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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
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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.
Acknowledgements
Supported in part by NIH Research grant HL-63775
and a grant from Medtronic Physio-Control. The
authors would like to thank Sharon Melnick and
Katherine Walcott for their help in the preparation of
this manuscript.
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