Electrophysiologic basis by which epinephrine facilitates defibrillation after prolonged episodes of ventricular fibrillation

LABORATORY INVESTIGATION

Electrophysiologic Basis by Which Epinephrine Facilitates Defibrillation After Prolonged Episodes of Ventricular Fibrillation

From the Division of Cardiology, George Washington University Medical Center, Washington, DC.

William O. Suddath, MD Yuri Deychak, MD P. Jacob Varghese, MD, FRCP

Author contributions are provided at the end of this article. Received for publication September 8, 1999. Revisions received June 30, 2000, and January 31, 2001. Accepted for publication March 8, 2001. Presented at the 44th Annual Scientific Session of the American College of Cardiology, New Orleans, LA, March 1995. Address for reprints: P. Jacob Varghese, MD, FRCP, Division of Cardiology, George Washington University Medical Center, 2150 Pennsylvania Avenue, Suite 4-422, Washington, DC 20037; 202-994-4177, fax 202-994-3673; E-mail [email protected]. Copyright © 2001 by the American College of Emergency Physicians. 0196-0644/2001/$35.00 + 0 47/1/115540 doi:10.1067/mem.2001.115540

Study objective: Even though epinephrine has been shown to decrease the electrical stability of the heart, it is used extensively in cardiac resuscitation. The objective of this study is to document electrophysiologic parameters of epinephrine, which would facilitate defibrillation. Methods: In 20 swine, electrically induced ventricular fibrillation was allowed to continue for 10 minutes. Animals were then randomly assigned to receive either intracardiac injection of 1 mg of epinephrine or 10 mL of normal saline solution. Synchronization and dispersion of the repolarization of fibrillatory waves and cycle length were measured. Results: As the ventricular fibrillation continued, cycle length was prolonged, and synchronization and dispersion deteriorated. With epinephrine, cycle length shortened from 416±21 to 204±23 ms (P<.005), synchronization improved from 114±13 to 61±10 ms (P<.05), and dispersion narrowed from 84±10 to 49±8 ms (P<.005). Normal saline solution had no effect. Successful resuscitation was achieved in all 10 animals administered epinephrine and only 1 animal in the saline solution group. Conclusion: Epinephrine’s effect on cycle length, synchronization, and dispersion of repolarization of fibrillatory waves may be the mechanism with which it facilitates defibrillation. [Suddath WO, Deychak Y, Varghese PJ. Electrophysiologic basis by which epinephrine facilitates defibrillation after prolonged episodes of ventricular fibrillation. Ann Emerg Med. September 2001;38:201-206.]

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INTRODUCTION

Sudden cardiac death is a major public health problem in this country. Many approaches have been adopted to tackle this public health challenge, and the 2 major approaches are early defibrillation and improved resuscitative measures. Improvement in resuscitation can be achieved by incorporating new methods and a better understanding of measures that are currently used. Epinephrine is considered an integral part of resuscitation. It is part of the advanced cardiac life support protocol1 and recommended by the American Heart Association in their guidelines for cardiac resuscitation.2 A majority of the studies of epinephrine have emphasized its effect on hemodynamics.3 Epinephrine’s main effect is to increase systemic vascular resistance by its action on peripheral vessels. This increase in systemic vascular resistance plays a critical role in improving coronary blood flow, which in turn alters electrophysiologic properties of the heart. These altered electrical properties of the heart may facilitate resuscitation, and a better understanding of these properties might help to improve the outcome of resuscitation. What is the known effect of epinephrine on the electrical stability of the heart? Epinephrine has been shown to lower the ventricular fibrillation threshold.4 In smallanimal hearts, epinephrine shortens the cycle length of ventricular fibrillation and stabilizes fibrillation.5 In these hearts, epinephrine reduces the number of episodes of spontaneous defibrillation. In a study of patients with automatic internal defibrillators, epinephrine has been shown to increase the defibrillation threshold.6 The above studies suggest that epinephrine has a deleterious effect on the electrical stability of the heart, and yet it is extensively used in resuscitative measures. This apparent contradiction may be because none of the above studies has evaluated the effect of epinephrine on the characteristics of ventricular fibrillation wave forms and how that can facilitate defibrillation. Most of the studies in ventricular fibrillation and defibrillation have been performed, with fibrillation lasting only 2 or 3 minutes. This is not a true reflection of what happens in the majority of clinical situations. Most of the out-of-hospital resuscitation occurs after a prolonged period of ventricular fibrillation, usually between 8 and 10 minutes, and in a significant proportion of patients, it is much later.7 There are a few studies in which electrical activity of the heart is evaluated after 10 minutes of ventricular fibrillation and describe how resuscitative measures change these electrical activities. Such a study is

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essential to our ability to significantly alter the outcome of out-of-hospital cardiac resuscitation. The purpose of the present study was threefold: first to document the electrical activity of the heart after prolonged episodes of ventricular fibrillation (ie, 10 minutes), second to evaluate how these electrical activities change with administration of epinephrine and cardiac massage, and last to demonstrate how the epinephrinemediated changes facilitate successful defibrillation. M AT E R I A L S A N D M E T H O D S

All animal procedures were approved by the institutional animal care and use committee of the George Washington University Medical Center and conform with the US public health service guide for the care and use of laboratory animals. Twenty domestic swine weighing between 30 and 45 kg were anesthetized initially with ketamine, 0.2 mg/kg, followed by pentobarbital and 3.6 mg/kg thiamytal sodium (Bio-tal) intravenously. All animals were intubated, and ventilator support was maintained with a Harvard respirator. Blood gases were kept at the physiologic range by adjusting the respirator. Bilateral femoral and carotid arterial cutdown were performed for arterial and venous cannulation. The heart was exposed through a midline sternotomy and was positioned in a pericardial cradle. Two epicardial patch electrodes (Guidant/Cardiac Pacemaker Inc., Indianapolis, IN) were positioned on the surface of the heart: one anteriorly and the other posteriorly. They were secured by suture into the epicardium and anchoring to the pericardium. These electrodes were used to defibrillate the heart. Monophasic action potentials (MAPs) were recorded from the endocardium by using standard MAP catheters with a deflecting tip. Epicardial MAP was recorded with handheld probes. Systemic and pulmonary arterial pressures, oximetry, and temperature with a rectal probe were monitored continuously. A lead-II ECG, MAPs from the right and left ventricular endocardium and epicardium, pressures from the systemic and pulmonary arteries, and time lines were displayed on the oscilloscope of electronics for medicine VR16 and recorded every minute during the 10 minutes of ventricular fibrillation and the 5 minutes of resuscitation. Ventricular fibrillation was achieved by applying alternating current to the surface of the heart. During ventricular fibrillation, the respirator was switched off. After 10 minutes of ventricular fibrillation and 5 minutes of resuscitation, the heart was defibrillated with a single 40-J shock

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by using an external cardioverter defibrillator (Guidant/ Cardiac Pacemaker Inc.). All animals were allowed to fibrillate for 10 minutes. At the end of this period, they were randomized to intracardiac administration of either 1 mg of epinephrine or 10 mL of normal saline solution. Ventilator support was restarted, and open-chest cardiac massage was initiated. These resuscitative measures were continued for a period of 5 minutes. Defibrillation was then attempted with a single 40-J shock. The outcome was recorded. Continuous variables are expressed as means and SDs. We compared mean differences between 10 minutes of ventricular fibrillation with those of epinephrine and normal saline for all parameters by using the paired Student t test. Significance was indicated by a P value below .05. R E S U LT S

Three parameters were measured during ventricular fibrillation and resuscitation: cycle length, synchronization of repolarization, and dispersion of repolarization of fibrillatory waves.

Cycle length of fibrillatory waves is measured from the onset of depolarization of one MAP to the next MAP and reported in milliseconds (Figure 1). Synchronization of repolarization of fibrillatory waves is measured at the termination of the repolarization of the endocardial MAP to the epicardial MAP at a given time. In the recordings in which the repolarization is interrupted with another wave front, then the downslope of the action potential is extended to intersect the base line. For the purpose of this study, this point of intersection is taken as the termination point of repolarization. Dispersion is measured from the termination of the repolarization of the shortest MAP to the longest at a given site (ie, endocardium or epicardium) for a given period of time. This is done by superimposing the entire MAP recorded in that period of time, as shown in Figure 2. In each of the 3 parameters, 10 measurements were always made, and the average of the 10 was reported as the result. Ten swine received epinephrine, and the other 10 received saline solution. All swine in the epinephrine and

Figure 2. Figure 1.

Methods used to measure cycle length in sinus rhythm (top) and ventricular fibrillation (VF; bottom).

Minute-to-minute variation in the dispersion of repolarization. With 10 minutes of ventricular fibrillation (VF), this dispersion increased from 2 to 88 ms. Five minutes after administration of epinephrine, this dispersion improved to 44 ms. The solid line is the shortest MAP, and the dotted line is the longest MAP.

Monophasic action potentials

Monophasic action potentials: Dispersion of repolarization

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cardiac massage groups were resuscitated, whereas only 1 of the 10 saline group was successfully resuscitated. Cycle length continued to prolong as the fibrillation continued. At the end of 10 minutes of ventricular fibrillation, the mean cycle length was 416±21 ms. This was shortened with epinephrine to 204±23 ms (P<.005). In the control group receiving normal saline solution, the cycle length was further prolonged from 398±41 to 462±87 ms (P<.1). The change in cycle length with 10 minutes of ventricular fibrillation and the effect of epinephrine and normal saline solution on the cycle length are shown in Figure 3. As the ventricular fibrillation continued, the synchronization between endocardium and epicardium was widened. At the end of 10 minutes of fibrillation, the synchronization of repolarization between endocardium and epicardium was 114±13 ms. With epinephrine, this was 61±10 ms (P<.05), whereas with normal saline solution, there was no significant change (ie, 119±13 to 111±11 ms). These changes in synchronization are shown in Figure 4. With 10 minutes of ventricular fibrillation, dispersion increases significantly. Administration of epinephrine results in reduction in dispersion values approaching baseline values. There is no significant change in the dispersion values with normal saline solution. At 10 minutes, dispersion was 84±10 ms, and with administration of epinephrine, it narrowed to 49±8 ms (P<.05). With normal saline, the 10-minute dispersion value of 85±6 ms

increased to 122±8 ms (P<.05). Minute-to-minute change in dispersion of repolarization with resuscitation is shown in Figure 2, and the effect of epinephrine and normal saline solution on dispersion is shown in Figure 5. We also observed that there was a significant decrease in the amplitude of the MAP as the ventricular fibrillation continued for 10 minutes. The decrease in the amplitude of the MAP occurred first in the epicardium followed by in the endocardium. With administration of the epinephrine, the amplitude increased significantly in both areas. DISCUSSION

Although epinephrine has been extensively used in cardiac resuscitation, the electrophysiologic basis for its salutary effect is unknown. That is the reason this study was undertaken. Three parameters were studied during ventricular fibrillation. Cycle length of the fibrillatory waves prolonged as the ventricular fibrillation progressed. Both synchronization and dispersion of repolarization widened with increasing duration of fibrillation. We also observed that the amplitude of the fibrillatory waves decreased as the fibrillation continued. With administration of epinephrine, the cycle length of the fibrillatory

Figure 4. Figure 3.

Means±SD of cycle lengths with 10 minutes of ventricular fibrillation and 5 minutes of resuscitation. With administration of epinephrine, cycle length shortened from 416±21 to 204±23 ms (P<.005), whereas with normal saline solution, cycle lengths prolonged to 462±87 ms.

Means±SD of synchronization of repolarization of ventricular fibrillatory waves. At the end of 10 minutes of ventricular fibrillation, synchronization between the endocardium and epicardium was 114±13 ms. With administration of epinephrine, synchronization improved to 61±10 ms (P<.05), whereas normal saline solution had no effect. Synchronization of repolarization (N=10)

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waves shortened, the amplitude increased, and both synchronization and dispersion narrowed. To understand the electrophysiologic basis of defibrillation, Sweeney et al8 studied the effect of electrical shock on the action potentials. Their study showed that an electrical shock extends phase 3 of the action potential and thus prolongs refractoriness. This prolongation of refractoriness prevents an oncoming fibrillatory wave front to re-excite and maintain fibrillation. Similar findings were reported by Swartz et al9 while studying monophasic and biphasic waveforms in defibrillation. Biphasic waveforms decrease defibrillation thresholds because they prolong action potential duration more than the monophasic. In isolated cell cultures, they showed that the second phase of the biphasic wave form prolongs the action potential duration further and thus extends the refractory period.10 Similar findings were shown by Dillon,11 with monophasic wave forms in rabbit hearts. He used optical recordings so that shock artifacts would not distort action potential recordings. These studies confirm that one of the effects of shock is to prolong action potential duration. In addition to the prolongation of the action potential, Dillon12 has also shown that a shock given during fibrillation synchronizes the repolarization of the subsequent action potentials. This synchronization of repolarization prevents any oncoming wave front reactivation of the area

Figure 5.

Means±SD of dispersion of repolarization with 10 minutes of ventricular fibrillation and 5 minutes of resuscitation. The dispersion increased to 84±10 ms at the end of 10 minutes of ventricular fibrillation. With administration of epinephrine, it is narrowed to 49±8 ms (P<.05). Administration of normal saline solution resulted in a further increase to 122±8 ms (P<.05). Dispersion of repolarization (N=10) Milliseconds 140 Epinephrine Normal saline

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and continuation of fibrillation. Synchronization of repolarization of the fibrillatory waves is another mechanism through which an electrical shock terminates fibrillation. What is the role of synchronization and dispersion of repolarization in defibrillation? Ventricular fibrillation is maintained because of the inhomogenous recovery of the myocardium. This recovery pattern gets worse as the ventricular fibrillation continues because of the lack of synchronization and widening of dispersion of repolarization. Epinephrine, as shown in our study, narrows dispersion and improves synchronization of repolarization, resulting in a more homogenous recovery of the myocardium. As the shock defibrillates the myocardium, with this recovery pattern, no pockets of ventricular fibrillation will be able to re-excite the myocardium. This results in a stable rhythm. Synchronization of repolarization has been reported helpful in other forms of defibrillation. Varghese et al13 reported the mechanism of spontaneous defibrillation in rabbit heart. In this model, they evaluated cycle length and synchronization of repolarization during fibrillation and spontaneous defibrillation. With the onset of fibrillation, cycle length shortens and synchronization becomes worse. Before spontaneous defibrillation, cycle length prolongs, and synchronization improves. It appears that synchronization of repolarization of fibrillatory waves is an important factor in spontaneous defibrillation. Our present study also shows that synchronization of repolarization improves significantly after epinephrine, and this may be the mechanism with which it facilitates defibrillation. Amplitude of the electrograms during fibrillation has been shown to be a predictor of successful defibrillation.14 There is a direct relationship with the duration of fibrillation and amplitude of the electrogram. As the fibrillation continues, the electrogram continues to lose its amplitude. We have also observed, in this study, that epinephrine increases amplitude of the electrogram, and this may also facilitate defibrillation. Are the electrophysiologic changes seen with epinephrine a direct effect on the myocardium or can the effect be through its effect on the peripheral vascular resistance and increased coronary blood flow? Tovar et al15 studied the effect of epinephrine in spontaneously beating cultured cells of the chick embryo. These studies demonstrated that epinephrine significantly shortens the cycle length and the refractiveness of the beating cells. Bransford et al5 evaluated the effect of epinephrine on isolated, perfused, fibrillating rabbit heart. As shown in the present study, they also showed that epinephrine significantly

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shortens the cycle length of the fibrillatory waves. These studies suggest that the electrophysiologic effect of epinephrine is a direct effect on the myocardium rather than a secondary effect of the improved coronary blood flow. Limitations of this study include the difficulty of recording MAPs as fibrillation continues. With prolonged fibrillation, the amplitude of fibrillatory waves decreases significantly, and the measurement of synchronization and dispersion becomes difficult. Extensive effort was made to select clearly demarcated action potentials to make our measurements. Similarly, MAP recordings can be difficult at the time of cardiac massage. We have attempted to overcome these difficulties by making certain that we have recorded action potentials with clearly marked onset of depolarization and termination of repolarization. In this way, we have been able to make valid measurements. In summary, in this animal model, we have demonstrated that 3 electrophysiologic parameters (ie, cycle length, synchronization, dispersion of action potentials) may be the mechanism with which epinephrine facilitates defibrillation. A better understanding of the action of epinephrine may help us define its role in resuscitation.

11. Dillon SM. Official recordings in the rabbit heart show that defibrillation strength shocks prolong the duration of depolarization and the refractory period. Circ Res. 1991;69:842-856. 12. Dillon SM. Synchronized repolarization after defibrillation shocks. A possible component of the defibrillation process demonstrated by optical recordings in rabbit heart. Circulation. 1992;85:1865-1878. 13. Varghese PJ, Bramsford PP, Tovar OH, et al. Mechanism of spontaneous defibrillation in the rabbit heart [abstract]. J Am Coll Cardiol. 1993;21:306A. 14. Weaver WD, Cohh LA, Dennis D, et al. Amplitude of ventricular fibrillation wave form and outcome after cardiac arrest. Ann Intern Med. 1985;102:53-55. 15. Tovar OH, Milne KB, Bransford PP, et al. Epinephrine facilitates fibrillation by shortening action potential duration and refractory period at ventricular tachycardia/fibrillation cycle lengths [abstract]. Pace. 1993;16:866.

Author contributions: WOS and PJV conceived the idea for the study. WOS, YD, and PJV designed and conducted the experiments. All authors acquired the data and analyzed and interpreted it. WOS wrote the initial manuscript, and WOS and PJV wrote the revisions. PJV and WOS take overall responsibility for the paper.

REFERENCES 1. Guidelines for CPR and Emergency Cardiac Care. Emergency Cardiac Care Committee and Sub Committees. American Heart Association. Part III adult advanced cardiac life support. JAMA. 1992;268:2199-2241. 2. Cummins RO, Ornako JP, Thies WH, et al. Improving survival from sudden cardiac arrest: the ‘Chain of Survival’ concept: a statement for health professionals from the Advanced Cardiac Life Support Sub Committee and the Emergency Cardiac Care Committee, American Heart Association. Circulation. 1991;83:1832-1847. 3. Michael JR, Guerci AD, Koehla RC, et al. Mechanisms by which epinephrine augments cerebral and myocardial perfusions during cardiopulmonary resuscitation in dogs. Circulation. 1984;69:822-835. 4. Han J, Garcia de Jalon P, Moe GK. Adrenergic effects on ventricular vulnerability. Circ Res. 1964;14:516-524. 5. Bransford PP, Varghese PJ, Tovar OH, et al. Epinephrine reduces ventricular fibrillation threshold and stabilizes fibrillation by reducing cellular refractory period during fibrillation [abstract]. Pace. 1993;16:866. 6. Sousa J, Kou W, Calkins H, et al. Effect of epinephrine on the efficacy of the internal cardioverter-defibrillator. Am J Cardiol. 1992;69:509-512. 7. Lombardi G, Gallagher J, Gennis P. Outcome of out-of-hospital cardiac arrest in New York City: The Pre-Hospital Arrest Survival Evaluation (PHASE) Study. JAMA. 1994;271:678-683. 8. Sweeney RJ, Gill RM, Stienberg MI, et al. Ventricular refractory period extension caused by defibrillation shocks. Circulation. 1990;82:965-972. 9. Swartz JF, Jones JL, Jones RE, et al. Biphasic wave forms enhance defibrillation success by prolonging refractoriness to refibrillating wave fronts [abstract]. J Am Coll Cardiol. 1990;15:72A. 10. Swartz JF, Jones JL, Jones RE, et al. The conditioning forepulse of biphasic defibrillation wave forms enhances refractoriness to fibrillation wave fronts. Circ Res. 1991;68:438-449.

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