while blood pressure, heart rate, aortic flow, pulmonary capillary wedge pressure, and ECG (lead II) were monitored continuously. The infusion was stopped when ventricular arrhythmias started. Pilot experiments had demonstrated that the animals could not be resuscitated from larger doses of bupivacaine. The animals in this study were resuscitated, then used in a separate protocol.
Hemodynamic variables and ECG were recorded with a polygraph and stored on magnetic tape for later analysis. A singe blood sample to determine the bupivacaine concentration was drawn from each animal just after the infusion was stopped. Blood was collected in heparinized tubes and centrifuged, and the resulting plasma was frozen at -20°C until bupivacaine assays were performed.
Bupivacaine concentrations in plasma were measured by using high-performance liquid chromatography, using an ultraviolet detector operating at a wavelength of 210 nm. The sensitivity of the assay was <0.1 µg/mL; the interday coefficient of variation at 10 µg/mL was <3% (4).
Values of systolic, diastolic, and mean arterial pressure, heart rate, pulmonary capillary wedge pressure, peak aortic flow, mean aortic flow, and ECG amplitude and intervals were extracted from the oscillograph record. Values at baseline and after each 10 mL of bupivacaine had been infused (but not at the very end of infusion) were entered into a computer for analysis using a standard statistical package. Data were averaged at each time point, and variance was expressed as the standard deviation of the mean. Total peripheral resistance was calculated as the quotient of mean arterial pressure and cardiac output. Linear regression analysis was used to test the relationship between the elements of ECG morphology, such as R-wave amplitude and cardiac output, in each animal. The hemodynamic and electrophysiologic values during the administration of bupivacaine were tested for significance against baseline values by using one-way analysis of variance with linear contrasts. A P value <0.05 was considered significant.
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Results |
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The concentration of bupivacaine in the animals' plasma was 16.0 ± 6.8 µg/mL 30 s after the infusion. No gross motor evidence of seizure activity was noted in these halothane-anesthetized, paralyzed animals. Arterial blood gas analysis showed pH 7.41 ± 0.04, PCO2 36 ± 4 mm Hg, and PO2 315 ± 66 mm Hg at the start of bupivacaine infusion.
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Discussion |
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Bupivacaine caused no significant changes in blood pressure, despite a 41% decrease in cardiac output, because of a simultaneous increase in peripheral resistance. The QRS complex of the surface ECG widened with increasing doses of bupivacaine, and the R-wave amplitude decreased. These ECG changes were closely correlated with the decrease in cardiac output.
Assumptions
We used an aortic flow probe for cardiac output measurement. This method does not include the coronary blood flow fraction of cardiac output. However, coronary blood flow is only approximately 4% of cardiac output and usually changes in parallel with aortic flow.
We assumed that the residual effect of ketamine given at induction was small during the experimental protocol. The animals used in the study were anesthetized with halothane, and we assumed that the effect of this anesthetic on the results are predictable. Halothane certainly depresses ventricular contractility dose-dependently, and it may have augmented the depression from bupivacaine (5), although these anesthetics act through different mechanisms. The animals were anesthetized with small-dose halothane (0.6% end-tidal); thus, a major contribution to the myocardial depression resulting from bupivacaine seems unlikely.
Halothane alone has little effect on intraventricular conduction (6), a major determinant of ECG morphology. Although an adverse interaction between bupivacaine and halothane on intraventricular conduction in dogs has been reported (5), an altered cardiac output or bupivacaine clearance seems to be a more likely explanation for these results than a true pharmacodynamic interaction. Thus, we assumed that alterations in QRS morphology were the result of bupivacaine alone.
We measured bupivacaine concentrations only at the end of the experiment. We assumed that plasma levels increased as the infusion progressed. However, it is unlikely that the constant infusion produced a linear increase in bupivacaine concentrations because cardiac output decreased simultaneously. Thus, the bupivacaine concentration in the central compartment probably increased more rapidly at the end of the infusion.
No gross motor evidence of seizure activity was noted in these halothane-anesthetized animals; however, it is possible that seizure activity occurred but was not apparent because the animals were paralyzed. Seizures might well have influenced the hemodynamic changes we observed. However, we assumed that this was not the case. Rutten et al. (7) reported that convulsive doses of bupivacaine (1 mg/kg) in awake sheep caused a marked increase in heart rate, arterial pressure, cardiac output, and myocardial contractility. There were no sudden increases in these variables during our experiment, which suggests no major effect on cardiovascular control centers. Bernards et al. (8) studied pigs and did not observe convulsions until a plasma bupivacaine concentration of 18.4 ± 3.9 µg/mL was reached. This concentration is higher than that used in the present study. Badwell et al. (9) administered bupivacaine 1.0 mg · kg-1 · min-1 to young pigs anesthetized with halothane until cardiac arrest occurred and did not observe seizures.
Interpretation
Arterial blood pressure was well maintained up to the point of near-cardiac arrest in our animals. The direct negative inotropic effect of bupivacaine on the heart (10) decreased the cardiac output, but this was counterbalanced by an increase in vascular resistance. Several investigators have observed no change or an increase in arterial blood pressure in animals (11) and humans (2,3), but the phenomenon has not been explored in detail.
Vasoconstriction mediated by bupivacaine occurs in arterioles of rat cremaster muscle (12) and rat portal vein (13). Jorfeldt et al. (14) demonstrated a 20%–40% increase in systemic resistance in humans at a plasma bupivacaine concentration of approximately 2 µg/mL, which is considerably lower than the concentrations used in our study. Hogan et al. (15) examined the direct effects of bupivacaine on splanchic capacitance vessels and demonstrated significant constriction with the same concentration used in our study. The mechanism for vessel constriction with bupivacaine is not known. Although all calculated resistance values increased during the administration of bupivacaine in the present study, this might not occur in a model involving complete cardiac arrest because tissue hypoxia would tend to cause arterial vasodilation.
Both central and peripheral mechanisms have been proposed for bupivacaine's cardiotoxicity (10,16–17). The direct administration of small amounts of bupivacaine into the lateral cerebral ventricle (which affects the vasomotor centers of the hypothalamus and medulla) causes cardiac dysrhythmias (16). Direct effects on cardiac contractility and conduction have been demonstrated by the intracoronary injection of bupivacaine (10,17). This dose-dependent depression of contraction results in a decrease in systolic wall thickening (10).
The change we observed in QRS morphology likely results from bupivacaine's effect on the conduction system of the heart. Bupivacaine impairs intracardiac electrical conduction, even at relatively slow heart rates, by causing sustained blockade of sodium channels (18). A decrease in the maximal rate of depolarization has been observed in canine Purkinje fibers (19,20). Impulse conduction time is prolonged in all parts of the heart (21). These effects result in a "smearing" of the QRS complex, with a resulting decrease in R-wave amplitude on the surface ECG.
A second possible reason for decreased R-wave amplitude is an increase in ventricular size. Coyle et al. (22) reported significant dilation of the right ventricle during a bupivacaine infusion and severe conduction changes as the toxic episode progressed. A close inverse relationship between end-diastolic ventricular volume and R-wave amplitude has been shown in patients with enlarged hearts (23).
In our study, bupivacaine increased T-wave amplitude at all but the largest dose, but the response was more variable than the change in R-wave amplitude. In cats, IV bupivacaine (1.4 mg/kg) caused T-wave elevation 1–3 s after the injections (24), and in children, intravascular bupivacaine with epinephrine caused increased T-wave amplitude (25). This study supports our contention that the ECG should be watched closely during a bupivacaine injection.
Limitations
We performed this study in anesthetized and paralyzed pigs with a constant infusion rate of bupivacaine. This situation might not be comparable to a clinical situation of an inadvertent intravascular injection of bupivacaine. The rate of infusion and the rapidity with which a particular blood level is achieved will influence the cardiovascular and central nervous system (CNS) response (26). It has been shown, in human volunteers, that the onset of CNS symptoms and the resulting plasma concentration is related to the infusion rate of the local anesthetic. More rapid infusion rates result in an earlier onset of CNS symptoms at lower concentrations, compared with slower infusion rates that require a higher plasma concentration before CNS symptoms appear. In this study, we analyzed the events during a bupivacaine infusion up to a total dose of 150 mg. The infusion was stopped short of cardiac arrest; therefore, the interpretation is limited to the prearrest events.
We conclude that the arterial blood pressure is a misleading guide to cardiovascular status during bupivacaine overdose in pigs. R-wave amplitude of the ECG may be a better indicator of an impending cardiac arrest. Clinically, we might be able to discover an intravascular injection by closely observing the ECG for changes in morphology of the QRS complex, immediately halt the injection, and thus prevent profound bupivacaine intoxication.
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Acknowledgments |
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References |
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This article has been cited by other articles:
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  Y. Oda, T. Funao, K. Tanaka, and A. Asada Vasodilation Increases the Threshold for Bupivacaine-Induced Convulsions in Rats Anesth. Analg., March 1, 2004; 98(3): 677 - 682. [Abstract] [Full Text] [PDF]
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M. Tanaka, R. Nitta, and T. Nishikawa Increased T-Wave Amplitude After Accidental Intravascular Injection of Lidocaine Plus Bupivacaine Without Epinephrine in Sevoflurane-Anesthetized Child Anesth. Analg., April 1, 2001; 92(4): 915 - 917. [Full Text] [PDF]
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