Anesth Analg 2004;98:1426-1431
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000108488.05900.A8
CRITICAL CARE AND TRAUMA
A Comparison of Epinephrine and Vasopressin in a Porcine Model of Cardiac Arrest After Rapid Intravenous Injection of Bupivacaine
Viktoria D. Mayr, MD,
Claus Raedler, MD,
Volker Wenzel, MD,
Karl H. Lindner, MD, and
Hans-Ulrich Strohmenger, MD
Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University, Innsbruck, Austria
Address correspondence to Viktoria Mayr, MD, Leopold-Franzens-University, Department of Anesthesiology and Critical Care Medicine, Anichstrasse 35, 6020 Innsbruck, Austria. Address e-mail to viktoria.mayr{at}uibk.ac.at Address reprint requests to Hans-Ulrich Strohmenger, MD, Leopold-Franzens-University, Department of Anesthesiology and Critical Care Medicine, Anichstrasse 35, 6020 Innsbruck, Austria.
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Abstract
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In a porcine model, we compared the efficacy of epinephrine, vasopressin, or the combination of epinephrine and vasopressin with that of saline placebo on the survival rate after bupivacaine-induced cardiac arrest. After the administration of 5 mg/kg of a 0.5% bupivacaine solution IV, ventilation was interrupted for 3 ± 1 min (mean ± SD) until asystole occurred. Cardiopulmonary resuscitation (CPR) was initiated after 1 min of cardiac arrest. After 2 min of CPR, 28 animals received, every 5 min, epinephrine; vasopressin; epinephrine combined with vasopressin; or placebo IV. Three minutes after each drug administration, up to 3 countershocks (3, 4, and 6 J/kg) were administered; all subsequent shocks were 6 J/kg. Blood was drawn throughout the experiment for the determination of plasma bupivacaine concentration. In the vasopressin/epinephrine combination group, all pigs survived (P < 0.01 versus placebo); in the vasopressin group 5 of 7, in the epinephrine group 4 of 7, and in the placebo group none of 7 swine survived. The plasma concentration of total bupivacaine showed no significant difference among groups. In this model of bupivacaine-induced cardiac arrest, CPR with a combination of vasopressin and epinephrine resulted in significantly better survival rates than in the placebo group.
IMPLICATIONS: Although cardiovascular collapse occurs mostly immediately after rapid injection of a local anesthetic in the presence of anesthesiologists, resuscitation may be difficult, and the outcome is usually poor. In this model of bupivacaine-induced cardiac arrest, cardiopulmonary resuscitation with a combination of vasopressin and epinephrine resulted in significantly better survival rates than in the placebo group.
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Introduction
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Cardiac arrest, or even death, due to intoxication with local anesthetics resulting from an accidental intravascular injection or from rapid absorption from the administration site, has been reported (1,2). In particular, cardiovascular collapse due to bupivacaine overdose is difficult to treat, and successful resuscitation may be difficult (3,4). Therefore, therapy of this potentially dangerous complication of regional anesthesia has been the focus of research for many years (5–9).
Arginine vasopressin has been primarily used for management of esophageal varices and diabetes insipidus, but since the early 1990s there has been mounting evidence that this drug is also beneficial during cardiopulmonary resuscitation (CPR). In adult porcine CPR preparations with ventricular fibrillation or postcountershock pulseless electrical activity, arginine vasopressin improved myocardial blood flow (10), cerebral oxygen delivery, resuscitability, and neurological recovery better than did epinephrine. In the clinical setting, arginine vasopressin has been shown to improve coronary perfusion pressure (11), hasten the return of spontaneous circulation, and increase the 24-h survival rate (12). In a resuscitation setting after bupivacaine cardiovascular toxicity, however, vasopressin has not been investigated in comparison with the standard resuscitation vasoconstrictive drug epinephrine or with placebo.
Therefore, this study was performed to compare the efficacy of epinephrine, vasopressin, or the combination of epinephrine and vasopressin with that of saline placebo on the survival rate after bupivacaine-induced cardiac arrest in pigs. Our hypothesis was that there would be no differences in study end-points between groups.
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Methods
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This investigation was approved by the Austrian Federal Animal Investigational Committee, and the animals were managed in accordance with American Physiological Society and institutional guidelines. This study was performed according to Utstein-style guidelines (13) on 28 adult pigs of either sex weighing 30–40 kg. All pigs were fasted overnight but had free access to water. One hour before surgery, the pigs were premedicated with azaperone (a neuroleptic drug; 4 mg/kg IM) and atropine (0.1 mg/kg IM). Anesthesia was induced with a bolus dose of ketamine (20 mg/kg IM), propofol (1–2 mg/kg IV), and piritramide (30 mg IV) given via an ear vein (14). The animal was placed on a U-shaped board, and the trachea was intubated during spontaneous respiration.
Thereafter, the animal’s lungs were ventilated with a volume-controlled ventilator (EV-A; Draeger, Lübeck, Germany) with 35% oxygen in 65% nitrous oxide at 15 breaths/min and with a tidal volume adjusted to maintain normocapnia. Anesthesia was maintained with isoflurane (
1%–2%) in 65% nitrous oxide and piritramide IV as needed, and muscle relaxation was provided by a continuous infusion of pancuronium (0.2 mg · kg–1 · h–1). Depth of anesthesia was judged according to arterial blood pressure and heart rate. If cardiovascular variables indicated a reduced depth of anesthesia, additional piritramide was given and the concentration of isoflurane was increased. Ringer’s solution (6 mL · kg–1 · h–1) and 3% gelatin solution (4 mL · kg–1 · h–1) were infused during the preparation phase to replace fluid and blood loss. Cardiac rhythm was monitored with a standard lead II electrocardiogram (ECG). One 7F saline-filled catheter was advanced via femoral cutdown into the right atrium for measurement of right atrial pressure and for drug administration; another catheter was advanced via femoral cutdown into the thoracic aorta for measurement of aortic blood pressure and withdrawal of arterial blood samples. A 7.5F pulmonary artery catheter was inserted into the pulmonary artery via cutdown in the neck to measure pulmonary artery pressure, cardiac output, and core temperature. The intravascular catheters were attached to pressure transducers (Model 1290A; Hewlett-Packard, Böblingen, Germany) that were aligned at the level of the right atrium; all pressure tracings were recorded with a data acquisition system (Port 2000; Dewetron, Graz, Austria). Cardiac output was measured by the thermodilution technique, and cardiac index was calculated by dividing cardiac output by body weight. End-tidal carbon dioxide was measured with an infrared absorption analyzer (Sirecust 960; Siemens, Erlangen, Germany).
After the preparation phase, animals were allowed to stabilize for 30 min at 1.00% isoflurane and room air (21% oxygen). Body temperature was maintained with a heating blanket at 38.5°C. The animals were paralyzed with pancuronium 8 mg/kg to avoid gasping, 15 mg of piritramide was given, and an initial dose of 5000 U of heparin was administered IV to prevent intracardiac clot formation. Prearrest hemodynamic variables were measured. Isoflurane administration was stopped immediately before bupivacaine injection.
After the control period, 5 mg/kg of a 0.5% bupivacaine solution was administered once IV as a bolus injection in the central venous catheter. Each injection was followed immediately by a 5.0-mL flush of saline solution. Pilot studies had demonstrated that in this porcine model, animals could not be resuscitated from larger doses of bupivacaine.
To simulate the clinical situation of a tonic-clonic seizure with ceasing spontaneous respiration, mechanical ventilation was stopped immediately after bupivacaine administration and was interrupted for 3 ± 1 min (mean ± SD) until asystole occurred. Advanced cardiac life support was initiated 1 min after cardiac arrest occurred (the ECG showed asystole and aortic blood pressure decreased to hydrostatic pressure). CPR was performed manually, and mechanical ventilation was resumed with the same setting as before the induction of cardiac arrest, but with 100% oxygen. Chest compressions at 100/min were always performed by the same investigator, who was blinded to the hemodynamic and end-tidal CO2 monitor tracings. After 2 min of basic life support CPR, 28 animals were randomly assigned to receive, every 5 min, epinephrine (45, 45, or 200 µg/kg; n = 7); vasopressin (0.4, 0.4, or 0.8 U/kg; n = 7); epinephrine combined with vasopressin (45/0.4, 45/0.4, or 200/0.8, µg/kg and U/kg, respectively; n = 7) diluted to 10 mL of normal saline; or placebo (normal saline; n = 7) IV followed by a 20-mL saline flush. All investigators were blinded to the study drugs.
Hemodynamic variables were measured 90 s after each drug administration during CPR. Cardiac rhythm after the first drug administration was ventricular fibrillation in all animals. Therefore, 3 min after the first drug administration, up to 3 monophasic countershocks (3, 4, and 6 J/kg) were administered. Later in the experiment, after the second and third drug administration, animals were defibrillated at an energy setting of 6 J/kg only if ventricular fibrillation was present. If a nonshockable rhythm was present, the animal was not defibrillated. If asystole or pulseless electrical activity was present after the ninth defibrillation attempt, the experiment was terminated. Arterial and mixed venous blood samples, as well as blood for the determination of plasma bupivacaine concentration, were drawn before arrest; after bupivacaine administration, during basic life support; 90 s after each drug administration; and at 5, 15, 30, and 60 min after restoration of spontaneous circulation. Central venous blood was collected in heparinized tubes, stored on ice, and centrifuged, and the resulting plasma was frozen at –20°C until bupivacaine assay was performed. Total and free plasma concentrations of bupivacaine were measured with high-performance liquid chromatography and ultraviolet detection. The detection limit is approximately 30 ng/mL and is therefore suitable for clinical practice (15).
The return of spontaneous circulation was defined as an unassisted pulse with a systolic arterial blood pressure of 
80 mm Hg for 5 min. In the postresuscitation phase, hemodynamic variables were measured after 5, 15, 30, and 60 min. Anesthesia was restarted after a return of spontaneous circulation. Surviving animals did not receive any additional medication, such as dopamine, phenylephrine, or lidocaine. After the experimental protocol was finished, the animals were killed with an overdose of potassium chloride and fentanyl; all pigs were then necropsied to check correct positioning of the catheters and damage to the ribcage and internal organs.
Data were tested for normal distribution by using the Kolmogorov-Smirnov test with the Lilliefors correction. Two-way analysis of variance was used to determine statistical significance between the groups and between time-based measurement within each group and was corrected for multiple comparisons by the Scheffé method. Measurements are reported as mean ± SD. Survival rates were analyzed with Fisher’s exact test and the Bonferroni correction for multiple comparisons. A two-tailed P < 0.05 was considered statistically significant.
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Results
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Before cardiac arrest, there were no statistically significant differences in weight, temperature (data not presented), or hemodynamic variables among groups (Table 1). Body temperature was maintained with a heating blanket at 38.5°C throughout the experiment. In the vasopressin/epinephrine combination group, all pigs survived (P < 0.01 versus placebo); in the vasopressin group 5 of 7, in the epinephrine group 4 of 7, and in the placebo group none of 7 swine survived (Table 1). Coronary perfusion pressure was significantly higher (P < 0.05) 90 s after the first injection of the vasopressin/epinephrine combination versus vasopressin alone, epinephrine alone, or saline placebo (Fig. 1). During the postresuscitation phase, cardiac index was significantly (P < 0.05) more rapid in the epinephrine group than in the vasopressin or vasopressin/epinephrine combination groups (Table 1). Immediately after the return of spontaneous circulation, the heart rate was significantly (P < 0.05) higher in the epinephrine group than in the vasopressin group (Table 1). The plasma concentration of total bupivacaine throughout the study showed no significant difference between groups (Table 2). At 90 s after the second drug administration, the free bupivacaine concentration in the vasopressin group was significantly larger in comparison to the saline placebo and epinephrine groups.
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Figure 1. Pulmonary perfusion pressure during cardiopulmonary resuscitation. Values are given as mean ± SD. BLS = basic life support; DA 1 and DA 2 = administration of vasopressin 0.5 U/kg in combination with epinephrine 45 µg/kg, epinephrine 45 µg/kg, vasopressin 0.4 U/kg, or placebo; DA 3 = administration of vasopressin 0.8 U/kg in combination with epinephrine 200 µg/kg, epinephrine 200 µg/g, vasopressin 0.8 U/kg, or placebo. $P < 0.05 versus basic life support;  P < 0.05 versus epinephrine; #P < 0.05 versus vasopressin; *P < 0.05 versus saline placebo.
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Table 2. Total and Free Bupivacaine Concentration During Cardiopulmonary Resuscitation and After Return of Spontaneous Circulation
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Discussion
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In this model of bupivacaine-induced cardiac arrest, we demonstrated that CPR with a combination of vasopressin and epinephrine resulted in significantly better survival rates than with placebo. Concerning hemodynamic variables during CPR, coronary perfusion pressure after the vasopressin/epinephrine combination was significantly higher than in the epinephrine, vasopressin, or placebo groups.
Although cardiovascular collapse occurs mostly immediately after rapid injection of a local anesthetic in the presence of anesthesiologists, successful resuscitation may be difficult, and the outcome is usually poor (1). Accidental IV injection of bupivacaine is observed especially during use of techniques that require relatively large volumes of local anesthetics, such as epidural or brachial plexus anesthesia. Moreover, successful resuscitation after bupivacaine cardiovascular toxicity has been reported to be more difficult than after other local anesthetics (8,16). As such, accidental intravascular injection of bupivacaine may induce a marked decrease in myocardial contractility and dramatically impairs cardiac electrophysiology, mainly ventricular conduction (17); this results in profound cardiovascular depression (18).
Various strategies to treat bupivacaine-induced cardiac arrest have been investigated. Clonidine, an 
2-adrenoceptor agonist, given prophylactically, should delay the toxic manifestations of bupivacaine overdose and does not accentuate the subsequent hypotension (19). Profound cardiovascular depression by bupivacaine in pigs was effectively reversed by amrinone, because it increases cardiac output through actions on cyclic adenosine monophosphate (cAMP) and intracellular Ca2+ in situations in which sympathomimetics are without effect. Amrinone may provide a superior alternative to the presently recommended pharmacologic therapy in cases of severe bupivacaine-induced toxicity (9,18). Pretreatment with a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and, therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity (20). With regard to the model design, isoflurane and nitrous oxide, but not propofol, were used to maintain anesthesia in our study.
The use of epinephrine to treat bupivacaine-induced cardiac arrest or cardiovascular depression has remained controversial for many years. In the presence of toxic bupivacaine concentrations, even large doses of epinephrine could not increase cAMP production to levels achieved by subtherapeutic concentrations of epinephrine in the absence of bupivacaine. Thus, because bupivacaine inhibits cAMP production, it may exacerbate cardiovascular depression by reducing the ability of epinephrine to increase blood pressure (21).
Vasopressin has been shown to be an effective vasoconstrictive drug to improve resuscitability in different cardiac arrest settings. Even in asphyxial cardiac arrest, vasopressin in combination with epinephrine was shown to improve the survival rate (22).
It is surprising that identical combinations of vasopressin and epinephrine with regard to arterial blood pressure were definitely superior to vasopressin alone or epinephrine alone in this model of bupivacaine-induced cardiac arrest, but this is similar to a previous asphyxia model (22). Although accidental IV injection of a large dose of bupivacaine is usually associated with tonic-clonic seizures with ceasing spontaneous respiration, the degree of asphyxia may not be as severe as in the aforementioned asphyxia model. In that study, we speculated that depleted catecholamine levels were the reason why vasopressin in combination with epinephrine, but not vasopressin or epinephrine alone, improved perfusion pressures (22). Thus, we are unable to determine why the combination of vasopressin and epinephrine was the best vasopressor in this model, but a coronary perfusion pressure that was more than double that in all other groups is a strong argument. In fact, if these results can be extrapolated to humans, it may even be advisable to combine vasopressin and epinephrine once it is determined that initial CPR management does not result in the return of spontaneous circulation.
The largest plasma concentration of total bupivacaine measured in our study was 7 µg/mL, and this was clearly larger than the maximum plasma concentration of total bupivacaine of 2–2.5 µg/mL that Berde (23) made the standard value for his dosing guideline. Also, the total bupivacaine plasma concentration in our study was even larger than the threshold plasma concentrations associated with onset of central nervous system toxicity in humans, which range from 2 to 4 µg/mL for bupivacaine (24). There were no significant differences in bupivacaine plasma concentrations among the groups, and there was also no significant difference in base excess. The most likely explanation for the markedly better survival rate in the vasopressin/epinephrine combination group compared with the placebo group may be the significantly higher coronary perfusion pressure after each of the three drug administrations, because the coronary perfusion pressure is an important value for a successful return of spontaneous circulation (25).
Some limitations of this study should be noted, including different vasopressin receptors in pigs (lysine vasopressin) and humans (arginine vasopressin), which may result in a different hemodynamic response to exogenously administered arginine vasopressin. However, the circulatory effects of arginine vasopressin, as administered in this investigation, may be even greater in humans than in pigs. Also, the use of potent anesthetics may have impaired cardiovascular function and autonomic control in our pigs. Furthermore, we are unable to explain the increased free bupivacaine concentration in the vasopressin group compared with the epinephrine, placebo, and combination groups. Moreover, we omitted defibrillation attempts on purpose on starting CPR to determine the hemodynamic effects of the study drugs during the resuscitation attempt. Finally, we are unable to determine whether this result of a porcine study can be extrapolated to CPR in humans.
In conclusion, in this model of a bupivacaine-induced cardiac arrest model, the vasopressin/epinephrine combination resulted in better survival rates than vasopressin, epinephrine, or placebo alone.
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Acknowledgments
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Supported in part by the Austrian National Bank, Science Project 8599, Vienna, Austria.
We are indebted to Birgit Weber, Justus Liebig University, Department of Anesthesiology and Critical Care Medicine, Giessen, Germany, for the measurement of plasma bupivacaine concentrations.
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Footnotes
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No author has a conflict of interest with regard to the drugs or devices used in this study.
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References
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Accepted for publication November 4, 2003.
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Abstract
Introduction
