Anesth Analg 2003;96:1743-1749
© 2003 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
Survival with Full Neurologic Recovery After Prolonged Cardiopulmonary Resuscitation with a Combination of Vasopressin and Epinephrine in Pigs
Karl H. Stadlbauer, MD*,
Horst G. Wagner-Berger, MD*,
Volker Wenzel, MD*,
Wolfgang G. Voelckel, MD*,
Anette C. Krismer, MD*,
Günter Klima, MD
,
Klaus Rheinberger, MSc*,
Sebastian Pechlaner, BS*,
Viktoria D. Mayr, MD*, and
Karl H. Lindner, MD*
Departments of *Anesthesiology and Critical Care Medicine and
Histology, Leopold-Franzens-University, Innsbruck, Austria
Address correspondence and reprint requests to Karl-Heinz Stadlbauer, MD, Leopold-Franzens-University, Department of Anesthesiology and Critical Care Medicine, Anichstrasse 35, 6020 Innsbruck, Austria. Address e-mail to karl-heinz.stadlbauer{at}uibk.ac.at
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Abstract
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We sought to determine the effects of a combination of vasopressin and epinephrine on neurologic recovery in comparison with epinephrine alone and saline placebo alone in an established porcine model of prolonged cardiopulmonary resuscitation (CPR). After 4 min of cardiac arrest, followed by 3 min of basic life support CPR, 17 animals were randomly assigned to receive, every 5 min, either a combination of vasopressin and epinephrine (vasopressin [IU/kg]/epinephrine [µg/kg]: 0.4/45, 0.4/45, and 0.8/45; n = 6), epinephrine alone (45, 45, and 200 µg/kg; n = 6), or saline placebo alone (n = 5). After 22 min of cardiac arrest, including 18 min of CPR, defibrillation was attempted to achieve the return of spontaneous circulation. Aortic diastolic pressure was significantly (P < 0.01) increased 90 s after each of 3 vasopressin/epinephrine injections versus epinephrine alone versus saline placebo alone (mean ± SEM: 69 ± 3 mm Hg versus 45 ± 3 mm Hg versus 29 ± 2 mm Hg, 63 ± 4 mm Hg versus 27 ± 3 mm Hg versus 23 ± 1 mm Hg, and 52 ± 4 mm Hg versus 21 ± 3 mm Hg versus 16 ± 3 mm Hg, respectively). Spontaneous circulation was restored in six of six vasopressin/epinephrine pigs, whereas six of six epinephrine and five of five saline placebo pigs died (P < 0.01). Neurologic evaluation 24 h after successful resuscitation revealed only an unsteady gait and was normal 5 days after the experiment in all vasopressin/epinephrine-treated animals. In conclusion, in this porcine model of prolonged CPR, repeated vasopressin/epinephrine administration, but not epinephrine or saline placebo alone, ensured long-term survival with full neurologic recovery.
IMPLICATIONS: We present a study to evaluate the effects of a combination of vasopressin and epinephrine during prolonged cardiopulmonary resuscitation on neurological outcome in pigs. We found that all pigs treated with a combination of vasopressin and epinephrine could be resuscitated and had full neurologic recovery observed over an entire period of 5 days.
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Introduction
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The new international cardiopulmonary resuscitation (CPR) guidelines recommend 1 mg of epinephrine IV or 40 IU of vasopressin IV as equally effective for adult patients with shock-refractory ventricular fibrillation (1,2). Unfortunately, because of lack of clinical evidence, the CPR guidelines do not specifically state whether only vasopressin or epinephrine should be administered, which may result in an injection of both vasopressin and epinephrine during cardiac resuscitation. In fact, because the CPR guidelines state that vasopressin should be injected only once (1,2), epinephrine would almost automatically be injected later if return of spontaneous circulation does not occur immediately. Although this strategy seems to make sense, we found that developing a combination of CPR drugs is extremely difficult because of multiple permutations between drugs (3). Furthermore, although we found that vasopressin profoundly increases cerebral blood flow during CPR, we detected smaller cerebral blood flow values in one model when vasopressin was combined with epinephrine (4). Moreover, potential side effects of vasopressor drugs given during CPR may have an effect on long-term survival; for example, when endothelin was given during CPR, coronary perfusion pressure dramatically improved, but an endothelin-induced catastrophic increase in systemic vascular resistance caused rapid death in the postresuscitation phase (5).
When the aforementioned laboratory experience is extrapolated to the clinical setting, it is possible that well meant CPR recommendations, such as injecting vasopressin and epinephrine (1,2), are less effective than anticipated or may even cause harm. Therefore, we assessed the effects of a repeated injection of a combination of vasopressin and epinephrine on neurologic recovery in an established porcine model of prolonged cardiac arrest that is sensitive to detect adverse effects of CPR drugs. Our null hypothesis was that there would be no differences in study end points between groups.
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Methods
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This project was approved by the Austrian Federal Animal Investigational Committee, and the animals were managed in accordance with the American Physiological Society, institutional guidelines, and the Position of the American Heart Association on Research Animal Use, as adopted on November 11, 1984. Animal care and use were performed by qualified individuals supervised by veterinarians, and all facilities and transportation complied with current legal requirements and guidelines. Anesthesia was used in all surgical interventions, all unnecessary suffering was avoided, and research was terminated if unnecessary pain or fear resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care. This study was performed according to Utstein-style guidelines (6) on 17 healthy 12- to 16-wk-old swine weighing 30 to 40 kg. The animals were fasted overnight but had free access to water. The pigs were premedicated with azaperone (4 mg/kg IM) and atropine (0.1 mg/kg IM) 1 h before surgery, and anesthesia was induced with propofol (1–2 mg/kg IV). After intubation during spontaneous respiration, the pigs were ventilated with a volume-controlled ventilator (Draeger, EV-A Lübeck, Germany) with 100% oxygen at 20 breaths/min and with a tidal volume adjusted to maintain normocapnia. Anesthesia was maintained with propofol (6 to 8 mg · kg-1 · h-1) and a single injection of piritramide (30 mg) (7). Muscle paralysis was achieved with 0.2 mg · kg-1 · h-1 of pancuronium after intubation. Lactated Ringer’s solution (6 mL · kg-1 · h-1) and a 3% gelatin solution (4 mL · kg-1 · h-1) were administered in the preparation phase. A standard lead III electrocardiogram (ECG) was used to monitor cardiac rhythm; depth of anesthesia was judged according to blood pressure and heart rate. If cardiovascular variables indicated a reduced depth of anesthesia, additional propofol and piritramide were given. Body temperature was maintained between 38.0°C (100.4°F) and 39.0°C (102.2°F).
An 18-gauge catheter was advanced into the right femoral artery in an aseptic manner for withdrawal of arterial blood samples and measurement of arterial blood pressure. Blood pressure was measured with a saline-filled catheter attached to a pressure transducer (Model 1290A; Hewlett-Packard, Böblingen, Germany) that was calibrated to atmospheric pressure at the level of the right atrium; pressure tracings were recorded with a data acquisition system (Dewetron port 2000, Graz, Austria; and Datalogger, custom-made software). Arterial blood gases were measured with a blood gas analyzer (Chiron, Walpol, MA).
Fifteen minutes before cardiac arrest, 5000 U of heparin was administered IV to prevent intracardiac clot formation; 0.8 mg/kg of piritramide and 0.2 mg/kg of pancuronium were given, and prearrest variables were measured. A 50-Hz, 60-V alternating current was then applied through two subcutaneous needle electrodes to induce ventricular fibrillation. Cardiac arrest was defined as the point at which aortic pressure decreased profoundly to hydrostatic pressure and the ECG showed ventricular fibrillation; ventilation was stopped at that point. After 4 min of untreated ventricular fibrillation, basic life support CPR was performed manually, and mechanical ventilation was resumed with the same setting as before the induction of cardiac arrest. Chest compressions were always performed by the same investigator at a rate of 100/min, guided by acoustical audiotones, with no knowledge of hemodynamic and end-tidal carbon dioxide monitor tracings.
After 3 min of basic life support CPR, 17 animals were randomly assigned to receive, every 5 min, either a vasopressin/epinephrine combination (vasopressin [IU/kg]/epinephrine [µg/kg]: 0.4/45, 0.4/45, and 0.8/45; n = 6) (8), epinephrine alone (45, 45, and 200 µg/kg; n = 6), or saline placebo alone (n = 5). All drugs were diluted to 10 mL with normal saline and injected into an ear vein, which was followed by 20 mL of saline flush (investigators were blinded to the drugs). After 22 min of cardiac arrest, up to 5 countershocks were administered with an energy of 3, 4, and 6 J/kg. If asystole or pulseless electrical activity was present after defibrillation, the experiment was terminated. Return of spontaneous circulation was defined as an unassisted pulse with a systolic arterial pressure of more than 80 mm Hg lasting for at least 5 min. When indicated, surviving animals received infusions of dopamine, phenylephrine, nalbuphine, or amiodarone. When blood pressure, acid-base status, and metabolic function returned to normal values, the pigs were weaned from the ventilator, extubated, and returned to their cages; neurologic evaluation according to the Neurologic Deficit Score (9) was performed 24 h and 5 days after successful CPR (Appendix 1). Afterward, the pigs were killed with an overdose of fentanyl, propofol, and potassium chloride.
Values are expressed as mean ± SEM. The comparability of weight and baseline data was verified by using one-way analysis of variance. To identify statistically significant differences of diastolic aortic pressure among the three groups, one-way analysis of variance was used, followed by a Tukey’s post hoc test. Survival rates were compared by using Fisher’s exact test; we considered a value of P < 0.05 statistically significant.
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Results
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There were no differences in weight, hemodynamic variables, or blood gases among groups before the induction of ventricular fibrillation and the first drug administration during CPR. Pigs treated with a vasopressin/epinephrine combination during CPR had a significantly higher aortic diastolic pressure at all points in time after each of three drug administration compared with epinephrine alone or saline placebo alone (P < 0.01; Fig. 1). Six of six animals treated with vasopressin/epinephrine, but zero of six treated with epinephrine alone and zero of five treated with saline placebo alone had a return of spontaneous circulation after defibrillation (P < 0.01; Table 1). All surviving animals required a vasopressor infusion for 
2 h in the postresuscitation phase; additionally, one pig was treated with amiodarone because of cardiac arrhythmias. Six of six vasopressin/epinephrine pigs had normal blood gas values 6 ± 1 h after successful CPR and could be subsequently extubated (Table 2). Neurologic evaluation 24 h after successful resuscitation revealed an unsteady gait in all vasopressin/epinephrine animals, with a neurologic deficit score of 10 out of 400. Six of six vasopressin/epinephrine pigs were drinking and eating within 24 h after the experiment and had normal levels of consciousness, respiration, and behavior; 5 days after the experiment, the neurologic deficit score was 0 out of 400.
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Table 1. Numbers of Shocks Performed After 22 Minutes of Cardiac Arrest and Electrocardiogram Rhythms After the Last Countershock
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Table 2. Arterial Blood Gas Variables, Base Excess, and Lactate Values Before Defibrillation and During the Postresuscitation Phase
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Discussion
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In this porcine model, vasopressin/epinephrine, but not epinephrine alone or saline placebo alone, maintained diastolic aortic pressure at 45 mm Hg during prolonged CPR. Accordingly, six of six epinephrine and five of five saline placebo pigs died, whereas six of six vasopressin/epinephrine animals survived for five days and had full neurologic recovery.
This model simulates sudden cardiac arrest with 4 minutes of ventricular fibrillation followed by 3 minutes of basic and 15 minutes of advanced cardiac life support. We deliberately omitted defibrillation attempts on starting CPR and immediately after drug administration to simulate prolonged CPR with repeated vasopressor administration. Although the 45 µg/kg epinephrine dose used in our porcine study is larger than the 1-mg dose recommended for clinical use (1,2), the combination of vasopressin with epinephrine in this model reflects an established optimal dose (8). In that model, we have observed that perfusion pressure during the 15 minutes of advanced cardiac life support is highly predictive of whether the heart and brain will survive. Thus, if a given CPR intervention maintains perfusion of the heart and brain for such a prolonged period (18 minutes) during CPR with subsequent full neurologic recovery, it may be judged effective. We therefore suggest that this model is rather a tough challenge for a CPR intervention, because adverse effects would have a significant chance to surface during 15 minutes of advanced cardiac life support and, equally important, during the 5 days after successful CPR.
In a previous experiment of asphyxia cardiac arrest in adult pigs, we showed that the combination of vasopressin with epinephrine was superior to either vasopressin alone or epinephrine alone (8). This observation was entirely new and surprising and suggests that the usual approach of pharmacological CPR management—administration of identical drugs and dosages for patients presenting with cardiac arrest due to dysrhythmic or asphyxia cardiac arrest—may have to be reconsidered. In fact, it is possible that when the degree of ischemia is fundamental, such as during asphyxia, or if advanced cardiac life support is prolonged, a combination of vasopressin with epinephrine could be beneficial. Thus, if initial CPR efforts with epinephrine are not immediately successful, it may be beneficial to administer another vasopressor drug, such as vasopressin, or a combination of both drugs instead of increasing the epinephrine dosage. This laboratory experience is in full agreement with previous lifesaving observations in 8 in-hospital CPR patients who did not respond to advanced cardiac life support with 2 to 15 mg of epinephrine during prolonged (15 to 25 min) resuscitation efforts but had a return of spontaneous circulation after subsequent injection of 40 IU of vasopressin (10). Similarly, 4 of 10 patients undergoing prolonged CPR efforts (40 minutes) with 18 mg of epinephrine had a return of spontaneous circulation after subsequent injection of 1 IU/kg of vasopressin (11). When these observations are extrapolated, either vasopressin or epinephrine may be effective after a short duration of cardiac arrest; however, when cardiac arrest and/or CPR efforts are prolonged, a combination of vasopressin/epinephrine may be especially beneficial. This is in full agreement with an in-hospital cardiac arrest study (12) with a short time of ischemia, indicating comparable outcome with vasopressin versus epinephrine.
In a previous CPR model, we investigated a combination of vasopressin/epinephrine in regard to cerebral and myocardial blood flow (4). It is interesting to note that cerebral blood flow during CPR was significantly decreased after vasopressin/epinephrine compared with vasopressin alone (25 versus 50 mL/min per 100 g), but no significant differences in myocardial blood flow during CPR were detected. Although we measured cerebral blood flow in that model (4), we were unable to determine whether this reduction of cerebral perfusion would result in neurological dysfunction during long-term survival. For example, when we showed full neurologic recovery after prolonged CPR, we used repeated injections of vasopressin (13), which usually increases cerebral blood flow to levels of 50 to 80 mL/min per 100 g (14). In this study, we observed comparable effects of vasopressin/epinephrine compared with vasopressin alone (15) on diastolic aortic pressure, but we detected that the combination of vasopressin and epinephrine indeed resulted in long-term survival with full neurologic recovery. In contrast to our previous study (4), we used a smaller epinephrine dose in this study (45 versus 200 µg/kg), which may indicate that the epinephrine dosage may have an important effect on vasopressor effects. Namely, because vasopressin and epinephrine target different extracellular vasopressin and catecholamine receptors, the vasoconstrictive effects of both drugs vary significantly depending on the vascular beds. As such, vasopressin has been found to have a vasodilatory effect on the cerebral vasculature (4), whereas epinephrine may even impair cerebral blood flow despite an increase in perfusion pressure (16). As such, epinephrine may disturb vasopressin-mediated vasodilatation in the cerebral vasculature (4) and result in decreased blood flow to the brain. However, the absolute threshold of cerebral perfusion needed for complete neurologic recovery is unknown. Although we are unable to state the exact extent of cerebral blood flow in this study, the results may simply speak for themselves. Namely, combining optimal dosages of epinephrine and vasopressin both improves perfusion pressure in different underlying pathophysiologies of cardiac arrest and ensures survival with full neurologic recovery.
Shortly after successful defibrillation, blood gas analysis in surviving animals indicated a development toward normalization, thus suggesting that weaning of ventilatory and vasopressor support was possible. It is interesting to note that only one of six surviving pigs had cardiac arrhythmias and was successfully treated with amiodarone. These findings are in contrast with the experience of an earlier study (13), in which the surviving animals were difficult to manage in the postresuscitation phase because of cardiac arrhythmias, atelectasis, and hypotension. Unfortunately, we are unable to determine whether the combination of vasopressin/epinephrine given during CPR was the underlying reason for fewer intensive care problems after the return of spontaneous circulation. However, it confirms that to achieve full recovery after cardiac arrest, both excellent management of advanced cardiac life support and careful optimization of organ function in the postresuscitation phase are fundamentally important (17). Similar to our previous experiment (13), the only neurologic deficit of all vasopressin-/epinephrine-treated animals 24 hours after the return of spontaneous circulation was an unsteady gait, which disappeared within another day.
Some limitations of this study should be noted. First, because these experiments were performed under general anesthesia, there may have been a cerebroprotective effect that may have contributed to the favorable outcome. Second, to prevent the risk of infections or sepsis, we monitored blood pressure with an arterial catheter only; therefore, we were not able to measure cerebral blood flow, coronary perfusion pressure, or mixed venous blood gases during the experiment. Furthermore, different vasopressin receptors in pigs (lysine vasopressin) and humans (arginine vasopressin) may result in a different hemodynamic response to exogenously administered arginine vasopressin, as in this study. However, the circulatory effects of arginine vasopressin may even be greater in humans than in pigs. Finally, we used young, healthy pigs that were free of atherosclerotic disease.
In conclusion, in this porcine model of prolonged CPR, repeated vasopressin/epinephrine administration, but not epinephrine or saline placebo alone, ensured long-term survival with full neurologic recovery.
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Appendix 1
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Acknowledgments
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Supported by the Austrian National Bank, Vienna, Austria; a dean’s grant for Medical School graduates of the Leopold-Franzens-University, Innsbruck, Austria; the Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University, Innsbruck, Austria; and Austrian Science Foundation Grant P14169-MED, Vienna, Austria.
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Footnotes
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No author has a conflict of interest regarding drugs or devices discussed in this article.
Presented in part at the 75th Scientific Sessions of the American Heart Association, Chicago, IL, November, 2002.
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References
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Accepted for publication February 24, 2003.
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Abstract
Introduction
, continuous line), epinephrine alone (
, dashed line), or saline placebo alone (
, dotted line). DA 1 = 0.4 IU/kg of vasopressin combined with 45 µg/kg of epinephrine versus 45 µg/kg of epinephrine alone versus saline placebo; DA 2 = 0.4 IU/kg of vasopressin combined with 45 µg/kg of epinephrine versus 45 µg/kg of epinephrine alone versus saline placebo; DA 3 = 0.8 IU/kg of vasopressin combined with 45 µg/kg of epinephrine versus 200 µg/kg of epinephrine alone versus saline placebo; BLS = basic life support; ACLS = advanced cardiac life support. The horizontal dashed line indicates the approximate threshold that usually makes successful defibrillation likely. Time is given in minutes ('). *P < 0.01, vasopressin/epinephrine versus epinephrine alone and saline placebo; 
P < 0.01, epinephrine alone versus saline placebo.
