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PATIENT SAFETY

A Comparison of the Combination of Epinephrine and Vasopressin with Lipid Emulsion in a Porcine Model of Asphyxial Cardiac Arrest After Intravenous Injection of Bupivacaine

Viktoria D. Mayr, MD^*, Lukas Mitterschiffthaler, BS^*, Andreas Neurauter, MEng^*, Christian Gritsch, MRer.nat.^*, Volker Wenzel, MD^*, Tilko Müller, MD, Günter Luckner, MD^*, Karl H. Lindner, MD^*, and Hans-Ulrich Strohmenger, MD^*

From the Departments of *Anesthesiology and Critical Care Medicine, and Urology, Innsbruck Medical University, Innsbruck, Austria.

Address correspondence and reprint requests to Dr. Viktoria Mayr, Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Address e-mail to viktoria.mayr{at}i-med.ac.at.

Abstract

BACKGROUND: In a porcine model, we compared the effect of the combination of vasopressin/epinephrine with that of a lipid emulsion on survival after bupivacaine- induced cardiac arrest.

METHODS: After administration of 5 mg/kg of a 0.5% bupivacaine solution IV, ventilation was interrupted for 2 ± 0.5 (mean ± sd) min until asystole occurred. Cardiopulmonary resuscitation (CPR) was initiated after 1 min of untreated cardiac arrest. After 2 min of CPR, 10 animals received, every 5 min, either vasopressin combined with epinephrine or 4 mL/kg of a 20% lipid emulsion. Three minutes after each drug administration, up to three countershocks (4, 4, and 6 J/kg) were administered; all subsequent shocks with 6 J/kg. Blood for determination of the plasma bupivacaine concentration was drawn throughout the experiment.

RESULTS: In the vasopressor group, all five pigs survived, whereas none of five pigs in the lipid group had restoration of spontaneous circulation (P < 0.01). There was no significant difference between groups in the plasma concentration of total bupivacaine.

CONCLUSION: In this model of a bupivacaine-induced cardiac arrest, the vasopressor combination of vasopressin and epinephrine compared with lipid emulsion resulted in higher coronary perfusion pressure during CPR and survival rates.

As the general public's median age increases, regional anesthesia remains an efficient and popular strategy to facilitate surgery. However, cardiac arrest, and even death, due to intoxication with local anesthetics resulting from an accidental intravascular injection, drug overdose, or rapid absorption from the administration site have been reported.1–3 Unfortunately, cardiovascular collapse due to bupivacaine overdose is difficult to treat, and successful cardiopulmonary resuscitation (CPR) may be difficult.4,5 Therefore, therapy of this potentially dangerous complication of regional anesthesia has been a focus of research for many years.6–10

Arginine vasopressin has been shown to be beneficial during CPR. In adult porcine CPR preparations, arginine vasopressin improved myocardial blood flow,11 cerebral oxygen delivery, resuscitability, and neurological recovery better than epinephrine. In a large study with 1219 adult patients with prehospital cardiac arrest, arginine vasopressin was similarly effective to epinephrine, whereas combining arginine vasopressin and epinephrine was superior to epinephrine alone in a subgroup analysis.12 We have previously shown, after bupivacaine-induced cardiac arrest in the laboratory, that CPR with the combination of vasopressin and epinephrine resulted in significantly higher survival rates than with placebo.13 However, IV infusion of a lipid emulsion has been observed to attenuate the adverse cardiotoxic effects of bupivacaine,14 and may even increase survival after bupivacaine-induced cardiac arrest,15 thus making injection of a vasopressor unnecessary.

Therefore, we compared the efficacy of the combination of vasopressin/epinephrine with a lipid emulsion on hemodynamic variables and survival after simulated inadvertent bupivacaine-induced cardiac arrest in pigs. Our hypothesis was that there would be no differences in study end-points between groups.

METHODS

Surgical Preparation and Measurements
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 guidelines16 on 10 adult pigs of either gender, 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 (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), and piritramid (30 mg IV) given via an ear vein.17 The animals were placed on a U-shaped board, and their tracheas were intubated during spontaneous respiration.

Thereafter, the animals’ lungs were ventilated with a volume-controlled ventilator (Draeger EV-A, Lübeck, Germany) with 35% O₂ at 15 breaths/min, and with a tidal volume adjusted to maintain normocapnia. During the preparation phase, anesthesia was maintained with isoflurane (end-tidal concentration approximately 1%–2%) and piritramid IV as needed; 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 or clinical evaluation indicated a reduced depth of anesthesia (i.e., systolic arterial blood pressure exceeded 140 mm Hg or heart rate exceeded 100 bpm), additional piritramid was given, and the concentration of isoflurane was increased, i.e., both opiate and volatile anesthesia dosage were based on clinical requirements. 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 avoid hypovolemia. Cardiac rhythm was monitored using a standard lead II electrocardiogram. 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 (Dewetron port 2000, Graz, Austria). Cardiac output was measured once before cardiac arrest by the thermodilution technique, and cardiac index was calculated by dividing cardiac output by body weight. During CPR, measuring cardiac output is not validated with the thermodilution technique. End-tidal carbon dioxide (CO₂) was measured with an infrared absorption analyzer (Sirecust 960, Siemens, Erlangen, Germany).

Experimental Protocol
After the preparation phase and during a stabilization phase before induction of cardiac arrest, all animals were treated following a standardized protocol to provide comparable baseline conditions and comparable depth of anesthesia in the two groups: Animals were allowed to stabilize for 30 min at 1.00% end-tidal isoflurane and room air (21% oxygen). Body temperature was maintained with a heating blanket at approximately 38.5°C. The animals were paralyzed with 0.2 mg/kg pancuronium to avoid gasping, 15 mg piritramid was given, and a dose of 5.000 IU heparin was administered IV to prevent intracardiac clot formation. Prearrest hemodynamic variables including coronary perfusion pressure (which was defined as the arteriovenous pressure difference between aortic and central venous diastolic pressure) were then measured. Isoflurane administration was stopped immediately before bupivacaine injection.

After baseline measurements, 5 mg/kg of a 0.5% bupivacaine solution was administered once IV as a bolus injection via the central venous catheter. Each drug injection was followed immediately by a 20 mL flush of saline solution.

To simulate the clinical situation of a tonic-clonic seizure with ceasing spontaneous respiration, mechanical ventilation was stopped immediately after bupivacaine administration, and interrupted until asystole occurred. Advanced cardiac life support was initiated 1 min after cardiac arrest had occurred (defined as the electrocardiogram showing asystole, and aortic blood pressure decreasing to hydrostatic pressure). CPR was performed manually, and mechanical ventilation was resumed with the same setting as before induction of cardiac arrest, but with 100% oxygen. Chest compressions at a rate of 100/min were always performed by the same investigator blinded to the hemodynamic and end-tidal CO₂ monitor tracings. After 2 min of basic life support CPR, 10 animals were randomly assigned to receive either 4 mL/kg lipid emulsion (Intralipid 20%, Fresenius Kabi, Graz, Austria) (n = 5) followed by a continuous infusion of 0.5 mL · kg^–1 · min^–1 for 10 min;15 or every 5 min vasopressin combined with epinephrine (0.4/45, 0.4/45, 0.8/200 U/kg and µg/kg; n = 5) diluted to 10 mL normal saline. Lipid emulsion pigs received saline injections during corresponding time points of drug injections, whereas vasopressor-treated pigs received a continuous infusion of 0.5 mL · kg^–1 · min^–1 saline. The investigators were not only blinded to drug treatment, but also to arterial blood pressure during CPR as coronary perfusion pressure is a decisive predictor of restoration of spontaneous circulation (ROSC) in animals and in humans.

Hemodynamic variables including coronary perfusion pressure were measured 90 s after each drug administration during CPR. Three minutes after the first drug administration, up to three monophasic countershocks (3, 4, and 6 J/kg) were administered if ventricular fibrillation was present. After the second and third drug administration, animals were defibrillated with 6 J/kg only if ventricular fibrillation was present; a nonshockable rhythm was not defibrillated. If asystole or pulseless electrical activity was present after the ninth defibrillation attempt, the experiment was terminated. Blood samples were drawn prearrest, and with additional blood for determining plasma bupivacaine concentrations after bupivacaine administration during basic life support, and 90 s after each drug administration. For determination of plasma bupivacaine concentration, central venous blood was collected in heparinized tubes, stored on ice, centrifuged, and the plasma was frozen at –20°C until bupivacaine analysis was performed. The total and free plasma concentration of bupivacaine was measured using high-performance liquid chromatography, and UV-detection. The detection limit is about 30 ng/mL, and is therefore suitable for clinical practice.18

ROSC was defined as an unassisted pulse with a systolic arterial blood pressure of 80 mm Hg 5 min. In the postresuscitation phase, hemodynamic variables were measured after 5, 15, 30, and 60 min. Anesthesia was restarted after ROSC. Surviving animals did not receive any additional medication such as dopamine, phenylephrine, or lidocaine. After finishing the experimental protocol, the animals were killed with an overdose of potassium chloride and fentanyl; all pigs were then necropsied to check correct positioning of the catheters, damage to the ribcage, and internal organs.

Statistical Analysis
Data were tested for normal distribution using Kolmogorov-Smirnov test. Two-way analysis of variance (ANOVA) was used to determine statistical significance between groups, and between time-based measurements within each group, respectively, 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. A two-tailed P < 0.05 was considered statistically significant.

RESULTS

Before cardiac arrest, there were no statistically significant differences in mean arterial blood pressure, mean pulmonary artery blood pressure, end-tidal CO₂, or cardiac index between groups (data not presented). By analogy before cardiac arrest, there were no statistically significant differences in weight or temperature (data not presented). In the vasopressor group, all five pigs survived; whereas in the lipid group, none of five swine had ROSC (P < 0.01). Coronary perfusion pressure was significantly (P < 0.01) higher 90 s after the first and second injection of the vasopressin/epinephrine combination versus lipid (Fig. 1). Arterial pH was significantly higher after the first and second injection of the vasopressin/ epinephrine combination versus lipid (Table 1), and central venous Pco₂ was significantly lower (P < 0.04) after the second drug administration of the vasopressin/ epinephrine combination versus lipid (Table 1). Plasma concentrations 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 vasopressor group was significantly (P < 0.01) higher in comparison to the lipid group.

View larger version (11K): [in this window] [in a new window]   Figure 1. Coronary perfusion pressure before cardiac arrest and during cardiopulmonary resuscitation (CPR). Values are given as mean ± sd. BL = baseline; CPR 90 = 90 s after start of CPR; DA I = 90 s after administration of 0.4 U/kg vasopressin in combination with 45 µg/kg epinephrine, or 4 mL/kg lipid; DA II = 90 s after administration of 0.4 U/kg vasopressin in combination with 45 µg/kg epinephrine, or at the same point in time 0.5 mL · kg–1 · min–1 lipid infusion; DA III = 90 s after administration of 0.8 U/kg vasopressin in combination with 200 µg/kg epinephrine, or at the same point in time 0.5 mL · kg–1 · min–1 lipid infusion; *P < 0.05 versus lipid.

DISCUSSION

In this model of bupivacaine-induced cardiac arrest, a vasopressor combination of epinephrine with vasopressin significantly improved both coronary perfusion pressure and short-term survival when compared with injection of a lipid infusion.

Pilot experiments in this model revealed that an IV injection of 10 mg/kg bupivacaine resulted in refractory cardiac arrest with no chance of ROSC. This is in contrast to a previous preparation in dogs using 10 mg/kg bupivacaine,15 but may have been due to the more sensitive cardiocirculatory physiology in pigs compared with that in dogs. The 5 mg/kg bupivacaine dosage in our model may be more clinically realistic than 10 mg/kg to simulate toxic levels, since this reflects about a double dosage over recommended levels for humans. The entire bupivacaine dosage was injected via a central venous line within 10–20 s; this setting may not exactly reflect the typical clinical situation, as the entire injected amount immediately went quickly into the central blood stream. In our study, the highest bupivacaine plasma concentration was 3.4 µg/mL, which was clearly higher than the maximum recommended bupivacaine plasma concentration of 2–2.5 µg/mL,19 and similar to the threshold (2–4 µg/mL), which is usually associated with central nervous system toxicity in humans.20 We therefore suggest that our model with inadvertent IV bupivacaine injection, subsequent apnea and cardiac arrest within approximately 2 min after injection and CPR within another minute reflects a clinically realistic setting.

Since a lipid infusion given before cardiac arrest increased the bupivacaine dose required to induce cardiac arrest, this strategy has been suggested as an alternative to treat a bupivacaine overdose.14 The underlying mechanism for this observation may be that the injected lipid extracts the lipid-soluble bupivacaine molecules from the aqueous plasma phase, thus "absorbing" bupivacaine.15 Although this approach focuses on evacuating bupivacaine, the underlying pathophysiology of bupivacaine toxicity during advanced life support needs to be considered as well. There are approximately 12 putative sights of action that may contribute to bupivacaine toxicity, including inhibition of intracellular cyclic adenosine monophosphate production.21 The latter mechanism may substantially contribute to cardiovascular depression by reducing the ability of epinephrine to increase arterial blood pressure during a CPR attempt. Since the action pathway of vasopressin does not depend on cyclic adenosine monophosphate,22 vasopressin may be an adjunct drug to epinephrine in bupivacaine-associated cardiac arrest.13 In fact, after simulated inadvertent IV injection of bupivacaine resulting in cardiac arrest, vasopressin combined with epinephrine was superior to either drug alone or saline placebo.13

In the present study, in contrast to previous observations, we were unable to document an advantage of injecting lipid. A coronary perfusion pressure of 20–30 mm Hg has been shown to be crucial for ROSC.23 In experimental cardiac arrest, open-chest cardiac massage greatly increased coronary perfusion pressure to about this critical threshold, and improved survival compared with closed-chest compression substantially;24 but open-chest CPR is not standard clinical practice to resuscitate a nontraumatic cardiac arrest victim. Vasopressor treatment including epinephrine or vasopressin during closed-chest compressions has clearly shown advantageous increases in coronary perfusion pressure compared with closed-chest CPR performed in either four-legged animals25 or in humans.26 In a previously published canine model, CPR including lipid administration was probably successful, since an adequate coronary perfusion pressure was achieved using open-chest CPR. In our study, using closed-chest CPR, mean coronary perfusion pressure in the lipid group was clearly below this critical threshold of 20–30 mm Hg during the entire CPR phase, and none of the animals survived. On the other hand, closed-chest compression including administration of epinephrine/vasopressin resulted in an significantly increased coronary perfusion pressure and ROSC of all animals, whereas mere open-chest CPR performed by Weinberg's group resulted in poor outcome. We conclude that excellent coronary perfusion pressure is the basis for improving outcome after bupivacaine-induced cardiac arrest. Whether additional infusion of a lipid emulsion may be helpful to attenuate the adverse cardiotoxic effects of bupivacaine cannot be proven with our model.

Our study is limited in several ways. Different vasopressin receptors in pigs (lysine vasopressin) and humans (arginine vasopressin) may result in a different hemodynamic response to exogenously administered arginine vasopressin. However, the circulatory effects of arginine vasopressin, as administered in the present investigation, may be even greater in humans than in pigs. Chest configuration in small mammal models, large mammal models, or humans is quite different. Therefore, it is possible that different study results could be explained by different efficacy of external cardiac massage. Since it is ethically unacceptable to perform the study in awake animals, it was performed under general anesthesia, which is not necessarily the situation that will occur in the clinical setting. General anesthesia may have potential confounding effects, and the presence of isoflurane may alter cardiac effects of both bupivacaine and resuscitation drugs. Butyrophenone azaperone is a neuroleptic drug, which was used for the premedicating swine. Its cardiovascular effects, including hypotension and bradycardia, are mediated, at least in part, by depressed excitability of the autonomic nervous system, including peripheral blockade. As duration of action of azaperone is several hours; it is possible that its cardiovascular effects affected outcome compared with the findings of others in this area. By analogy, we used ketamine for induction of anesthesia; the cardiovascular effects of which are characterized by sympathetic nervous stimulation, including transient increase of norepinephrine and epinephrine plasma concentrations. Ketamine, particularly in combination with atropine, seems to be a stimulating anesthetic combination, which also may have affected our results in comparison to the results published by other study groups. On the other hand, ketamine's duration of action is short, and prior administration of a tranquilizer mitigates the hemodynamic effects. Piritramid is an opioid that does not seriously affect cardiovascular function. Further, we are unable to explain an increased free bupivacaine concentration in the vasopressor combination pigs, and the role of gelatin in changing the binding of bupivacaine is completely unknown. We omitted defibrillation attempts on purpose upon starting CPR to determine the hemodynamic effects of the study drugs during the CPR attempt. We deliberately chose this protocol including early scoring to simulate a clinically realistic setting to restore spontaneous circulation at the earliest opportunity. Mean coronary perfusion pressure in the lipid group was clearly below a critical coronary perfusion pressure threshold during the entire CPR phase; thus, it is not surprising that none of the animals in the lipid group survived. However, it cannot be excluded that we may have missed survival at later times among the lipid-treated animals without achieving a coronary perfusion pressure of at least 20–30 mm Hg. Finally, we are unable to determine whether our result in this porcine study can be extrapolated to CPR in humans.

In conclusion, in this model of a bupivacaine-induced cardiac arrest, the vasopressor combination compared with the lipid emulsion resulted in higher survival rates and coronary perfusion pressure during CPR.

ACKNOWLEDGMENTS

We are indebted to Mrs. Elekal, Justus Liebig University, Department of Anesthesiology and Critical Care Medicine, Justus-Liebig University Giessen, Germany, for measurement of plasma bupivacaine concentrations.

Footnotes

Accepted for publication June 13, 2007.

Supported, in part, by the Austrian National Bank, Science Project No. 11343, Vienna, Austria.

No author has a conflict of interest in regards of drugs or devices being used in this study.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Mayr, V. D. Articles by Strohmenger, H.-U. Search for Related Content PubMed PubMed Citation Articles by Mayr, V. D. Articles by Strohmenger, H.-U. Related Collections Mechanisms Patient Safety Preclinical Pharmacology Pharmacology