Special Report

Pulseless Electric Activity

Definition, Causes, Mechanisms, Management, and Research Priorities
for the Next Decade: Report From a National Heart, Lung, and Blood
Institute Workshop
Robert J. Myerburg, MD; Henry Halperin, MD; Debra A. Egan, MSc, MPH; Robin Boineau, MD;
Sumeet S. Chugh, MD; Anne M. Gillis, MD; Joshua I. Goldhaber, MD;
David A. Lathrop, PhD; Peter Liu, MD; James T. Niemann, MD; Joseph P. Ornato, MD;
George Sopko, MD, MPH; Jennifer E. Van Eyk, PhD; Gregory P. Walcott, MD;
Myron L. Weisfeldt, MD; Jacqueline D. Wright, DrPH; Douglas P. Zipes, MD

S udden cardiac arrest (SCA) remains an important public

health challenge. Despite a dramatic decrease in the age-
adjusted risk of SCA, the cumulative number of fatal SCAs
in the United States remains large. Estimates range from
<170 000 to >450 000 fatal SCAs per year; a figure in the
range of 300 000 to 370 000 per year is likely the best current
estimate.1 SCA appears to account for ≈50% of all cardiovas-
cular deaths,2 and it is estimated that 50% of the SCAs are
the first clinical expression of previously undiagnosed heart
disease.2,3 Most out-of-hospital cardiac arrests (80%) occur in
private homes or other living facilities.4
Electric mechanisms associated with SCA are broadly
classified into tachyarrhythmic and nontachyarrhythmic cat-
Downloaded from http://ahajournals.org by on October 4, 2018
mechanisms than VT/VF. Whether this also reflects the emer-
gence of greater absolute numbers of PEA and asystole, as
suggested in other studies,7,9 possibly as a result of broader
deployment of emergency rescue systems with longer aver-
age response times, or evolving changes in patient substrate
remains to be determined.
As preventive and therapeutic interventions for VT/VF
were developing, PEA and asystole did not receive a great
deal of attention. Currently, however, PEA should receive
greater attention on the basis of the combination of its increas-
ing proportion of the SCA spectrum, its much lower survival
rate than that after VT/VF arrests, emerging suggestions that
survival may be improved, and uncertainty whether there is

egories, the latter including pulseless electric activity (PEA;
formerly referred to as electromechanical dissociation), asys-
tole, extreme bradycardia, and other mechanisms often associ-
ated with noncardiac factors (Table). The first approaches to
the problem of SCA focused on ventricular fibrillation (VF)
and pulseless ventricular tachycardia (VT). An early impact
on the prevention and treatment of VF and VT was realized
in patients with acute coronary syndromes >50 years ago,5
followed by the development of strategies for responding to
out-of-hospital cardiac arrest, implantable cardioverter-defi-
brillators, and defibrillation by lay responders.
Data from the Seattle emergency rescue system6 and else-
where7–9 have identified progressive reductions in the number
of responses to SCA over 2 to 3 decades. This change was due
primarily to a reduction in the number of ventricular tachyar-
rhythmic events identified by emergency medical services
responders. In the Seattle data, the incidences of PEA and
asystole had not changed over the 3 decades of observation
and therefore have emerged as proportionately more frequent
a proportional versus an absolute increase in incidence. The
definitions, prognostics, and potential for improvements in
therapeutic opportunities for PEA, in contrast to asystole, are
of sufficient interest and complexity that this condition now
warrants a strong investigative focus within the spectrum of
SCA mechanisms and management challenges. Expanding
mechanism-related concepts offers the hope for both better
stratification and development of more effective therapeutic
interventions.
Because of the increasing prevalence of and limited scien-
tific information on PEA, the National Heart, Lung, and Blood
Institute sponsored a workshop on PEA that convened on June
6, 2012, in Bethesda, MD.10 It was designed to explore current
knowledge and future directions for research in the predic-
tion, prevention, and management of PEA, as well as probable
mechanistic pathways that might translate to clinical care.
The working group participants had expertise in basic, clini-
cal, and epidemiological aspects of SCA generally and PEA in
particular. This article summarizes the deliberations, focusing

From the University of Miami Miller School of Medicine, Miami, FL (R.J.M.); Johns Hopkins Medical Institutions (H.H., J.E.V.E., M.L.W.); National
Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (D.A.E., R.B., D.A.L., G.S., J.D.W.); Cedars-Sinai Heart Institute, Los
Angeles, CA (S.S.C., J.I.G.); University of Calgary, Calgary, AB, Canada (A.M.G.); University of Toronto, Toronto, ON, Canada (P.L.); UCLA Harbor
Medical Center, Torrance, CA (J.T.N.); Virginia Commonwealth University Medical Center, Richmond (J.P.O.); University of Alabama at Birmingham,
Birmingham (G.P.W.); and the Krannert Institute of Cardiology, Indianapolis, IN (D.P.Z.).
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
113.004490/-/DC1.
Correspondence to Robert J. Myerburg, MD, Division of Cardiology, Jackson Memorial Hospital, Central Bldg, Room C-401, 1611 NW 12th Ave,
Miami, FL 33136. E-mail rmyerbur@med.miami.edu
(Circulation. 2013;128:2532-2541.)
© 2013 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.004490

2532
 Myerburg et al   Pulseless Electrical Activity   2533

Table.  Tachyarrhythmic and Nontachyarrhythmic Cardiac Arrest

Primary Arrhythmias Electrical Mechanisms Mechanical Mechanisms
Tachyarrhythmic cardiac arrest
 VF Absence of organized ventricular depolarization Absence of LVWM
 Pulseless VT Organized ventricular pattern; rapid rate Absent LVWM or LVWM insufficient for organ perfusion
Secondary arrhythmias
 Sinus tachycardia; other Sinus or other SV rhythm; narrow QRS Obstruction to cardiac blood flow; hypovolemia
Nontachyarrhythmic cardiac arrest
 PEA, primary (initial rhythm)
  With residual LV contraction Organized QRS complexes, usually wide LVWM insufficient for organ perfusion
  Without LV contraction Organized QRS complexes, usually wide Absence of LVWM
 PEA, secondary
  
Postshock Regular or irregular QRS complexes, usually wide Absent LVWM or LVWM insufficient for organ perfusion
  
Primary noncardiac Regular or irregular QRS complexes, usually wide Usually LVWM insufficient for organ perfusion; LVWM
may be absent
 Agonal PEA Slow, usually irregular, wide QRS Absence of LVWM
 Ventricular asystole Absent ventricular electric activity; exclude fine VF Absence of LVWM
LV indicates left ventricular; LVWM, left ventricular wall motion; PEA, pulseless electric activity; SV, supraventricular; VF, ventricular fibrillation; and VT,
ventricular tachycardia.

on the identification of current scientific gaps and areas that
require National Heart, Lung, and Blood Institute leadership,
facilitation, and support for scientific and clinical progress.
Definition of PEA
At present, there is no single unifying definition for PEA.
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the Resuscitation Outcomes Consortium and data from the
Cardiac Arrest Registry to Enhance Survival network dem-
onstrate an incidence of PEA arrests ranging from 19% to
23%, with the remaining ≈50% of patients initially having
asystole.13
This striking decline in the frequency of VT/VF and the rel-

The common denominator is the presence of spontaneous
organized cardiac electric activity in the absence of blood
flow sufficient to maintain consciousness and absence of a
rapid spontaneous return of adequate organ perfusion and
consciousness (see the Table). The latter qualifier excludes
transient losses of blood flow such as vasovagal syncope that
have clinical implications different from those of true PEA.
Therefore, the workshop participants defined PEA as a syn-
drome characterized by the absence of a palpable pulse in an
unconscious patient with organized electric activity other than
ventricular tachyarrhythmia on ECG. The definition excludes
subjects with nonpulsatile assist devices. ECG patterns asso-
ciated with PEA vary (Table), and the electric activity may
occur at a rate and rhythm that would otherwise be expected to
be associated with circulation. The definition of PEA does not
include the agonal pattern of slow, very wide QRS complexes
at the end of a prolonged cardiac arrest.
Emerging Epidemiological Patterns of PEA
Thirty years ago, nearly 70% of the initial ECGs recorded
during cardiac arrests showed VF or pulseless VT.11 Recent
data from several large population cohorts including >40 000
patients demonstrate proportions of initial VT/VF in the range
of 20% to 25%.12,13 In the Seattle study,6 61% of cardiac arrests
responded to by emergency medical services had VF identi-
fied as the initial rhythm in 1979 to 1980 compared with 41%
in 1999 to 2000. In contrast, PEA was identified as the first
rhythm recorded in 17% of the victims in the earlier period
compared with 28% in the later period. In parallel with this
reduced frequency of VT/VF, recent unpublished data from
ative and possibly absolute increase in PEA and asystole as the
initial rhythm may be attributable to a number of interacting
environmental, clinical, pharmacological, or strategic inter-
ventional factors. At least one of these may be analyzed in the
context of the location of cardiac arrests. From Resuscitation
Outcomes Consortium data based on 12 930 total arrests
stratified by location, VT/VF occurred in 22% of 9564 arrests
occurring in homes, 13% of 1324 occurring in nursing homes
or residence facilities, and 51% of 2042 arrests occurring in
a public location.14 Thus, one might conclude that for arrests
occurring in public locations and likely benefiting from rapid
recognition and management, the incidence of VT/VF is not
much lower than 30 years ago. However, patients who have
cardiac arrests in the home or in a nursing home, where the
incidence of VT/VF is reduced, may be older, may have more
severe chronic conditions, or may be subject to delays in rec-
ognition and initial responses. The decline in VT/VF may also
be contributed to by the increase in implantable cardioverter-
defibrillators in patients with systolic heart failure15 and the
increasing use of aggressive pharmacological management of
heart failure, particularly β-blockers,16 which may suppress
VT/VF and result in an increase in cardiac arrests related to
both PEA and asystole. However, these potential determinants
of the increasing burden of PEA need further investigation.
The overall Resuscitation Outcomes Consortium survival
rate for treated patients with PEA arrests surviving to hospi-
tal discharge was ≈8%. This compares with 30.5% for VT/
VF arrests. Survival from PEA arrests in public settings was
14.9% and from arrests in the home was 7.5%. Similar low
survival rates were reported by the Cardiac Arrest Registry
 2534  Circulation  December 3/10, 2013
to Enhance Survival Network.13 However, data from 1 report
suggest that survival from PEA arrests appears to be improv-
ing over time. Among 627 PEA arrests treated in Seattle from
2000 to 2004, survival to 1 month was 9.9% and survival to 1
year was 6.2%. In the period from 2005 to 2010, of 760 PEA
arrests, 14.6% of patients survived to 1 month and 11.5% sur-
vived to 1 year.17 The adjusted odds ratio (OR) for improved
survival across the 2 periods was 1.51 (95% confidence inter-
val [CI], 1.07–2.11) at 1 month and 1.90 (95% CI, 1.27–2.85)
at 1 year. There were similar improvements in the frequency
of return of spontaneous circulation (ROSC), survival to dis-
charge, and cerebral performance category 1 to 2 at discharge.
The authors of this study attribute the increase in survival rates
to the improvement in resuscitation techniques over the past
decade. In a study of in-hospital cardiac arrests in pediatric
and adolescent subjects <18 years of age between 2000 and
2009, an increase in the frequency of PEA was observed that
was associated with an increase in survival to hospital dis-
charge over time.18
Mechanisms and Pathophysiology of PEA
Defining the pathobiology and management of PEA has been
limited by the lack of clinically relevant laboratory models.
Asphyxia is the traditional experimental method of inducing
PEA arrest, and this model, in various forms, has been used
since the 1960s.19 However, asphyxia is not a common clinical
cause of out-of-hospital PEA arrest in the adult population.
In autopsy studies, ≈50% of cases of PEA may be ascribed
to a primary cardiac event.20 In 1 study, PEA as the initial
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rhythm was observed in 50% to 60% of cardiac arrests with
onsets witnessed by advanced rescuers (paramedics) and was
not preceded by a reported respiratory event.21 Finally, up to
one third of patients resuscitated from cardiac arrest caused
by PEA undergo a percutaneous intervention for acute coro-
nary occlusion and ST-segment–elevation myocardial infarc-
tion, suggesting that PEA may be an initial arrhythmic event
resulting from acute ischemia.22 In the 1980s, PEA after
countershock of prolonged, untreated VF was introduced as a
method for studying its pathophysiology.23,24 This model does
not replicate primary PEA; it is more similar to PEA after a
shock terminating prolonged VF. Observations during resus-
citation after postshock PEA have demonstrated evidence of
metabolic and electrolyte disturbances that could sustain PEA
after defibrillation.25 Whether these are causes, conditioning
influences, or therapeutic targets requires further clarification.
A possible role of the parasympathetic nervous system in pri-
mary PEA has been indirectly evaluated in an asphyxia model
in which surgical or chemical (high-dose atropine) vagotomy
was performed after the induction of PEA with asphyxia.
ROSC was more likely after surgical vagotomy, but high-dose
atropine had no beneficial effect. The mechanistic benefit of
vagotomy was unclear.26
The apparent increase in PEA over the last 2 decades has
paralleled the increasing use of β-blockers and other medi-
cations for the management of ischemic heart disease and
congestive heart failure. The potential relationship between
drug therapy and the apparently increasing incidence of PEA
is important. Only 1 laboratory study has attempted to evalu-
ate the impact of long-term drug therapy (propranolol and
captopril) on the outcome of ischemia induced by coronary
occlusion in a rat model.27 Although prearrest drug therapy
increased the VF threshold in the animal model, it is unclear
from the reported data whether the study drugs facilitated
the occurrence of PEA.28 Drugs affecting the central nervous
system have been implicated recently, but further studies are
needed to define any causal relationships.
Cellular Mechanisms and
Contractile Dysfunction
For some time, acute coronary occlusion has been known to
result in a sudden loss of contractile force. The most likely
cause is abrupt loss of tissue turgor, also known as the reverse
garden hose effect.29 The mechanism underlying the garden
hose effect is uncertain but may be related to loss of opti-
mum cross-bridge overlap (eg, Starling mechanism) when
the erectile effect of the vasculature is abrogated. Because
intracellular calcium (Ca2+) is critical for regulating myo-
cardial contraction30 (see Appendix I in the online-only Data
Supplement), an alternative hypothesis is that loss of vascular
pressure alters vasotropic feedback, which modulates trig-
gered Ca2+ entry or myofilament Ca2+ sensitivity. Metabolic
consequences of ischemia likely contribute to further con-
tractile dysfunction31 (see Appendix II in the online-only
Data Supplement). This may be of particular importance for
PEA following countershock after prolonged VF. It is impor-
tant to recognize that many of the metabolic changes are also
associated with chronic heart failure.32.33 Thus, metabolic
stress could contribute to loss of contractility, leading to PEA
in patients with advanced heart failure.
Inotropic agents, particularly β-agonists, have been the
mainstay of therapy for PEA34 on the basis of considerations
of molecular factors involved in contractile function and dys-
function. β-Agonists phosphorylate L-type Ca2+ channels,
ryanodine receptors, the sarcoplasmic reticulum calcium
ATPase regulator phospholamban, and myofilaments not only
to increase trigger Ca2+ entry into the cell but also to synchro-
nize Ca2+ release from a loaded SR and improve myofilament
Ca2+ responsiveness. There is, however, a time-dependent
loss of contractile function in response to the metabolic stress
of acute ischemia. Because the mechanisms for this loss are
unknown, further studies to elucidate these mechanisms are
needed to provide a rational basis for future therapies. In addi-
tion, whether myofilament Ca2+ sensitizers such as levosimen-
dan or other agents may be of additional or greater benefit in
the setting of PEA has yet to be determined.
PEA may occur when the host response to a dramatic stress
on the cardiovascular system is inadequate or inappropri-
ate. An important response that was recently recognized is
overwhelming stress leading to rapid activation of the intrin-
sic immune system, causing direct acute depression of car-
diac function or decoupling of electromechanical synchrony,
resulting in PEA. Innate immune activation also produces
cardiokines, which in circulation may lead to profound vaso-
dilation and ventricular arterial decoupling, also setting the
stage for arrhythmias.35 Recent understanding of the signaling
pathways involved in innate immune activation offers poten-
tial areas of further research and therapy.

Clinical associations between the presence of inflammatory
cytokines and SCA have been established. In the Metabolic
Efficiency With Ranolazine for Less Ischemia in Non–
ST-Elevation Acute Coronary Syndromes–Thrombolysis in
Myocardial Infarction 36 (MERLIN-TIMI 36) trial, elevation
of cytokines such as osteoprotegerin was the best predictor of
early sudden death after myocardial infarction.36 Furthermore,
the proposed benefit of N-3 fatty acids on cardiac mortality
after myocardial infarction and in heart failure has also been
attributed at least partially to the anti-inflammatory effects of
N-3 fatty acids.37
The production of cytokines/cardiokines such as tumor
necrosis factor and the interleukin family of cytokines may
acutely depress cardiac function. This has been attributed to
the effect on phosphatidylinositol 3 kinase isoforms and lipid-
signaling intermediates such as sphingosine-1, which may
directly interfere with Ca2+ signaling.38 More recently, there
have been data to suggest that the high-mobility group box
1 or alarmin family of signals may also directly depress car-
diac function and Ca2+ kinetics.39 However, this effect may be
partially ameliorated through phosphatidylinositol 3 kinase-γ
blockade, suggesting possible avenues for host protection.
There has been a significant interest in the role of hormones,
namely relaxin, in SCA. This natural hormone increases in
women during pregnancy and has been studied in acute heart
failure.40 Its mechanisms of action are not well known. In
the setting of acute ischemic arrest, relaxin was able to sig-
nificantly reduce the adverse outcomes of asystole, ventricular
tachyarrhythmias, or bradycardiac arrests, possibly through
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anti-inflammatory effects by inhibiting mast cell activation.41
Further research is needed to weigh the role of immune,
inflammatory, or hormonal modulation of PEA pathways,
especially in the context of underlying comorbidities such as
diabetes mellitus, heart failure, and other proinflammatory
disease states. An intriguing hypothesis, based on the possi-
bility that β-blockers protect against the expression of VT/VF
during ischemia, is that inflammatory signals may allow PEA
to emerge by default.
In contrast to VT/VF for which electric arrhythmogenesis
may be associated with channelopathies, there are no specific
channel dysfunction mechanisms currently known to contrib-
ute to the rapid loss of contractile function associated with
PEA. However, one could hypothesize and test for the func-
tional changes in L-type Ca2+ channels and ryanodine receptors
described in Appendix II in the online-only Data Supplement as
acquired channel defects. Even more speculative is the possi-
bility that genetic susceptibilities to rapid reductions in L-type
Ca2+ channel and ryanodine receptor activity, in response to
metabolic stress, result in a more profound contractile failure
in some individuals compared with others.
Risk Factors
Older age is more likely to be associated with PEA and
asystole than with VF or VT,42,43 and the proportion of PEA
among cases of SCA increases with age: from 10% to 12%
in those 13 to 49 years of age to 18% in those >50 years
of age.44 In addition, an analysis from the Oregon Sudden
Unexpected Death Study (Oregon SUDS) showed that older
age was a significant predictor of future PEA after adjustment
Myerburg et al   Pulseless Electrical Activity   2535
for other demographic variables, arrest circumstances, and
comorbidities.45
Sex is also associated with the presenting arrhythmia dur-
ing SCA. Several studies have shown that women are sig-
nificantly more likely than men to manifest PEA.45–47 In the
Oregon SUDS, approximately one third of women presented
with PEA,45 and after adjustment for demographics, Utstein
data elements, and disease burden, female sex remained a sig-
nificant predictor of PEA (OR, 1.48; 95% CI, 1.05–2.09).48
However, women appear to have a survival advantage over
men for SCA resuscitation outcomes. Even though women
are more likely to manifest with PEA and rates of success-
ful resuscitation are significantly lower after PEA compared
with VT/VF, rates of survival from overall cardiac arrest are
significantly higher in women compared with men (OR, 1.85;
95% CI, 1.12–3.04).48
Several studies report an association between black race
and the propensity to present with PEA.45,48,49 In 3 suburban
counties in Michigan, 21% of blacks versus 14% of whites
presented with PEA.50 In the Oregon SUDS, black race was
strongly associated with PEA as opposed to VF (OR, 2.64;
95% CI, 1.29–5.38) after adjustment for age, sex, resuscita-
tion variables, and comorbidities.45,48
Hypoxia has long been recognized as a component of PEA
pathophysiology, which may explain why pulmonary disease
is a significant independent predictor of PEA.45 In the Oregon
SUDS, men with pulmonary disease were 3-fold more likely
than men without pulmonary disease to have PEA (versus VF/
VT) as their presenting arrhythmia (OR, 3.17; 95% CI, 1.86–
5.42). In another study that examined the association of SCA
with deterioration resulting from chronic obstructive pulmo-
nary disease, 40% presented with PEA.51 In a small autopsy
series, significant pulmonary disease was observed in 20% of
patients with PEA.52
In a retrospective analysis from the Oregon SUDS, a life-
time clinical history of syncope was identified as a novel asso-
ciation with PEA48 and remained a significant determinant of
PEA after adjustment for other conditions (OR, 2.64; 95% CI,
1.31–5.32). The preponderance of syncope among PEA cases
was not explained by an increased prevalence of conduction
system disease, leading to the interesting possibility that in a
subgroup of patients, severe hypotension caused by periph-
eral vascular failure or a malignant form of vasovagal syncope
may account for manifestation with PEA.
There is conflicting information on the role of medications
in the pathophysiology of PEA. A study from Youngquist et
al16 analyzed the prevalence of prescription medications among
179 cases of SCA and reported that 49% of patients with
PEA were on β-blockers compared with 20% of VF patients.
However, this univariate analysis was based on a complex sta-
tistical analysis that did not specifically adjust for drugs other
than β-blockers and calcium channel blockers or other condi-
tions. Recently, the Oregon SUDS group reported results from
a comprehensive assessment of prescription drugs in a larger
population of >800 patients, also accounting for the presence
of cardiac/noncardiac disease conditions.53 Specific classes
of medications with either negative or positive cardiac ino-
tropic effects were evaluated for association with occurrence
of PEA versus VF/VT. In multivariate analyses, the use of
 2536  Circulation  December 3/10, 2013

antipsychotic drugs was a significant and independent risk fac- of the inciting causes combined with drugs that improve con-
tor for PEA, possibly related to their negative inotropic effects. tractility. In the absence of a specific therapy for the reversal
In contrast to other studies,16 no relationship was identified of PEA, analogous to failed electric intervention for VT/VF,
between β-blocker use and the occurrence of PEA in this study. various support therapies for maintaining viability and cen-
tral nervous system function are being developed and evalu-
ated in parallel with new approaches to PEA. The support
Clinical Expression and Subsets therapies are not specific for PEA, having implications for
PEA is classified primarily as cardiac and noncardiac in ori-
asystole and resistant VT/VF also, but they are particularly
gin and is subclassified according to specific causes in each
important for PEA.
category. Noncardiac causes of PEA include profound hypo-
Resuscitation guidelines emphasize the need to identify and
volemia such as major bleeding caused by a ruptured aortic
treat other potentially reversible causes of PEA while perform-
aneurysm, or by trauma or obstruction to the circulation result-
ing standard resuscitation. These include acute myocardial
ing from massive pulmonary embolism, cardiac tamponade,
ischemia, acidosis, hypoxia, hyperkalemia and hypokalemia,
or tension pneumothorax. The initial rhythm accompanying
hypothermia, hypoglycemia, hypocalcemia, and toxins/drug
PEA resulting from these causes is generally sinus tachycar-
overdose. Significant hyperkalemia, hypocalcemia, and hypo-
dia, which evolves to severe sinus bradycardia, PEA, asys-
glycemia, however, are not commonly associated with PEA.57
tole, and ultimately death in the absence of an intervention.
The presence of residual left ventricular contraction dur-
The clinical history guides the differential diagnosis. In these
ing resuscitation from SCA may be identified by emergency
settings, myocardial contractile function may be normal or
echocardiographic techniques.58 The absence of residual left
mildly to moderately impaired, but the heart is generally able
ventricular contraction is common in secondary (postdefibril-
to generate a reduced pulse pressure and to return to normal
lation) PEA. This circumstance has a lower probability of
or near-normal function with volume repletion or obstruction
responding to currently available therapies for PEA and has
relief. Early identification of treatable conditions is critical for
an ominous prognosis. Less is known about the causes and
survival. The workshop did not address these states.
therapeutic opportunities in primary PEA, in which it is the
PEA resulting from cardiac causes is classified as primary
mechanism present at the onset of cardiac arrest. It is gen-
when it is the initial mechanism of a cardiac arrest or sec-
erally assumed that primary PEA in the setting of end-stage
ondary when it follows spontaneous or electric termination
heart disease and postdefibrillation PEA characterized by res-
of VT/VF. It is difficult to distinguish whether PEA after
toration of sinus or junctional electric mechanisms without a
shock therapy is secondary to myocardial injury/mechanical
pulse are a consequence of the extent of underlying disease
paralysis caused by the shock or reperfusion or merely the
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and are not generally amenable to successful interventions

manifestation of end stage pump failure after VT/VF has
been terminated by a defibrillation shock. Insights into this
distinction and the determination of the potential clinical
relevance require further study. In patients with implantable
defibrillators who died suddenly, 16% of the deaths were
attributable to primary PEA, and 30% of those patients had
postshock PEA.54 Postshock PEA was associated with a
lower left ventricular ejection fraction and a greater preva-
lence of symptomatic heart failure. The determinants and
mechanisms of primary cardiac PEA in patients without
severe heart failure require further study and are areas
of inquiry with the potential to develop interventions to
improve survival.
Clinical and Experimental
Management Strategies
The guidelines for cardiopulmonary resuscitation (CPR) and
emergency cardiac care provide management algorithms that
have similar initial stages but diverge once shockable or non-
shockable rhythms are identified.55 The presence of a shock-
able rhythm calls for rapid deployment of a defibrillator
with some variation in preshock actions determined by the
circumstances of individual cases.56 An initial nonshockable
rhythm calls for continued CPR with a concomitant rapid
evaluation to identify and manage reversible noncardiac
causes such as hypovolemia, trauma, vascular obstruction,
and acute respiratory failure. These mechanisms are com-
monly characterized by the presence of PEA with residual
left ventricular contractions and may respond well to reversal
with currently available therapies.
Because PEA is a common mechanism of SCA associ-
ated with massive pulmonary embolism,59 consideration has
been given to the use of thrombolytic therapy when respond-
ing to PEA. This concept is particularly rational when there
is suspicion of pulmonary embolism as the mechanism,
although studies to date have not shown any benefit for the
use of thrombolysis during cardiac arrest when all present-
ing rhythms were included60 or when just PEA was included.61
However, the latter study was small; on the basis of its limited
clinical and autopsy data, the incidence of pulmonary embo-
lism appeared to be very small. Further studies are needed to
determine efficacy. Risk-versus-benefit estimates of its use for
high-probability pulmonary embolism cases are also neces-
sary because hypovolemia secondary to blood loss is another
cause of noncardiac PEA that may be difficult to distinguish
during initial responses.
Finally, even less is known about primary PEA as the mech-
anism of onset of cardiac arrest in acute coronary syndromes.
Whether this is a consequence of a decreased incidence of VT/
VF in this setting, possibly related to β-blocker therapy, in
conjunction with systemic circulating cardiodepressive sig-
nals remains to be elucidated. This area of the PEA spectrum
invites investigative efforts into mechanisms and future spe-
cific therapies.
CPR: Chest Compressions
Numerous studies have shown that improved blood flow
during CPR results in increased survival. Standard chest

compression techniques, including newly introduced modi-
fications such as hands-only CPR,55 are the mainstay of
conventional strategies. Mechanical devices offer more con-
sistent chest compressions, potentially increasing blood flow
during CPR with the potential to improve survival, although
further study is required. This is especially relevant for PEA
because a rapid ROSC is more difficult to achieve with non-
shockable SCA mechanisms. The ability to achieve and reli-
ably monitor sufficient and consistent blood flow is central
to improving outcomes from SCA regardless of mechanism
or cause.
Monitoring Cardiac Motion During CPR
The ability of echocardiography and capnography to predict
survival of cardiac arrest patients in the emergency department
has been studied (see Appendix III in the online-only Data
Supplement). Of the 2 diagnostic tests, only capnography was
a significant predictor of survival. Both the echocardiographic
detection of cardiac activity and end-tidal carbon dioxide lev-
els >16 mm Hg were significantly associated with improved
resuscitation in the emergency department, but stepwise
logistic regression analysis demonstrated that prediction of
survival with capnography was not enhanced by the addition
of echocardiography. However, both strategies should be stud-
ied further in light of the observation of enhanced in-hospital
survival with longer resuscitation efforts.62 Echocardiography
and capnography may help to identify subgroups with better
or worse survivability and potentially to define futility of con-
tinued resuscitation.
Downloaded from http://ahajournals.org by on October 4, 2018
CPR: Mechanical Devices
There has been interest in recent years in the development and
application of mechanical devices for use in CPR responses.
The general concept is to achieve uniformity and maximum
efficiency in circulatory support during prolonged arrests. The
strategy appears most appropriate for victims in whom prompt
electric restoration of rhythm is not feasible, particularly PEA
and asystole.
Active Compression and Decompression CPR
Active compression and decompression CPR uses the addi-
tion of an integral suction cup that provides active return of the
chest to the neutral, uncompressed position. The theory behind
this intervention is that the active decompression generates
negative intrathoracic pressure during chest decompression
that augments venous return and increases forward flow on the
next compression. Laboratory studies have shown improved
hemodynamics with the use of the device.63 There are manual
versions of this device, as well as electrically and pneumati-
cally operated versions.64 One trial has shown improved sur-
vival to discharge when active decompression from a manual
device was combined with the impedance threshold device,
the latter enhancing the negative intrathoracic pressure gener-
ated during chest decompression.65
Load-Distributing Band
A load-distributing band device66 is designed to allow sub-
stantial additional force to be applied to the chest by distrib-
uting the force over most of the chest. Recent trials showed
Myerburg et al   Pulseless Electrical Activity   2537
improved hemodynamics, with coronary perfusion pressures
above the level generally associated with improved survival.
Clinical trial results have been mixed and are dependent on the
way that the studies are implemented.
Because of the greater dependence on CPR in PEA, these
technologies may be more important for subgroups of patients
with SCA caused by nonshockable rhythms. In addition, these
automatic mechanical devices are intended to provide high-
quality CPR during ambulance transport. Enhancements to the
devices that are needed to make substantial differences in out-
comes include reducing costs, improving blood flow–generat-
ing capabilities, reducing interruptions in chest compression,
and reducing deployment time.
Synchronized Chest Compression
In addition to the use of mechanical devices, the use of chest
compressions synchronized to residual cardiac contractions
has been investigated as a way of further augmenting blood
flow during CPR. A porcine model of controlled progres-
sive hypoxia was used to induce PEA with peak aortic pres-
sures targeted to 50 mm Hg, which is below the level that
produces a palpable pulse.67 Systolic synchronization was
associated with statistically significant increases in relax-
ation-phase aortic pressure and coronary perfusion pres-
sure. Thus, synchronizing chest compressions with residual
cardiac activity may augment blood flow and survival, and
further studies are needed to define the role of synchronized
chest compression in treating PEA. Whether synchronized
enhancement of contractions at a slower PEA rate is equiva-
lent to or better than standard unsynchronized CPR com-
pressions at a rate of ≈100 compressions per minute remains
to be determined.
Standard Pharmacological Interventions
Vasoconstrictors have been studied extensively for improv-
ing blood flow and outcomes from CPR, including PEA,68
but little is known about the hemodynamics during clinical
resuscitation. For example, resuscitation guidelines call for
repeated doses of epinephrine during CPR in the absence of
an obvious “treatable cause” of PEA, even though rescuers
usually have no way of knowing either the patient’s inotropic
status or whether the patient’s systemic vascular resistance is
high or low. Vasoconstrictors augment blood flow and survival
in animal models but have not been associated with improved
survival in clinical trials, potentially because of their late
administration, after the patients were no longer viable, and
potentially also because of inconsistent chest compressions
and concomitant variable amounts of blood flow generated by
chest compression.
Experimentally, epinephrine was compared with vaso-
pressin after 15 minutes of cardiac arrest and 3 minutes of
chest compression in 18 pigs randomly treated with 0.8 U/kg
vasopressin or 200 μg/kg epinephrine. Spontaneous circula-
tion was restored in 8 of 9 in the vasopressin group and 1
of 9 in the epinephrine group (P=0.003). Vasopressin signifi-
cantly increased left ventricular myocardial and total cerebral
blood flow during CPR and ROSC.69 In 2 clinical studies, epi-
nephrine increased the rate of ROSC, but it did not increase
 2538  Circulation  December 3/10, 2013
survival to hospital discharge.70,71 In another study, an increase
in the dose of epinephrine during resuscitation of patients with
asystole and PEA was an independent risk factor for unfavor-
able functional outcome and mortality.70 In a study compar-
ing vasopressin and epinephrine for SCA without return of
circulation, the 2 drugs performed similarly for victims with
VF and PEA, but vasopressin performed somewhat better for
asystole.72 There was also a suggestion that vasopressin fol-
lowed by epinephrine may have added benefit in victims of
refractory cardiac arrest. A subsequent study comparing the
combination of epinephrine and vasopressin with epinephrine
alone did not demonstrate added benefit for the combination,73
but asystole was identified as the initial rhythm in 83% of the
patients, so the potential benefit for VF and PEA remains
unknown. Further studies of the role of vasopressors in PEA
might clarify their potential benefit.
Sodium nitroprusside is a vasodilator that may reduce
ischemia and may have direct tissue salvage effects. The
added benefit of sodium nitroprusside with enhanced CPR
on 24-hour survival rates after cardiac arrest was studied in
an experimental pig model.74 Enhanced CPR was defined as
the inclusion of active compression-decompression CPR, an
inspiratory impedance threshold device, and abdominal bind-
ing. Sodium nitroprusside with enhanced CPR significantly
improved hemodynamics, resuscitation rates, and 24-hour
survival rates with good neurological function after cardiac
arrest compared with standard CPR or enhanced CPR alone.
Whether sodium nitroprusside with enhanced CPR will
improve survival outcomes in clinical cardiac arrests resulting
Downloaded from http://ahajournals.org by on October 4, 2018
from PEA requires further study.
Atropine is generally no longer recommended for PEA.55 In
1029 adults with PEA from the Survey of Survivors After Out-
of-Hospital Cardiac Arrest in the Kanto Area, Japan (SOS-
KANTO) study,75 the use of atropine with epinephrine was
associated with a significantly lower 30-day survival rate than
the use of epinephrine alone.
Newly Emerging Pharmacological
Interventions
Cyclosporine is a promising drug on the basis of the con-
cept that PEA in many instances results from myocardial
damage during reperfusion, somewhat similar to the basis
for postconditioning (see below). Cyclosporine inhibits the
formation of mitochondrial permeability transition pore, a
key component of lethal reperfusion injury, in response to
the calcium overload and reactive oxygen species that allow
damage to mitochondria.76 Its relevance may be related
to an observation of reduced infarct size in patients with
ST-segment–elevation myocardial infarction after reperfu-
sion.77 Reperfusion injury may have a pathophysiology simi-
lar to that which occurs in some patients who develop PEA
after defibrillation.
Curcumin, a polyphenolic compound derived from tur-
meric, may have protective effects against myocardial injury
through attenuation of oxidative stress and inflammation. It is
a selective inhibitor of Toll-like receptor 2, a receptor mem-
brane protein expressed on the cell surface that recognizes
foreign substances and then signals a response from cells of
the immune system. In 1 study, Sprague-Dawley rats were fed
curcumin 1 week before cardiac ischemia/reperfusion injury.
Cardiac contractility, connexin43, fibrosis, and other variables
improved compared with a control group. These results sug-
gest that selective inhibition of Toll-like receptor 2 by cur-
cumin could be preventive and therapeutic for myocardial
injury and thereby for PEA.78
Critical Tissue Protection
Intra-Arrest Hypothermia
Hypothermia induced after ROSC has been shown to improve
outcomes. There are generally many hours of delay in achiev-
ing therapeutic hypothermia after successful resuscitation, and
earlier induction of hypothermia may enhance its therapeutic
benefits. The effects of intra-CPR hypothermia with and with-
out volume loading on ROSC and infarction size were inves-
tigated in a coronary occlusion model of cardiac arrest79 (see
Appendix IV for details). The results suggest that intra-CPR
hypothermia significantly reduces myocardial infarction size.
Elimination of volume loading further improves outcomes.
Given the substantial benefit that may be achieved with intra-
CPR induction of hypothermia, improved methods for gen-
erating intra-CPR hypothermia are needed. The techniques
should be sufficiently simple to use that they may be used out
of the hospital by responders.
Extracorporeal Oxygenation
For patients who have received adequate conventional or
mechanically supported CPR initiated early after the onset of
PEA without ROSC up to hospital arrival, the potential ben-
efit of extracorporeal membrane oxygenation should be evalu-
ated. This is viewed as adjunctive to other strategies such as
induced hypothermia.
Postarrest Conditioning
Ischemic postconditioning with “stuttering” reintroduction of
blood flow after prolonged ischemia has been shown to offer
protection against ischemia/reperfusion injury to the myocar-
dium and brain. Four 20-second pauses during the first 3 min-
utes of standard CPR was studied as a method for improving
postresuscitation cardiac and neurological function in a por-
cine model of prolonged untreated cardiac arrest.80 Eighteen
pigs that were intubated and anesthetized with isoflurane had
15 minutes of untreated VF followed by standard CPR (see
Appendix V in the online-only Data Supplement). Animals
receiving standard CPR plus postconditioning had statistically
significant improvement in left ventricular ejection fraction at
1 and 4 hours compared with animals receiving standard CPR
alone. Neurological function at 24 hours also significantly
improved with standard CPR plus postconditioning compared
with standard CPR alone. Similar data were obtained in a post-
countershock model of PEA. Thus, ischemic postconditioning
improved postresuscitation cardiac function and facilitated
neurological recovery after 15 minutes of untreated cardiac
arrest in pigs. This type of controlled pauses in chest com-
pression is an intriguing and potentially promising method for
improving outcomes and should be studied further.

Summary and Future Research Opportunities
On the basis of the current state of knowledge of PEA, in con-
junction with its increased prevalence compared with tachyar-
rhythmic cardiac arrests, its historically poor outcome, and
emerging suggestions that opportunities for better outcomes
may be feasible, the working group made a series of recom-
mendations that constitute a road map for future research.
The workshop participants produced a working definition of
the PEA syndrome and, on the basis of the literature, support
the differentiation of primary and secondary forms of PEA. It
was recognized that many different experimental and clinical
conditions may lead to the PEA syndrome. However, it is not
clear whether there is a final common pathway at the cellular
level for each of these conditions. Traditional experimental
models of the PEA syndrome differ substantially from condi-
tions in the majority of clinical cases. The Oregon SUDS, the
Cardiac Arrest Registry to Enhance Survival, the Resuscitation
Outcomes Consortium, and surveillance data on medication
use before arrest suggest that there may be important patient
“host factors” associated with PEA as the initial documented
cardiac arrest rhythm. These observations are intriguing, but
it is not clear whether these associations signal a causal rela-
tionship that may provide insight into the pathophysiologi-
cal mechanisms underlying PEA. Several relatively simple
and inexpensive modalities, potentially useful for further
PEA classification, are readily available. Echocardiographic
and end-tidal carbon dioxide observations provide real-time
insight into the potential causes and prognosis of PEA, but
little is known about the hemodynamics during clinical resus-
Downloaded from http://ahajournals.org by on October 4, 2018
citation. Therefore, methods to estimate the inotropic status
and systemic vascular resistance during resuscitation would
be potentially useful.
The working group makes the following recommendations:
1. Develop a taxonomic classification of the known experi-
mental and clinical conditions associated with PEA.
2. Conduct future experimental and clinical studies and
report them using this taxonomic classification.
3. Identify new experimental models that better mimic the
clinical conditions leading to the syndrome of PEA to
elucidate the intracellular pathways that result in the
syndrome of PEA. Development and refinement of such
models should be a high priority, contributing to the
design of pilot studies in humans.
4. Capture and analyze accurate additional data elements
in existing and future cardiac arrest surveillance, notably
prior illnesses and current medications, to further eluci-
date the relationship between patient host factors and the
initial documented cardiac arrest rhythm.
5. Collect genetic, proteomic, and biomarker data on both
experimental models and clinical subjects that may lead
to a better understanding of the pathophysiology of PEA.
6. Obtain real-time hemodynamic information during
resuscitation, particularly when PEA occurs, to guide
pharmacological management. Perform noninvasive
technologies such as bioimpedance and bioreactance in
experimental cardiac arrest and PEA models to deter-
mine whether they can track hemodynamics accurately
enough during low-flow states to be of potential use
clinically. For those with promising results, consider
Myerburg et al   Pulseless Electrical Activity   2539
conducting clinical studies of hemodynamically guided
pharmacological intervention (eg, vasoconstrictor/vaso-
dilator/inotropic therapy) during PEA.
7. Consider the merits of pilot testing of PEA-specific
interventions in humans on the basis of promising exper-
imental data such as synchronized mechanical chest
compression and vasodilator therapy.
8. Conduct experimental and pilot clinical studies focus-
ing on earlier application of therapeutic hypothermia,
particularly when initiated during ongoing resuscitation.
As a general principle, adequate pilot data are needed to
justify the investment in large clinical trials addressing the
multiple aspects of PEA cited in this article. This warrants
the support of smaller, hypothesis-generating studies address-
ing prevention and treatment of PEA. The goal of support for
hypothesis-generation studies, in parallel with hypothesis-
testing studies, is to identify pathways worthy of investigation
into this problem of major public health significance.
Disclosures
Dr Halperin receives consultant fees and grant support from Zoll
Circulation, Inc. Dr Gillis receives research support from Medtronic,
Inc. Dr Walcott receives research support from Physio-Control, Inc.
The remaining authors report no conflicts.
References
1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ; American Heart
Association Statistics Committee and Stroke Statistics Subcommittee.
Heart disease and stroke statistics—2012 update: a report from the
American Heart Association. Circulation. 2012;125:e2–e220.
2. Fishman GI, Chugh SS, Dimarco JP, Albert CM, Anderson ME, Bonow
RO, Buxton AE, Chen PS, Estes M, Jouven X, Kwong R, Lathrop
DA, Mascette AM, Nerbonne JM, O’Rourke B, Page RL, Roden DM,
Rosenbaum DS, Sotoodehnia N, Trayanova NA, Zheng ZJ. Sudden car-
diac death prediction and prevention: report from a National Heart, Lung,
and Blood Institute and Heart Rhythm Society Workshop. Circulation.
2010;122:2335–2348.
3. Myerburg RJ. Sudden cardiac death: exploring the limits of our knowl-
edge. J Cardiovasc Electrophysiol. 2001;12:369–381.
4. Weisfeldt ML, Everson-Stewar S, Sitlani C, Rea T, Aufderheide TP,
Atkins DL, Bigham B, Brooks SC, Foerster C, Gray R, Ornato JP, Powell
J, Kudenchuk PJ, Morrison LJ; Resuscitation Outcomes Consortium
Investigators. Ventricular tachyarrhythmias after cardiac arrest in public
versus at home. N Engl J Med. 2011;364:313–321.
5. Braunwald E: Cardiovascular medicine at the turn of the millennium:
Triumphs, concerns, and opportunities. N Engl J Med. 1997; 337:1360–1369.
6. Cobb LA, Fahrenbruch CE, Olsufka M, Copass MK. Changing inci-
dence of out-of-hospital ventricular fibrillation, 1980-2000. JAMA.
2002;288:3008–3013.
7. Herlitz J, Andersson E, Bång A, Engdahl J, Holmberg M, Lindqvist J,
Karlson BW, Waagstein L. Experiences from treatment of out-of-hospital
cardiac arrest during 17 years in Göteborg. Eur Heart J. 2000;21:1251–1258.
8. Agarwal DA, Hess EP, Atkinson EJ, White RD. Ventricular fibrilla-
tion in Rochester, Minnesota: experience over 18 years. Resuscitation.
2009;80:1253–1258.
9. Väyrynen T, Boyd J, Sorsa M, Määttä T, Kuisma M. Long-term changes
in the incidence of out-of-hospital ventricular fibrillation. Resuscitation.
2011;82:825–829.
10. Myerburg RJ, Halperin H, Egan D, Chugh SS, Ewy G, Van Eyk J, Gillis A,
Goldhaber J, Liu P, Niemann J, Ornato JP, Walcott G, Weisfeldt M, Zipes
DP, Boineau R, Lathrop D, Sopko G, Wright J; NHLBI Working Group.
Pulseless electrical activity (PEA): definition, causes, mechanisms, manage-
ment, and research priorities for the next decade: executive summary.
http://www.nhlbi.nih.gov/meetings/workshops/pulseless.htm. Accessed
November 12, 2013.
11. Myerburg RJ, Conde CA, Sung RJ, Mayorga-Cortes A, Mallon SM,
Sheps DS, Appel RA, Castellanos A. Clinical, electrophysiologic and
 2540  Circulation  December 3/10, 2013
hemodynamic profile of patients resuscitated from prehospital cardiac
arrest. Am J Med. 1980;68:568–576.
12. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP,
Rea T, Lowe R, Brown T, Dreyer J, Davis D, Idris A, Stiell I; Resuscitation
Outcomes Consortium Investigators. Regional variation in out-of-hospital
cardiac arrest incidence and outcome. JAMA. 2008;300:1423–1431.
13. Mader TJ, Nathanson BH, Millay S, Coute RA, Clapp M, McNally B;
CARES Surveillance Group. Out-of-hospital cardiac arrest outcomes
stratified by rhythm analysis. Resuscitation. 2012;83:1358–1362.
14. Weisfeldt ML, Everson-Stewart S, Sitlani C, Rea Thomas, Aufderheide
TP, Atkins DL, Bingham B, Brooks SC, Foerster C, Gray R, Ornato JP,
Powell J, Kudenchuk PJ, Morrison LJ; ROC Investigators. Eplerenone in
patients with systolic heart failure and mild symptoms. N Engl J Med.
2011;364:11–19.
15. Hulleman M, Berdowski J, de Groot JR, van Dessel PF, Borleffs CJ, Blom
MT, Bardai A, de Cock CC, Tan HL, Tijssen JG, Koster RW. Implantable
cardioverter-defibrillators have reduced the incidence of resuscitation for
out-of-hospital cardiac arrest caused by lethal arrhythmias. Circulation.
2012;126:815–821.
16. Youngquist ST, Kaji AH, Niemann JT. Beta-blocker use and the chang-
ing epidemiology of out-of-hospital cardiac arrest rhythms. Resuscitation.
2008;76:376–380.
17. Kudenchuk PJ, Redshaw JD, Stubbs BA, Fahrenbruch CE, Dumas F,
Phelps R, Blackwood J, Rea TD, Eisenberg MS. Impact of changes in
resuscitation practice on survival and neurological outcome after out-
of-hospital cardiac arrest resulting from nonshockable arrhythmias.
Circulation. 2012;125:1787–1794.
18. Girotra S, Spertus JA, Li Y, Berg RA, Nadkarni VM, Chan PS; American
Heart Association Get With The Guidelines–Resuscitation Investigators.
Survival trends in pediatric in-hospital cardiac arrests: an analysis from
Get With The Guidelines-Resuscitation. Circ Cardiovasc Qual Outcomes.
2013;6:42–49.
19. Berg RA, Kern KB, Otto CW, Samson RA, Sanders AB, Ewy GA.
Ventricular fibrillation in a swine model of acute pediatric asphyxial car-
diac arrest. Resuscitation. 1996;33:147–153.
20. Kürkciyan I, Meron G, Behringer W, Sterz F, Berzlanovich A, Domanovits
H, Müllner M, Bankl HC, Laggner AN. Accuracy and impact of presumed
Downloaded from http://ahajournals.org by on October 4, 2018
cause in patients with cardiac arrest. Circulation. 1998;98:766–771.
21. De Maio VJ, Stiell IG, Wells GA, Spaite DW. Cardiac arrest witnessed
by emergency medical services personnel: descriptive epidemiology, pro-
dromal symptoms, and predictors of survival: OPALS study group. Ann
Emerg Med. 2000;35:138–146.
22. Dumas F, Cariou A, Manzo-Silberman S, Grimaldi D, Vivien B, Rosencher
J, Empana JP, Carli P, Mira JP, Jouven X, Spaulding C. Immediate percuta-
neous coronary intervention is associated with better survival after out-of-
hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of
hospital Cardiac ArresT) registry. Circ Cardiovasc Interv. 2010;3:200–207.
23. Vincent JL, Thijs L, Weil MH, Michaels S, Silverberg RA. Clinical and
experimental studies on electromechanical dissociation. Circulation.
1981;64:18–27.
24. Ewy GA. Defining electromechanical dissociation. Ann Emerg Med.
1984;13(pt 2):830–832.
25. Urban P, Scheidegger D, Buchmann B, Barth D. Cardiac arrest and blood
ionized calcium levels. Ann Intern Med. 1988;109:110–113.
26. DeBehnke DJ. Effects of vagal tone on resuscitation from experimental
electromechanical dissociation. Ann Emerg Med. 1993;22:1789–1794.
27. Wang H, Tang W, Ristagno G, Li Y, Sun S, Wang T, Weil MH. The poten-
tial mechanisms of reduced incidence of ventricular fibrillation as the pre-
senting rhythm in sudden cardiac arrest. Crit Care Med. 2009;37:26–31.
28. Gessman LJ. Do beta-blockers and ACE inhibitors decrease the duration
of ventricular fibrillation, or cause spontaneous conversion of ventricular
fibrillation? Crit Care Med. 2009;37:329–330.
29. Kitakaze M, Marban E. Cellular mechanism of the modulation of con-
tractile function by coronary perfusion pressure in ferret hearts. J Physiol.
1989;414:455–472.
30. Bode EF, Briston SJ, Overend CL, O’Neill SC, Trafford AW, Eisner DA.
Changes of SERCA activity have only modest effects on sarcoplasmic
reticulum Ca2+ content in rat ventricular myocytes. J Physiol. 2011;589(pt
19):4723–4729.
31. Rovetto MJ, Whitmer JT, Neely JR. Comparison of the effects of anoxia
and whole heart ischemia on carbohydrate utilization in isolated working
rat hearts. Circ Res. 1973;32:699–711.
32. Liao R, Nascimben L, Friedrich J, Gwathmey JK, Ingwall JS. Decreased
energy reserve in an animal model of dilated cardiomyopathy: relationship
to contractile performance. Circ Res. 1996;78:893–902.
33. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabo-
lism in the normal and failing heart. Physiol Rev. 2005;85:1093–1129.
34. Goldhaber JI, Hamilton MA. Role of inotropic agents in the treatment of
heart failure. Circulation. 2010;121:1655–1660.
35. Nian M, Lee P, Khaper N, Liu P. Inflammation and cytokines in post-
myocardial infarction remodeling. Circ Res. 2004;94:1543–1553.
36. Røysland R, Bonaca MP, Omland T, Sabatine M, Murphy SA, Scirica BM,
Bjerre M, Flyvbjerg A, Braunwald E, Morrow DA. Osteoprotegerin and
cardiovascular mortality in patients with non-ST elevation acute coronary
syndromes. Heart. 2012;98:786–791.
37. Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R,
Malarkey WB, Hwang BS, Blackburn E. Omega-3 fatty acids, oxidative
stress, and leukocyte telomere length: a randomized controlled trial. Brain
Behav Immun. 2013;28:16–24.
38. Oral H, Dorn GW 2nd, Mann DL. Sphingosine mediates the immediate
negative inotropic effects of tumor necrosis factor-alpha in the adult mam-
malian cardiac myocyte. J Biol Chem. 1997;272:4836–4842.
39. Xu H, Su Z, Wu J, Yang M, Penninger JM, Martin CM, Kvietys PR, Rui
T. The alarmin cytokine, high mobility group box 1, is produced by viable
cardiomyocytes and mediates the lipopolysaccharide-induced myocardial
dysfunction via a TLR4/phosphatidylinositol 3-kinase gamma pathway. J
Immunol. 2010;184:1492–1498.
40. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg
BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu
MI, Grinfeld LR, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K,
Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin TM,
Metra M; RELAXin in Acute Heart Failure (RELAX-AHF) Investigators.
Serelaxin, recombinant human relaxin-2, for treatment of acute heart
failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet.
2013;381:29–39.
41. Nistri S, Cinci L, Perna AM, Masini E, Mastroianni R, Bani D. Relaxin
induces mast cell inhibition and reduces ventricular arrhythmias in a swine
model of acute myocardial infarction. Pharmacol Res. 2008;57:43–48.
42. Engdahl J, Bång A, Lindqvist J, Herlitz J. Factors affecting short- and
long-term prognosis among 1069 patients with out-of-hospital cardiac
arrest and pulseless electrical activity. Resuscitation. 2001;51:17–25.
43. Polentini MS, Pirrallo RG, McGill W. The changing incidence of ventric-
ular fibrillation in Milwaukee, Wisconsin (1992–2002). Prehosp Emerg
Care. 2006;10:52–60.
44. Kitamura T, Iwami T, Nichol G, Nishiuchi T, Hayashi Y, Nishiyama
C, Sakai T, Kajino K, Hiraide A, Ikeuchi H, Nonogi H, Kawamura T;
Utstein Osaka Project. Reduction in incidence and fatality of out-of-
hospital cardiac arrest in females of the reproductive age. Eur Heart J.
2010;31:1365–1372.
45. Teodorescu C, Reinier K, Dervan C, Uy-Evanado A, Samara M, Mariani
R, Gunson K, Jui J, Chugh SS. Factors associated with pulseless electric
activity versus ventricular fibrillation: the Oregon Sudden Unexpected
Death Study. Circulation. 2010;122:2116–2122.
46. Herlitz J, Engdahl J, Svensson L, Young M, Angquist KA, Holmberg S. Is
female sex associated with increased survival after out-of-hospital cardiac
arrest? Resuscitation. 2004;60:197–203.
47. Kim C, Fahrenbruch CE, Cobb LA, Eisenberg MS. Out-of-hospital car-
diac arrest in men and women. Circulation. 2001;104:2699–2703.
48. Teodorescu C, Reinier K, Uy-Evanado A, Ayala J, Mariani R, Wittwer L,
Gunson K, Jui J, Chugh SS. Survival advantage from ventricular fibril-
lation and pulseless electrical activity in women compared to men: the
Oregon Sudden Unexpected Death Study. J Interv Card Electrophysiol.
2012;34:219–225.
49. Galea S, Blaney S, Nandi A, Silverman R, Vlahov D, Foltin G, Kusick
M, Tunik M, Richmond N. Explaining racial disparities in incidence
of and survival from out-of-hospital cardiac arrest. Am J Epidemiol.
2007;166:534–543.
50. Chu K, Swor R, Jackson R, Domeier R, Sadler E, Basse E, Zaleznak H,
Gitlin J. Race and survival after out-of-hospital cardiac arrest in a subur-
ban community. Ann Emerg Med. 1998;31:478–482.
51. Herlitz J, Rosenfelt M, Bång A, Axelsson A, Ekström L, Wennerblom B,
Löwhagen O, Palmqvist M, Holmberg S. Prognosis among patients with
out-of-hospital cardiac arrest judged as being caused by deterioration of
obstructive pulmonary disease. Resuscitation. 1996;32:177–184.
52. Pirolo JS, Hutchins GM, Moore GW. Electromechanical dissociation:
pathologic explanations in 50 patients. Hum Pathol. 1985;16:485–487.
53. Teodorescu C, Reinier K, Uy-Evanado A, Chugh H, Gunson K, Jui J,
Chugh SS. Antipsychotic drugs are associated with pulseless electrical
activity: the Oregon Sudden Unexpected Death Study. Heart Rhythm.
2013;10:526–530.

54. Mitchell LB, Pineda EA, Titus JL, Bartosch PM, Benditt DG. Sudden
death in patients with implantable cardioverter defibrillators: the impor-
tance of post-shock electromechanical dissociation. J Am Coll Cardiol.
2002;39:1323–1328.
55. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway
CW, Kudenchuk PJ, Ornato JP, McNally B, Silvers SM, Passman RS,
White RD, Hess EP, Tang W, Davis D, Sinz E, Morrison LJ. Part 8: adult
advanced cardiovascular life support: 2010 American Heart Association
guidelines for cardiopulmonary resuscitation and emergency cardiovascu-
lar care. Circulation. 2010;122(suppl 3):S729–S767.
56. Berg RA, Hemphill R, Abella BS, Aufderheide TP, Cave DM, Hazinski
MF, Lerner EB, Rea TD, Sayre MR, Swor RA. Part 5: adult basic life
support: 2010 American Heart Association guidelines for cardiopul-
monary resuscitation and emergency cardiovascular care. Circulation.
2010;122(suppl 3):S685–S705.
57. Desbiens NA. Simplifying the diagnosis and management of pulseless electri-
cal activity in adults: a qualitative review. Crit Care Med. 2008;36:391–396.
58. Blaivas M, Fox JC. Outcome in cardiac arrest patients found to have car-
diac standstill on the bedside emergency department echocardiogram.
Acad Emerg Med. 2001;8:616–621.
59. Courtney DM, Sasser HC, Pincus CL, Kline JA. Pulseless electrical activ-
ity with witnessed arrest as a predictor of sudden death from massive pul-
monary embolism in outpatients. Resuscitation. 2001;49:265–272.
60. Böttiger BW, Arntz HR, Chamberlain DA, Bluhmki E, Belmans A, Danays
T, Carli PA, Adgey JA, Bode C, Wenzel V; TROICA Trial Investigators;
European Resuscitation Council Study Group. Thrombolysis during resusci-
tation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359:2651–2662.
61. Abu-Laban RB, Christenson JM, Innes GD, van Beek CA, Wanger KP,
McKnight RD, MacPhail IA, Puskaric J, Sadowski RP, Singer J, Schechter
MT, Wood VM. Tissue plasminogen activator in cardiac arrest with pulse-
less electrical activity. N Engl J Med. 2002;346:1522–1528.
62. Goldberger ZD, Chan PS, Berg RA, Kronick SL, Cooke CR, Lu M,
Banerjee M, Hayward RA, Krumholz HM, Nallamothu BK; American
Heart Association Get With The Guidelines—Resuscitation (formerly
National Registry of Cardiopulmonary Resuscitation) Investigators.
Duration of resuscitation efforts and survival after in-hospital cardiac
arrest: an observational study. Lancet. 2013;380:1473–1481.
Downloaded from http://ahajournals.org by on October 4, 2018
63. Halperin HR, Paradis N, Ornato JP, Zviman M, Lacorte J, Lardo A, Kern
KB. Cardiopulmonary resuscitation with a novel chest compression
device in a porcine model of cardiac arrest: improved hemodynamics and
mechanisms. J Am Coll Cardiol. 2004;44:2214–2220.
64. Rubertsson S, Silfverstolpe J, Rehn L, Nyman T, Lichtveld R, Boomars
R, Bruins W, Ahlstedt B, Puggioli H, Lindgren E, Smekal D, Skoog G,
Kastberg R, Lindblad A, Halliwell D, Box M, Arnwald F, Hardig BM,
Chamberlain D, Herlitz J, Karlsten R. The study protocol for the LINC
(LUCAS in Cardiac Arrest) study: a study comparing conventional
adult out-of-hospital cardiopulmonary resuscitation with a concept with
mechanical chest compressions and simultaneous defibrillation. Scand J
Trauma Resusc Emerg Med. 2013;21:5.
65. Aufderheide TP, Frascone RJ, Wayne MA, Mahoney BD, Swor RA,
Domeier RM, Olinger ML, Holcomb RG, Tupper DE, Yannopoulos D,
Lurie KG. Standard cardiopulmonary resuscitation versus active compres-
sion-decompression cardiopulmonary resuscitation with augmentation of
negative intrathoracic pressure for out-of-hospital cardiac arrest: a ran-
domised trial. Lancet. 2011;377:301–311.
66. Ong ME, Ornato JP, Edwards DP, Dhindsa HS, Best AM, Ines CS, Hickey
S, Clark B, Williams DC, Powell RG, Overton JL, Peberdy MA. Use of
an automated, load-distributing band chest compression device for out-of-
hospital cardiac arrest resuscitation. JAMA. 2006;295:2629–2637.
67. Paradis NA, Halperin HR, Zviman M, Barash D, Quan W, Freeman
G. Coronary perfusion pressure during external chest compression in
pseudo-EMD, comparison of systolic versus diastolic synchronization.
Resuscitation. 2012;83:1287–1291.
68. Nordseth T, Olasveengen TM, Kvaløy JT, Wik L, Steen PA, Skogvoll
E. Dynamic effects of adrenaline (epinephrine) in out-of-hospital
Myerburg et al   Pulseless Electrical Activity   2541
cardiac arrest with initial pulseless electrical activity (PEA). Resuscitation.
2012;83:946–952.
69. Wenzel V, Lindner KH, Prengel AW, Maier C, Voelckel W, Lurie KG,
Strohmenger HU. Vasopressin improves vital organ blood flow after pro-
longed cardiac arrest with postcountershock pulseless electrical activity in
pigs. Crit Care Med. 1999;27:486–492.
70. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S.
Prehospital epinephrine use and survival among patients with out-of-hos-
pital cardiac arrest. JAMA. 2012;307:1161–1168.
71. Arrich J, Sterz F, Herkner H, Testori C, Behringer W. Total epinephrine
dose during asystole and pulseless electrical activity cardiac arrests is
associated with unfavourable functional outcome and increased in-hospi-
tal mortality. Resuscitation. 2012;83:333–337.
72. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH;
European Resuscitation Council Vasopressor During Cardiopulmonary
Resuscitation Study Group. A comparison of vasopressin and epineph-
rine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med.
2004;350:105–113.
73. Gueugniaud PY, David JS, Chanzy E, Hubert H, Dubien PY, Mauriaucourt
P, Bragança C, Billères X, Clotteau-Lambert MP, Fuster P, Thiercelin D,
Debaty G, Ricard-Hibon A, Roux P, Espesson C, Querellou E, Ducros L,
Ecollan P, Halbout L, Savary D, Guillaumée F, Maupoint R, Capelle P,
Bracq C, Dreyfus P, Nouguier P, Gache A, Meurisse C, Boulanger B, Lae
C, Metzger J, Raphael V, Beruben A, Wenzel V, Guinhouya C, Vilhelm C,
Marret E. Vasopressin and epinephrine vs. epinephrine alone in cardiopul-
monary resuscitation. N Engl J Med. 2008;359:21–30.
74. Yannopoulos D, Matsuura T, Schultz J, Rudser K, Halperin HR, Lurie KG.
Sodium nitroprusside enhanced cardiopulmonary resuscitation improves
survival with good neurological function in a porcine model of prolonged
cardiac arrest. Crit Care Med. 2011;39:1269–1274.
75. Nagao K, Yagi T, Sakamoto T, Koseki K, Igarashi M, Ishimatsu S, Sato A,
Hori S, Kanesaka S, Hamabe Y, Saito D, Kitamura S, Nonaka A, Katsumi
A, Sakurai A, Suzuki H, Imai H, Miyauchi H, Suga H, Tomioka J, Imai K,
Kiyota K, Arima K, Takuhiro K, Matsuda K, Takahashi K, Naito M, Yagi
M, Honma M, Sasaki M, Suzuki M, Nakano M, Fugiyoshi N, Kozima N,
Harada N, Ohashi N, Suzuki N, Moriwaki R, Takahashi R, Kikuchi S,
Noda S, Oda S, Imaki S, Fugikawa T, Kikuno T, Kamohara T, Suda T, Ishii
T, Irabu T, Sadahiro T, Ikeda T, Tanaka T, Obayashi T, Ogawa T, Miyahara
Y, Nakagawa Y, Tokuyasu Y, Tawara Y, Haga Y, Minowa Y, Tanaka Y,
Sasaki Z, Fudouzi Z; Survey of Survivors After Out-of-Hospital Cardiac
Arrest in Kanto Area, Japan (SOS-KANTO) Study Group. Atropine sul-
fate for patients with out-of-hospital cardiac arrest due to asystole and
pulseless electrical activity. Circ J. 2011;75:580–588.
76. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochon-
drial permeability transition pore opening: a new paradigm for myocardial
preconditioning? Cardiovasc Res. 2002;55:534–543.
77. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti
R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch
C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier
JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury
in acute myocardial infarction. N Engl J Med. 2008;359:473–481.
78. Kim YS, Kwon JS, Cho YK, Jeong MH, Cho JG, Park JC, Kang JC, Ahn Y.
Curcumin reduces the cardiac ischemia-reperfusion injury: involvement of the
toll-like receptor 2 in cardiomyocytes. J Nutr Biochem. 2012;23:1514–1523.
79. Yannopoulos D, Zviman M, Castro V, Kolandaivelu A, Ranjan R, Wilson
RF, Halperin HR. Intra-cardiopulmonary resuscitation hypothermia with
and without volume loading in an ischemic model of cardiac arrest.
Circulation. 2009;120:1426–1435.
80. Segal N, Matsuura T, Caldwell E, Sarraf M, McKnite S, Zviman M,
Aufderheide TP, Halperin HR, Lurie KG, Yannopoulos D. Ischemic post-
conditioning at the initiation of cardiopulmonary resuscitation facilitates
functional cardiac and cerebral recovery after prolonged untreated ven-
tricular fibrillation. Resuscitation. 2012;83:1397–1403.
Key Words: arrhythmias, cardiac ◼ death, sudden, cardiac ◼ heart arrest