JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
9, 2017
Listen to this manuscripts Medicine, Regions Hospital, St. Paul, Minnesota; dDivision of Cardiothoracic Surgery, University of Minnesota School of Medicine,
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
VOL. 70, NO.
2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.06.059
ORIGINAL INVESTIGATIONS
Coronary Artery Disease in Patients
With Out-of-Hospital Refractory
Ventricular Fibrillation Cardiac Arrest
Demetris Yannopoulos, MD,a Jason A. Bartos, MD, PHD,a Ganesh Raveendran, MD,a Marc Conterato, MD,b
Ralph J. Frascone, MD,c Alexander Trembley, BS,b Ranjit John, MD, PHD,d John Connett, PHD,e David G. Benditt, MD,a
Keith G. Lurie, MD,a Robert F. Wilson, MD,a Tom P. Aufderheide, MDf
ABSTRACT
BACKGROUND The prevalence of coronary artery disease (CAD) among patients with refractory out-of-hospital (OH)
ventricular brillation (VF)/ventricular tachycardia (VT) cardiac arrest is unknown.
OBJECTIVES The goal of this study was to describe the prevalence and complexity of CAD and report survival to
hospital discharge in patients experiencing refractory VF/VT cardiac arrest treated with a novel protocol of early transport
to a cardiac catheterization laboratory (CCL) for extracorporeal life support (ECLS) and revascularization.
METHODS Between December 1, 2015, and December 1, 2016, consecutive adult patients with refractory OH VF/VT
cardiac arrest requiring ongoing cardiopulmonary resuscitation were transported by emergency medical services to the
CCL. ECLS, coronary angiography, and percutaneous coronary intervention were performed, as appropriate. Functionally
favorable survival to hospital discharge (Cerebral Performance Category 1 or 2) was determined. Outcomes in a historical
comparison group were also evaluated.
RESULTS Sixty-two (86%) of 72 transported patients met emergency medical services transport criteria. Fifty-ve
(89%) of the 62 patients met criteria for continuing resuscitation on CCL arrival; 5 had return of spontaneous circulation,
50 received ECLS, and all 55 received coronary angiography. Forty-six (84%) of 55 patients had signicant CAD, 35
(64%) of 55 had acute thrombotic lesions, and 46 (84%) of 55 had percutaneous coronary intervention with 2.7
2.0
stents deployed per patient. The mean SYNTAX score was 29.4
13.9. Twenty-six (42%) of 62 patients were discharged
alive with Cerebral Performance Category 1 or 2 versus 26 (15.3%) of 170 in the historical comparison group (odds ratio:
4.0; 95% condence interval: 2.08 to 7.7; p < 0.0001).
CONCLUSIONS Complex but treatable CAD was prevalent in patients with refractory OH VF/VT cardiac arrest who also
met criteria for continuing resuscitation in the CCL. A systems approach using ECLS and reperfusion seemed to improve
functionally favorable survival. (J Am Coll Cardiol 2017;70:110917) 2017 by the American College of Cardiology
Foundation.
From the aDivision of Cardiology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota;
b
Department of Emergency Medicine, North Memorial Medical Center, Robbinsdale, Minnesota; cDepartment of Emergency
Minneapolis, Minnesota; eDivision of Biostatistics, University of Minnesota, Minneapolis, Minnesota; and the fDepartment of
Emergency Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. This work was supported by a philanthropic gift of
the Bakken Family and the Robert K. Eddy Endowment for Resuscitation Medicine. Dr. Benditt has served as a consultant for
Medtronic and Zoll; and has equity in Medtronic and Abbott. Dr. Lurie has a patent for impedance threshold and active
compression-decompression devices with royalties paid; and is a consultant for Zoll. Dr. Aufderheide has served as the primary
investigator for studies sponsored by JDP Therapeutics and Hospital Quality Foundation. All other authors have reported that they
have no relationships relevant to the contents of this paper to disclose.
Manuscript received May 14, 2017; revised manuscript received June 21, 2017, accepted June 22, 2017.
1110 Yannopoulos et al. JACC VOL. 70, NO. 9, 2017

CAD in Out-of-Hospital Refractory Ventricular Fibrillation AUGUST 29, 2017:110917

T
ABBREVIATIONS he vast majority of all survivors of Early EMS transport exclusion criteria included:
AND ACRONYMS out-of-hospital cardiac arrest 1) cardiac arrest of noncardiac etiology (e.g., blunt or
(OHCA) present to emergency medi- penetrating traumatic arrest, burn-related, exsangui-
ACLS = advanced cardiac life
support
cal services (EMS) with an initial shockable nation, hanging, known overdose); 2) contraindica-
rhythm (ventricular brillation [VF]/pulse- tions to mechanical CPR; 3) known pregnancy;
CAD = coronary artery disease
less ventricular tachycardia [VT]) (13). Even 4) nursing home residents; 5) valid do not resuscitate/
CCL = cardiac catheterization
laboratory with this favorable presenting rhythm, do not intubate orders; and 6) known terminal illness
CPC = Cerebral Performance
>60% of patients with VF/VT are refractory (e.g., cancer; end-stage liver, kidney, or heart disease).
Category to current treatment and never achieve re- North Memorial and St. Paul Fire EMS systems
CPR = cardiopulmonary turn of spontaneous circulation (ROSC) or participated in the protocol. These 2 agencies service
resuscitation they die before they are admitted to the hos- a population of 570,000 people in an area of
ECLS = extracorporeal life pital (4). approximately 1,100 square miles within a 30-min
support
Currently, the American Heart Association driving radius from the University of Minnesota. Pa-
EMS = emergency medical Advanced Cardiac Life Support (ACLS) tients meeting criteria were mobilized with ongoing
services
guidelines recommend treating patients with CPR by using a LUCAS 2 automated CPR device
LUCAS = Lund University
refractory VF/VT at the scene of cardiac ar- (Physio-Control, Inc., Redmond, Washington) that
Cardiac Arrest System
rest for 30 to 45 min until they have ROSC or compressed the chest 100 times/min. All patients had
OH = out-of-hospital
are declared dead (5). an advanced airway device placed. An inspiratory
OHCA = out-of-hospital
cardiac arrest
Building on recent studies showing impedance threshold device (ResQPOD, Zoll Medical,
improved functionally favorable survival by Roseville, Minnesota) was used in all cases (2,13,14).
PCI = percutaneous coronary
intervention rapid reversal of coronary artery ischemia Ventilation was provided in accordance with standard
ROSC = return of spontaneous after successful resuscitation following ACLS protocols (5,15). Patient treatment continued in
circulation VT/VF OHCA (611), we implemented a new, the ambulance, and ACLS was performed until the
VF = ventricular brillation systems-based approach that included early patients arrived in the CCL (5).
VT = ventricular tachycardia EMS transport of patients with refractory A team of interventional cardiologists provided
VF/VT to an ST-segment elevation myocar- rotating around-the-clock call for response within
dial infarctionreceiving hospital with ongoing me- 20 min of activation. Every patient requiring CPR on
chanical cardiopulmonary resuscitation (CPR). On arrival was placed on the CCL table with the LUCAS
arrival at the cardiac catheterization laboratory (CCL), device operating. The initial arterial access and
early circulatory support with extracorporeal life ECLS initiation details have been described previ-
support (ECLS), immediate angiography after ECLS, ously (12). At the initial arterial puncture, arterial
and percutaneous coronary intervention (PCI) were blood gas and lactic acid samples were sent for
performed, as indicated. The present article describes processing.
the prevalence of coronary artery disease (CAD), ECLS was initiated in all patients meeting early
incidence of acute coronary occlusion/stenosis, and transport criteria who had no Resuscitation Discon-
the inuence of reperfusion therapy on functionally tinuation Criteria and had not obtained ROSC by that
favorable survival rates to hospital discharge in pa- time (Figure 1). ECLS was performed with a pre-
tients with refractory OH VF/VT cardiac arrest. primed CardioHelp circuit consisting of a centrifugal
pump (Maquet Rotaow, Maquet Cardiovascular,
SEE PAGE 1118 LLC, Wayne, New Jersey). Interventional cardiolo-
gists placed all devices.
METHODS Once hemodynamic/perfusion stability was ob-
tained with either achievement of ROSC or initiation
The University of Minnesota refractory VF/VT proto- of ECLS, coronary angiography was performed and
col has been described elsewhere (12). Briey, early revascularization accomplished based on the clinical
EMS transport criteria were as follows: 1) VF/VT judgment of the interventional cardiologist. All cor-
OHCA as the rst presenting rhythm; 2) 18 to 75 years onary interventions were performed with intrave-
of age; 3) three EMS-delivered direct current shocks nous heparin and an activated clotting time target of
and 300 mg of intravenous/intraosseous amiodarone 250 to 300 s. At the initiation of ECLS, all patients
without achieving ROSC; 4) body morphology able to received a bolus of unfractionated heparin (100 U/kg).
accommodate a Lund University Cardiac Arrest Sys- At the end of the case, all patients treated with PCI
tem (LUCAS) automated CPR device; and 5) estimated were given aspirin and ticagrelor through a nasogas-
transfer time from the scene to the CCL of <30 min tric tube. If the nasogastric tube could not be placed,
(Figure 1). cangrelor was infused intravenously until ticagrelor
JACC VOL. 70, NO. 9, 2017
AUGUST 29, 2017:110917
could be given. Standard doses were used for each of
the medications (1619).
Every patient arriving at the CCL was already hy-
pothermic, with an average core temperature (blood
temperature measured by the ECLS console) of 34 C
(34.3
0.7 C). The patient was maintained at 34  C for
24 h, except in the case of bleeding complications,
when it was increased to 36  C (2022). The criterion
for hospital admission after ECLS initiation was
achievement of sustained organized electrical rhythm
with or without mechanical cardiac contraction. A
multidisciplinary team of cardiology critical care,
neurocritical care, and cardiothoracic surgery physi-
cians managed patients admitted to the hospital in
the cardiac intensive care unit.
Survival to hospital discharge with Cerebral Per-
formance Category (CPC) 1 or 2 was the primary
outcome. Secondary outcomes were 3-month survival
with CPC 1 or 2 and protocol-based complications.
The Institutional Review Board of the University of
Minnesota approved the anonymous data analysis
and chart review extraction for this publication.
Informed consent was waived. Historical comparison
group patients were identied by using an anony-
mized cardiac arrest database (Cardiac Arrest Registry
to Enhance Survival) (1,23).
To provide a historical group for the primary
outcome comparison, resuscitation outcome data
were analyzed from an immediately prior time
period, starting January 1, 2014, and ending
November 1, 2015, from the same 2 participating EMS
systems with the following criteria: 1) OHCA of pre-
sumed cardiac etiology; 2) rst presenting rhythm of
VF/VT; 3) 18 to 75 years of age; and 4) received
intravenous/intraosseous amiodarone 300
Nursing home residents and patients with known
terminal illness (e.g., cancer; end-stage liver, kidney,
or heart disease) were excluded. Baseline
mographic, cardiac arrest, and medical history char-
acteristics are shown in Table 1.
A single, nonadjusted comparison was performed
between our cohort and the historical comparison
group with a Fisher exact test. Data are presented as
mean
SD.
RESULTS
From December 1, 2015, to December 1, 2016, a total
of 72 patients with OHCA were transported by EMS.
Sixty-two (86%) of the 72 patients met criteria for
early EMS transport and represent the study popu-
lation. Seven of these 62 (11%) patients met CCL
Resuscitation Discontinuation Criteria on arrival and
were declared dead. Fifty-ve (89%) of 62 patients
Yannopoulos et al. 1111
CAD in Out-of-Hospital Refractory Ventricular Fibrillation
F I G U R E 1 University of Minnesota Refractory VF/VT OHCA Protocol
Out of Hospital
Determine Early EMS Transport Criteria
OHCA of presumed cardiac etiology
VF or VT as first presenting rhythm
18-75 years of age
Received three EMS-delivered DC shocks and 300mg of amiodarone
IV/IO without achieving ROSC
Body morphology able to accommodate LUCAS automated CPR device
Estimated transfer time from the scene to the CCL of < 30 minutes.
If Patient Meets Early EMS Transport Criteria, Transport to CCL
Ongoing Mechanical CPR with ITD
Continued ACLS (limit epinephrine to 3 mg total), Defibrillation
PRN en Route
Initial CCL Assessment
Arterial and venous access under ultrasound
Obtain ABGs and serum lactate
Determine the presence of the CCL Resuscitation Discontinuation Criteria
ETCO2 on CCL Arrival < 10 mm Hg
PaO2 < 50 mm Hg or O2 Sat < 85%
Serum Lactate > 18 mmol/L
Patient has one or more of the above criteria.
Terminate Resuscitation
Declare Dead
Patient has none of the above criteria.
ROSC Present: Immediate Coronary Angiography, PCI as appropriate
No ROSC: Initiate ECLS
Place venous/arterial cannulas 25 Fr/17 Fr (men) and 25 Fr/15Fr (women)
Coronary Angiography, PCI as appropriate immediately following ECLS
IABP Placement if PCI Performed
Continue ACLS/ECLS for up to 90 minutes following angiography and PCI
NO sustained organized electrical
mg. rhythm after 90 minutes: declare dead
de-
Sustained organized electrical rhythm with or without mechanical
cardiac contraction:
Admit to the Hospital (CICU)
The criteria and decision-making process from emergency medical services (EMS)
evaluation through cardiac catheterization laboratory (CCL) assessment and treatment
are shown. Timely patient delivery to the CCL, evidence of adequate cardiopulmonary
resuscitation (CPR)-generated perfusion, hemodynamic stabilization on CCL arrival, and
reperfusion therapy were the 4 pillars of the protocol. ABG arterial blood gas;
ACLS advanced cardiac life support; CICU cardiac intensive care unit; DC direct
current; ECLS extracorporeal life support; ETCO2 end-tidal carbon dioxide;
Hg mercury; IABP intra-aortic balloon pump; ITD impedance threshold device;
IV/IO intravenous/intraosseous; LUCAS Lund University Cardiac Arrest System; O2
Sat fraction of oxygen-saturated hemoglobin; OHCA out-of-hospital cardiac arrest;
PaO2 arterial partial pressure of oxygen; PCI percutaneous coronary intervention;
PRN pro re nata or as needed; ROSC return of spontaneous circulation;
VF ventricular brillation; VT ventricular tachycardia.
1112 Yannopoulos et al. JACC VOL. 70, NO. 9, 2017

CAD in Out-of-Hospital Refractory Ventricular Fibrillation AUGUST 29, 2017:110917

medical history was low (5 of 55 [9%]), and no patient

T A B L E 1 Patient Demographic Characteristics, Medical History, and
Resuscitation Characteristics of the 62 Patients Meeting Early EMS Transport
or family member reported ischemic symptoms in the
Criteria and the 170 Patients of the Historical Comparison Group weeks, days, or immediate period before the cardiac
arrest. Thirty-four (55%) of 62 cardiac arrests occurred
University of
Minnesota in the home, 52 (84%) of 62 received bystander CPR,
Historical Refractory VF/VT
and all patients presented to EMS with VF/VT.
Comparison Program Group
Group (n 170) (n 62) The average time from the 911 call to CCL arrival was
Male 124 (73.0) 44 (71.0) 58
17 min. The mean time required to initiate ECLS
Age, yrs 56
7 58
10 was 6.1
1.8 min from CCL arrival. The time from
Age distribution ECLS to balloon ination was 6.0
3.0 min.
<40 yrs 20 (12.0) 5 (8.0)
Fifty-ve patients received coronary angiography.
4060 yrs 79 (48.0) 33 (53.0)
Acute thrombotic lesions were present in 35 (64%) of
6175 yrs 71 (40.0) 24 (39.0)
the 55 patients, whereas 18 (33%) of the 55 had
Race
Asian 14 (8.0) 4 (6.0) chronic total occlusions. Forty-six (84%) of 55 had
Black 24 (14.0) 9 (14.0) signicant CAD (>70% stenosis), and PCI was per-
White 132 (78.0) 49 (80.0) formed in all 46 (100%) patients. Single-vessel dis-
Medical history ease was present in 14 (30%) of 46 patients, and
Diabetes 38 (22.0) 12 (19.0) $2-vessel disease was present in 32 (70%) of 46 pa-
CAD 22 (13.5) 5 (9.0)
tients. Stents were implanted in 45 (98%) of 46 pa-
Hypertension 63 (37.0) 30 (48.0)
tients, with a mean of 2.7
2.0 implanted stents/
Hyperlipidemia 54 (32.0) 23 (36.0)
Smoking 47 (28.0) 14 (23.0)
patient. The mean SYNTAX score was 29.4
14
Coronary artery bypass graft NA 5 (9.0) (Table 2) (24).
Congestive heart failure NA 8 (13.0) Forty-seven (76%) of 62 patients were admitted to
Alcoholism NA 3 (5.0) the hospital (cardiac intensive care unit). Twenty-
Location of cardiac arrest eight (45%) of the 62 patients were discharged alive,
Home 81 (48.0) 34 (55.0)
and 26 (42%) of 62 were discharged with favorable
Public location 89 (52.0) 28 (45.0)
neurological function (CPC 1 or 2). Two (3%) of the 62
Cardiac arrest witnessed 130 (77.0) 50 (80.0)
patients were discharged with unfavorable neuro-
Bystander CPR performed 127 (75.0) 52 (84.0)
Resuscitation time intervals logical function (CPC 3 and 4, respectively). At
Time from 911 call to EMS arrival, min 7.2
6.5 6.2
4.6 3 months, 26 (42%) of the 62 patients were alive, and
Time from 911 call to CCL arrival, min NA 58.0
17.7 all had normal neurological function (CPC 1). At
Time from 911 call to ECLS, min NA 64.0
13.2 3 months, 2 (3%) of the 62 patients were alive with
Time to CCL entry on ECLS, min NA 6.1
1.8 CPC 3 and 4.
CCL entry-to-balloon time, min NA 12.0
3.0
Left ventricular function was severely compro-
Values are n (%) or mean
SD.
mised in all admitted patients for the rst 48 h, but
CAD coronary artery disease; CCL cardiac catheterization laboratory; signicant recovery was observed within 5 days. An
CPR cardiopulmonary resuscitation; ECLS extracorporeal life support; EMS emergency
medical services; NA data not available in the Cardiac Arrest Registry to Enhance Survival
intra-aortic balloon pump was inserted in 25 (45%) of
database; VF/VT ventricular brillation/ventricular tachycardia. 55 patients. The mean left ventricular ejection frac-
tion in survivors was 18
19% at 24 h, 34
19% at
48 h, 43
16% at 5 days, and 48
11% at hospital
received continued CCL resuscitation and coronary discharge. After CCL treatment, ECLS was continued
angiography. Five (9%) of 55 patients had sustained for 3.0
2.0 days.
ROSC, and 50 (91%) of 55 patients had ECLS initiated We observed the following vascular complications
before coronary angiography. Forty-six (84%) of from ECLS placement. Four patients had signicant
these 55 patients had revascularization with PCI. Of retroperitoneal bleeding requiring transfusion of
the 50 ECLS patients, 8 were declared dead in the multiple units of blood product. Three patients
CCL after 90 min because of failure to achieve a developed an ischemic leg after thrombosis of the
sustained organized electrical rhythm. Forty-seven distal perfusion catheters. Two of those patients had
(76%) of the 62 EMS-transported patients were the cannulas removed, and there were no long-term
admitted to the hospital (Figure 2). complications. One patient developed an ischemic
Patient demographic characteristics, medical leg while still requiring cardiopulmonary mechanical
history, and resuscitation characteristics are shown in support and was placed on central ECLS for an addi-
Table 1. The majority were white men with a mean age tional week. The patient was discharged from the
of 58
10 years. The incidence of known CAD in the hospital with CPC 1.
JACC VOL. 70, NO. 9, 2017
AUGUST 29, 2017:110917
F I G U R E 2 Patient Flow Diagram
72 Patients Transported by EMS
(Admitted to CCL)
62/72 (86%) Patients Met Early EMS Transport Criteria
(Study Population)
55/62 (89%) Patients had Continued CCL Resuscitation and Received Coronary Angiography
5/55 (9%) had ROSC Prior to CCL Arrival
50/55 (91%) placed on ECLS prior to coronary angiography
46/55 (84%) patients received PCI
47/62 (76%) Patients Admitted to the Hospital (CICU)
Patient ow diagram from EMS transport to hospital admission (CICU). DNR do not resuscitate; other abbreviations as in Figure 1.
Of the 47 patients admitted to the hospital, 19 were
declared dead within 5
2 days. The 28 survivors
were discharged from the hospital after 14
18 days.
The following factors were associated with survival
to hospital discharge: 1) earlier arrival of rst re-
sponders after the 911 call; 2) lower lactic acid levels;
3) intermittent or sustained ROSC before arrival at the
CCL; 4) higher end-tidal carbon dioxide upon CCL
arrival; and 5) the presence of CAD as a reversible
cause (Table 3).
The historical comparison group (170 patients) had
an average age of 56
7 years, 73% were men, and
78% were white. Cardiac arrest occurred at home 48%
of the time, and 75% had bystander CPR (Table 1).
Consistent with the EMS protocol at that time,
Yannopoulos et al. 1113
CAD in Out-of-Hospital Refractory Ventricular Fibrillation
10/72 (14%) Excluded Not Meeting Early EMS
Transport Criteria
3 - Manual CPR Only
1 - Pectus Excavatum
2 - Morbid Obesity
3 - Time from 911 Call to CCL > 90 minutes
1 - Age > 80 years; terminal cancer
1 - Stage IV renal cell cancer
2 - DNR discovered on CCL arrival
7/62 (11%) met CCL Discontinuation of Resuscitation
Criteria and Declared Dead
8/50 (16%) ECLS Patients Declared
Dead in CCL Due to Failure to Achieve
Sustained Organized Electrical
Rhythm after 90 Minutes
resuscitation efforts were continued at the scene for
45 to 60 min, until ROSC was achieved or death was
declared. In the historical comparison group, 26
(15.3%) of the 170 patients survived to hospital
discharge with CPC 1 or 2 versus 26 (42%) of 62 pa-
tients with the current refractory VF/VT protocol
(odds ratio: 4.0; 95% condence interval: 2.08 to 7.7;
p < 0.0001). This historical comparison group had a
ROSC rate (37.0% vs. 35.9%) and rate of functionally
favorable survival (15.3% vs. 18.8%) comparable to
the study patients in ALPS (Amiodarone, Lidocaine,
or Placebo Study), which also evaluated patients with
refractory VF/VT OHCA (Central Illustration) (25).
The proportion of patients achieving each stage
of the resuscitation continuum from emergency
1114 Yannopoulos et al. JACC VOL. 70, NO. 9, 2017

CAD in Out-of-Hospital Refractory Ventricular Fibrillation AUGUST 29, 2017:110917

of a variable incidence of CAD based on angiographic

T A B L E 2 Angiographic Findings and Procedural Outcomes
ndings have been available only in patients resus-
Angiographic ndings
citated from OHCA (6). Advances in improved CPR
Normal or clinically insignicant CAD (#70% stenosis) 9/55 (16)
hemodynamics and emergent ECLS now make it
Clinically signicant CAD (>70% stenosis) 46/55 (84)
Single-vessel disease 14/46 (30) possible to evaluate and treat refractory OHCA.
2-Vessel disease 12/46 (26) We found a high prevalence of complex CAD, acute
3-Vessel disease 20/46 (44) thrombotic lesions, and chronic total occlusions in
Disease location the refractory OH VF/VT cardiac arrest patient group.
Left main 7/46 (15) The mean SYNTAX score of 29.4
13.9 reported in the
LAD 40/46 (87)
present study reects the complexity and severity of
LCx 24/46 (52)
the CAD observed (24). This nding, combined with
RCA 23/46 (50)
Prior coronary artery bypass graft 5/55 (9)
the relatively high survival rates in our patients un-
Chronic total occlusion present 18/55 (33) dergoing revascularization, substantiates a role of
Patients with acute thrombotic lesions 35/55 (64) acute and/or chronic ischemia in the persistence of
Patients with chronic disease 33/55 (60) VF/VT cardiac arrest refractory to standard treatment.
Acute on chronic lesion 23/55 (42) The severity of underlying coronary pathology is
SYNTAX score 29.4
13.9
presumably causative or at least signicantly
Procedural outcomes
contributory in the majority of patients. As such,
Patients with stent implanted 45/46 (98)
continued treatment of this patient group with
No. of stents/patient 2.7
2.0
Intra-aortic balloon pump inserted 25/55 (45)
noninvasive strategies, such as ACLS protocols and
medications, are unlikely to signicantly improve
Values are n/N (%) or mean
SD. Coronary angiography was performed in 55 patients, and survival without addressing reversal of the underly-
percutaneous coronary intervention was performed in 46 patients.
CAD coronary artery disease; LAD left anterior descending artery; LCx left circumex
ing pathophysiology.
artery; RCA right coronary artery. A relevant nding of our study is that this patient
group seems to be treatable. The availability of me-
chanical CPR, allowing safe and continued treatment
department arrival to hospital discharge in both
during EMS transport while providing optimized
groups is compared in Figure 3, highlighting the dif-
blood ow during CPR, was central to our protocol.
ferences provided by ECLS capability.
The application of ECLS also makes treatment of
DISCUSSION these patients feasible. With ECLS, immediate ROSC
is not an outcome necessary for admission to the
We report, for the rst time, the incidence of CAD in hospital and subsequent survival. ECLS provides
consecutive patients with refractory OH VF/VT mechanical/articial ROSC for a patient group other-
cardiac arrest undergoing emergent coronary angi- wise unable to initially achieve it; it also offers the
ography. Previously, achievement of ROSC after car- opportunity to diagnose and treat reversible coronary
diac arrest was a requirement before consideration of artery occlusion present in the majority of patients. In
emergent angiography. Accordingly, previous reports addition, ECLS provides a necessary bridge to recov-
ery from severe cardiogenic shock and stunned
myocardium. We observed a remarkably predictable
T A B L E 3 Resuscitation Characteristics of Survivors and Patients Who Died recovery from severe left ventricular dysfunction
Survivors Deaths
over a 2- to 5-day period if continued ECLS hemody-
Patients With Refractory VF/VT (n 28) (n 34) p Value namic support was provided.
Age, yrs 57
11 59
10 0.3 Given the complexity and severity of documented
Time from 911 call to rst response arrival, min 4.1
4.6 7.1
4.6 0.03 CAD, it is notable that the incidence of previously
Bystander CPR 93 71 0.1
known CAD was low, and no patient or family mem-
Time from 911 call to CCL entry, min 55
16.7 62
14.9 0.07
ber reported ischemic symptoms in the weeks, days,
Time from CCL entry on ECLS, min 6.2
2 5.8
3 0.5
or immediate period before their event. Thus, cardiac
ETCO2 on arrival 42
15 31
10 0.04
pH on ECLS opening ABG 7.13
0.1 7.04
0.2 0.08 arrest was the rst clinical manifestation of well-
Lactate level at CCL arrival, mmol/l 10.1
3.9 13.3
3.3 0.05 established, severe CAD in the majority of patients.
Presence of CAD 88 68 0.01 The survival rates seen in our study are prelimi-
Cardiac arrest witnessed 89 74 0.11 narily encouraging. Our EMShospital emergency
care system, focused on early EMS transport and
Values are mean
SD or %.
ABG arterial blood gas; ETCO2 end-tidal carbon dioxide; other abbreviations as in Table 1.
reperfusion therapy, seemed to improve the rate of
functionally favorable survival to hospital discharge
JACC VOL. 70, NO. 9, 2017 Yannopoulos et al. 1115
AUGUST 29, 2017:110917 CAD in Out-of-Hospital Refractory Ventricular Fibrillation

C ENTR AL I LL U STRA T I O N Refractory Cardiac Arrest Due to VF/VT and the University of Minnesota
ECLS/PCI Protocol

Yannopoulos, D. et al. J Am Coll Cardiol. 2017;70(9):110917.

The University of Minnesota refractory ventricular brillation (VF) protocol mobilizes patients with failed initial resuscitation with ongoing cardiopulmonary
resuscitation (CPR) to enter the cardiac catheterization laboratory (Cath Lab) where extracorporeal life support (ECLS) is implemented as a bridge to coronary
angiography, intervention, and recovery. The program has identied that 86% of the patients had severe coronary artery disease. Survival to hospital discharge was
45%. Historical control subjects treated with the previous standard of care had access to the hospital only after return of spontaneous circulation (ROSC) was
achieved and, as such, survival was poor. AHA American Heart Association; ECMO extracorporeal membrane oxygenation; PCI percutaneous coronary
intervention; VT ventricular tachycardia.

(42%) versus that of the historical comparison group
(15.3%). Whether this apparent survival advantage
can be sustained or generalized to other centers re-
mains to be determined. Irrespective, this experience
supports the contention that successful treatment of
this patient population can be achieved (Central
Illustration).
An important concern raised with aggressive
resuscitation protocols is the possibility that many
survivors would be left with severe neurological im-
pairments. However, our initial experience is reas-
suring in that 26 (93%) of 28 survivors were alive with
normal function (CPC 1) at 3 months. These patients
were often in the prime of their lives and have a
reasonable expectation for continued quality and
duration of life. Despite being refractory to standard
treatment, the initial rate of unfavorable functional
survival (2 of 62 [3%]) seems comparable with unfa-
vorable outcomes reported for all patients with car-
diac arrest treated with current therapy
Nonetheless, the risk/benet ratio of this approach
warrants careful and continued assessment.
Our study is, to our knowledge, the largest that has
been reported in the United States. The SAVE-J (Study
of Advanced Cardiac Life Support for Ventricular
Fibrillation with Extracorporeal Circulation in Japan)
trial, performed in Japan, was a prospective observa-
tional study comparing 454 patients with VF/VT arrest
admitted to 46 hospitals over 3 years (26). Of these,
234 patients were provided ECLS. Patients received
ECLS if they were admitted to an ECLS-capable center,
whereas patients admitted to non-ECLS centers
received standard therapy. Overall 1-month survival
was improved in the ECLS group versus the non-ECLS
group (29% vs. 6%). Johnson et al. (27) reported 26
cases of refractory cardiac arrest over a 7-year period
with only 42% of those patients presenting with
VF/VT. The University of Minnesota and SAVE-J co-
horts were similar with regard to age, sex, location,
and other demographic characteristics, and they both
exclusively included patients treated for OHCA due to
refractory VF/VT. Of note, both cohorts had identical
proportions of patients who presented with acute
(4). coronary syndromes (64%). Differences that favored
survival in the University of Minnesota cohort
compared with the SAVE-J cohort were: 1) higher
bystander CPR rates (84% vs. 48.8% for SAVE-J); and
2) higher proportion of patients who had witnesses to
1116 Yannopoulos et al. JACC VOL. 70, NO. 9, 2017

CAD in Out-of-Hospital Refractory Ventricular Fibrillation AUGUST 29, 2017:110917

meeting criteria for the protocol was missed from

F I G U R E 3 Comparison of Proportional Success in Patient Outcome Along the
Resuscitation Continuum Between the Refractory VF/VT Protocol and the
inclusion during the reported period. EMS providers
Historical Comparison Group over-transported 10 (14%) of 72 patients who did not
meet EMS transport criteria. False-positive protocol
n = 170 n = 62 activations were inevitable given this time-sensitive
100%
intervention and are currently being addressed with
90%
ongoing EMS quality improvement processes. A cost
80% n = 47 analysis was beyond the scope of this initial experi-
70% ence. However, an analysis of quality-adjusted life-
years will be important and informative for this
60%
% of Patients

approach as it becomes more widely applied.

50%
n = 28
n = 26 CONCLUSIONS
40% n = 63
n = 51
30% Complex but treatable CAD was prevalent in patients
*
20% n = 30 with refractory OH VF/VT cardiac arrest who also met
n = 26
n=5
criteria for continuing resuscitation in the CCL. A
10%
systems approach using ECLS and reperfusion
0%
All Patients ROSC on Hospital Hospital DC with CPC 1&2 seemed to improve functionally favorable survival.
ED Arrival Admission DC

Historical Comparison Group UoM Refractory VF Protocol ADDRESS FOR CORRESPONDENCE: Dr. Demetris Yan-
nopoulos, University of Minnesota, UMNCardiology
Proportional success at different stages of the resuscitation continuum comparing the Division, 420 Delaware Street SE, MMC 508,
University of Minnesota (UoM) refractory VF/VT protocol versus the historical Minneapolis, Minnesota 55455. E-mail: yanno001@
comparison group. The capability to achieve mechanical/articial ROSC with ECLS
umn.edu.
resulted in a higher proportion of patients admitted to the hospital. *Functionally
favorable survival to hospital discharge, p < 0.0001. CPC Cerebral Performance
Category; DC discharge; ED emergency department; other abbreviations as in PERSPECTIVES
Figure 1.

COMPETENCY IN MEDICAL KNOWLEDGE:

their cardiac arrest (80% vs. 71% for SAVE-J). The
major difference that favored survival in the SAVE-J
cohort compared with the University of Minnesota
cohort was the much shorter time from the 911 call to
hospital arrival (29 min vs. 58 min). Finally, in the
CHEER (Mechanical CPR, Hypothermia, ECMO and
Early Reperfusion) trial, Stub et al. (28) enrolled 11
patients with OHCA, and all presented with VF. Two
had ROSC on arrival. Of the 9 patients placed on ECLS,
3 survived, and 5 of 11 survived to hospital discharge
(45% survival rate), very similar to our reported
outcomes.
STUDY LIMITATIONS. The generalizability of our
experience is unknown. Functionally favorable sur-
vival rates may increase or decrease with broader
experience. As with any clinical protocol, selection
bias cannot be excluded. Nonetheless, no patient
Complex but treatable CAD seems to be highly prev-
alent in patients experiencing refractory OH VF/VT
cardiac arrest. A system of care including rapid
transport of patients with ongoing refractory VF/VT to
the hospital, where ECLS and reperfusion can be
provided, improved functionally favorable survival.
This approach substantiates a role of acute and/or
chronic ischemia in the persistence of VF/VT cardiac
arrest refractory to standard treatment.
TRANSLATIONAL OUTLOOK: Prospective clinical
trials are necessary to delineate the aspects of this
protocol critical for improved survival. Meanwhile, as
the clinical availability of ECLS increases, use of this
technology to treat patients with refractory cardiac
arrest is likely to increase.

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KEY WORDS cardiopulmonary
resuscitation, emergent cardiac care, sudden
cardiac death