Resuscitation 85 (2014) 657663

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Clinical Paper
Early coronary angiography and induced hypothermia are
associated with survival and functional recovery after
out-of-hospital cardiac arrest

Clifton W. Callaway
a,
, Robert H. Schmicker
b
, Siobhan P. Brown
b
, J. Michael Albrich
c
,
Douglas L. Andrusiek
d
, Tom P. Aufderheide
e
, James Christenson
d
, Mohamud R. Daya
f
,
David Falconer
g
, Ruchika D. Husa
h
, Ahamed H. Idris
i
, Joseph P. Ornato
j
, Valeria E. Rac
g
,
Thomas D. Rea
b
, Jon C. Rittenberger
a
, Gena Sears
b
, Ian G. Stiell
k
, ROC Investigators
a
University of Pittsburgh, Pittsburgh, PA, United States
b
University of Washington, Seattle, WA, United States
c
Legacy Health System, Portland, OR, United States
d
University of British Columbia, Vancouver, BC, United States
e
Medical College of Wisconsin, Milwaukee, WI, United States
f
Oregon Health and Science University, Portland, OR, United States
g
University of Toronto, Toronto, ON, United States
h
University of California, San Diego, La Jolla, CA, United States
i
University of Texas, Southwestern, Dallas, TX, United States
j
Virginia Commonwealth University, Richmond, VA, United States
k
University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, United States
a r t i c l e i n f o
Article history:
Received 4 November 2013
Received in revised form
16 December 2013
Accepted 20 December 2013
Keywords:
Heart arrest
Hypothermia
Coronary angiography
Percutaneous coronary intervention
Fibrinolysis
a b s t r a c t
Background: The rate and effect of coronary interventions and induced hypothermia after out-of-hospital
cardiac arrest (OHCA) are unknown. We measured the association of early (24h after arrival) coronary
angiography, reperfusion, and induced hypothermia with favorable outcome after OHCA.
Methods: We performed a secondary analysis of a multicenter clinical trial (NCT00394706) conducted
between 2007 and 2009 in10North American regions. Subjects were adults (18 years) hospitalized after
OHCA with pulses sustained 60 min. We measured the association of early coronary catheterization,
percutaneous coronary intervention, brinolysis, and induced hypothermia with survival to hospital
discharge with favorable functional status (modied Rankin Score 3).
Results: From 16,875 OHCA subjects, 3981 (23.6%) arrived at 151 hospitals with sustained pulses. 1317
(33.1%) survived to hospital discharge, with 1006 (25.3%) favorable outcomes. Rates of early coronary
catheterization (19.2%), coronary reperfusion (17.7%) or induced hypothermia (39.3%) varied among
hospitals, and were higher in hospitals treating more subjects per year. Odds of survival and favorable
outcome increased with hospital volume (per 5 subjects/year OR 1.06; 95%CI: 1.041.08 and OR 1.06;
95%CI: 1.04, 1.08, respectively). Survival and favorable outcome were independently associated with
early coronary angiography (OR 1.69; 95%CI 1.062.70 and OR 1.87; 95%CI 1.153.04), coronary reper-
fusion (OR 1.94; 95%CI 1.342.82 and OR 2.14; 95%CI 1.463.14), and induced hypothermia (OR 1.36;
95%CI 1.011.83 and OR 1.42; 95%CI 1.041.94).
Interpretation: : Early coronary intervention and induced hypothermia are associated with favorable
outcome and are more frequent in hospitals that treat higher numbers of OHCA subjects per year.
2014 Elsevier Ireland Ltd. All rights reserved.

A Spanish translated version of the abstract of this article appears as Appendix

in the nal online version at http://dx.doi.org/10.1016/j.resuscitation.2013.12.028.

Corresponding author at: 400A Iroquois, 3600 Forbes Avenue, Pittsburgh, PA

15260, United States.
E-mail address: callawaycw@upmc.edu (C.W. Callaway).
1. Introduction
Out-of-hospital cardiac arrest (OHCA) is the third leading cause
of death in North America, aficting an estimated 382,000 persons
in the US per year,
1
with a case-mortality rate of 94.7%.
2
Reversal
of cardiac arrest requires rapid restoration of cardiac activity using
debrillation, reperfusion, mechanical or pharmacological support.
0300-9572/$ see front matter 2014 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.resuscitation.2013.12.028
658 C.W. Callaway et al. / Resuscitation 85 (2014) 657663
Differences betweencommunities andemergencymedical services
(EMS) response systems contribute to differences in survival after
OHCA between regions.
2,3
In-hospital interventions after OHCA
47
may prevent secondary
injury and ameliorate ischemia-reperfusion injury to multiple
organs, especially the heart and brain.
8
Induced hypothermia,
9,10
coronary artery reperfusion,
1113
hemodynamic optimization,
7,14
ventilator management
15
and neurological prognostication
16
all
can inuence outcomes. However, the use of these interventions is
variable. While there are a number of European studies about the
prevalence of hypothermia implementation,
1719
in North America
neither the prevalence of these intervention nor the relationship of
these interventions with patient outcomes have been measured.
This study was a planned secondary analysis of a randomized
controlled trial to examine the relationship between in-hospital
interventions and outcomes after OHCA in a large North American
network. The parent trial tested the inuence of two EMS inter-
ventions, which were found to have no effect on outcome.
20,21
The
primary hypothesis of this study was that early coronary angiogra-
phy or reperfusion and induced hypothermia are associated with
survival and favorable functional status after OHCA.
2. Methods
2.1. Study design and setting
Between June 2007 and October 2009, 10 US and Canadian clin-
ical sites in the Resuscitation Outcomes Consortium(ROC) enrolled
consecutive OHCApatients treated by 150 EMS agencies in a multi-
center, randomizedcontrolledtrial (ROC-PRIMED; clinicaltrials.gov
NCT00394706). This trial tested the effect on functional recovery
and on survival to hospital discharge of performing cardiopul-
monary resuscitation (CPR) for a brief (30s) interval or for 3min
prior to rhythm analysis and debrillation attempt for ventricu-
lar brillation (VF). The trial simultaneously compared the effect
of using an impedance threshold device (ITD) with using a sham
device. Neither the CPR strategies nor the ITD device affected sur-
vival or functional outcome.
20,21
Institutional reviewboards or research ethics boards at all sites
and hospitals granted an Exception from Informed Consent for
enrollment. As soon as feasible, we notied surviving subjects or
their legally authorized representatives about the study and pro-
vided opportunity to withdrawfromcontinued data collection. We
reviewed hospital medical records for all subjects until hospital
discharge. Primary outcomes were available for all subjects in this
secondary study.
2.2. Patient population
This secondary analysis studied all screened or randomized
adult (age >18 years) subjects with OHCA, dened as receiving
chest compressions froma professional provider or a rescue shock
froma debrillator. We included only subjects who were delivered
to any of 151 participating hospitals with a pulse or who regained a
pulse in the emergency department, and who survived for >60min
after hospital arrival, because these subjects were potential recip-
ients of in-hospital interventions. We excluded subjects for whom
resuscitation efforts were discontinued prior to hospital arrival
or for whom no pulse was established even after hospital arrival
(Fig. 1). Patients with EMS-witnessed cardiac arrest and patients
withtracheostomies were includedalthoughthese subgroups were
excluded fromsome out-of-hospital interventions in ROC-PRIMED.
We excluded prisoners, pregnant women, patients with do not
resuscitate directives made prior to EMS treatment, and patients
Fig. 1. Subjects included and excluded fromanalysis.
with blunt, penetrating or burn-related trauma or with cardiac
arrest due to exsanguination.
2.3. Data collection
Research coordinators abstracted data into web-based case
report forms fromEMS andhospital records andfromthe electronic
data captured by EMS monitordebrillators. The Data Coordinat-
ing Center trained data abstractors, provided on-line assistance
with ambiguous cases, and performed site visits and audits to
ensure data integrity. Automated within-form and between-form
data checks followed by written resolution of conicting data were
performed to reduce errors.
2.4. Interventions and covariates
We recorded whether any coronary angiography was per-
formed, whether the angiographywas early(<24hfromadmission)
or >24h after admission, and whether a percutaneous coronary
intervention (PCI) was performed. More precise timing of PCI was
not available in this dataset. We noted the acute administration
of any brinolytic drugs. Because acute coronary artery reper-
fusioncanbe accomplishedusing brinolysis or PCI, we examineda
composite intervention of early coronary reperfusion therapy (any
brinolysis or PCI).
We denedinducedhypothermia as any active attempt tolower
core body temperature at the hospital. We recorded the time of
the rst attempt to initiate hypothermia, the time when rewarm-
ing began, and the lowest temperature achieved. In this cohort,
documented efforts to lower body temperature by EMS were rare
(n=188 cases), and the time of initiation of hypothermia for those
cases was dened as the time of hospital arrival.
We recorded the presence or absence of ST-elevation myocar-
dial infarction (STEMI) on the rst ECG obtained at the hospital,
in-hospital events (stroke, seizures, bleeding requiring transfusion,
pulmonary edema, recurrent cardiac arrest, organ failure, pneumo-
nia or sepsis, myocardial infarctionat anytime), andhospital length
of stay.
Prior studies using different data sets reported associations
between the number of cardiac arrest subjects treated at each
C.W. Callaway et al. / Resuscitation 85 (2014) 657663 659
hospital and survival.
46
Therefore, we examined the number of
ROC study subjects admitted to each hospital per year, both as a
continuous variable and categorically (59, 1019, 2029, 3039,
>40subjects per hospital). Whenasubject was transferredfromone
hospital toanother ontherst hospital day, thesecondhospital was
considered the treating hospital.
2.5. Study outcomes
The primary outcome was survival to hospital discharge with
favorable functional status dened as modied Rankin Score
(mRS <3). Survival to hospital discharge was dened as transfer
from an acute care hospital to rehabilitation, skilled nursing or
home residence. The mRS at hospital discharge was determined by
review of clinical records using a standard instrument. Research
coordinators assigned the circumstances of in-hospital death to
one of four categories: (1) medically unable to support (multiple
organ failure, intractable shock or recurrent arrest), (2) brain death,
(3) withdrawal of life sustaining treatment for non-neurological
reasons (for example, advanced directives or antecedent terminal
illness), and (4) withdrawal of life sustaining treatment based on
neurological prognosis.
2.6. Sample size and statistical analysis
The original trial proposed to enroll 14,154 subjects to have
90% power for detecting a difference in favorable functional recov-
ery between treatments of 5.3% versus 6.7%, but was stopped for
futility according to a priori stopping rules after 16,875 subjects
were screened of whom12,579 subjects were randomized to study
treatments.
We examined the relationship of outcome with the individual
interventions and with clinical features of the patients using unad-
justed and adjusted odds ratios. Separate models were created for
the outcome of survival to hospital discharge and survival with
mRS <3 at hospital discharge. Adjusted odds ratios were estimated
using multivariable logistic regression including covariates a priori
thought to potentially confound the relationship between outcome
and each intervention: sex, age (modeled as a cubic spline with
nodes at 40, 60); interval fromEMS dispatch to rst agency arrival
(cubic splinewithnodes at 4, 12); rst EMS rhythm(VT/VF, asystole,
PEA, perfusing rhythm, AED no-Shock/Unknown); witnessed col-
lapse (EMS, bystander, not witnessed, unknown); bystander CPR;
study site; meanCPRfraction(cubic spline witha node at 0.4); pub-
lic location of collapse. We also included covariates associated with
each intervention a posteriori: advanced airway placement; home
residence prior to arrest; subjects treated at that hospital per year
(cubic spline with node at 20); time from left scene to ED arrival
(cubic spline with nodes at 5, 20, 40); time from EMS arrival to
return of spontaneous circulation (cubic spline with node at 20);
and total prehospital epinephrine dose (cubic spline with nodes
at 4, 8). Because coronary artery bypass grafting (CABG), and the
placement of a permanent pacemaker or implantable cardioverter-
debrillator (ICD) are generally offered only to patients who will
clearly survive hospitalization, these variables were not considered
to be potential predictors of survival or outcome. Likewise, coro-
nary angiography performed more than 24h after OHCA is prone
to be selectively provided to survivors, and was not included as a
predictor of survival or outcome.
Collinearity between covariates was checked with variation
ination factor (VIF). Data management was performed in S-PLUS
(version 6.2.1, 2003, Insightful Corporation, Seattle, WA), while
regression analysis was performed in Stata (Release 11, 2009, Stat-
aCorp, College Station, TX).
Fig. 2. Rates of (A) early coronary angiography, and (B) induced hypothermia versus
number of subjects treated at each hospital per year for All Subjects and for Subjects
with VF as initial rhythm. Rates of (C) survival to hospital discharge and favorable
functional outcome (mRS <3) versus number of subjects treated at each hospital per
year. Hospitals treating <5 subjects total were excluded. The number of hospitals (n)
in each stratumis indicated.
3. Results
Of 16,875 subjects treated by EMS, 3981 (23.6% of all subjects)
arrived at a hospital and had pulses lasting for >60min (Fig. 1). A
total of 1317 subjects (33.1% of hospitalized; 7.8% of total) survived
to hospital discharge, and1006 (25.3%of hospitalized; 6.0%of total)
had favorable functional status at hospital discharge (Table 1).
Subjects were treatedin151hospitals witha medianof 262(IQR
172, 419) beds of which 72 (47.7%) had residency programs, and 21
(14.0%) were level 1 trauma centers. The majority (n=92, 60.9%)
of hospitals had a cardiac catheterization lab. Hospitals treated a
median of 12.3 (IQR 5.525.3) study subjects per year.
The clinical features of 765 (19.2%) hospitalized subjects who
received early coronary angiography, and 705 (17.7%) who had
early coronary reperfusion (either PCI or brinolysis) are in Table 1.
660 C.W. Callaway et al. / Resuscitation 85 (2014) 657663
Table 1
Baseline characteristics of subjects (PEA, pulseless electrical activity; VT/VF, ventricular tachycardia/ventricular brillation; AED, automatic external debrillator; CPRfraction,
proportion of each minute during cardiac arrest with uninterrupted chest compressions).
All hospitalized
subjects
Induced hypothermia
subjects
*
Early coronary
angiography subjects
**
Reperfusion subjects
(PCI or brinolytics)
***
n 3981 1566 765 705
Median age (IQR) 67.0 (55.0,
79.0)
63.0 (53.0, 75.0) 62.0 (53.0, 71.0) 62.0 (53.0, 72.0)
Male, n (%) 2541 (63.8%) 1096 (70.0%) 595 (77.8%) 538 (76.3%)
Public location, n (%) 800 (20.1%) 417 (26.6%) 257 (33.6%) 230 (32.6%)
Living at home prior to event, n (%) 3100 (88.8%) 1402 (91.5%) 739 (96.6%) 676 (96.6%)
Initial rhythm
VT/VF, n (%) 1619 (40.7%) 879 (56.1%) 591 (77.3%) 546 (77.4%)
PEA, n (%) 1089 (27.4%) 309 (19.7%) 79 (10.3%) 77 (10.9%)
Asystole, n (%) 929 (23.3%) 308 (19.7%) 70 (9.2%) 59 (8.4%)
AED no-shock, n (%) 274 (6.9%) 65 (4.2%) 18 (2.4%) 16 (2.3%)
Unknown, n (%) 18 (0.5%) 2 (0.1%) 2 (0.3%) 3 (0.4%)
Witnessed collapse
EMS, n (%) 587 (14.7%) 91 (5.8%) 149 (19.5%) 155 (22.0%)
Bystander, n (%) 2136 (53.7%) 987 (63.0%) 476 (62.2%) 429 (60.9%)
Unknown, n (%) 69 (1.7%) 19 (1.2%) 11 (1.4%) 15 (2.1%)
Not Witnessed, n (%) 1189 (29.9%) 469 (29.9%) 129 (16.9%) 106 (15.0%)
Bystander CPR 1651 (41.5%) 771 (49.2%) 364 (47.6%) 301 (42.7%)
Median dispatch EMS arrival interval,
minutes (IQR)
5.4 (4.2, 7.0) 5.3 (4.1, 6.6) 5.3 (4.0, 6.7) 5.4 (4.2, 6.8)
Median dispatch return of pulses
interval, minutes (IQR)
22.8 (17.0,
30.0)
21.9 (16.6, 28.0) 20.9 (15.1, 28.1) 21.0 (15.0, 28.0)
Median depart scene hospital arrival
interval, minute (IQR)
7.1 (4.8, 10.3) 7.3 (4.8, 10.5) 7.7 (5.0, 11.0) 7.4 (4.8, 10.8)
Epinephrine used, n (%) 2858 (71.8%) 1198 (76.5%) 468 (61.2%) 413 (58.6%)
Median epinephrine dose (mg) (IQR) 2.0 (1.0, 3.0) 2.0 (1.0, 3.0) 2.0 (1.0, 3.0) 2.0 (1.0, 3.0)
Advanced airway placed by EMS, n (%) 3499 (87.9%) 1487 (95.0%) 614 (80.3%) 555 (78.7%)
Median CPR fraction (IQR) 0.71 (0.59,
0.82)
0.71 (0.59, 0.81) 0.69 (0.54, 0.79) 0.65 (0.53, 0.76)
STEMI, n (%) 573 (17.5%) 266 (17.0%) 356 (48.4%) 338 (47.9%)
*
All listed variables were associated with receiving induced hypothermia, p<0.05.
**
All listed variables except call-dispatch interval, depart scene-hospital arrival interval and advanced airway were associated with receiving early angiography, p<0.05.
***
All listed variables except bystander CPR, call-dispatch interval, depart scene-hospital arrival interval and call-ROSC interval were associated with reperfusion, p<0.05.
The proportion of patients receiving early angiography varied
across hospitals (range 075% among hospitals treating 5 or more
subjects per year), and was associated with the number of subjects
treatedannually at eachhospital (OR1.01; 95%CI 1.01, 1.02) (Fig. 2).
Early coronary angiography (n=356, 62.1%) or brinolysis (n=81,
14.1%) was provided to 76.3% of 573 subjects for whomSTEMI was
identied on initial ECG. Early angiography (n=409, 12.0%) or bri-
nolysis (n=109, 3.2%) was provided to 15.2% of the remaining 3408
subjects.
Induced hypothermia was provided to 1566 subjects (39.3%)
with clinical features described in Table 1 including 54.3% of
patients with an initial rhythm of VF (n=879) and 29.6% of sub-
jects with non-VF (n=684). The proportion of patients treated
with hypothermia varied between hospitals (range 083% among
hospitals that treated 5 or more subjects per year) and was asso-
ciated with the number of subjects treated annually by each
hospital (OR 1.02; 95%CI 1.02, 1.03) (Fig. 2). Clinical features of
induced hypothermia included initiation at a median of 106 (IQR
53.6226.5) min after return of pulses, median duration of 24 (IQR
1826.7) h and median lowest documented temperature of 32

C
(IQR 31.533.0).
Each increase in ve treated subjects per year at a hospital was
associated with an increase in the odds of survival (OR 1.06; 95%CI:
1.04, 1.08) and survival with favorable functional status (OR 1.06;
95%CI: 1.04, 1.08) (Fig. 2). In-hospital events wererecordedfor 2922
(73.4%) subjects including circumstance of death for 2130 (81.5%)
of 2613 subjects with in-hospital death (Table 2). Withdrawal of
life-sustaining treatment for neurological reasons was the most
commoncircumstance preceding in-hospital death(61.2%of cases)
and was highest among hypothermia subjects (69.3%). Among sur-
vivors of cardiac arrest with VF as an initial rhythm, an ICD was
implanted in 35.0%, including 44.5% of survivors without STEMI,
and in 54.1% of survivors with neither PCI nor CABG.
Survival (64.7%) and favorable recovery (54.0%) were higher
among subjects receiving early coronary angiography than among
subjects not receiving early angiography (27.1% and 18.4%). Among
all subjects treated with hypothermia, survival (40.7%) and favor-
able recovery (30.4%) were higher than among subjects not treated
with hypothermia (30.3% and 21.9%). After adjusting for all covari-
ates, early coronary angiography, any coronary reperfusion and
induced hypothermia were independently associated with sur-
vival to hospital discharge andfavorable functional status (Table 3).
There was no signicant interactionbetweenthe hospital interven-
tions, but the subset of patients withbothcoronary reperfusionand
hypothermia (n=355) had high rates of survival (n=225; 63.4%)
and favorable functional recovery (n=188; 53.0%). No covariables
were collinear (all had VIF <10).
4. Discussion
This studyconrms that use of inducedhypothermia anda strat-
egy of early coronary angiography and reperfusion are associated
with survival and favorable functional outcomes after OHCA. These
are the largest prospective data from a North American cohort to
date to provide estimates of the rate early coronary angiography
(19.2%) and induced hypothermia (39.3%) for OHCA patients. These
procedures are used more often in hospitals that treat higher num-
bers of OHCA subjects, and the number of subjects treated at each
hospital is associated with rates of patient survival and favorable
functional recovery.
These data conrmthat acute coronary interventions are associ-
ated with improved outcome after OHCA. Acute coronary occlusion
C.W. Callaway et al. / Resuscitation 85 (2014) 657663 661
Table 2
In-hospital events (WLST, withdrawal of life-sustaining treatment).
All hospitalized
subjects
Induced hypothermia
subjects
Early coronary
angiography subjects
Reperfusion subjects
(PCI or brinolytics)
Total 3981 1566 765 705
In-hospital complications
Stroke/intracranial hemorrhage 136 (3.4%) 31 (2.0%) 19 (2.5%) 18 (2.6%)
Seizures 260 (6.5%) 132 (8.4%) 39 (5.1%) 31 (4.4%)
Severe bleeding 106 (2.7%) 42 (2.7%) 29 (3.8%) 22 (3.1%)
Pulmonary edema 133 (3.3%) 67 (4.3%) 39 (5.1%) 38 (5.4%)
Rearrest 181 (4.5%) 96 (6.1%) 56 (7.3%) 49 (7.0%)
Fractures/internal injuries 69 (1.7%) 24 (1.5%) 14 (1.8%) 13 (1.8%)
Acute respiratory distress syndrome 67 (1.7%) 42 (2.7%) 18 (2.4%) 11 (1.6%)
Liver failure 69 (1.7%) 25 (1.6%) 8 (1.0%) 8 (1.1%)
Renal failure 470 (11.8%) 204 (13.0%) 83 (10.8%) 63 (8.9%)
Sepsis 196 (4.9%) 75 (4.8%) 32 (4.2%) 29 (4.1%)
Pneumonia 554 (13.9%) 284 (18.1%) 122 (15.9%) 99 (14.0%)
Myocardial infarction 681 (17.1%) 324 (20.7%) 309 (40.4%) 315 (44.7%)
None noted 2105 (52.9%) 718 (45.8%) 284 (37.1%) 260 (36.9%)
Circumstances preceding in-hospital death
Multiple organ failure 123 (5.8%) 38 (4.3%) 17 (6.3%) 17 (7.4%)
Recurrent cardiac arrest 175 (8.2%) 63 (7.1%) 42 (15.6%) 46 (20.0%)
Intractable shock 88 (4.1%) 39 (4.4%) 28 (10.4%) 27 (11.7%)
Brain death 223 (10.5%) 74 (8.3%) 20 (7.4%) 19 (8.3%)
WLST non-neurological reasons 216 (10.1%) 58 (6.5%) 16 (5.9%) 16 (7.0%)
WLST neurological reasons 1305 (61.2%) 619 (69.3%) 146 (54.1%) 105 (45.7%)
Hospital length of stay
Median length of stay survivors (IQR) 11.0 (6.0, 20.0) 14.0 (8.5, 22.0) 10.0 (6.0, 17.5) 11.0 (6.0, 19.5)
Median length of stay in-hospital
death (IQR)
1.0 (0.0, 4.0) 3.0 (1.0, 6.0) 3.0 (1.0, 6.0) 3.0 (1.0, 6.0)
occurs inupto70%of patients resuscitatedfromcardiac arrest.
1113
Observational studies indicate that coronary angiography and suc-
cessful PCI are associated with improved survival.
12,13,22
In this
study, reperfusion therapy was instituted for the majority of
subjects diagnosed with STEMI (76%), indicating that antecedent
cardiac arrest is not a barrier to aggressive care, although this rate
is below the 100% that would be recommended by Guidelines.
However, observational data cannot conrm a causal relationship
between intervention and outcome, because there is a real risk
that clinicians selected those patients most likely to benet using
variables not measured in this study. Nevertheless, these data sup-
port recommendations to consider early coronary reperfusion for
patients with return of pulses after OHCA.
23
Future studies should
collect detailed information about provider decision making to
intervene early in specic cases.
This study cannot determine whether presence of coma on
hospital arrival reduced enthusiasm for early coronary interven-
tions, because level of consciousness was not recorded. Clinical
features (Tables 1 and 2) of patients with early angiography and
less frequent withdrawal of life sustaining treatment for neuro-
logical reasons suggest that some of these patients may have been
awakeat hospital arrival. Nevertheless, excellent survival (63%) and
favorable functional recovery (53%) inthe hypothermia withreper-
fusion group support recommendations to consider both therapies
concurrently in comatose patients.
2224
The overall rate of cardiac catheterization (12%) or brinolysis
(3.2%) for non-STEMI cases appears low. These rates are similar to
the rate (11%) in a German study,
22
but much lower than the rate
(73%) reported in a French study.
25
Higher rates of angiography
are probably justied, because angiography for consecutive post-
cardiac arrest patients identies signicant coronary lesions in
58%
13
or 45%
26
of non-STEMI patients. Arecent scientic statement
discussed howinterventional cardiologists in the United States are
incentivized to avoid performing angiography on patients with
high risk of death from neurological injury.
27
Unfortunately, this
environment may deprive many patients of potentially benecial
therapy.
This study provides the rst direct estimate of the rate of
induced hypothermia use after OHCA in North America (39.3%).
Prior estimates relied on provider surveys.
2830
The present data
are a good estimate of North American practice because we
sampled 151 hospitals, including both the academic medical cen-
ters associated with investigators and neighboring community
hospitals with no academic afliation. The rate of hypothermia
use is low given that international guidelines have recom-
mended use of induced hypothermia since 2003.
23,31
Hospitals
that treated higher numbers of post-cardiac arrest subjects were
more likely to induce hypothermia (Fig. 2) and to utilize early
coronary angiography, suggesting that higher volume centers
more often implement guideline-based practice. In a recent study,
Table 3
Association of interventions with outcomes.
Survival to hospital discharge (N=1368) MRS <3 (N=1006)
N Odds ratio Adjusted odds ratio
a
N Odds ratio Adjusted odds ratio
a
Early coronary angiography (N=765) 495(64.7%) 4.08 (3.65, 4.56) 1.69 [1.06,2.70] 413(54.0%) 4.32 (3.81, 4.90) 1.87 [1.15, 3.04]
Reperfusion subjects (PCI or
brinolytics) (N=705)
377(62.4%) 5.30 (4.74, 5.93) 1.94 [1.34, 2.82] 324(53.6%) 5.98 (5.27, 6.78) 2.14 [1.46, 3.14]
Induced hypothermia (N=1566) 637(40.7%) 1.60 (1.43, 1.78) 1.36 [1.01, 1.83] 476(30.4%) 1.56 (1.38, 1.77) 1.42 [1.04, 1.94]
a
Adjusted for sex, rst rhythm, witnessed collapse, bystander CPR, ROC site, advance airway inserted by EMS, public location of collapse, age, hospital cases per year,
epinephrine dose, mean CPR fraction, intervals from911 call to EMS arrival, EMS arrival to return of pulses, and depart scene to ED arrival.
662 C.W. Callaway et al. / Resuscitation 85 (2014) 657663
temperature management protocols using 36

Cor 33

Cresultedin
equivalent survival.
24
Those data suggest that induced hypother-
mia may be associated with better outcome in our study and in
others
22
because it is a marker of protocolized, aggressive, hospital
care, rather than because of specic effects of temperature.
Caution is required when interpreting the association between
induced hypothermia and favorable outcomes in multivariable
models (Table 3). The lower rate of advanced airway use in non-
hypothermia subjects may indicate that some in this group were
awake at hospital arrival, which would inate the rate of good
outcomes in the non-hypothermia group, although the association
between hypothermia and outcomes persisted in the multivari-
able model corrected for use of EMS advanced airways. Conversely,
the higher rates of hypothermia subjects who were living at home
prior to arrest and who were younger suggest that hypothermia
may be selectively applied to patients suspected to have better
chances for recovery. While multivariable models attempt toadjust
for these factors, future studies of hypothermia should prospec-
tively determine eligibility for hypothermia and baseline levels of
coma in order to make clear comparisons.
32
Finally, any effect of
induced hypothermia is intertwined with the effects of the asso-
ciated ancillary care such as fever suppression, sedation, blood
pressure management, and neurological evaluations.
7
The rate of secondary prevention with ICD implantation for
survivors of VF was low (35.0%). Survival after VF cardiac arrest
is an indication for ICD unless an acute reversible cause of the
VF is identied.
33
ICD implantation was more frequent among VF
survivors who did not receive reperfusion therapy (46.8%). Never-
theless, future studies should examine the reasons why secondary
prevention is not used more often after VF OHCA.
Higher numbers of subjects treated by each hospital were asso-
ciated with improved outcomes. This result is consistent with
associations noted in prior data,
46
but contrasts with ndings in
other data sets.
34,35
The present per-patient analysis of specic in-
hospital interventions, for which hospital volume was a surrogate
marker in prior studies, conrmed that guideline-based care such
as early coronary reperfusionandhypothermia are usedmore often
in hospitals that treat higher numbers of OHCA patients (Fig. 2).
Other series have noted that the choice of destination hospital is
related to the probability of receiving specic therapies associated
with survival.
36
These data support the need for systems of care
that ensure that all OHCA patients have reliable access to coro-
naryinterventions andprotocolizedcare that includes temperature
management.
37
Finally, many subjects died within one day after hospitaliza-
tion. Longer (median 3 days, Table 2) survival for subjects who
died after reperfusion or hypothermia therapy may indicate that
patients who are very unstable immediately after hospital arrival
do not survive long enough to receive advanced therapies. In order
tofurther improvein-hospital survival, futurestudies shouldexam-
ine in detail the reasons for early mortality. Overall, withdrawal of
life sustaining treatment because of poor neurological status was
the most frequently noted reason for in-hospital death (Table 2).
This fact emphasizes the need for accurate and systematic deter-
mination of prognosis after cardiac arrest.
16
Strengths of this study include prospective data collection
during a trial, assuring that the information is accurate and of
high quality. Trial interventions were completed prior to hospi-
tal admission and were unlikely to affect in-hospital care. The
implementation of the parent trial also involved rigorous train-
ing and monitoring of EMS care, ensuring that out-of-hospital
care was of high quality in all regions. Selection bias was unlikely
because all subjects were identied at the time of EMS treatment,
and study sites included all OHCA in their regions. Addition-
ally, we adjusted for most known confounders with multivariable
regression.
5. Limitations
This observational study cannot establish causal connections
between hospital interventions, survival and functional outcome.
Survival bias may contribute to apparent benecial effects of
coronary reperfusion or hypothermia, because patients who are
very unstable and die soon after cardiac arrest are less likely to
receive further interventions. Clinician assessment of prognosis
through unmeasured variables may have inuenced the selection
of patients for treatment.
6. Conclusions
Early coronary angiography and induced hypothermia are asso-
ciated with improved outcomes after OHCA. Hospitals that treat
a higher numbers of OHCA subjects are more likely to attempt
early coronary reperfusion and to induce hypothermia, and these
hospitals have higher rates of favorable outcome.
Conict of interest statement
There are no reported conicts of interest directly related to
this work. The ROC is supported by a series of cooperative agree-
ments to nine regional clinical centers and one Data Coordinating
Center (5U01 HL077863 University of Washington Data Coordi-
natingCenter, HL077866Medical Collegeof Wisconsin, HL077867
University of Washington, HL077871 University of Pittsburgh,
HL077872 St. Michaels Hospital, HL077873 Oregon Health and
Science University, HL077881 University of Alabama at Birming-
ham, HL077885 Ottawa Hospital Research Institute, HL077887
University of Texas SWMedical Ctr/Dallas, HL077908 University
of California San Diego) from the National Heart, Lung and Blood
Institute in partnership with the National Institute of Neurological
Disorders andStroke, USArmyMedical ResearchandMaterial Com-
mand, The CanadianInstitutes of HealthResearch(CIHR) Institute
of Circulatory andRespiratory Health, Defence ResearchandDevel-
opment Canada and the Heart, Stroke Foundation of Canada and
the American Heart Association. The content is solely the responsi-
bility of the authors and does not necessarily represent the ofcial
views of theNational Heart, LungandBloodInstituteor theNational
Institutes of Health.
Acknowledgements
A preliminary version of these data was presented as a Poster
and Abstract at the American Heart Association Scientic Sessions
(Resuscitation Science SymposiumMeeting) on November 3, 2012.
Circulation 2012: 126: A154.
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