Full text of DOI:10.1111/j.1553-2712.2001.tb01155.x

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
909
SPECIAL CONTRIBUTIONS
Bench to Bedside: Resuscitation from Prolonged
Ventricular Fibrillation
M
ARK G. ANGELOS, MD, JAMES J. MENEGAZZI, P
HD,
CLIFTON W. CALLAWAY, MD, P
HD
Abstract. Ventricular fibrillation (VF) remains the two phases; phase I, achieving ROSC, and phase II,
most common cardiac arrest heart rhythm. Defibril- treatment of reperfusion injury. The focus in both
lation is the primary treatment and is very effective phases of resuscitation remains the heart and brain,
if delivered early within a few minutes of onset of VF. as prolonged VF remains primarily a two-organ dis-
However, successful treatment of VF becomes in- ease. These two organs are most sensitive to oxygen
creasingly more difficult when the duration of VF ex- and substrate deprivation and account for the vast
ceeds 4 minutes. Classically, successful cardiac arrest majority of early post-resuscitation mortality and
resuscitation has been thought of as simply achieving morbidity. This review focuses first on the initial re-
restoration of spontaneous circulation (ROSC). How- suscitation (achieving ROSC) and then on the reper-
ever, this traditional approach fails to consider the fusion issues affecting the heart and brain. Key
high early post–cardiac arrest mortality and morbid- words: ventricular fibrillation; cardiac arrest; resus-
ity and ignores the reperfusion injuries, which are citation; heart; brain. ACADEMIC EMERGENCY
manifest in the heart and brain. More recently, re- MEDICINE 2001; 8:909–924
suscitation from cardiac arrest has been divided into
ENTRICULAR fibrillation (VF) remains the arrest has been divided into two phases. The first
V
most frequent arrhythmia associated with phase of resuscitation is obtaining ROSC and the
human cardiac arrest. Despite a well-defined treat- second phase is supporting heart and brain dys-
ment modality, defibrillation, the overall survival function in the early reperfusion period (Fig. 1).
rate from an out-of-hospital VF cardiac arrest re- The focus in both phases of resuscitation remains
mains very low. The window of time for successful the heart and brain, as prolonged VF remains pri-
resuscitation with defibrillation alone is very nar- marily a two-organ disease. These two organs are
row—lasting only a few minutes. Generally this most sensitive to oxygen and substrate deprivation
time is less than the time required to bring a de- and account for the vast majority of early post-re-
fibrillator to the patient. Beyond this brief time suscitation mortality and morbidity. In this review
we focus first on the initial resuscitation (achieving
ROSC) and then on the reperfusion issues affect-
ing the heart and brain. An understanding of heart
and brain reperfusion is critical in designing fu-
ture successful therapies for resuscitation from
prolonged episodes of VF.
window of a few minutes, therapies in addition to
defibrillation are frequently needed. Classically,
resuscitation has primarily been thought of as
achieving restoration of spontaneous circulation
(ROSC). More recently, resuscitation from cardiac
P
HASE I: ACHIEVING ROSC
From the Department of Emergency Medicine, Ohio State Uni-
versity (MGA), Columbus, OH; and the Department of Emer-
gency Medicine, University of Pittsburgh (JJM, CWC), Pitts-
burgh, PA.
Section editors: Charles B. Cairns, MD, Division of Emergency
Medicine, University of Colorado Health Sciences Center, Den-
ver, CO, and Edward A. Panacek, MD, Division of Emergency
Medicine, UC Davis Medical Center, Sacramento, CA.
Received May 15, 2001; accepted May 23, 2001.
Address for correspondence and reprints: Mark G. Angelos,
MD, Department of Emergency Medicine, The Ohio State Uni-
versity, 016 Prior Health Sciences Library, 376 West Tenth Av-
enue, Columbus, OH 43210-1270; Fax: 614-292-7658; e-mail:
angelos.1@osu.edu
Initial Resuscitation. Initial resuscitation of the
heart from VF has the goal of restoring organized
electrical and contractile function. Defibrillation is
the only advanced life support (ALS) intervention
that works, but it is extremely time-sensitive. The
success rate for defibrillation declines by approxi-
mately 10% per minute of VF.1–3 The most recent
Advanced Cardiac Life Support (ACLS) guidelines
continue to espouse immediate defibrillation as the
initial therapeutic intervention for the treatment

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PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
Figure 1. Resuscitation from prolonged ventricular fibrillation (VF) consists of first achieving restoration of spon-
taneous circulation (ROSC) (phase I resuscitation) followed by heart and brain resuscitation (phase II resuscita-
tion). Optimal therapy during phase II ultimately will have to begin during phase I for best results, as significant
reperfusion injury happens within the first minutes of reperfusion. CPR = cardiopulmonary resuscitation; KATP
adenosine triphosphate = sensitive potassium; NA/H = sodium/hydrogen.
=
of all cases of VF and pulseless ventricular tachy- pulses restored, but the majority (58%) had ECG
cardia.4 Defibrillation is to be repeated up to three conversion to asystole/PEA. Thus, while the first
times before any other intervention is attempted. defibrillation was associated with the greatest like-
The rationale for using three stacked shocks would lihood of success, the second and third shocks had
seem to be supported by the fact that transtho- rapidly diminishing returns. So, in spite of the fact
racic impedance decreases with each subsequent that transthoracic impedance has been reported to
shock.5–7 Theoretically, this drop in impedance decrease with subsequent shocks, the clinical use
should result in more energy being delivered to the of using three stacked shocks of increasing energy
myocardium and a greater likelihood of affecting a did not result in increased defibrillation success.
critical mass of myocardial tissue.
Indeed, using three consecutive shocks without
But does the likelihood of successful defibrilla- other interventions interspersed may increase the
tion in humans increase during the first three likelihood of putting patients into asystole or PEA.
countershocks? A report from Hargarten et al., The strategy of delivering three successive defib-
which summarizes the results of defibrillation dur- rillation attempts prior to any other ALS interven-
ing a ten-year period in Milwaukee, suggests tions should be questioned.
otherwise.8 They looked at the results of the first
three defibrillation attempts in 1,497 patients with Defibrillation-induced Myocardial Injury. De-
witnessed, coarse VF. Of these patients, only 12% fibrillation is not an innocuous therapy. Passing
had a pulse restored after the first defibrillation, electrical current through the myocardium has
while 34% had an electrocardiogram (ECG) been demonstrated to cause both microscopic and
rhythm change to asystole or pulseless electrical macroscopic lesions, including myocardial necro-
activity (PEA). Since asystole and PEA are gener- sis.9,10 Defibrillation has also been shown to ad-
ally more refractory to resuscitation than VF, it versely affect enzyme activity,11 produce lactate,12
can be argued that having an ECG change from increase mitochondrial dysfunction,13 and decrease
VF to either asystole or PEA is a negative outcome. myocardial contractility.14 Interestingly, above a
So the odds ratio for having an unfavorable ECG certain threshold, increased shock energy can ac-
rhythm change to having pulses restored is 2.8 for tually decrease the efficacy of defibrillation.15
the first shock. After the second shock, 4% had Thus, the optimum energy level for defibrillation
pulses restored, while 16% converted to asystole/ should have the highest likelihood of success,
PEA (odds ratio of 4.0). Following the third shock, while causing the minimum amount of myocardial
2% got a pulse back, while 8% went from VF to damage. Various defibrillation waveforms differ in
asystole/PEA (odds ratio 4.0). Overall, the empiric efficacy at a given dose of energy, prompting the
use of three consecutive shocks for the initial treat- question what is the best defibrillation waveform
ment of VF resulted in 18% of patients’ having for use in the initial resuscitation of VF?

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
911
Monophasic vs Biphasic Waveforms. Most form shocks was conducted in patients during au-
transthoracic defibrillators in use today deliver tomated implantable cardioverter defibrillator
monophasic defibrillation waveforms. This tech- (AICD) surgery. Transthoracic shocks of 130 J bi-
nology has remained relatively unchanged for the phasic were compared with 200-J monophasic
past 30 years. Monophasic waveforms have only a shocks. This study showed that the two energy lev-
positive current; thus, the shape of the waveform els and waveforms produced similar first-shock
is determined by the speed and slope at which the successes, but that the biphasic group demon-
energy rises and falls. All monophasic waveforms strated fewer post-shock ECG abnormalities.28
begin with a positive upslope in current. If the cur- This study suggests that biphasic waveforms seem
rent gradually returns to zero, the shape is de- to be superior to monophasic waveforms on all
scribed as being ‘‘damped sinusoidal.’’ If the wave- fronts. However, most of the studies cited above
form drops instantly to zero, it is called ‘‘truncated were conducted in electrophysiology labs studying
exponential.’’ In contrast, biphasic waveforms, on VF of very short duration (15–30 seconds). It is not
the other hand, have both a positive phase and a immediately clear whether these findings can be
negative phase. Current is first pulsed in the pos- extrapolated to prolonged VF as is encountered in
itive direction, then the energy flow is reversed the out-of-hospital arena.
and crosses zero into the negative direction
(Fig. 2).
Two recent studies have compared biphasic and
monophasic transthoracic defibrillations in swine
While biphasic waveform use is relatively new, models of prolonged VF. The first study delivered
it has been extensively researched during the past escalating doses (first shock 2.5 J/kg, second shock
17 years.16–19 Biphasic defibrillation has been 3.5 J/kg, and third shock 4.5 J/kg) of energy for
shown to have superior defibrillating properties for both waveforms after 8 minutes of untreated VF,
both internal18,20–22 and external defibrillation.23,24 plus 1 minute of external chest compression and
Biphasic waveforms require less energy to achieve oxygen ventilation.29 This study showed that bi-
effective defibrillation when compared with mono- phasic defibrillation (7/17) produced a superior
phasic waveforms.21–24 Biphasic defibrillation is rate of ROSC when compared with monophasic de-
also associated with less post-shock myocardial fibrillation (1/17), but there was no difference in
damage and dysfunction at equivalent energy lev- one-hour survival rates. The second study com-
els.25–27 A multicenter trial comparing truncated bi- pared a fixed dose of biphasic defibrillation (150 J
phasic shocks with monophasic damped sine wave- first three shocks) with an escalating dose of mon-
Figure 2. The biphasic and damped sinusoidal waveforms used as delivered to a 75-ohm impedance. Reprinted
with permission from: Scheatzle MD, Menegazzi JJ, Allen TL, Durham SB. Evaluation of biphasic transthoracic
defibrillation in an animal model of prolonged ventricular fibrillation. Acad Emerg Med. 1999; 6:880–6.

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PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
ophasic defibrillation (200 J, 300 J, and 360 J) af- but these devices are designed to treat VF of very
ter 5 minutes of untreated VF.30 This study dem- short duration. There are very few studies directly
onstrated that the two waveforms produced simi- comparing biphasic and monophasic defibrillations
lar first-shock success rates (i.e., terminated VF) for the treatment of prolonged VF, and these have
and similar incidences of post-shock PEA with sub- shown no substantial differences in outcomes. Bi-
sequent shocks. There was also no difference in the phasic waveforms might have a safety advantage
numbers of animals that were successfully resus- over monophasic, but few studies have compared
citated. Taken together, these studies suggest bi- similar doses of energy (making it difficult to de-
phasic defibrillation is at least as good as mono- termine whether it is the waveform or the lower
phasic defibrillation. If, however, there is a safety energy that is responsible for decreased damage/
advantage to the use of biphasic waveform defib- dysfunction). It is not presently known which
rillation, this would seem to confer an advantage waveform is superior for defibrillating the human
to biphasic defibrillation over monophasic defibril- heart after prolonged VF. Futhermore, the opti-
lation.
mum energies for defibrillation, regardless of
The first biphasic automated external defibril- waveform, have not yet been determined.
lator (AED) was approved for use in the United
States in 1996. These devices use a fixed dose (150 Analysis of VF Waveform to Discriminate Early
J) of energy for all shocks. An early post-market VF and Prolonged VF. The problem, of course,
surveillance study showed that the devices termi- is that in the emergency setting, the duration of
nated VF at a high rate, when used on victims of VF is rarely known with any certainty or reliabil-
out-of-hospital cardiac arrest.31 In this study, the ity. One exception is when the onset of VF is ac-
authors report a first-shock successful rhythm con- tually witnessed by health care providers. In these
version rate of 89%, but an ROSC rate of only 56%. limited cases, immediate defibrillation is always
However, such reports must be interpreted with the initial treatment of choice. But what about the
care. Many studies utilize definitions of ‘‘success- more typical cases where a call for an apneic,
ful’’ that include ECG rhythm changes to PEA and pulseless patient is received by an emergency med-
even asystole. While electrophysiologists might ical services (EMS) dispatch unit and an ALS am-
consider these rhythms successful because they bulance cannot reach the patient for 6 or 8
terminate VF in the isolated setting of the electro- minutes? Advanced Cardiac Life Support training
physiological laboratory, most emergency physi- suggests that experienced clinicians can develop
cians would consider these to be less than success- the ability to differentiate very early (coarse) VF
ful because patients in these rhythms so rarely from very late ( fine) VF. Most experienced clini-
survive to hospital discharge.
cians also have a sense of which of these two
rhythms is more likely to result in successful de-
Defibrillation Energy Levels. It remains un- fibrillation. Is there a way to quantify these char-
clear whether low fixed, high, or escalating doses acteristics in waveform and, thus, relate them to
of energy are most effective. One recent study in the duration of time in VF? The answer may lie in
humans compared higher-energy transthoracic bi- chaos theory and applied fractal geometry.
phasic defibrillation (200 J) with low-energy bi-
phasic (130 J) and monophasic defibrillation at 200 Chaos Properties of VF. At first glance VF may
J.32 Conducted during AICD testing, the duration appear to consist of mere random fluctuation in the
of VF was again of short duration (mean Ϯ SD 19 electrical waveform. On closer inspection it ap-
Ϯ 10 seconds). Higher-energy biphasic defibrilla- pears to have chaotic properties, i.e., there is a
tion produced better first-shock results with a quantifiable underlying structure to the waveform.
100% success rate (39/39 attempts), compared with Whether chaos is actually present in VF has been
low-energy biphasic (83%, 39/47) and monophasic the subject of debate in the scientific literature.33–
(90%, 61/68) waveforms. These defibrillation rates 35 A recent study that analyzed the entire digitized
of the monophasic and low-energy biphasic wave- ECG waveform (not just peak-to-peak variability)
forms were not significantly different from each seems to offer proof that VF does indeed have cha-
other. At this writing, these data are the first evi- otic properties.36 In this study analyzing both por-
dence that increasing biphasic energy for the first cine and human VFs, under varying recording con-
shock may improve defibrillation success rates. ditions, Sherman et al. demonstrated that a flat,
Again, because the VF episodes were of very short ring-like, two-dimensional attractor could be con-
duration, these results may not be transferable to structed from VF recordings.36 Calculation of the
the type of VF that is encountered in the out-of- correlation and embedding dimensions, as well as
hospital environment.
Lyapunov and Hurst exponents, supported the
In summary, biphasic waveform defibrillation premise that the VF waveform possesses chaotic,
has become the industry standard for AICD use, nonrandom structure. These calculations consis-

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
913
tently demonstrate that VF is chaotic rather than tage of not being contaminated by extraneous fluc-
random. The scaling exponent is one estimate of tuations in amplitude. It was also noted that the
the fractal self-similarity dimension of the VF scaling exponent could be used to differentiate
waveform that was shown to correlate closely with early VF (<4 minutes) from late VF (>4 minutes)
the duration of VF, indicating that it might have (Fig. 3). Others have suggested that 4 minutes of
some clinical utility. Scaling exponent values are VF is an important treatment marker after which
low immediately after the onset of VF (mean Ϯ SD optimal treatment of prolonged VF may differ from
1.18 Ϯ 0.03), gradually increase through the first the optimal treatment of early VF.
5 minutes (1.29 Ϯ 0.06), and begin to plateau at
The scaling exponent does seem to be more than
12–14 minutes of VF (1.75 to 1.89) (Fig. 3). A low just a measure of VF duration. It may be useful in
scaling exponent value indicates VF of short du- predicting the outcome of defibrillation. In a pre-
ration and a high value indicates prolonged VF.
liminary study of 75 human AED recordings, the
Detailed examination of the scaling exponent pre-shock value of the scaling exponent predicted
showed that this measure not only correlates with the success or failure of the defibrillation.38 This
the duration of VF, but also is independent of am- study demonstrated that lower values of the scal-
plitude.37 This is an extremely important charac- ing exponent (indicating early VF) were associated
teristic. Amplitude of the ECG varies greatly from with return of organized electrical activity
patient to patient, and can be affected by many (ROEA), ROSC, and survival to hospital discharge.
other variables (type and size of electrode, elec- Receiver operating characteristic (ROC) curves re-
trode placement, lead selection, gain, skin resis- vealed that the scaling exponent accounted for 0.70
tance, body habitus, etc.). Thus, a quantitative tool of the area under the curve for predicting ROEA,
for estimating the duration of VF that is indepen- and an area under the curve of 0.84 for predicting
dent of recording conditions will have the advan- survival to hospital discharge.
Figure 3. Ventricular fibrillation (VF) waveform morphology changes after prolonged VF in swine. This change
can be measured using the scaling exponent, a statistic that is normalized for amplitude and therefore is indepen-
dent of recording conditions. Quantitative measures allow stratification of subjects into early or late (prolonged) VF.

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PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
Potential Clinical Applications. Therefore, we cocktail of drugs (that included an antioxidant)
may soon have the ability to use information con- and delayed countershock with the ACLS ap-
tained in the ECG signal to guide the use of elec- proach.44 When a combination of drugs and CPR
trical therapy. For example, it will soon be possible was given over a 2-minute period prior to the first
to determine the probability of successful defibril- shock, eight of eight (100%) of the animals had
lation in real time using the scaling exponent or ROSC and all (100%) survived to the one-hour end-
other quantitative ECG measures.39,40 If the prob- point. The group that was shocked first had three
ability of defibrillation success is high, then im- of eight (38%) attain ROSC with only one of eight
mediate defibrillation would be advised. If the (13%) surviving for one hour.
probability of defibrillation success is low, indicat-
In one of the most important studies in recent
ing prolonged VF, then other therapies [cardiopul- years, Cobb et al. conducted a prospective popula-
monary resuscitation (CPR) and drug administra- tion-based study in more than 1,100 cases of hu-
tion] would be advised prior to defibrillation (with man out-of-hospital VF.45 They introduced a 90-sec-
re-evaluation of the scaling exponent after the in- ond pretreatment therapy of CPR prior to
terventions have had time to take effect). The ju- defibrillation in an existing emergency medical
dicious use of defibrillation could result in a re- technician (EMT) AED program. They observed
duction of the number of patients who are shocked that pretreatment with 90 seconds of CPR was as-
out of VF into commonly lethal ECG rhythms (i.e., sociated with an increase in the rate of survival to
asystole and PEA). The fact that the initial ECG hospital discharge (30%) when compared with im-
characteristics may be able to identify patients mediate defibrillation (24% survival to discharge).
who will survive to hospital discharge has impli- The difference in survival rates was even more
cations for the entire chain of survival. Such real- pronounced when VF was prolonged (more than 4
time measures could potentially allow individual- minutes). These findings in two independent lab-
ized and titrated therapy rather than purely oratories, in two different higher-order species (ca-
algorithmic approaches.
nine and swine), coupled with one human study of
out-of-hospital VF, are strongly suggestive of the
Perfusion Prior to Defibrillation for Prolonged need to explore alternative therapies. The simpli-
VF. Since electrical therapy seems to be the only fied approach for treating all VF (shock–shock–
effective intervention we have to offer patients, the shock) may not be the optimum therapy, especially
push to make AED technology widely available, when VF is prolonged.
i.e., public access defibrillation (PAD), seems well
If the first defibrillation attempt is to be de-
founded.41 However, a wealth of evidence suggests layed in patients who are known to have been in
that defibrillation of prolonged VF may harm some prolonged VF, it remains unclear what the best al-
patients by converting their ECG rhythms from VF ternative therapy should be. The best choice of
to a more resuscitation-refractory rhythm. A small drug therapy prior to the first defibrillation at-
body of evidence suggests that other interventions tempt in prolonged VF is unclear. Some evidence
prior to the first defibrillation attempt (when VF shows that none of the drugs in the current ACLS
is prolonged) may improve defibrillation success.
armamentarium are associated with improved
Several basic science investigations provide in- overall outcome in the treatment of cardiac ar-
sight into the possible benefit of delaying defibril- rest.46,47 While epinephrine and, more recently, va-
lation. The first study was conducted in dogs after sopressin have been recommended to improve flow,
7.5 minutes of VF.42 This investigation compared human trials of single drug therapies have failed
immediate defibrillation with the use of high-dose to show significant improvement in survival to hos-
epinephrine (HDE) and 90 seconds of CPR prior to pital discharge.48–51 It is highly unlikely that there
defibrillation. Immediate defibrillation resulted in will ever be a single ‘‘magic bullet’’ drug to reverse
ROSC in three of 14 (21%) compared with nine of the complex physiologic cascade triggered by pro-
14 (64%) animals pretreated with HDE and CPR, longed VF. Thus, the use of perfusion drug cock-
which improved coronary perfusion prior to defib- tails (rather than singular drug treatments) for the
rillation. A second study done in swine, after 8 treatment of prolonged VF is a critical area for fu-
minutes of untreated VF, compared immediate de- ture research.
fibrillation with the administration of a four-drug
cocktail and 2 minutes of CPR before the first Perfusion Therapies. Therapy of VF is ex-
shock.43 This study showed that a drugs/CPR-first tremely time-sensitive. In contrast to acute myo-
approach resulted in a higher rate of ROSC (7/9, cardial infarction (AMI), the regional equivalent of
77%) and one-hour survival (4/9, 44%) when com- cardiac arrest, where the time frame to recover vi-
pared with defibrillation first (ROSC 2/9, 22%, and ability is measured in hours, in the global ischemia
one-hour survival 0/9, 0%). A follow-up study by of cardiac arrest, viability is measured in minutes.
the same investigators compared an expanded No effective pumping action occurs while the heart

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
915
ventricle continues to fibrillate. Traditionally we injury in the heart consist of 1) ventricular ar-
have relied on chest compressions to generate rhythmias and 2) left ventricular (LV) dysfunction.
some initial level of flow to facilitate defibrillation
If cardiac arrest times are relatively short, re-
after prolonged VF. Reliance solely on chest com- perfusion may result in a milder form of reperfu-
pression (standard CPR) techniques after pro- sion injury similar to myocardial stunning, which
longed VF is wholly inadequate for reperfusion, as has been best described after regional ischemia.63
the degree of blood flow generated is so low. Stud- The characteristics of myocardial stunning are re-
ies of CPR suggest this initial low CPR-generated versibility of contractile dysfunction with time and
blood flow further diminishes as the time of cardiac the absence of necrosis. In successfully resusci-
arrest lengthens.52 Future extra-cardiac circula- tated cardiac arrest victims, in the absence of on-
tory adjuncts, if utilized in a timely manner, could going ischemia (i.e., no coronary occlusion), the
provide this early reperfusion without a total re- post-ischemic LV dysfunction may be reversible. In
liance on the ischemic heart. Such adjuncts might other cases following ROSC, persistent LV contrac-
include closed chest cardiopulmonary bypass53,54 tile dysfunction may be secondary to ongoing ische-
and various enhancers of chest compression (i.e., mia from a low blood flow state or to myocardial
compressible vests that generate circumferential stunning or a combination of both mechanisms.
pressure)55 or adjuncts to improve CPR.56,57
Heart—Post-ischemic Dysfunction. The under-
lying mechanisms responsible for myocardial stun-
PHASE II: REPERFUSION
INJURY IN
ning differ some from those of classic reperfusion
injury. Whereas most reperfusion injury is medi-
ated by inflammatory injury from endothelial dys-
function and neutrophil activation, nonlethal isch-
emia with myocardial stunning is thought to be
oxidant-mediated rather than inflammatory-medi-
ated.64 Neutrophils, so prominent in the inflam-
matory cascades of reperfusion injury, do not ap-
pear to play a major role in myocardial stunning,
perhaps due to insufficient activation of chemotac-
tic factors, complement, and cellular adhesion mol-
ecules.65,66 Unlike myocardial infarction, the dura-
tion of ischemia in the successfully resuscitated
cardiac arrest heart is generally initially of insuf-
ficient duration to result in myocardial necrosis.
Instead, the early LV dysfunction is more likely
due to myocardial stunning.
H
EART AND RAIN
B
Only about 20% of cardiac arrest patients with
ROSC survive to hospital discharge.58 Most deaths
occur during the first 48 hours of intensive care,59
mainly due to cardiovascular or neurologic dys-
function. Indeed, the incidence of critical impair-
ment in organ systems other than the heart and
brain is relatively low, not high.60–62 The duration
of circulatory arrest is probably the largest deter-
minant of neurologic outcome and severity of re-
perfusion injury. With reperfusion of the heart and
brain, a number of metabolic processes accelerate.
Over hours to days these processes may lead to
worsening heart and brain injury, culminating
with early in-hospital mortality despite the initial
successful ROSC.
Myocardial Stunning. The two main criteria that
define myocardial stunning are 1) abnormal ven-
tricular function despite normal blood flow and 2)
the reversibility of myocardial dysfunction.67 Both
of these criteria are absent with myocardial ische-
mia. The underlying mechanisms thought to be re-
sponsible for myocardial stunning are 1) reactive
oxygen species (ROS) injury and 2) intracellular
calcium overload. Both mechanisms are thought to
result in contractile protein dysfunction. The basis
for the oxyradicals hypothesis is the burst of ROS
generation that occurs with the reintroduction of
oxygen to the ischemic tissue. These ROS have an
unpaired electron, which makes them highly re-
active within the cell and can result in damage to
proteins, unsaturated lipids, and DNA. It appears
that ROS injury at the cellular level may directly
damage the contractile proteins, resulting in con-
tractile protein dysfunction. This tenet is sup-
ported by experiments in which cardiac muscle ex-
Heart—Reperfusion. With the re-establishment
of blood flow, the function of a number of metabolic
and inflammatory pathways are accelerated within
the heart. Reperfusion injury is manifested across
a wide spectrum of severity, with the most severe
injury resulting in stimulation of multiple inflam-
matory pathways, leading to severe cellular dys-
function, necrosis, and apoptotic cell death. Reper-
fusion in the heart is initially characterized by a
hyperemia due to the hypoxic dilatation of the vas-
culature. With recovery of reactivity, often the ini-
tial hyperemia is followed by a hypoperfused state,
and in some areas of the heart a ‘‘no reflow’’ phe-
nomenon may occur. The ‘‘no reflow’’ phenomenon
in the microvascular bed is thought to be due to
capillary occlusion secondary to platelet/neutro-
phil occlusion, endothelial cell swelling, and im-
paired endothelial cell function resulting in re-
duced nitric oxide release. This has been best
characterized in regional myocardial ischemia and posed to ROS showed the same contractile
reperfusion. Clinical manifestations of reperfusion dysfunction as seen in stunned myocardium.68 The

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PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
second major hypothesis is transient intracellular Heart—Potential Reperfusion Therapies
calcium overload resulting in decreased respon-
Inotropic Support. In the early post-resuscita-
siveness of the contractile filaments to calcium.69
tion period, if myocardial dysfunction compromises
Intracellular calcium overload, which occurs with
adequate tissue perfusion (including myocardial
reperfusion, is thought to trigger myofilament dys-
perfusion), inotropic support may be required. This
function, leading to excitation contraction uncou-
treatment may be both effective and detrimental.
pling and decreased myocardial force with each
Studies in regional myocardial ischemia models of
contraction. Most likely myocardial stunning is
stunning note myocardial dysfunction can be re-
due to a combination of the two mechanisms.
versed with epinephrine.77 In another study of re-
gional ischemia in a swine model, dobutamine ef-
fectively improved myocardial function in the
Post-arrest LV Contractile Dysfunction. Post–
cardiac arrest LV dysfunction has been described
stunned myocardium, but at a metabolic price.
in animal models. The degree of LV dysfunction
increases as the length of ischemic VF increases.70
Creatine phosphate was noted to decrease, and lac-
tate to increase, in the stunned myocardium.78 An-
Post-resuscitation myocardial dysfunction in a
other study in swine noted reversal of dysfunction
swine model of VF with 4 minutes of global isch-
with dobutamine, with no creatine phosphate over-
emia followed by 8 minutes of CPR and then defi-
shoot as was seen in control during reperfusion,
brillation was characterized by reduced contractile
function and ventricular dilation.71 In a swine
and adenosine triphosphate (ATP) levels were
maintained.79 In a VF cardiac arrest swine model,
model of VF cardiac arrest of 10 or 15 minutes,
dobutamine was shown to reverse early post-re-
both systolic dysfunction and diastolic dysfunction
suscitation myocardial dysfunction.80
were noted between two and five hours after initial
resuscitation. This dysfunction was characterized
by diffuse systolic wall motion abnormalities, de-
creased ejection fraction, increased end-systolic
volume, reduced cardiac output, and decreased tau
(a function of isovolumetric relaxation). All of these
parameters were improved at 24 hours and re-
turned to normal by 48 hours.72 This study sug-
gests that if early post-VF dysfunction can be sup-
ported and ongoing ischemia prevented, contractile
function can recover.
Epinephrine used during resuscitation may ex-
acerbate the post-resuscitation dysfunction. In a
rat model of VF cardiac arrest, epinephrine was
compared with phenylephrine, epinephrine ϩ es-
molol, and placebo. The dP/dt and the survival
time were significantly depressed in the post-re-
suscitation period compared with phenylephrine.
This effect was ameliorated in the epinephrine ϩ
esmolol group, suggesting beta-1 agonist activity
may exacerbate the early post-resuscitation dys-
function.73 A confounding factor in this study was
the significant higher defibrillation requirement in
the epinephrine group, which could itself be re-
sponsible for increased dysfunction. In a separate
study without adrenergic agents, the degree of
post-resuscitation dysfunction was directly propor-
tional to the defibrillation energy used.74 In an-
other study with the same model, both carbon di-
oxide (CO2)-generating and CO2-consuming buffer
agents administered during CPR seemed to lessen
post-resuscitation myocardial dysfunction.75 How-
ever, a later study by the same group found greater
post-resuscitation myocardial dysfunction after ad-
ministration of buffer in combination with an ad-
Metabolic Support. With the onset of ischemia,
anaerobic metabolism allows for a temporary, al-
beit reduced, ongoing level of high-energy phos-
phate synthesis. Eventually glycolysis is inhibited
by the accumulation of by-products, reduced nico-
tinamide adenine dinucleotide (NADH), lactate,
and protons.81 Restoration of normal perfusion (re-
perfusion) does not necessarily result in the heart’s
resuming regular metabolic function. Tricarboxylic
acid (TCA) cycle function may be depressed sec-
ondary to depletion of TCA cycle intermediates.
The heart is capable of utilizing different sub-
strates depending on concentration and workload.
This is true of the perfused fibrillating heart as
well.82 During reperfusion, the heart preferentially
utilizes free fatty acids due to high circulating lev-
els of free fatty acids, as a result of high concen-
trations of circulating catecholamines. Free fatty
acid oxidation inhibits glucose uptake and glucose
oxidation (by inhibiting pyruvate dehydrogenase).
Free fatty acid oxidation requires higher levels of
oxygen consumption that result in oxygen wastage.
In addition, free fatty acid metabolites during is-
chemia are themselves toxic to the myocardium.83
Post-ischemic metabolic support for the heart
has primarily consisted of increasing myocardial
glucose uptake and utilization and repletion of
TCA intermediates and amino acids. During isch-
emia, with some preserved flow allowing for glu-
cose delivery to the myocytes, ATP derived from
glycolysis is preferentially used to maintain mem-
brane integrity.84 With reperfusion, glucose is the
preferred substrate of the heart, resulting in better
function with less oxygen utilization. Glucose, in-
renergic agent as compared with an adrenergic sulin and potassium (GIK) have been utilized in
with placebo.76
patients following AMI and cardiac surgery with

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
917
TABLE 1. Potential Reperfusion Therapies for the Heart and Brain
Heart*
Brain
Inotropes (dobutamine)
Metabolic (GIK, amino acids)
Excitatory amino acid antagonists
Antioxidants
Antioxidants (SOD, catalase, melatonin, vitamin E)
KATP openers (nicorandil, aprikalim)
Hypothermia
Blood flow promotion
Growth factors
ϩ
ϩ
Na /H exchange inhibitors (cariporide)
ϩ2
ϩ2
Ca blockers (calpain inhibitors, Ca channel blockers)
Caspase or calpain inhibitors
*GIK = glucose, insulin, and potassium; SOD = superoxide dismutase; KATP = adenosine triphosphate-sensitive potassium;
ϩ
ϩ
ϩ2
NA /H = sodium/hydrogen; Ca = calcium.
some success. Most of the early AMI studies were tase (SOD), and catalase. Glutathione oxidation in
inconclusive. However, a recent meta-analysis of cells (including myoctyes) reduces hydrogen per-
randomized, placebo-controlled studies in AMI
showed a 28% reduction in early mortality with
GIK treatment.85 A recent multicenter trial, ECLA,
noted a significant reduction in early AMI mortal-
ity with GIK.86 However, a second multicenter
study failed to show any benefit with GIK follow-
ing AMI.87 Further trials are anticipated to resolve
this issue. In the post-ischemic heart, insulin in-
creases myocyte glucose uptake by translocation of
glucose transporters within the cell membrane, de-
creases plasma free fatty acid levels, and may di-
rectly stimulate pyruvate dehydrogenase, thereby
promoting TCA cycle function.88 Large doses of in-
sulin were noted in animal models to have an ino-
tropic effect.89 Recently, we noted that GIK admin-
istration during reperfusion following global
ischemia in the isolated perfused heart improved
post-ischemic LV function and recovery of high-en-
ergy phosphates.90,91
Amino acid replacement has been shown to im-
prove hemodynamic outcome in postoperative
hearts.92 Specifically, postoperative infusions of
amino acids, glutamate, and aspartate have shown
some benefit. The value of repleting these amino
acids is probably due to their role in the malate–
aspartate shuttle, which transfers reducing equiv-
alents from NADH in the cytosol to the mitochon-
dria where they are utilized in the electron-
transport chain. Another amino acid that may
have a role in the reperfusion period is arginine,
due to its metabolism to nitric oxide. The value of
these metabolic therapies in the setting of early
resuscitation from VF cardiac arrest is not known.
oxide to water. Superoxide dismutase changes su-
peroxide radical to hydrogen peroxide, which is
then reduced to water by either glutathione or cat-
alase. Other intracellular ROS-reducing agents
(antioxidants) include ascorbate, vitamin E, and
beta-carotene. These mechanisms protect the cell
unless the increase in ROS overwhelms the cellu-
lar defenses as may occur during reperfusion fol-
lowing a period of ischemia. With ischemia reper-
fusion, there is a burst of ROS, which overwhelms
the cellular defenses and results in cellular injury.
A number of studies have investigated the use
of antioxidants to ameliorate ROS injury during
early reperfusion of the myocardium. In earlier ex-
periments using regional ischemia models, anti-
oxidant therapy consisting of SOD and catalase
was shown to improve regional contractile function
after 15 minutes of occlusion and three hours of
reperfusion.93–95 This constituted indirect evidence
that ROS were associated with reperfusion myo-
cardial injury. Later studies provided more direct
evidence for the role of ROS-mediated reperfusion
injury. Using a spin trap analysis, alpha-phenyl N-
tert-butyl nitrone (PBN), and electron spin reso-
nance in the anesthetized open-chest dog model,
Bolli et al. noted free radical production was pro-
portional to the intensity of ischemia before reper-
fusion and was markedly decreased with SOD and
catalase.96 They noted improved post-ischemic sys-
tolic wall thickening with antioxidant therapy.
This finding was confirmed in the conscious, non-
anesthetized dog model, where a burst of ROS was
noted at the time of reperfusion after 15 minutes
of regional ischemia and peaked at 1–2 minutes
after reperfusion. Antioxidants attenuated this
ROS burst and improved wall function following
reperfusion.97
Antioxidants. Oxidative stress with formation of
ROS is an ongoing process, being a normal by-
product of aerobic metabolism. From molecular ox-
ygen, reactive intermediates of superoxide, hydro-
gen peroxide, and hydroxyl radicals are all formed.
All of theses compounds are characterized by an
unpaired electron, which makes them highly re-
active. Under normal circumstances the cell is able
to deal with this oxidative stress through its own
intrinsic reducing pathways. These internal anti-
Antioxidant therapy for cardiac arrest has been
investigated in cardiac arrest models as part of a
broader ‘‘reperfusion cocktail’’ therapy.44,98 How-
ever, it is difficult to isolate the role of antioxidants
independent of the other cocktail components in
these studies. In models of ischemia–reperfusion,
oxidants include glutathione, superoxide dismu- other ROS scavengers have shown amelioration of

918
PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
reperfusion injury and myocardial stunning. Mel- multiple species of ischemic reperfusion models to
atonin, a hydroxyl radical scavenger, was noted to improve post-ischemic LV function, to conserve
improve recovery of post-ischemic LV function.99 ATP during ischemia, to enhance ATP regenera-
Vitamin E was noted to scavenge peroxyl radicals tion during reperfusion, and to decrease myocar-
and reduce the incidence of VF with reperfusion.100 dial infarct size.106,107 These agents appear to be
Alpha-tocopherol analogs have inhibited lipoperox- most effective when given before the onset of isch-
ide production and decreased incidence of reper- emia. The effect of these agents given during re-
fusion arrhythmias.101
perfusion only is very weak, suggesting much of
In summary, antioxidant therapies have been their benefit may occur during ischemia.108 An-
shown, in numerous basic science and animal stud- other potential obstacle to their use in clinical
ies of myocardial ischemia and reperfusion, to models of ischemia and reperfusion is their signif-
ameliorate ROS production and improve post-is- icant vasodilatory activity leading to profound hy-
chemic contractile dysfunction. This is, however, potension. This hypotension has been circum-
less well studied in models of cardiac arrest. A pri- vented in models where KATP channel openers were
mary obstacle to antioxidant therapy in cardiac ar- given intracoronary.109 While these agents have not
rest is the need to administer the antioxidant prior been specifically investigated in cardiac arrest,
to reperfusion so as to be in the tissues during they may be of potential benefit in cardiac arrest
early reperfusion. Studies indicate they are most if they could be administered during ischemia
effective when given pre-ischemia.
prior to reperfusion.
Na؉/H؉ Exchange (NHE). With reperfusion of
the ischemic heart, preservation of the intracellu-
lar acidosis has been shown to improve post-isch-
emic function.110 It is thought that the rise in in-
tracellular pH early in reperfusion makes the
myofilaments vulnerable to injury. Other studies
have shown that reduction of the intracellular cal-
KATP Channel Openers. KATP channels were first
described in ventricular myocytes by Noma.102
During ischemia, these channels open, allowing
the egress of intracellular potassium to the extra-
cellular space. Physiologic concentrations of ATP
inhibit channel opening and thus these channels
were initially termed ‘‘ATP-dependent potassium
channels.’’ Subsequently, a number of other mod-
ulators of the KATP channels have been noted.
These include pH, fatty acids, nitric oxide, SH-re-
dox state, G-proteins, and various ligands, includ-
ing adenosine. As a result, these KATP channels are
now termed ‘‘ATP-sensitive potassium channels.’’
An important role of these channels in ischemia
and reperfusion has recently been elucidated. KATP
channel opening seems to be the mediator of
ischemic preconditioning. Administration of KATP
channel blockers completely abolishes precondi-
tioning. Adenosine A1 receptor activates KATP chan-
nel opening, and conversely administration of
adenosine A1 blockers extinguishes precondition-
ing, suggesting a common signaling pathway. Cur-
rent thoughts are that adenosine A1 receptor ac-
tivation mobilizes protein kinase C (PKC), which
in turn activates KATP channel opening. Blocking
these channels abolishes the ischemic pre-condi-
tioning response.103 More recent evidence suggests
that it is not the sarcolemmal KATP channels that
mediate cardioprotection, but instead the mito-
chondrial KATP channels.104
ϩ2
cium (Ca ) overload, which occurs at the time of
reperfusion, improves post-ischemic myocardial
ϩ
ϩ2
function. The sodium/calcium (Na /Ca ) ex-
changer in the cell is responsible for the intracel-
ϩ2
lular Ca overload, which occurs at the time of
reperfusion. During ischemia, the sodium/hydro-
ϩ
ϩ
gen (Na /H ) exchanger is stimulated as H ions
accumulate within the ischemic cell.111 The Na /
ϩ
ϩ2
Ca exchanger is stimulated during reperfusion
ϩ
by the increased intracellular Na concentrations,
which result in large part from the stimulation of
ϩ
ϩ
the Na /H exchanger by the decreasing intracel-
ϩ
lular pH during ischemia. As a result, H is
ϩ
pumped out of the cell and Na is pumped in. With
ϩ
ϩ2
reperfusion, the Na /Ca exchanger is activated,
ϩ2
and Ca is pumped into the cell in exchange for
ϩ
the electro-neutral Na , which is pumped out. The
ϩ2
result is intracellular Ca overload.112
A number of recent studies have focused on spe-
ϩ
ϩ
cific blockers of the Na /H exchange. Isolated per-
fused rat hearts treated with cariporide, a specific
ϩ2
NHE blocker, had lower [Ca ]i (intracellular) and
prolonged lower pHi during early reperfusion com-
pared with control hearts.113 In another study, iso-
lated guinea pig hearts treated with cariporide had
improved post-ischemic function, higher creatine
phosphate levels during reperfusion, and de-
This mechanism seems to be important in myo-
cardial stunning as well. Utilization of a KATP chan-
nel opener, aprikalim, in a canine model of 15-
minute coronary artery occlusion followed by
reperfusion was noted to improve post-ischemic
ϩ
creased [Na ]i during ischemia.114 In both of theses
contractile dysfunction (myocardial stunning).105
A
studies, cariporide was given pre-ischemia, which
number of agents, including nicorandil, pinacidil, limits its clinical utilization in reperfusion of car-
cromakalim, and aprikalim, have been shown in diac arrest. Currently, cariporide is undergoing

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
919
Figure 4. Multiple mechanisms of injury are active at different times during brain reperfusion. Interventions
targeting events during ischemia and early reperfusion (such as free radicals) will have less efficacy if delayed,
whereas interventions that target later events (such as altered gene expression) may have longer therapeutic
windows.
clinical trials in acute myocardial infarction pa- present in many tissues, including the myocar-
tients.115–117
dium. Support for calpain-induced contractile dys-
function is found in studies that show exposure of
the myofilaments to calpain I reproduces the same
type of myofilament dysfunction without ischemia.
This dysfunction is reversed or prevented by co-
incubation of the myofilaments with calpastin, a
calpain inhibitor.125 Use of calpain inhibitors in
models of ischemia and reperfusion has shown im-
proved function in isolated perfused hearts.126,127
Calcium Blockers. Calcium channel blockers
have been known to lessen the effects of myocar-
dial ischemia.118,119 Calcium channel blockers have
also been effective in various models of ischemia
and reperfusion in diminishing the degree of myo-
cardial stunning.120,121 This effect, however, may be
primarily mediated by the effects during ischemia
rather than at the time of reperfusion. Presumably
by modifying the ischemic insult, one indirectly
ameliorates the reperfusion injury, as the duration
and extent of ischemia determine the severity of
the injury induced by reperfusion. Calcium chan-
nel blockers seem to be of limited value when given
after reperfusion. Calcium channel blockers may
also be effective as ROS scavengers during isch-
emia and reperfusion.122
Brain—Reperfusion. Many of the metabolic
changes observed in the reperfused heart are also
present in the reperfused brain. Analogous to post-
ischemic myocardial dysfunction, a period of global
brain dysfunction clinically manifest as coma often
follows global brain ischemia, even when ultimate
neurologic recovery is favorable. The biochemical
complexities of reperfusion brain injury have re-
cently been reviewed126 and are beyond the scope
of this paper. However, a brief overview of mech-
anisms that are potential targets for therapy dur-
ing and after resuscitation can highlight implica-
tions for treatment of patients with prolonged
cardiac arrest (Fig. 4).
ϩ2
Various studies suggest that Ca availability
within the cell is not diminished in stunned myo-
cardium. Instead, the contractile response to cal-
cium appears to be diminished. Immunohisto-
chemistry studies suggest that the underlying
problem is diminished myofilament responsiveness
to calcium.123,124 Contractile dysfunction is due to
damage to the contractile proteins, which occurs at Brain Reperfusion. Several triggers of neuronal
the time of reperfusion, but was not seen during death are present during ischemia and immedi-
ischemia.125 Some investigators have postulated ately after reperfusion of the ischemic brain: en-
that this injury to contractile proteins is the result ergy failure, excitatory amino acid release, and
of calcium-activated proteases, such as calpain I.69 free radical generation. However, these changes
The calcium overload, which occurs in reperfused appear to be transient. High-energy phosphates re-
myocytes, is sufficient to activate calcium-acti- turn to near normal levels within 20 minutes of
vated proteases known as calpains. Calpains are reperfusion.127 Likewise, elevated excitatory amino

920
PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
acid levels return to near normal levels within 30– sion.154 Clinical trials of induced hypothermia are
60 minutes.128 Finally, oxidative stress detected by ongoing.155
depletion of cellular antioxidants occurs immedi-
ately after reperfusion and recovers within two
CONCLUSIONS
hours.129
During the subacute phase of brain reperfusion,
Taken together, these data illustrate that the
brain, like the heart, suffers a period of depressed
function after cardiac arrest during which the mo-
lecular manifestations of injury continue to unfold.
Reversal of the no-flow state after prolonged VF
must occur in minutes in order to both obtain
ROSC (phase I resuscitation) and limit heart and
brain dysfunction following ROSC (phase II resus-
citation). Although initial cardiac arrest resusci-
tation (phase I) must occur within minutes, the in-
jury and dysfunction associated with reperfusion
may persist for hours to days. Different tailored
therapies may be needed for phase I and phase II
resuscitation. With improved understanding of the
complex pathways involved in ischemia and reper-
fusion in the heart and brain, a cocktail combina-
tion of therapies will probably be needed. This
post-resuscitation dysfunctional period is another
window of therapeutic opportunity that may be
used to decrease the high post–cardiac arrest mor-
bidity and mortality.
regional and global cerebral hypoperfusion can be
accompanied by altered gene expression. Cerebral
hypoperfusion occurs both regionally and globally
after reperfusion130,131 and can result in secondary
brain injury. During the same interval of reperfu-
sion, increased activation of several specific tran-
scription factors is observed.132 Consequently, par-
ticular genes are expressed at increased levels
after global ischemia,133 including both gene prod-
ucts associated with programmed cell death134–136
and those associated with neuronal survival.137 Fi-
nally, neuronal death occurs over hours and days
after reperfusion, and is associated with increases
in certain cell death effectors. These effectors in-
clude Bax protein expression,134,135 enzyme release
from mitochondria,138 caspase activation,136 and
DNA cleavage.139
Therapeutic Interventions. Two earlier multi-
center studies specifically tested the use of thio-
pental and a calcium channel blocker, lidoflazine,
in clinical cardiac arrest. Both trials were designed
to evaluate the best neurologic recovery achieved
at six months following administration of pento-
barbital140 and lidoflazine141 soon after ROSC. In
both studies, the study drug was administered
early after ROSC in comatose cardiac arrest sur-
vivors. There was no difference in six-month sur-
vival or in best neurologic recovery achieved with
either treatment.
In preclinical studies, drugs targeted at specific
mechanisms of brain injury, including excitatory
amino acid antagonists,142,143 free radical scaven-
gers,144 and reduced oxygen tension,145 have failed
to produce any dramatic improvement in neurol-
ogic outcome. Treatment after reperfusion already
may be too late to alter outcome. Recently caspase
inhibtors have shown equivocal effects on ischemic
neuronal injury.146,147 Perhaps by the time these ef-
fectors of cell death are activated, neuronal injury
has progressed too far to allow functional recovery.
Less specific physical manipulations have
shown more robust improvement. Induction of
mild hypothermia, for example, can dramatically
improve neuronal survival after cerebral arterial
occlusion or cardiac arrest.148–150 In contrast to
drugs, this type of physical manipulation can in-
terfere with many of the early triggers of brain in-
jury151,152 as well as intracellular signaling path-
ways controlling gene expression.153 Similarly,
controlled hypertension and optimal blood rheol-
References
1. Becker LB. The epidemiology of sudden death. In: Paradis
NA, Halperin H, Nowak R (eds). Cardiac Arrest: The Science
and Practice of Resuscitation Medicine. Baltimore, MD: Wil-
liams & Wilkins, 1996.
2. Eisenberg MS, Horwood BT, Cummins RO, et al. Cardiac
arrest and resuscitation: a tale of 29 cities. Ann Emerg Med.
1990; 19:179–86.
3. Larsen MP, Eisenberg MS, Cummins RO, Hallstrom AP.
Predicting survival from out-of-hospital cardiac arrest: a
graphic model. Ann Emerg Med. 1993; 22:1652–8.
4. Emergency Cardiac Care and Committee and Subcommit-
tees, American Heart Association. Guidelines for cardiopul-
monary resuscitation. Part 6: Advanced Cardiovascular Life
Support, Section 2: Defibrillation. Resuscitation. 2000; 46:109–
13.
5. Kerber RE, Grayzel J, Hoyt R, Marcus M, Kennedy J.
Transthoracic resistance in human defibrillation: influence of
body weight, chest size, serial shocks, paddle size and paddle
contact pressure. Circulation. 1981; 63:676–82.
6. Sirna SJ, Ferguson DW, Charbonnier F, Kerber RE. Factors
affecting transthoracic impedance during electrical cardiover-
sion. Am J Cardiol. 1988; 62:1048–52.
7. Dahl CF, Ewy GA, Ewy MD, Thomas ED. Transthoracic im-
pedance to direct current discharge: effect of repeated counter-
shocks. Med Instrum. 1976; 10:151–4.
8. Hargarten KM, Steuven HA, Waite EM, et al. Prehospital
experience with defibrillation of coarse ventricular fibrillation:
a ten year review. Ann Emerg Med. 1990; 19:157–62.
9. DiCola VC, Freedman GS, Downing SE, Zaret L. Myocar-
dial uptake of technetium-99m stannous pyrophosphate follow-
ing direct current transthoracic countershock. Circulation.
1976; 54:980–6.
10. Doherty PW, McLaughlin PR, Billingham M, Hernoff R,
Goris ML, Harrison DC. Cardiac damage produced by direct
current countershock applied to the heart. Am J Cardiol. 1979;
43:225–32.
11. Ehsani A, Eqy GA, Sobel BE. Effects of electrical counter-
ogy can mitigate regional cerebral hypoperfu- shock on serum creatine phosphokinase (CPK) isoenzyme ac-

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
921
tivity. Am J Cardiol. 1976; 37:12–8.
34. Gray RA, Pertsov AM, Jalife J. Spatial and temporal or-
12. Trouton PG, Allen JD, Young LK, Rooney JJ, Adgey AAJ. ganization during cardiac fibrillation. Nature. 1998; 392:20–1.
Metabolic changes and mitochondrial disfunction early follow- 35. Witkowski FX, Leon LJ, Penkoske PA, et al. Spatiotem-
ing transthoracic countershocks in dogs. PACE. 1989; 12: poral evolution of ventricular fibrillation. Nature. 1998; 392:
1827–34.
78–82.
13. Warner ED, Dahl C, Eqy GA. Myocardial injury from 36. Sherman LD, Callaway CW, Menegazzi JJ. Ventricular fi-
transthoracic defibrillator countershock. Arch Pathol. 1975; 99: brillation exhibits dynamical properties and self-similarity. Re-
55–63.
suscitation. 2000; 47:163–73.
14. Wilson CM, Allen JD, Bridges JB, Adgey AAJ. Death and 37. Callaway CW, Sherman LD, Menegazzi JJ, Scheatzle MD.
damage caused by multiple direct current shocks: studies in Scaling structure of electrocardiographic waveform during pro-
animal model. Eur Heart J. 1989; 10:528–36.
longed ventricular fibrillation in swine. Pacing Clin Electro-
15. Cates AW, Wolf PD, Hillsley RE, Souza JJ, Smith WM, physiol. 2000; 2:180–91.
Ideker RE: The probability of defibrillation success and the in- 38. Callaway CW, Sherman LD, Mosesso VN, Dietrich TJ,
cidence of postshock arrhythmia as
strength. PACE. 1994; 17:1208–17.
a
function of shock Holt E, Clarkson MC. Scaling exponent predicts defibrillation
success for out-of-hospital ventricular fibrillation cardiac ar-
16. Schuder JC, Gold JH, Stoeckle H, McDaniel WC, Cheung rest. Circulation. 2001; 103:1656–61.
KN. Transthoracic ventricular defibrillation in the 100kg calf 39. Watson JN, Addison PS, Clegg GR, Holzer M, Sterz F, Rob-
with symmetrical one-cycle bi-directional rectangular wave ertson CE. A novel wavelet transform based analysis reveals
stimuli. IEEE Trans Biomed Eng. 1983; 30:415–22.
17. Jones JL, Jones RE, Balasky G. Improved cardiac cell ex-
citation with symmetrical biphasic defibrillator waveforms. Am
J Physiol. 1987; 253:H1418–H1424.
18. Chapman PD, Vetter JW, Souza JJ, Wetherbee JN, Troup
PJ. Comparison of monophasic with single and dual capacita-
tor biphasic waveforms for nonthoracotomy canine internal fi-
brillation. J Am Coll Cardiol. 1989; 14:242–5.
19. Gliner BE, Lyster TE, Dillion SM, Bardy GH. Transtho-
racic defibrillation of swine with monophasic and biphasic
waveforms. Circulation. 1995; 92:1634–43.
20. Wyse DG, Kavanagh KM, Gillis AM, et al. Comparison of
biphasic and monophasic shocks for defibrillation using a non-
thoracotomy system. Am J Cardiol. 1993; 71:197–202.
21. Winkle AW, Mead RH, Ruder MA, et al. Improved low-
energy defibrillation efficacy in man with the use of a biphasic
truncated exponential waveform. Am Heart J. 1989; 117:
122–7.
22. Bardy GH, Ivey TD, Allen MD, Johnson G, Mehra R,
Greene HL. A prospective randomized evaluation of biphasic
versus monophasic waveform pulses on defibrillation efficacy
in humans. J Am Coll Cardiol. 1989; 14:728–33.
23. Greene HL, Dimarco JP, Kudenchuck PJ, et al. Compari-
son of monophasic and biphasic defibrillating pulse waveforms
for thransthoracic cardioversion. Am J Cardiol. 1995; 75:1135–
8.
24. Swartz JF, Fletcher RD, Karasik PE. Optimization of bi-
phasic waveforms for human nonthoracotomy defibrillation.
Circulation. 1993; 88:2646–54.
25. Jones JL, Milne KB. Dysfunction and safety factor
strength–duration curves for biphasic defibrillator waveforms.
Am J Physiol. 1994; 266:H263–H271.
26. Osswald S, Trouton TG, O’Nunain SS, Holden HB, Ruskin
JN, Garan H. Relation between shock-related myocardial in-
jury and defibrillation efficacy of monophasic and biphasic
shocks in a canine model. Circulation. 1994; 90:2501–9.
27. Reddy RK, Gleva MJ, Gliner BE. Biphasic transthoracic
defibrillation causes fewer ECG ST-segment changes after
shock. Ann Emerg Med. 1997; 30:127–34.
28. Bardy GH, Marchlinski FE, Sharma AD, et al. Multicenter
comparison of truncated biphasic shocks and standard damped
sine wave monophasic shocks for transthoracic ventricular de-
fibrillation. Circulation. 1996; 94:2507–14.
29. Scheatzle MD, Menegazzi JJ, Allen TL, Durham SB. Ev-
alutaion of biphasic transthoracic defibrillation in an animal
model of prolonged ventricular fibrillation. Acad Emerg Med.
1999; 6:880–6.
30. Niemann JT, Burian D, Garner D, Lewis RJ. Monophasic
versus biphasic transthoracic countershock after prolonged
ventricular fibrillation in a swine model. J Am Coll Cardiol.
2000; 36:932–8.
hidden structure in ventricular fibrillation. Resuscitation.
2000; 43:121–7.
40. Eftestøl, T, Sunde K, Aase SO, Husøy JH, Steenb PA.
‘‘Probability of successful defibrillation’’ as a monitor during
CPR in out-of-hospital cardiac arrested patients. Resuscitation.
2001; 48:245–54.
41. Automatic External Defibrillation Task Force, Weisfeldt
ML, Kerber RE, McGoldrick RP, et al. American Heart Asso-
ciation report on the Public Access Defibrillation Conference
December 8–10, 1994. Circulation. 1995; 92:2740–7.
42. Niemann JT, Cairns CB, Sharma J, Lewis RJ. Treatment
of prolonged ventricular fibrillation, immediate countershock
versus high-dose epinephrine and CPR preceding counter-
shock. Circulation. 1992; 85:281–7.
43. Menegazzi JJ, Davis EA, Yealy DM, et al. An experimental
algorithm versus standard Advanced Cardiac Life Support in
a swine model of out-of-hospital cardiac arrest. Ann Emerg
Med. 1993; 22:235–9.
44. Menegazzi JJ, Seaberg DC, Yealy DM, Davis EA, MacLeod
BA. Combination pharmacotherapy with delayed countershock
vs standard Advanced Cardiac Life Support after prolonged
ventricular fibrillation. Prehosp Emerg Care. 2000; 4:31–7.
45. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of
cardiopulmonary resuscitation prior to defibrillation in pa-
tients with out-of-hospital ventricular fibrillation. JAMA. 1999;
281:1182–8.
46. Van Walraven C, Stiell IG, Wells GA, Hebert PC, Vandem-
heen K, the OTAC Study Group. Do Advanced Cardiac Life
Support drugs increase resuscitation rates from in-hospital
cardiac arrest? Ann Emerg Med. 1998; 32:544–53.
47. Steill IG, Wells GA, Hebert PC, Laupacis A, Weitzman BN.
Association of drug therapy with survival in cardiac arrest-
limited role of Advanced Cardiac Life Support drugs. Acad
Emerg Med. 1995; 2:264–73.
48. Brown CG, Martin DR, Pepe PE, et al. A comparison of
standard-dose and high-dose epinephrine in cardiac arrest out-
side the hospital. N Engl J Med. 1992; 327:1051–5.
49. Steill IG, Hebert PC, Weitzman BN, et al. High-dose epi-
nephrine in adult cardiac arrest. N Engl J Med. 1992; 327:
1045–50.
50. Abramson NS, Safar P, Sutton-Tyrell K, Craig MT, for the
BRCT III Study Group. A randomized clinical trial of escalat-
ing doses of high dose epinephrine during cardiac resuscitation
[abstract]. Crit Care Med. 1995; 23:A178.
51. Gueugniaud P-V, Mols P, Goldstein P, et al. A comparison
of repeated high doses of epinephrine for cardiac arrest outside
the hospital. N Engl J Med. 1998; 339:1595–601.
52. Lee SK, Vaagenes P, Safar P, Effect of cardiac arrest time
on cortical cerebral blood flow during subsequent standard ex-
ternal cardiopulmonary resuscitation in rabbits. Resuscitation.
1989; 17:105–17.
53. Nagao K, Hayashi N, Kanmatsuse K, et al. Cardiopulmo-
nary cerebral resuscitation using emergency cardiopulmonary
bypass, coronary reperfusion therapy and mild hypothermia in
patients with cardiac arrest outside the hospital. J Am Coll
Cardiol. 2000; 36:776–83.
54. Reich H, Angelos M, Safar P, Sterz F, Lenov Y. Cardiac
resuscitability with cardiopulmonary bypass after increasing
fibrillation time in dogs. Ann Emerg Med. 1990; 19:887–90.
31. Poole JE, White RD, Kanz KG. Low-energy impedance-
compensating biphasic waveforms terminate ventricular fibril-
lation at high rates in victims of out-of-hospital cardiac arrest.
J Cardiovasc Electrophysiol. 1997; 8:1373–85.
32. Higgins SL, Herre JM, Epstein AE, et al. A comparison of
biphasic and monophasic shocks for external defibrillation.
Prehosp Emerg Care. 2000; 4:305–13.
33. Kaplan DT, Cohen RJ. Is fibrillation chaos? Circ Res. 1990;
67:886–92.

922
PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
55. Halperin HR, Tsitlik JE, Gelfand M, et al. A preliminary 79. Kida M, Fujiwara H, Uegaito T, et al. Dobutamine pre-
study of cardiopulmonary resuscitation by circumferential vents both myocardial stunning an phosphocreatine overshoot
compression of the chest with use of a pneumatic vest. N Engl without affecting ATP level. J Mol Cell Cardiol. 1993; 25:875–
J Med. 1993; 329:762–8.
85.
56. Tang W, Weil MH, Schock RB, et al. Phased chest and ab- 80. Kern KB, Hilwig RW, Berg RA, et al. Postresuscitation left
dominal compression–decompression. A new option for cardio- ventricular systolic and diastolic dysfunction. Treatment with
pulmonary resuscitation. Circulation. 1997; 95:1335–40.
dobutamine. Circulation. 1997; 95:2610–3.
57. Babbs CF. Efficacy of interposed abdominal compression– 81. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG.
cardiopulmonary resuscitation (CPR), active compression and Regulation of myocardial carbohydrate metabolism under nor-
decompression-CPR and Lifestick CPR: basic physiology in a mal and ischemic conditions. Potential for pharmacological in-
spreadsheet model. Crit Care Med. 2000; 28(11 suppl):N199– terventions. Cardiovasc Res. 1997; 33:243–57.
N202.
82. Angelos MG, Torres CAA, Rath DP, Zhu H, Beckley PD,
58. Callaway CW. Improving neurologic outcomes after out-of- Robitaille PML. In vivo myocardial substrate alteration during
hospital cardiac arrest. Prehosp Emerg Care. 1997; 1:45–54.
59. De Vos R, De Haes HCJM, Koster RW, De Haan RJ. Qual- 581–7.
perfused ventricular fibrillation. Acad Emerg Med. 1999; 6:
ity of survival after cardiopulmonary resuscitation. Arch Intern 83. Opie LH. Fuels: aerobic and anaerobic metabolism. In: The
Med. 1999; 159:249–54.
Heart Physiology, from Cell to Circulation, 3rd Edition. Phil-
60. Bjork RJ, Snyder BD, Campion BC, Lowenson RB. Medical adelphia: Lippincott–Raven, 1998.
complications of cardiopulmonary arrest. Arch Intern Med. 84. Weiss JN, Lamp ST. Glycolysis preferentially inhibitsATP-
ϩ
1982; 142:500–3.
sensitive K channels in isolated guinea pig cardiac myocytes.
61. Gaussorgues P, Gueugniaud PY, Vedrine JM, Salord F, Science. 1987; 238:67–9.
Mercatteelo A, Robert D. Bacteremia following cardiac arrest 85. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium
and cardiopulmonary resuscitation. Intens Care Med. 1988; 14: therapy for treatment of acute myocardial infarction: an over-
575–7.
view of randomized placebo-controlled trials. Circulation. 1997;
62. Mattana J, Singhala PC. Prevalence and determinants of 96:1152–6.
acute renal failure following cardiopulmonary resuscitation. 86. Diaz R, Paolasso EA, Piegas LS, et al. Metabolic modula-
Arch Intern Med. 1993; 153:235–9.
tion of acute myocardial infarction: the ECLA glucose-insulin-
63. Braunwald E, Kloner RA: The stunned myocardium: pro- potassium pilot trial. Circulation. 1998; 98:2227–34.
longed, postischemic ventricular dysfunction. Circulation. 87. Ceremuzynski L, Budaj A, Czepiel A, et al. Low-dose glu-
1982; 66:1146–9.
cose-insulin-potassium is ineffective in acute myocardial in-
64. Entman ML, Smith CW. Postreperfusion inflammation: a farction: results of a randomized multicenter Pol-GIK trial.
model for reaction to injury in cardiovascular disease. Cardio- Cardiovasc Drugs Ther. 1999; 13:191–200.
vasc Res. 1994; 28:1301–11.
88. Zaninetti D, Greco-Perotto R, Assimacopoulos-Jeannet F,
65. Juneau CF, Ito BR, del Balzo U, Engler RL. Severe neu- Jeanrenaud B. Effects of insulin on glucose transport and glu-
trophil depletion by leukocyte filters or cytotoxic drug does not cose transporters in rat heart. Biochem J. 1988; 250:277–283.
improve recovery of contractile function in stunned porcine 89. Lucchesi BR, Median M, Kniffen FJ. The positive inotropic
myocardium. Cardiovasc Res. 1993; 27:720–7.
action of insulin in the canine heart. Eur J Pharmacol. 1972;
66. Bolli RL. Role of neutrophils in myocardial stunning after 18:107–15.
brief ischaemia: the end of a six year old controversy (1987– 90. Angelos MG, Murray HN. Glucose-insulin-potassium
1993). Cardiovasc Res. 1993; 27:728–30.
(GIK) improves left ventricular function after global ischemia
67. Bolli R. Mechanism of myocardial ‘‘stunning.’’ Circulation. in the perfused rat heart [abstract]. Acad Emerg Med. 1999; 6:
1990; 82:723–8.
512.
68. Gao WD, Liu Y, Marban E. Selective effects of oxygen free 91. Angelos MG, Murray HN, Gorsline RT. Glucose, insulin
radicals on excitation–contraction coupling in ventricular mus- and potassium (GIK) improves myocardial bioenergetic recov-
cle. Circulation. 1996; 94:2597–604.
ery following global ischemia [abstract]. Circulation 1999;
69. Bolli R, Marban E. Molecular and cellular mechanisms of 100(suppl I):I-664.
myocardial stunning. Physiol Rev. 1999; 79:609–34.
92. Svedjeholm R, Hakanson E, Szabo Z. Metabolic interven-
70. Tang W, Weil MH, Sun S, Gazmuri RJ, Bisera J. Progres- tion for the ischemic and post-ischemic heart. Wien Klin Woch-
sive myocardial dysfunction after cardiac resuscitation. Crit enschr. 1999; 111:501–11.
Care Med. 1993; 21:1046–50.
93. Myers ML, Bolli R, Lekich RF, Hartley CJ, Roberts RL.
71. Gazmuri RJ, Weil MH, Bisera J, Tang W, Fukui M, McKee Enhancement of recovery of myocardial function by oxygen
D. Myocardial dysfunction after successful resuscitation from free-radical scavengers after reversible regional ischemia. Cir-
cardiac arrest. Crit Care Med. 1996; 24:992–1000.
culation. 1985; 72:915–21.
72. Kern KB, Hilwig RW, Rhee KH, Berg RA. Myocardial dys- 94. Gross GJ, Farber NE, Hardman HF, Warltier DC. Bene-
function after resuscitation from cardiac arrest: an example of ficial actions of superoxide dismutase and catalase in stunned
global myocardial stunning. J Am Coll Cardiol. 1996; 28:232– myocardium of dogs. Am J Physiol. 1986; 250:H372-H377.
40.
95. Przyklenk K, Kloner RA. Superoxide dismutase plus cat-
73. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ. alase improve contractile function in the canine model of the
Epinephrine increases the severity of postresuscitation myo- ‘‘stunned’’ myocardium. Circ Res. 1986; 58:148–56.
cardial dysfunction. Circulation. 1995; 92:3089–93.
96. Bolli R, Patel BS, Jeroudi MO, Lai EK, McCay PB. Dem-
74. Xie J, Weil MH, Sun S, et al. High-energy defibrillation onstration of free radical generation in ‘‘stunned’’ myocardium
increases the severity of postresuscitation myocardial dysfunc- of intact dogs with the use of the spin trap ␣-phenyl-N-tert-
tion. Circulation. 1997; 96:683–8.
butyl nitrone. J Clin Invest. 1988; 82:476–85.
75. Sun S, Weil MH, Tang W, Fukui M. Effects of buffer agents 97. Li XY, McCay PB, Zughaib M, Jeroudi MO, Triana JF, Bolli
on postresuscitation myocardial dysfunction. Crit Care Med. R. Demonstration of free radical generation in the ‘‘stunned’’
1996; 24:2035–41.
myocardium in the conscious dog and identification of major
76. Sun S, Weil MH, Tang W, Povoas HP, Mason E. Combined differences between conscious an open-chest dogs. J Clin In-
effects of buffer and adrenergic agents on postresuscitation vest. 1993: 92:1025–41.
myocardial function. J Pharmacol Exp Ther. 1999; 291:773–7. 98. Cerchiari EL, Sclabassi RJ, Safar P, Hoel TM. Effects of
77. Becker LC, Levine JH, DiPaula AF, Guarnieri T, Aversano combined superoxide dismutase and deferoxamine on recovery
T. Reversal of dysfunction in postischemic stunned myocar- of brainstem auditory evoked potentials and EEG after asphy-
dium by epinephrine and postextrasystolic potentiation. J Am xial cardiac arrest in dogs. Resuscitation. 1990; 19:25–40.
Coll Cardiol. 1986; 7:580–9.
99. Kaneko S, Okumura K, Numaguchi Y, et al. Melatonin
78. Schulz R, Guth BD, Pieper K, Marin C, Heusch G. Re- scavenges hydroxyl radical and protects isolated rat hearts
cruitment of an inotropic reserve in moderately ischemic myo- from ischemic reperfusion injury. Life Sci. 2000; 67:101–12.
cardium at the expense of metabolic recovery. Circ Res. 1992; 100. Walker MK, Vergely C, Lecour S, Adabie C, Maupoil V,
70:1282–95.
Rochette L. Vitamin E analogues reduce the incidence of ven-

ACADEMIC EMERGENCY MEDICINE • September 2001, Volume 8, Number 9
923
tricular fibrillations and scavenge free radicals. Fundam Clin ysis in the pathogenesis of stunned myocardium. Circ Res.
Pharm. 1998; 12:164–72. 1997; 80:393–9.
101. Abadie C, Ben Baouali A, Maupoil V, Rochette L. An al- 124. Matsumura Y, Kusuoka H, Inoue M, Hori M, Kamada T.
pha-tocopherol analogue with antioxidant activity improves Protective effect of the protease inhibitor leupeptin against
myocardial function during ischemia reperfusion in isolated myocardial stunning. J Cardiovasc Pharmacol. 1993; 22:135–
working rat hearts. Free Radic Biol Med. 1993; 15:209–15.
42.
ϩ
102. Noma A. ATP-regulated K channels in cardiac muscle. 125. Gao WE, Liu Y, Marban E: Mechanism of decreased myo-
Nature. 1983; 305:147–8.
filaments Ca2ϩ responsiveness in stunned rat ventricular myo-
103. Gross GJ, Garlid KD. ATP-sensitive potassium channels: cardium: relative roles of soluble cytosolic factors versus struc-
a review of their cardioprotective pharmacology. J Mol Cell tural alterations. Circ Res. 1996; 78:455–65.
Cardiol. 2000; 32:677–95.
126. Neumar RW. Molecular mechanisms of ischemic neuronal
104. Lui Y, Sato T, O’Rourke B, Marban E. MitochondrialATP- injury. Ann Emerg Med. 2000; 36:483–506.
dependent potassium channels: novel effectors of cardioprotec- 127. Eleff SM, Schleien CL, Koehler RC, et al. Brain bioener-
tion? Circulation. 1998; 97:2463–9.
getics during cardiopulmonary resuscitation in dogs. Anesthe-
105. Auchampach JA, Maruyama M, Cavero I, Gross GJ. siology. 1992; 76: 77–84.
Pharmacological evidence for a role of ATP-dependent potas- 128. Globus MYT, Ginsberg MD, Busto R. Excitotoxic index—
sium channels in myocardial stunning. Circulation. 1992; 86: a biochemical marker of selective vulnerability. Neurosci Lett.
311–9.
1991; 127: 39–42.
106. Grover G, Newburger J, Sleph P, et al. Cardioprotective 129. Katz L, Callaway CW, Kagan VE, Kochanek PM. Electron
effects of the potassium channel opener cromakalim: stereo-
selectivity and effects on myocardial adenine nucleotides. J
Pharmacol Exp Ther. 1991; 257:156–72.
spin resonance measure of brain antioxidant activity during
ischemia/reperfusion. Neuroreport. 1998; 9:1587–93.
130. White BC, Winegar CP, Henderson O, et al. Prolonged
hypoperfusion in the cerebral cortex following cardiac arrest
and resuscitation in dogs. Ann Emerg Med. 1983; 12:414–7.
131. Wolfson SK, Safar P, Reich H, et al. Dynamic heteroge-
neity of cerebral hypoperfusion after prolonged cardiac arrest
in dogs measured by the stable xenon/CT technique: a prelim-
inary study. Resuscitation. 1992; 23:1–20.
107. McPherson C, Pierce G, Cole W. Ischemic cardioprotec-
ϩ
tion by ATP-sensitive K channels involves high-energy phos-
phate preservation. Am J Physiol. 1993; 265:H1809–H1818.
108. Grover GJ, Garlid KD. ATP-sensitive potassium chan-
nels: a review of their cardioprotective pharmacology. J Mol
Cell Cardiol. 2000; 32:677–95.
109. D’Alonzo A, Darbenzio R, Rarham C, Grover G. Effects of
intracoronary cromakalim on post-ischaemic contractile func-
tion and action potential duration. Cardiovasc Res. 1992; 26:
1046–53.
132. Salmien A, Liu PK, Hsu CY. Alteration of transcription
factor binding activities in the ischemic rat brain. Biochem Bio-
phys Res Commun. 1995; 212:939–44.
133. Kiessling M, Stumm G, Xie Y, et al. Differential tran-
scription and translation of immediate early genes in the gerbil
hippocampus after transient global ischemia. J Cereb Blood
Flow Metab. 1993; 13:914–24.
134. Krajewski S, Mai JK, Krajewska M, Sikorska M, Mos-
sakowski MJ, Reed JC. Upregulation of bax protein levels in
neurons following cerebral ischemia. J Neurosci. 1995; 15:
6364–76.
135. Chen J, Zhu RL, Nakayama M, et al. Expression of the
apoptosis-effector gene, Bax, is up-regulated in vulnerable hip-
pocampal CA1 neurons following global ischemia. J Neuro-
chem. 1996; 67:64–71.
136. Chen J, Nagayama T, Jin K, et al. Induction of caspase-
3-like protease may mediate delayed neuronal death in the hip-
pocampus after transient cerebral ischemia. J Neurosci. 1998;
18:4914–28.
137. Chen J, Graham SH, Nakayama M, et al. Apoptosis re-
pressor genes Bcl-2 and Bcl-x-long are expressed in the rat
brain following global ischemia. J Cereb Blood Flow Metab.
1997; 17:2–10.
110. Kitakaze M, Weisfeldt ML, Marban E. Acidosis during
early reperfusion prevents myocardial stunning in perfused
hearts. J Clin Invest. 1988; 82:920–7.
ϩ
ϩ
111. Frelin C, Vigne P, Lazdunski M. The role of the Na /H
exchange system in the regulation of the internal pH in cul-
tured cardiac cells. Eur J Biochem. 1985; 149:1–4.
112. van Emous JG, Schreur JHM, Ruigrok TJC, Van Echteld
ϩ
ϩ
ϩ
ϩ
CJ. Both Na -K -ATPase and Na /H exchanger are immedi-
ately active upon post-ischemic reperfusion in isolated rat
hearts. J Mol Cell Cardiol. 1998; 30:337–48.
ϩ
ϩ
113. Stomer H, de Groot MCH, Horn M, et al. Na /H
exchange inhibition with HOE642 improves postischemic re-
covery due to attenuation of Ca2ϩ overload and prolonged aci-
dosis on reperfusion. Circulation. 2000; 101:2749–55.
ϩ
ϩ
114. Hartmann M, Decking UKM. Blocking Na /H exchange
ϩ
by cariporide reduces Na -overload in ischemia and is cardi-
oprotective. J Mol Cell Cardiol. 1999; 31:1985–995.
115. Ferguson JJ. Meeting highlights of the 48th Scientific
Sessions of the American College of Cardiology. Circulation.
1999; 100:570–5.
138. Krajewski S, Krajewska M, Ellerby LM, et al. Release of
caspase-9 from mitochondria during neuronal apoptosis and ce-
rebral ischemia. Proc Natl Acad Sci U S A. 1999; 96:5752–7.
139. MacManus JP, Buchan AM, Hill IE, Rasquinha I, Preston
E. Global ischemia can cause DNA fragmentation indicative of
apoptosis in rat brain. Neurosci Lett. 1993; 164:89–92.
140. Brain Resuscitation Clinical Trial I Study Group. Ran-
domized clinical study of thiopental loading in comatose sur-
vivors of cardiac arrest. N Engl J Med. 1986; 314:397–403.
141. Brain Resuscitation Clinical Trial II Study Group. A ran-
domized clinical study of a calcium-entry blocker (lidoflazine)
in the treatment of comatose survivors of cardiac arrest. N
Engl J Med. 1991; 324:1225–31.
142. Nellgard B, Wieloch T. Postischemic blockade of AMPA
but not NMDA receptors mitigates neuronal damage in the rat
brain following transient severe cerebral ischemia. J Cereb
Blood Flow Metab. 1992; 12:2–11.
143. Sterz F, Leonov, Y, Safar P, et al. Effect of excitatory
amino acid receptor blocker MK-801 on overall, neurologic and
morphologic outcome after prolonged cardiac arrest in dogs.
Anesthesia. 1989; 71:907–18.
116. Erhardt LR. GUARD During Ischemia Against Necrosis
(GUARDIAN) trial in acute coronary syndromes. Am J Cardiol.
1999; 83:23G–25G.
117. Rupprecht HJ, vom Dahl J, Terres W, et al. Cardiopro-
tective effects of the Na(ϩ)/H(ϩ) exchange inhibitor cariporide
in patients with acute anterior myocardial infarction under-
going direct PTCA. Circulation. 2000; 101:2902–8.
118. Ehring T, Boehm M, Heusch G. The calcium antagonist
nisoldipine improves the functional recovery of reperfused
myocardium only when given before ischemia. J Cardiovasc
Pharmacol. 1992; 20:63–74.
119. Heusch G. Myocardial stunning: a role for calcium antag-
onists during ischaemia? Cardiovasc Res. 1992; 26:14–19.
120. Przyklenk K, Kloner RA. Effect of verapamil on post-
ischemic ‘‘stunned’’ myocardium: importance of the timing of
treatment. J Am Coll Cardiol. 1988; 11:614–23.
121. Park S-W, Tang X-L, Qiu Y, Sun J-Z, Bolli R. Nisoldipine
attenuates myocardial stunning induced by multiple coronary
occlusions in conscious pigs and this effect is independent of
changes in hemodynamics or coronary blood flow. J Mol Cell
Cardiol. 1996; 28:655–66.
144. Silbergleit R, Haywood Y, Fiskum G, Rosenthal RE. Lack
of a neuroprotective effect from N-acetylcysteine after cardiac
arrest and resuscitation in a canine model. Resuscitation.
1999; 40:181–6.
122. Mak IT, Boehme P, Weglicki WP. Antioxidant effects of
calcium channel blockers against free radical injury in endo-
thelial cells. Correlation of protection with preservation of glu-
tathione levels. Circ Res. 1992; 70:1099–103.
123. Gao WD, Atar D, Liu Y, et al. Role of troponin I proteol- 145. Lipinski CA, Hicks SD, Callaway CW. Effect of normoxic

924
PROLONGED VF
Angelos et al. • RESUSCITATION FROM PROLONGED VF
ventilation on outcome after asphyxial cardiac arrest in rats. 151. Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I,
Resuscitation. 1999; 42:221–9.
Ginsberg MD. Effect of mild hypothermia on ischemia-induced
release of neurotransmitters and free fatty acids in rat brain.
Stroke. 1989; 20:904–10.
152. Kil HY, Zhang J, Piantadosi CA. Brain temperature al-
ters hydroxyl radical production during cerebral ischemia/re-
perfusion in rats. J Cereb Blood Flow Metab. 1996; 16:100–6.
153. Hicks SD, Parmele KT, DeFranco DB, Klann E, Callaway
CW. Hypothermia differentially increases ERK and JNK/
SAPK activation in hippocampus after asphyxial cardiac ar-
rest. Neuroscience. 2000; 98:677–85.
154. Leonov Y, Sterz F, Safar P, Johnson DW, Tisherman SA,
Oku K. Hypertension with hemodilution prevents multifocal
cerebral hypoperfusion after cardiac arrest in dogs. Stroke.
1992; 23:45–53.
155. Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hy-
pothermia to improve neurological outcome after cardiac ar-
rest. A clinical feasibility trial. Hypothermia After Cardiac Ar-
rest (HACA) Study Group. Stroke. 2000; 3:86–94.
146. Himi T, Ishizaki Y, Murota S. A caspase inhibitor blocks
ischaemia-induced delayed neuronal death in the gerbil. Eur J
Neurosci. 1998; 10:777–81.
147. Li H, Colbourne F, Sun P, Zhao Z, Buchan AM, Iadecola
C. Caspase inhibitors reduce neuronal injury after focal but not
global cerebral ischemia in rats. Stroke. 2000; 31:176–82.
148. Colbourne F, Li H, Buchan AM. Indefatigable CA1 sector
neuroprotection with mild hypothermia induced 6 hours after
severe forebrain ischemia in rats. J Cereb Blood Flow Metab.
1999; 19:742–9.
149. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Ste-
zoski SW, Alexander H. Delay in cooling negates the beneficial
effect of mild resuscitative cerebral hypothermia after cardiac
arrest in dogs: a prospective, randomized study. Crit Care Med.
1993; 21:1348–58.
150. Xiao F, Safar P, Radovsky A. Mild protective and resus-
citative hypothermia for asphyxial cardiac arrest in rats. Am
J Emerg Med. 1998; 16:17–25.
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