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Resuscitation 59 (2003) 59 /70 www.elsevier.com/locate/resuscitation Review article Do clinically relevant transthoracic defibrillation energies cause myocardial damage and dysfunction? Gregory P. Walcott a,*, Cheryl R. Killingsworth a, Raymond E. Ideker a,b,c a Cardiac Rhythm Management Laboratory, Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Volker Hall B140, 1670 University Blvd., Birmingham, AL 35294, USA b Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA c Department of Physiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA Received 6 January 2003; received in revised form 4 April 2003; accepted 4 April 2003 Abstract Sufficiently strong defibrillation shocks will cause temporary or permanent damage to the heart. Weak defibrillation shocks do not cause any damage to the heart but also do not defibrillate. A relevant and practical question is what range of shock energies is most likely to defibrillate while not causing damage to the heart. This question is most difficult to answer in the pre-hospital defibrillation setting where the patients’ size and shape vary, placement of the defibrillation patches vary, and the etiology of their arrhythmia varies. Unlike internal defibrillators, which are tested at implantation, efficacy of an external defibrillator is determined only once, when it is most needed. This review discusses shock damage and dysfunction caused by monophasic waveforms as well as biphasic waveforms. Evidence is presented suggesting that for perfused hearts, the threshold for damage is well above any shock size delivered clinically. For non-perfused hearts, both in humans and animals, evidence is presented that monophasic shocks of up to 5 J/kg do not cause any more cardiac damage/dysfunction than that associated with smaller shocks and that much of this damage is caused by the ischemic period itself rather than the shock. Although many patients can be defibrillated with 150 J (2.2 J/kg) biphasic shocks, some patients may require biphasic shocks up to 360 J (5 J/kg) to be defibrillated. Studies still need to be performed comparing the efficacy and damaging effects of 360 J biphasic shocks to 150 J biphasic shocks. Until those studies are completed, it seems reasonable to use the same 360 J (5 J/kg) energy limit for biphasic shocks as for monophasic shocks. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Defibrillation energies; Myocardial damage; Heart Resumo Choques suficientemente fortes para desfibrilhar causarão dano permanente ou temporário ao coração. Choques de desfibrilhação fracos não causam qualquer dano ao coração mas também não desfibrilham. Uma questão prática e relevante é saber qual é o nı́vel de energia de choque com maior probabilidade de ser eficaz na desfibrilhação sem causar dano cardı́aco. Esta questão é mais difı́cil de responder no contexto de desfibrilhação pré-hospitalar, onde a forma e o tamanho dos doentes varia, a colocação das pás de desfibrilhação varia e a etiologia de cada arritmia também varia. Ao contrário dos desfibrilhadores internos, que são testados na implantação, a eficácia de um desfibrilhador externo é determinada apenas uma vez, quando é mais necessária. Esta revisão discute a lesão e disfunção cardı́acas causadas por choques de ondas monofásicas e bifásicas. É apresentada evidência sugerindo que nos corações perfundidos o nı́vel para lesão está bem acima da dimensão de qualquer choque com propósito clı́nico. Para corações não perfundidos, quer em humanos quer em animais, é apresentada evidência de que choques monofásicos até 5 J/Kg não causam mais lesão/disfunção cardı́aca do que aquela associada a choques menores e que muito deste dano é causado pelo próprio perı́odo isquémico e não pelo choque. Embora muitos doentes possam ser desfibrilhados com choques bifásicos de 150 J (2,2 J/Kg), alguns doentes podem necessitar de choques bifásicos até 360 J (5 J/Kg). Continua a ser necessário realizar estudos comparando a eficácia e os efeitos lesionais entre choque bifásicos de 360 J e 150 J. Até estes estudos estarem completos parece * Corresponding author. Tel.: /1-205-975-4710; fax: /1-205-975-4720. E-mail address: [email protected] (G.P. Walcott). 0300-9572/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0300-9572(03)00161-8 60 G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 razoável usar o mesmo limite de energia de 360 J (5 J/Kg) para choques bifásicos e monofásicos. # 2003 Elsevier Ireland Ltd. All rights reserved. Palavras chave: Energias de desfibrilhação; Lesão miocárdica; Coração. Resumen Descargas desfibrilatorias suficientemente fuertes causarán daño temporal o permanente al corazón. Descargas de desfibrilación débiles no causan daño al corazón pero tampoco desfibrilan. Una pregunta relevante y práctica es cuál es el rango de energı́a de la descarga que sea probable que desfibrile al tiempo de que no cause daño al corazón. Esta pregunta es difı́cil de contestar en la desfibrilación prehospitalaria donde el tamaño y forma de del ‘paciente’ varı́an, la ubicación de los parches desfibrilatorios varı́an y la etiologı́a de suarritmia varı́a. Distinto de lo que ocurre con los desfibriladores implantables, que son probados al ser implantados, la eficacia de un desfibrilador externo es determinada solo una vez, cuando es mas necesario. Esta revisión discute el daño y disfunción causado por ondas monofásicas y bifásicas. Se presenta evidencia que sugiere que para corazones prefundidos, el umbral de daño está muy por encima de cualquier tamaño de descarga entregada clı́nicamente. En corazones sin perfusión, tanto en humanos como en animales, se presenta evidencia que descargas monofásicas hasta 5 J/kg no causan mayor daño / disfunción que aquel asociado con descargas menores y que mucho de este daño es causado por el perı́odo isquémico en si mismo mas que por la descarga. Aunque muchos pacientes pueden ser defibrilados con descargas bifásicas de 150 J (2.2 J/kg), algunos pacientes pueden requerir descargas bifásicas de hasta 360 Joules (5 J/kg) para ser desfibrilados. Aun es necesario realizar estudios que comparen la eficacia y el efecto dañino de descargas bifásicas de 360J y 150J. Hasta que estos estudios sean completados, parece razonable usar los mismos 360 J ( 5J/kg) como lı́mite de energı́a para descargas bifásica que para monofásica. # 2003 Elsevier Ireland Ltd. All rights reserved. Palabras clave: Energı́a de desfibrilación; Daño miocárdico; Corazón 1. Introduction 2. Shock field and defibrillation There is little doubt that defibrillation shocks of a large enough magnitude will cause damage to the heart, either temporarily or permanently [1]. There is also no doubt that defibrillation shocks of small enough magnitude will not cause any damage to the heart but also will not defibrillate the heart. The relevant, and more practical, question is what range of shock energies are most likely to defibrillate the heart while not causing damage to the heart. This question is most difficult to answer in the pre-hospital defibrillation setting where the patients’ size and shape vary, [2] placement of the defibrillation patches varies, [3] and the etiology of their arrhythmia varies [4]. Unlike internal defibrillators, which are tested at implantation, efficacy of an external defibrillator is determined only once, when it is most needed. The question of damage and dysfunction caused by monophasic waveform defibrillation was well reviewed in 1991 by Van Fleet and Tacker [5]. This review expands on that paper to include new data on shock damage and dysfunction caused by monophasic waveforms as well as by biphasic waveforms. This review also attempts to place a number of studies that have examined the question of damage and dysfunction following defibrillation into the context of what size shock is necessary to defibrillate. In order to understand how an electric shock defibrillates the heart and how an electric shock causes damage or dysfunction to the heart, one needs to understand the relationship between the defibrillation electrodes, the heart, the electric field that is generated in the heart during shock delivery through the heart and the changes in the transmembrane potential caused by this electric field. During a defibrillation shock, different amounts of current flow through different parts of the heart. According to Ohm’s law, the current density through each region of the heart is equal to the potential gradient in that region divided by the resistivity of that region of the heart. While current density is difficult to measure directly, techniques to measure potential gradient are well established so that most studies have investigated the potential gradient distribution caused by a shock rather than current density [6,7]. A defibrillation shock acts on the heart by changing the transmembrane potential of all the cells in the heart chambers being defibrillated. The relationship between shock strength and transmembrane potential change is complex and involves more than just the shock extracellular potential gradient field [8]. However, experimental data suggest that in order for shocks to defibrillate, they must generate a minimum potential gradient throughout the ventricles [9]. For normal hearts G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 following 10/30 s of ventricular fibrillation, the minimum potential gradient necessary for defibrillation depends on the characteristics of the defibrillation waveform. For typical monophasic waveforms, the minimum potential gradient necessary for defibrillation is approximately 6 V/cm. For typical biphasic waveforms, it is approximately 4 V/cm. The shock strength necessary to generate this minimum potential gradient can vary widely for different defibrillation electrodes and different electrode locations. Defibrillation from electrodes on the chest wall, as used with an automatic external defibrillator, can require 100/360 J of energy [10]. Defibrillation from electrodes on or in the heart, as used with an internal cardioverter-defibrillator, can require 5 /30 J of energy [11]. To a first approximation, using the same defibrillation waveform, the minimum potential gradient required anywhere in the heart is the same regardless of the electrode configuration and location; both the external and internal shocks must achieve the same minimum potential gradient throughout the ventricles [12]. 3. Electric field associated with external defibrillation Two factors mitigate a transthoracic shock’s effect on the heart. First, much of the current delivered by an external shock is shunted around the heart in the muscles of the chest wall and never reach it. Deale et al. measured the fraction of current that transverses a dog’s heart during transthoracic shock delivery and showed that approximately 4% of the current delivered to the chest wall reaches the heart [13]. Lerman et al. made the same measurement in humans during transthoracic shock delivery and again showed that approximately 4% of the current delivered to the chest wall actually reaches the heart [14]. Both studies showed that much of the current delivered during a transthoracic shock is shunted around the heart in the muscles of the chest wall. Second, the difference between the maximum and minimum potential gradient is much smaller for a transthoracic shock than it is for an internal shock. The shock potential gradient is not the same throughout the heart but varies from region to region. Shock potential gradients are highest near the shocking electrodes and fall off quickly with distance. For internal defibrillation, Wharton et al. showed that the shock potential gradient in the myocardium near the electrodes was about 30 times greater than in the myocardium distant from the electrodes [12]. The potential gradient had to be almost 200 V/cm near shocking electrodes located on the epicardium of the heart to create the minimum potential gradient of 6 /7 V/cm needed for defibrillation with a monophasic waveform far away from the shocking electrodes where the shock’s effect 61 was the weakest. In contrast, because the electrodes on the chest wall are distant from the heart, the difference between the highest and lowest potential gradient in the heart is not as great as it is for shocks delivered from electrodes directly on the heart [15]. Finite element modeling of transthoracic defibrillation of humans has shown that the ratio of maximum potential gradient to minimum potential gradient is approximately 4 /5 [16]. By extrapolation, during a transthoracic shock of a strength near the defibrillation threshold (the energy level which successfully defibrillates about 50% of the time), the maximum potential gradient on the heart is approximately 16/30 V/cm when the weakest potential gradient is 4/6 V/cm, the experimental magnitude needed for defibrillation. As described above, potential gradient is proportional to the current density in the tissue. An estimate of the adult 70 kg human defibrillation threshold is nominally 100 J for biphasic waveforms in current external defibrillators [17,18]. Therefore, a 100 J shock in an average patient generates a potential gradient of 4/5 V/ cm in the low potential gradient region and 20/30 V/cm in the high potential gradient regions. Since delivered current is proportional to the square root of energy provided impedance remains constant, the current delivered by a 360 J shock is slightly less than twice the current delivered by a 100 J shock. Therefore, the maximum potential gradient for a 360 J shock is approximately 40/60 V/cm. If a patient requires a larger shock than 100 J to be defibrillated, then one of two things occurs: (1) the minimum potential gradient necessary for defibrillation is increased above 4/6 V/ cm because of some pathology. This may occur during defibrillation of spontaneous ischemic arrhythmias [19,20]. In this case, a 360 J shock would expose a patient’s heart to a maximum potential gradient of 40/ 60 V/cm. Or (2), a 100 J shock does not generate a minimum potential gradient of 4 /6 V/cm throughout the heart, but a larger shock is necessary to generate this minimum potential gradient. This may occur if the patient has a high impedance [21] or the electrode location is changed [3]. In this case, a 360 J shock would expose a patient’s heart to a maximum potential gradient less than 40 /60 V/cm. 4. Safety factor studies The term safety factor is defined as the ratio of the current, voltage or energy necessary to cause damage or induce dysfunction to the current, voltage or energy necessary to either stimulate or defibrillate the heart. A larger safety factor is better than a smaller one since it allows a larger range of stimulus or shock strengths and a larger difference between the highest and lowest potential gradients that will stimulate or defibrillate 62 G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 Fig. 1. Example of first activation (upper panel) after a strong shock and the shock potential gradient causing conduction block (lower panel) in a dog. The upper panel shows the activation of the first paced cycle after an 850-V shock. The numbers refer to the local activation times (ms), referenced to the beginning of the stimulus. The interval between isochronal lines is 10 ms. Conduction was considered to be blocked at electrodes without activation times (m). The lower panel shows the potential gradient distribution during the shock. The numbers give the gradient in volts per centimeter (V/cm). Isogradient lines are located every 10 V/cm. The voltage gradients for electrodes at the edge of the recording array (black circles) were not calculated because of lack of surrounding electrodes. The wide solid line indicates the border between the region in which conduction occurred and the region in which conduction was blocked for the first postshock cycle. P, pacing electrode; S, shocking electrode (reproduced with permission [22]). without causing damage or dysfunction. Several different investigators have measured the safety factor for defibrillation. Babbs et al. concluded that external paddle currents five times the defibrillation threshold produced detectable histologic myocardial damage for a damped sinusoidal waveform [1]. Yabe et al. reported the ratio between the potential gradient that causes transient conduction abnormalities to the potential gradient necessary to defibrillate to be approximately 10 /13 for monophasic pulses (Fig. 1) [22]. Jones et al. determined the ratio of potential gradients that caused conduction abnormalities to that necessary to stimulate a resting myocyte to be approximately 20 [23]. Tovar and Tung found a ratio of about 20 for damaging myocardial current density to stimulating current density [24]. Since the defibrillation threshold has been reported to be approximately two to five times the stimulation threshold [25,26], collectively, these data suggest that the safety factor for monophasic waveforms is approximately 4/10 [16]. Safety factor also depends on waveform shape. Biphasic waveforms have been shown to have a higher safety factor than monophasic waveforms. In addition to showing that the safety factor for monophasic waveforms was 10 /13, Yabe et al. showed that the safety factor for biphasic waveforms was approximately 20 [22]. The reason for the improvement in safety factor is 2-fold. First, the voltage and energy necessary to defibrillate is lower for well-chosen biphasic waveforms than for monophasic waveforms [27 /29]. Second, the voltage and energy levels that result in damage or dysfunction are greater for biphasic waveforms than for monophasic waveforms. In Yabe et al. the voltage gradient that caused conduction block was 719/6 V/cm for biphasic waveforms while it was 649/4 V/cm for monophasic waveforms [22]. Jones et al. showed that for waveforms varying from 1 to 40 ms in total duration, the voltage that causes damage for asymmetric square biphasic waveforms in which phase 2 amplitude was one-half of the phase 1 amplitude was 149/3% (P B/ 0.005) higher than for monophasic control waveforms of the same total duration [30]. Thus, not only do biphasic waveforms defibrillate at a lower voltage or energy than do monophasic waveforms, but for a given voltage or energy are less likely to cause damage or induce dysfunction. 5. Damage caused by shocks Damage usually refers to either gross or histologic changes associated with shock delivery. Babbs et al. measured the extent of histologic damage and likelihood of death in a series of dogs receiving various sized transthoracic monophasic defibrillation shocks [1]. The results were presented as a series of dose /response curves for defibrillation efficacy, damage, and death (Fig. 2). Five times as much peak current was necessary to produce detectable histologic damage as was needed to defibrillate. And 22 times as much peak current was G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 Fig. 2. Percent of animals for effectiveness, toxicity, and mortality vs. energy for dogs given transchest damped sine wave defibrillation shocks. Myocardial infarction ('). Defib, defibrillation (reproduced with permission [1]). necessary to kill the animal as was necessary to defibrillate. In energy terms, the ratio of energy necessary to cause damage to the energy necessary to defibrillate was 20 and the ratio of energy necessary to cause death to the energy necessary to defibrillate was 320. These numbers do not exactly match the squared relationship described above because shock impedance tends to decrease with shock strength [31]. A surrogate for tissue damage has been detection of enzymes in the bloodstream that have been shown to correlate with cardiac cell death. A number of studies have looked at cardiac damage following cardioversion for atrial fibrillation where any enzyme release has been attributed to the cardioversion shock as opposed to defibrillation for cardiac arrest where enzyme release may be caused by myocardial ischemia or infarction. The initial studies measured the MB enzyme fraction of creatine kinase (CK) and showed large releases of CKMB 16 /24 h after cardioversion of atrial fibrillation [32,33]. A major problem with these studies, though, is that skeletal muscle damage can also release CK-MB [34]. Transthoracic defibrillation shocks have been shown to damage muscles of the anterior chest wall [35]. More recently, the availability of cardiac specific troponin T and I enzyme assays has enabled the discrimination between skeletal and myocardial muscle damage associated with elective cardioversion shocks. By virtue of their absence from the normal circulation and their high concentration in cardiac myocytes, the cardiac isoforms of troponin T and I are highly sensitive and specific markers of myocardial damage [36,37]. Following 72 elective cardioversions for atrial fibrillation or flutter using a maximum cumulative energy dose of 1280 J, Lund et al. found no elevations in troponin T and only a mild rise in troponin I in two patients [38]. Their experience is consistent with previous reports, which when combined with the Lund study, have shown 63 no elevation in troponin T among 293 patients undergoing elective transthoracic cardioversion with shocks up to 360 J. Ischemia may or may not make the heart more sensitive to the deleterious effects of defibrillation shocks. Therefore, results from studies of damage during cardioversion of atrial fibrillation in the hospital may not be applicable to estimating the damage caused by shocking spontaneous ventricular fibrillation after several minutes of no-flow ischemia in the prehospital setting. Grubb et al. measured cardiac enzymes in patients resuscitated from out-of-hospital cardiac arrest including patients who received no shocks [39]. A rise in CK-MB and cardiac troponin T occurred in almost all cases. Patients received from 0 to ]/2000 J of total defibrillation energy. There was a modest correlation between enzyme release for both troponin T and CKMB and the total defibrillation energy delivered among patients without electrocardiographic evidence of acute myocardial infarction (AMI). The total amount of delivered defibrillation energy was also positively correlated with the duration of CPR. Both the mechanical trauma and the hypoperfusion associated with CPR are additional possible explanations for the correlation between enzyme release and total defibrillation energy. A similar study performed by Müllner et al. examined the influence of chest compressions and external defibrillation on the release of cardiac enzymes in patients resuscitated from out-of-hospital cardiac arrest [40]. Using a multivariate stepwise linear regression model, they showed that CK-MB concentrations 12 h after CPR were positively associated with the presence of AMI, the duration of CPR, and the presence of cardiogenic shock in the post-resuscitation period, but Fig. 3. Association between serum cardiac troponin T (cTnT) concentrations measured 12 h after resuscitation and the number of defibrillation shocks administered during resuscitation in 53 patients with acute myocardial infarction (AMI) (/) and 34 patients without AMI (reproduced with permission [40]). 64 G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 were not significantly associated with the number of defibrillation shocks delivered (mean: 3, range: 1/6) (Fig. 3), or with the amount of epinephrine administered. Likewise, a similar model was constructed for troponin T concentrations 12 h after resuscitation and again, the number of defibrillation shocks administered was not significant in the model. These studies suggest that damage caused by defibrillation during CPR is either small or non-existent compared with the damage and dysfunction caused by the underlying pathology and period of no-flow ischemia. 6. Shock scaling by body size It is not always possible to measure the potential gradient in all regions of the heart studying either defibrillation efficacy or damage/dysfunction. Several investigators have shown that defibrillation shock success is directly related to body weight. Geddes et al. showed that the energy and current necessary to defibrillate using a damped sinusoidal monophasic waveform is related to body weight across different animal species [41]. Tacker et al. in a retrospective human clinical study, showed a reverse correlation between body weight and the percentage of patients successfully defibrillated by a given shock strength [2]. More recently, Zhang et al. has shown that the percent success for 70 and 100 J biphasic defibrillation shocks is inversely correlated with animal size [42]. Killingsworth et al. showed that the energy dose at the defibrillation threshold is proportional to the weight of the animal across a group of young swine ranging from 3.8 to 20 kg (Fig. 4) [43]. These studies suggest that energy dose/kg is a reasonable method to normalize shock strengths for different body sizes among and across species. Fig. 4. Defibrillation threshold energy in Joules (J) vs. body weight with pediatric (^) and adult (I) patches. The R2 values for the pediatric (dashed regression line) and adult patches (solid regression line) were 0.76 and 0.82, respectively (reproduced with permission [43]). 7. Dysfunction caused by shocks delivered to normal animal hearts Cardiac dysfunction as a function of shock strength has been examined by direct measurements such as a decrease in arterial or left ventricular pressures and/or changes in intrinsic myocardial contractility. Several studies have examined the effect on hemodynamics and on the ECG of transthoracic shocks delivered either during sinus rhythm or following short (10 /30 s) durations of ventricular fibrillation. Most of these studies have shown a transient change in hemodynamics that corrects in the seconds to minutes following the shock. Killingsworth et al. delivered transthoracic biphasic shocks to pigs of varying size (3.8 /20 kg) both in sinus rhythm and following 30 s of ventricular fibrillation [43]. Shocks varied from defibrillation threshold strength to 360 J. Contractility, as measured by left ventricular dP/dt, decreased from baseline in a shock strength dependent manner at 1, 10 and 30 s following the shock but had returned to baseline by 60 s for all shock strengths including the largest shocks in the smallest pigs, 90 J/kg. Likewise, ECG ST segment changes increased in a shock strength dependent manner at 1, 10, and 30 s following the shock but returned to baseline by 60 s for all shock strengths. Much of the hemodynamic alterations following the shock are thought to be due to the duration of the episode of ventricular fibrillation rather than to the shock itself. Panegrau and Abboud delivered 400 J capacitor discharge shocks to the chest wall of 14/24 kg dogs (17 /29 J/kg) following 15/30 s of fibrillation [44]. Immediately after the shock, they showed that postshock heart rate and mean arterial pressure were significantly lower than at baseline. Over the next 2/3 min, heart rate returned to baseline. By 1 min after the shock, mean arterial pressure had increased to a level greater than and then subsequently returned to baseline over the next 2 /3 min. In contrast, when the same shock was delivered to the chest wall during sinus rhythm, changes in hemodynamics were small and not statistically significant, with the exception of minimal reductions in mean arterial pressure. Kerber et al. reported no significant change in heart rate and aortic mean pressure following shocks of up to 100 J delivered to the epicardial surface or following damped sinusoidal shocks of up to 460 J delivered to the chest wall of 17 /45 kg (10 /27 J/kg) dogs during sinus rhythm [45]. When shocks of the same strength were delivered following 10/15 s of fibrillation, heart rate and mean arterial pressure transiently decreased. Park et al. have shown in humans that there is a negative logarithmic relationship between the duration of ventricular fibrillation and the return of systolic arterial pressure following defibrillation; longer periods of ventricular fibrillation G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 were followed by longer periods until arterial pressure recovery [46]. 8. Dysfunction caused by shocks delivered to ischemic animal hearts While many of the animal studies previously described involved hearts that were either non-ischemic or were exposed to ischemia only during a short duration of ventricular fibrillation, most transthoracic shocks are delivered to globally ischemic hearts because of a long duration of fibrillation in the pre-hospital setting. Studies of systolic and diastolic function following prolonged periods of ventricular fibrillation and defibrillation suggest that ischemic hearts may be more susceptible to a shock’s damaging effect than are nonischemic hearts. Yamaguchi et al. studied isolated rat hearts that were fibrillated for 8 min. Hearts were randomized to either ischemia or continued perfusion. Either 0.4 or 0.7 J monophasic damped sinusoidal shocks were delivered through epicardial electrodes [47]. Shocks caused significant impairment in systolic and diastolic function in a dose dependent fashion in the ischemic heart group. Changes in systolic and diastolic function were not seen in hearts that were continuously perfused during the 8 min of fibrillation time. Gazmuri et al. performed a similar study in isolated rat hearts but used 0.1 J monophasic damped sinusoidal shocks [48]. Six, 12 or no shocks were applied to hearts that were fibrillated for 25 min. The hearts were not perfused for the first 10 min of fibrillation and then were perfused at 20% of baseline for 15 min. No systolic dysfunction was seen after the delivery of 12 shocks compared with control hearts receiving no shocks (Fig. 5). Some diastolic dysfunction was seen following 12 shocks compared with control hearts but not following six shocks. Chapman et al. showed that defibrillation threshold was significantly correlated with left ventri- 65 cular mass [49]. If we scale these shocks to humans, then 0.1 J delivered to a /1.4 g rat heart, as done in the Gazmuri study, is equivalent to 21 J delivered to a 290 g human heart. Likewise, 0.4 J delivered to a /1.5 g rat heart, as done in the Yamaguchi study, is equivalent to 78 J delivered to a 290 g human heart. And 0.7 J delivered to a 1.5 g rat heart is equivalent to 137 J delivered to a 290 g human heart. Tang et al. compared the effect of single energy level, 150 J, biphasic shocks (3.3 /3.75 J/kg) and of escalating energy level, 200 /300 /360 J, monophasic shocks (4.4 /9 J/kg) on survival and post-shock cardiac function after either 4 or 7 min of ventricular fibrillation in a 40 /45 kg swine model. There was no difference in survival between the group that received the single dose biphasic shock and the group that received the escalating energy monophasic shocks. Hemodynamic indices and cardiac contractility indices, including mean arterial pressure, stroke volume, and left ventricular end-diastolic volume, were better in the single energy level biphasic shock group compared with the escalating energy monophasic waveform shock group. There were no differences in hemodynamic or contractility measures at 72 h [50]. Neimann et al. performed a similar study comparing constant energy 150 J biphasic shocks (4.2 /5.8 J/kg) to escalating energy, 200/300/360 J, monophasic truncated exponential shocks (5.5 /13.8 J/kg) after 5 min of ventricular fibrillation in a 26 /36 kg swine model. However, there was no difference in survival at 60 min following resuscitation between the two groups. Further, there were no differences in post-resuscitation hemodynamics and cardiac contractility indices, including mean arterial pressure, left ventricular dP/dt, and cardiac output [51]. These last two studies illustrate the conflicting data that are often obtained in different animal studies. Differences in protocols in each study, the type of anesthesia and the method of performing CPR, as well as the use of different indices of cardiac function can lead to conflicting conclusions. Both studies agree, though, that survival does not seem to be significantly influenced by shock size. Further, it should also be noted that if the shock magnitudes are expressed as a function of animal size, then the shocks in these studies are 1.6 /2.3 times larger than if the same studies were performed with 70 kg patients. 9. Mechanisms of damage Fig. 5. Mean9/ S.E.M. of heart rate, LVSP, left ventricular systolic pressure; BL, baseline; /dP/dtmax, maximal rate of pressure rise; / dP/dtmax, maximal rate of pressure decline for 0, 6 or 12 shocks. Data normalized and expressed as percentage of baseline values. Nine animals in each treatment group (reproduced with permission [48]). Several mechanisms have been described which may underlie the pathophysiological effects of high intensity electric shocks on cardiac tissue. These include electroporation, formation of oxygen derived free radicals, and conformational damage to ionic pumps or channels. All have in common damage to constituents of the cell 66 G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 membrane, which can result in a state in which ions can cross the cell membrane more freely [52]. Electroporation is a phenomenon in which the membrane of a cell exposed to high intensity electric field pulses is damaged. During the damaged period, the cell membrane is highly permeable to molecules present in the surrounding media through non-specific ‘holes’ in the cell membrane. Electroporation is frequently used to temporarily create openings in a cell membrane so that genetic material can enter the cell. Several studies have examined the electroporation phenomenon in cardiac myocytes. Tovar and Tung applied a step change in the transmembrane potential to isolated frog cells [24]. Monophasic shocks, 0.1 /100 ms in duration or symmetric (phase 2 /phase 1 amplitude and duration) biphasic shocks, 0.1 /10 ms total duration were applied. Step increases in membrane conductance, a marker for electroporation, occurred with a change in transmembrane potential of 400 /1000 mV. Breakdown potential decreased with increasing duration of the pulse. Neither waveform nor polarity affected the potential at which the step increase in membrane conductance occurred. To place these studies in perspective, it should be noted that the transmembrane potential changes a maximum of 100 mV in response to a shock potential gradient of up to 20 V/cm [53]. In a second study from Tung’s laboratory, multiple 10 ms 200 V/cm shocks were applied 10 s apart to chick embryo hearts in an effort to develop gene transfer techniques. Three shocks caused the uptake of propidium iodide, a 668 g/mol fluorescent DNA marker, in 6% of heart cells. Twelve shocks caused uptake in 11% of cells. Tissues were still viable for 48 h following the experiment [54]. In a similar study, Jones et al. shocked cultured chick embryo myocardial cells in media containing fluorescein isothiocyanate-labeled dextrans (FITC-dextrans) ranging in molecular mass from 4 to 70 kDa, using electric field stimulation 5 ms in duration and ranging in intensity from 0 to 200 V/cm [25]. The percentage of cells incorporating 4 /20-kDa dextrans increased in a dose-dependent manner. The 4- and 10kDa dextrans were incorporated beginning at intensities of 50 /100 V/cm. Dextran incorporation corresponded with shock intensities which produced a shock-induced arrest of spontaneous contraction lasting up to 1 min. The 20-kDa dextrans were incorporated following 150and 200-V/cm shocks. Shocks of these intensities also produced a transient post-shock contracture. Free radicals are ubiquitous compounds that occur naturally in biologic tissues. They contain a reactive unpaired electron, which can attack susceptible chemical groups on all classes of macro-molecules in the cell. Normally, the damage that free radicals cause is minimized by endogenous scavengers, which convert the free radicals to less reactive, and so less toxic, forms. Damage to cellular components and abnormal function may occur when free radical production exceeds the capacity of endogenous detoxification mechanisms. Defibrillation shocks delivered either directly to the heart or to the chest wall can produce free radicals. Caterine et al. delivered 10/100 J damped sinusoidal shocks via paddle electrodes held against the heart or 200 J shocks via paddle electrodes held against the chest wall of dogs during both sinus rhythm and ventricular fibrillation [55]. They showed that reactive oxygen species were increased in the coronary sinus effluent 5 /6 min following shock delivery. There was a significant linear relation between the shock energy and peak percent free radical increase. Shocks delivered to hearts after 30 s of ventricular fibrillation generated free radicals equal to but not greater than that observed during similar shocks delivered to hearts in sinus rhythm. Successive shocks of 100 J delivered two or five times did not cause greater free radical production than did a single 100-J shock, indicating that peak, not cumulative, energy is the principal determinant of free radical production. Smielecki et al. showed that plasma hydrogen peroxide concentration, a free radical reaction end product, was increased in the 10 min following cardioversion for atrial fibrillation or flutter [56]. Further, they showed a trend toward increased plasma hydrogen peroxide with increasing energy delivery. Increased free radical concentration has been correlated with both arrhythmia generation [57] and decreased contractility [58]. Electroporation and generation of reactive oxygen species may be related. Bonnofous et al. have shown that when Chinese hamster ovary cells in suspension are pulsed with DC shocks longer than 1 ms, both electroporation and generation of free radicals occurs and the threshold for generating both is the same, approximately 400 V/cm [59]. Further, they showed that cell death has the same threshold as free radical generation and electroporation. Based on these results, it may be that the generation of reactive oxygen species following shock delivery and electroporation may be different manifestations of the same phenomenon. Further studies are necessary to test this hypothesis. There are other components in the cell membrane that are potential targets for damage from large electrical shocks. It has been shown that the Na/K pump, a membrane spanning protein in the cell membrane, is susceptible to strong electrical pulses and is the source of up to 35% of the increase in membrane conductance seen following a strong electrical shock [60]. Recent data from voltage clamp studies of single skeletal muscle cells suggest that large transmembrane potentials may alter the conductance of ionic channels [61]. The transmembrane voltage step required to produce these changes in conductance was larger than that necessary to produce electroporation. A 4 ms /600 mV transmembrane shock pulse changed the conductivities of both sodium G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 and potassium channels whereas a /300 mV pulse resulted in a non-specific increase in membrane conductivity without changes in either the sodium or potassium channel conductivity consistent with electroporation. Recovery times are different for ion channel changes compared with electroporation changes. Recovery of the K channel conductance occurred over a period of tens of minutes compared with recovery from electroporation, which occurs over seconds to a few minutes. 67 tial with an amplitude up to three times greater than the paced action potential amplitude. This is in contrast to the non-ischemic region where the 100-V shock produced hyperpolarization in four hearts, and only a slight depolarization response in one heart (Fig. 6). This increased sensitivity of the transmembrane potential to a defibrillation shock suggests that shock fields may cause more damage or dysfunction to ischemic tissue than to normal tissue. 11. Physiology of post-shock dysfunction 10. Transmembrane potential changes due to shock Fundamentally, shocks defibrillate by causing a change in the transmembrane potential of the myocyte. Field stimulation delivered during both the refractory period of paced rhythm and during ventricular fibrillation have been shown to produce hyperpolarization in some myocardial regions and depolarization in other regions during the shock [62,63]. These changes are smaller than those reported to be necessary to cause electroporation or other damage. One study examined the changes in transmembrane potential during shock delivery to ischemic tissue. Holley et al. delivered shocks to regionally ischemic rabbit hearts during paced rhythm [64]. Following 7.5 min of ischemia, transmembrane potential changes caused by a 100 V shock delivered via two epicardial electrodes on either side of the ischemic region were significantly larger in the ischemic region than in the normal region. In the ischemic region, the shock elicited a depolarization response of the transmembrane poten- How phenomena like electroporation and free radical generation translate into physiologic changes is not entirely clear. Increases in intracellular calcium may be the common denominator. Shocks delivered to the epicardium in both rats and dogs produce diastolic dysfunction before producing systolic dysfunction [48]. Jones and Narayanan delivered a series of shocks to the chest wall of rats [65]. Immediately after shock delivery, the hearts were removed and sarcoplasmic reticulum enriched vesicles were isolated. The authors showed a decline in Ca2 uptake by the vesicles, which was negatively correlated with shock strength. The effect of the shock may be amplified during ischemia when Ca2 overload and diastolic dysfunction occurs secondary to the ischemia prior to the shock. It is not clear if these changes in the calcium uptake are a direct result of the shock or an indirect result secondary to increased intracellular calcium leaking through the cell membrane due to electroporation or membrane channel conformation changes. Fig. 6. Graph of the change in fluorescence amplitude over the duration of the shock (normalized as a percentage of paced action potential amplitude), and the timing of the shock during the action potential for monophasic (5 ms), biphasic (5/5 ms), biphasic (3/2 ms) and for normal (filled symbols) and ischemic (open symbols) tissue in five hearts (reproduced with permission [64]). 68 G.P. Walcott et al. / Resuscitation 59 (2003) 59 /70 12. Human studies Animal studies are useful in helping to point the way for future human subject research but cannot be relied on to direct patient treatment. Human defibrillation studies are hard to interpret, though, for a number of reasons: (1) the patients vary, (2) the causes of fibrillation vary, (3) the time to defibrillation varies, and (4) the care patients receive during and after resuscitation varies. The best way to control for all of these variables is to perform a well designed randomized prospective clinical trial. The most appropriate end point for these studies is survival to discharge from the hospital, which is the goal of all resuscitation attempts. Two clinical trials have been performed comparing the effect of shock energies on survival after pre-hospital sudden cardiac arrest. Weaver et al. compared the effect of two shock strengths on survival in humans [66]. A total of 249 patients were randomized to receive either one or two (as necessary) monophasic damped sinusoidal shocks of 175 or 320 J (2.5 or 4.6 J/kg for a 70 kg individual). If three shocks or more shocks were required, all subsequent shocks were 320 J. In a three-way analysis of variance, both return of spontaneous circulation and survival were inversely related to the total number of shocks delivered but neither of these outcomes was related to the level of energy used for the initial two defibrillation shocks. The higher energy shocks were more likely to leave the patient in atrio-ventricular block following multiple shocks, but this difference did not influence survival. Schneider et al. compared the effect of a protocol using a constant 150 J shock strength versus a protocol using an escalating 200/360 J shock strength [10]. The 150 J shock was a biphasic shock. Of the escalating 200/ 360 J shocks, 80% were monophasic truncated exponential shocks and 20% were monophasic damped sinusoidal shocks. In 115 patients with prehospital sudden arrest secondary to ventricular fibrillation, there was no difference in survival between the two shock types. An increased proportion of patients did have return of spontaneous circulation in the 150 J group compared with the 200 /360 J group, but this difference can be explained by the increased defibrillation efficacy of the biphasic waveform compared with the monophasic waveforms. If the comparison is limited to patients who were successfully defibrillated, 41 of 54 patients (75%) had return of spontaneous circulation in the 150 J group compared with 33 of 49 patients (67%) in the 200 /360 J group (P /NS). Both the Weaver study and the Schneider study suggest that there is neither increased survival nor decreased survival with the larger monophasic shocks. A comparison of low and high energy biphasic shocks has yet to be performed in the prehospital setting but is crucial for determining whether a constant low-strength or an escalating shock strength protocol is preferred with biphasic waveforms. 13. Summary Numerous studies have investigated the damaging effects of shocks up to 360 J delivered to both perfused and non-perfused hearts. Using the scaling argument presented above, 360 J shocks in 70 kg humans are about 5 J/kg. The evidence presented here suggests that for perfused hearts, the threshold for damage is well above this value. For non-perfused hearts, both in humans and animals, it appears that monophasic shocks of up to 5 J/kg are not associated with additional cardiac damage/dysfunction greater than that produced by the ischemic period itself and smaller shocks. Although many patients can be defibrillated with 150 J (2.2 J/kg) biphasic shocks, some patients may require biphasic shocks up to 360 J (5 J/kg) to be defibrillated. Studies still need to be performed comparing the efficacy and damaging effects of 360 J biphasic shocks to 150 J biphasic shocks, especially in humans. 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