PROTOCOL Open Access
Hyperinvasive approach to out-of hospital cardiac
arrest using mechanical chest compression
device, prehospital intraarrest cooling,
extracorporeal life support and early invasive
assessment compared to standard of care. A
randomized parallel groups comparative study
proposal. “Prague OHCA study”
Jan Belohlavek1*
, Karel Kucera2
, Jiri Jarkovsky3
, Ondrej Franek2
, Milana Pokorna2
, Jiri Danda2
, Roman Skripsky2
,
Vit Kandrnal3
, Martin Balik4
, Jan Kunstyr4
, Jan Horak1
, Ondrej Smid1
, Jaroslav Valasek2
, Vratislav Mrazek1
,
Zdenek Schwarz2
and Ales Linhart1
Abstract
Background: Out of hospital cardiac arrest (OHCA) has a poor outcome. Recent non-randomized studies of ECLS
(extracorporeal life support) in OHCA suggested further prospective multicenter studies to define population that
would benefit from ECLS. We aim to perform a prospective randomized study comparing prehospital intraarrest
hypothermia combined with mechanical chest compression device, intrahospital ECLS and early invasive
investigation and treatment in all patients with OHCA of presumed cardiac origin compared to a standard of care.
Methods: This paper describes methodology and design of the proposed trial. Patients with witnessed OHCA
without ROSC (return of spontaneous circulation) after a minimum of 5 minutes of ACLS (advanced cardiac life
support) by emergency medical service (EMS) team and after performance of all initial procedures (defibrillation,
airway management, intravenous access establishment) will be randomized to standard vs. hyperinvasive arm. In
hyperinvasive arm, mechanical compression device together with intranasal evaporative cooling will be instituted
and patients will be transferred directly to cardiac center under ongoing CPR (cardiopulmonary resuscitation). After
admission, ECLS inclusion/exclusion criteria will be evaluated and if achieved, veno-arterial ECLS will be started.
Invasive investigation and standard post resuscitation care will follow. Patients in standard arm will be managed on
scene. When ROSC achieved, they will be transferred to cardiac center and further treated as per recent guidelines.
Primary outcome: 6 months survival with good neurological outcome (Cerebral Performance Category 1–2).
Secondary outcomes will include 30 day neurological and cardiac recovery.
(Continued on next page)
* Correspondence: jan.belohlavek@vfn.cz
1
2nd Department of Medicine - Department of Cardiovascular Medicine, 1st
Faculty of Medicine, Charles University in Prague and General University
Hospital in Prague, U Nemocnice 2, Prague 2 128 00, Czech Republic
Full list of author information is available at the end of the article
© 2012 Belohlavek et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Belohlavek et al. Journal of Translational Medicine 2012, 10:163
http://www.translational-medicine.com/content/10/1/163
(Continued from previous page)
Discussion: Authors introduce and offer a protocol of a proposed randomized study comparing a combined
“hyperinvasive approach” to a standard of care in refractory OHCA. The protocol is opened for sharing by other
cardiac centers with available ECLS and cathlab teams trained to admit patients with refractory cardiac arrest under
ongoing CPR. A prove of concept study will be started soon. The aim of the authors is to establish a net of centers
for a multicenter trial initiation in future.
Ethics and registration: The protocol has been approved by an Institutional Review Board, will be supported by a
research grant from Internal Grant Agency of the Ministry of Health, Czech Republic NT 13225-4/2012 and has been
registered under ClinicalTrials.gov identifier: NCT01511666.
Keywords: Cardiac arrest, Hypothermia, Extracorporeal life support, Mechanical compression device, Invasive
assessment
Introduction
Cardiac arrest (CA) is a significant socio-economic
burden [1,2]. The aim of the care for patients suffering
from cardiac arrest is a neurologically intact survival,
ie, avoidance of irreversible organ damage, mainly the
brain hypoxic-reperfusion injury. However, neurologically
favourable survival in patients resuscitated worldwide by
emergency services is only 5–15%, eventually 8–40% in
patients with initially shockable rhythms [3]. In Prague,
in 2008, 493 patients were resuscitated by Prague Emergency
Medical Service (EMS) for OHCA (out of hospital
cardiac arrest). ROSC (return of spontaneous circulation)
was reached in 56% of cases, 43% survived the episode,
15% were discharged home with favourable neurological
outcome, however, back to the fully active life including
job attendance returned only 7% of the original cohort
[4]. A key prerequisite for a successful outcome is minimalization
of time delays, resuscitation quality, complex
intensive care and treatment of cardiac arrest cause [5-7].
So far, the only proven method for increased survival
with good neurological outcome is early initiation of
mild hypothermia and probably also the rapidly reached
target temperature [3,8]. However, the use of hypothermia
affects individual estimation of prognosis [9,10] and the
whole topic of hypothermia needs further evaluations
and studies including potentially beneficial intraarrest
cooling [11-15]. Recent systematic review on intraarrest
hypothermia confirmed its beneficial effect in terms of
survival and neurological outcome in an experimental
setting, however, clinical data on the efficacy of intraarrest
cooling are still limited [16-20].
Similarly, chest compression devices are being increasingly
used in OHCA, despite the fact that their role is
still controversial [21-25]. They provide uninterrupted
continuous compressions even during the transport, decrease
the demands on EMS crew and provide a bridge
to other methods like PCI (percutaneous coronary intervention)
or ECLS (extracorporeal life support)/ECMO
(extracorporeal membrane oxygenation) initiation [26,27].
Current European Resuscitation Council (ERC) guidelines
[26] consider mechanical compression devices, ie, LUCAS
(Lund University Cardiac Arrest System; Physio-Control
Inc./Jolife AB, Lund, Sweden) and Autopulse (LDB - load
distributing band; ZOLL, Chelmsford, MA, U.S.A.) to be
potentially beneficial, however, with not yet evidently
proven beneficial impact on patients survival and recommend
further randomized studies.
Accordingly, the indication of extracorporeal life support
devices during cardiopulmonary resuscitation (CPR)
is controversial in CA patients and no definitive role has
been determined. Encouraging results of ECLS for CA of
cardiac origin in adults were shown recently both for
IHCA (inhospital cardiac arrest) and OHCA [28-33], in
inhospital pediatric CA [34-36] and recently has been
even proposed for out of hospital “on scene” refractory
CA [37-39]. However, the results are still not satisfactory
yielding wide survival rate range from 4% [32] to 48%
[33]. This may be related to different definitions of refractory
CA, ie, from 10 [31] to 30 minutes [33] before
ECLS initiation is considered. For in hospital CA the survival
with good neurological outcome has been observed
in up to 20 to 42% of cases [26,28,30,40,41]. Therefore,
ECLS has been assigned a low-grade recommendation in
recent guidelines for inhospital cardiac arrest [42]. However,
the good results obtained in IHCA cardiac arrests
can not be automatically extrapolated to OHCA patients
because of longer transport times and possible delay in
ECLS initiation [43].
Therefore, we designed a randomized trial of “hyperinvasive
approach” encompassing all above mentioned
sophisticated methods and hypothesized, that changed
logistics of prehospital refractory OHCA management
and immediate on-admission ECLS institution might
bring beneficial impact on patient survival [44].
Assuming, that refractory cardiac arrest may be caused
by a treatable condition, all mentioned interventions
are approached as only temporizing techniques to allow
for further diagnostics and therapy, mainly the coronary
angiography ± PCI, eventually other investigations
and treatments (i.e. pulmonary angiography and catheter
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embolectomy, aortography or brain computed tomography,
CT).
The aim of this comparative study is to collect prospective,
randomized data on prehospital use of a chest compression
device combined with intraarrest evaporative
cooling as a bridge to in hospital emergency ECLS implantation
followed by immediate invasive diagnostics
and treatment in cases of witnessed OHCA of predominantly
cardiac origin to assess an impact of this combined
“hyperinvasive approach” on 6 months survival with
favourable neurological outcome (primary endpoint),
30 day neurological and cardiac recovery (secondary
outcomes), quality of life, safety and cost-effectiveness
(tertiary outcomes).
Hypotheses
We hypothesize, that the combination of above methods
will provide increased occurrence of primary and secondary
outcomes and will offer a reasonable quality of
life for survivors (assessed by SF-36 questionnaire). We
further suppose, that the combination of above methods
will be cost-effective as assessed by QALY (quality
adjusted life year) determination. We also expect same
occurrence of complications by using mechanical chest
compression device in comparison to manual massage
and increased rate of bleeding complications in ECLS,
however, compensated by survival benefit in otherwise
futile conditions.
Proposed study protocol
Until stated otherwise, study will be realized only during
working hours, ie, 8 AM to 4 PM, to facilitate inhospital
logistics and assure presence of key cathlab and ECMO
team members. After the official initiation of the study,
study coordinator in cardiac center will be notified by a
SMS (Short Message Service) alert on every occasion
when Prague EMS dispatch center will activate Rapid
Response Vehicle (RRV) for witnessed collapse suspected
from cardiac arrest or cardiac arrest witnessed by EMS
personnel. Coordinator will check for intensive care bed
and ECLS capacity and via the dispatch center will notify
the EMS team. See the outline of the study (Figure 1)
and study phases summarized in Table 1.
On arrival to the scene, patients will be evaluated by
an EMS physician to confirm OHCA and standard
ACLS (advanced cardiac life support) will be initiated.
After a minimum of 5 minutes of ACLS guided by emergency
physician and performance of all necessary initial
procedures according to recent guidelines and as per
physician decision on the scene (ie, defibrillations, airway
management, intravenous access establishment) and while
the patient is being resuscitated by other EMS team
members for continuing cardiac arrest (i.e. no ROSC
occurrence, continuous unconsciousness) screening for
study eligibility will be performed, see Table 2 for inclusion
and exclusion criteria. After the emergency physician on
scene evaluates the eligibility criteria and identifies a possibly
eligible patient, he directly contacts the cardiac center
coordinator by a mobile phone and when consensus
on eligibility is established including the bed capacity and
ECLS team availability, (Decision point 1 in the project
outline), randomization procedure will be performed by a
cardiac center coordinator on-line using a computer web
based randomization system. Study number will be
assigned to the patient and the treatment arm assignment
will be notified to the emergency physician on hold.
Patients will be randomized in a 1:1 design to hyperinvasive
or standard arm.
In hyperinvasive arm a mechanical chest compression
device (LUCAS) will be immediately instituted on
scene. Tympanic temperature will be measured, NIRS
(near infrared spectroscopy) monitoring and cooling by
RhinoChill device will be initiated as soon as possible,
realistically immediately after delivering the patient to
the ambulance car. Thereafter, patients will be transferred
directly to cardiac center cathlab under continuous
CPR to fulfill the timeline of reaching ECLS team
within 60 minutes after collapse. The use of drugs, further
defibrillations or other interventions during transport
will follow recent ERC guidelines. On admission to
cathlab, overall status, ROSC presence and ECLS inclusion/exclusion
criteria will be evaluated (Decision point 2
in the project outline, Figure 1). ECLS eligibility (Table 3):
no ROSC or ROSC with ongoing shock state (defined as
sustained hypotension below 90 mmHg of systolic pressure
or need for bolus doses of vasopressors to maintain
the circulation), admission to cathlab not later than
60 minutes after the collapse/initial call to EMS, no signs
of death or irreversible organ damage and no contraindications
to ECLS institution (known bleeding diathesis,
inadequate arterial and venous access for femoro-femoral
veno-arterial ECLS). If the ECLS team members reach
consensus on ECLS eligibility, it will be started as soon
as possible by a standard percutaneous femoro-femoral
approach. After ECLS institution, mild hypothermia will
be continued by means of extracorporeal circuit cooling
and immediate coronary angiography +/− PCI (eventually
pulmonary angiography, aortography or head CT if
cause of arrest still not obvious) will be performed in all
patients. If the patient randomized to hyperinvasive arm
reaches ROSC during the transport or after admission to
cathlab before ECLS institution, he will undergo initial
clinical assessment, ECG, urgent echocardiography and
will continue with invasive investigations as mentioned
above.
Patients randomized to a standard arm will be managed
by continued ACLS on site. The use of drugs, further
defibrillations or other interventions will follow recent
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ERC guidelines. Patients will also undergo NIRS monitoring.
If ROSC is achieved, patients will be transferred to
the same hospital to one of intensive care units (ICU),
emergency room or cathlab observational area and coronary
angiography/PCI will be performed in all patients
with STEMI (ST elevation myocardial infarction) identified
on any post ROSC 12 lead ECG or high risk nonSTEMI
defined by persistent ST segment depressions
or high risk for in hospital death according to GRACE
risk score, ie GRACE risk score > 140 points, predicted
mortality > 3%, http://www.outcomes.org/grace) [45,46].
Mild therapeutic hypothermia will be started as soon
as possible after ROSC (including prehospital cooling
on a discretion of the emergency physician), intraarrest
cooling will not be allowed in the standard arm. Stopping
resuscitation efforts will follow the recent ERC guidelines
which state continuing CPR while VF/VT is present and
at least 20 minutes when asystoly is an initial rhythm,
however, definitive decision will be on a discretion of
EMS physician.
Figure 1 Prague OHCA study outline. Abbreviations: ACLS: advanced cardiac life support; AG: angiography; ASAP: as soon as possible; BLS:
basic life support; CPC: cerebral performance category; CPR: cardiopulmonary resuscitation; CT: computed tomography; ECLS: extracorporeal life
support; EMS: emergency medical service; ERC: European Resuscitation Council; ICU: intensive care unit; I/E: inclusion/exclusion; NIRS: near infrared
spectroscopy; OHCA: out of hospital cardiac arrest; ROSC: return of spontaneous circulation; STEMI: ST elevation acute myocardial infarction;
TTE: transthoracic echocardiography.
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Table 1 Summary of study phases as per the proposed timeline and expected activities during respective time
intervals
Study phases Activities to be performed
Prerandomization
Phase 1 (Time 0 to Time 1) EMS is activated
Aimed to be < 10 min RRV and ambulance car are dispatched
Time 0 = collapse time Telephone assisted lay person BLS is started
Time 1 = EMS team on site Cardiac center is alerted
OHCA confirmed
Phase 2 (Time 1 to Time 2) ACLS is started by the first crew on site
Time 2 = randomization All initial procedures are performed (defibrillation/s, airway management, i.v. access establishment, etc.)
After a minimum of 5 minutes of ACLS guided by EMS physician eligibility for the study is considered
(Decision point 1)
Randomization is performed by phone call with cardiac center coordinator
Postrandomization Standard arm Hyperinvasive arm
Phase 3 (Time 2 to Time 3) Continue ACLS according to recent ERC guidelines,
start NIRS monitoring, no mechanical compression
device used, no intraarrest cooling
Start mechanical compression device, take
tympanic temperature, start NIRS monitoring,
start intraarrest cooling
Prehospital randomized phase
Time 3 = hospital admission ROSC assessment Immediate transport to cardiac center cathlab
under ongoing CPR, continue ACLS according
to recent ERC guidelinesIf ROSC, transport to cardiac center ICU
Prehospital cooling in case of stable ROSC is allowed If ROSC during transport, continue transport
to cathlab, continue cooling and proceed with
invasive assessment
If death on scene, autopsy at Inst. for Forensic
Medicine
If death on scene or during transport, autopsy
at Inst. for Forensic Medicine
Phase 4 (Time 3 to Time 4) Standard post cardiac arrest care, mild hypothermia
to 33-34°C ASAP
ROSC and shock assessment, urgent brief TTE
Time 4 = ECLS start – applies for
hyperinvasive arm, in standard
arm Time 4 = initial assessment
Initial assessment - if STEMI/high risk nonSTEMI
proceed to cathlab
ECLS I/E assessment
Continue NIRS If no ROSC, or ROSC + shock and no ECLS I/E
contraindications – immediate ECLS implantation
If death, autopsy at Inst. for Forensic Medicine Immediate invasive assessment (coronary AG, if
normal – pulmonary AG, if normal - aortography,
eventually brain CT)
Continue NIRS
Continue mild hypothermia to 33-34 C
If death, autopsy at Inst. for Forensic Medicine
Phase 5 (Time 4 to Time 5) Standard post cardiac arrest care Continue ECLS until weaning and discontinuation
Time 5 = 6 months evaluation
or time of death
Evaluation of cardiac and neurological recovery
within 30 days/until discharge
Assess ECLS related adverse events (bleeding,
need for blood products)
6 months survival with CPC 1–2 assessment Standard post cardiac arrest care
If death, autopsy at Inst. for Forensic Medicine Evaluation of cardiac and neurological recovery
within 30 days/until discharge
6 months survival with CPC 1–2 assessment
If death, autopsy at Inst. for Forensic Medicine
Abbreviations: ACLS: advanced cardiac life support; AG: angiography; ASAP: as soon as possible; BLS: basic life support; CPC: cerebral performance category; CPR:
cardiopulmonary resuscitation; CT: computed tomography; ECLS: extracorporeal life support; EMS: emergency medical service; ICU: intensive care unit; I/E:
inclusion/exclusion; NIRS: near infrared spectroscopy; OHCA: out of hospital cardiac arrest; ROSC: return of spontaneous circulation; STEMI: ST elevation acute
myocardial infarction; TTE: transthoracic echocardiography.
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Randomization process
The online randomization process during the ongoing
CPR has been selected to overcome selection bias in
cluster randomizations, because study arm assignment
before starting CPR can influence the decision making
[24]. Accordingly, chest compression device, i.e. LUCAS
has to be carried to all putative OHCA victims and will
be used only when randomization to hyperinvasive arm
occurs. This is somewhat inconvenient to EMS crew,
however, necessary to avoid unintentional bias. In contrary
to this, intranasal cooling will be started in the ambulance
vehicle, because carrying another device to the
scene would be too demanding and time delay for transporting
a patient from the scene to an ambulance car will
be negligible. The randomization phone call between
the emergency physician and coordinating cardiologist/
intensivist at the cardiac center is a crucial activity to
properly enroll the patients and fulfill the inclusion/exclusion
criteria. These phone calls have been already
trained during the seminars and investigator meetings
and should not last more than 60 sec. At the time of the
phone call, all the vital procedures performed by the
EMS physician are already done, and at least 3 other rescue
persons are on the scene. Thus, the physician can
safely make this phone call, while others are continuing
the CPR. The web based randomization system has been
chosen, to maximally shorten the necessary time. Only
following information will be requested after logging into
the system: patient estimated age and gender and confirmation
of I/E criteria. Immediately thereafter the patient
number and treatment assignment will be generated. For
the case of web randomization system failure, envelopes
with treatment arm assignment will be prepared in the
coordinating center, just next to the computer used for
randomization.
Post resuscitation care
All patients admitted to hospital in both arms will have
immediate biochemical evaluation, continuing neurological
monitoring by near-infrared spectroscopy and
brief urgent echocardiography. Nasal cooling in hyperinvasive
arm will continue until transition to systemic cooling
either by ECLS or by intravascular cooling catheter or
standard surface cooling combined with rapid intravenous
administration of cold normal saline (4°C, 20–30 ml/kg/
hour according to hemodynamic status) to reach target
temperature of 33°C as soon as possible. Target core
temperature will be maintained for 24 hours. After the
maintenance period, core temperature will be slowly raised
to normothermia of 37°C during 8 hours with a rewarming
rate of 0.5°C/hour in both groups. Body temperature will
then be maintained at normothermia 37 ±0.5°C until
72 hours from sustained ROSC in both treatment
groups, as long as the patient is in the ICU, using
pharmacotherapy or other temperature management
Table 2 Prague OHCA study inclusion and exclusion
criteria
Inclusion criteria Exclusion criteria
Age ≥18 and ≤ 65 years OHCA of presumed non-cardiac
cause
Wittnessed OHCA of presumed
cardiac cause
Unwitnessed collapse
Minimum of 5 minutes of ACLS
performed by emergency medical
service team without sustained
ROSC
Suspected or confirmed
pregnancy
Unconsciousness1
ROSC within 5 minutes of ACLS
performed by EMS team
ECLS team and ICU bed capacity
in cardiac center available
Conscious patient
Known bleeding diathesis or
suspected or confirmed acute
or recent intracranial bleeding
Suspected or confirmed acute
stroke
Known severe chronic organ
dysfunction or other limitations
in therapy
“Do not resuscitate” order or
other circumstances making
180 day survival unlikely
Known pre-arrest cerebral
performance category CPC ≥ 3
Abbreviations: OHCA: out-of hospital cardiac arrest; ACLS: advanced cardiac life
support; ROSC: return of spontaneous circulation; ECLS: extracorporeal life
support; ICU: intensive care unit; EMS: emergency medical service; CPC:
cerebral performance category.
1
defined as no response to verbal or painful stimuli during ACLS.
Table 3 Inclusion and exclusion criteria for initiation of ECLS in Prague OHCA study protocol
Inclusion criteria Exclusion criteria
No ROSC or ROSC with ongoing shock (defined as sustained hypotension
below 90 mmHg of systolic pressure or need for bolus doses of
vasopressors to maintain the circulation)
Signs of death or irreversible organ damage
Admission to cathlab not later than 60 minutes after the collapse/initial
call to EMS1
Known bleeding diathesis
Consensus of ECMO team members on ECLS initiation Inadequate arterial and/or venous access for femoro-femoral
cannulation
Abbbreviations: ECMO: extracorporeal membrane oxygenation; ECLS: extracorporeal life support; ROSC: return of spontaneous circulation.
1
if collapse time is not exactly known, initial call to EMS will be considered.
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systems whenever applicable. EMS and hospital personnel
will not be blinded during the treatment. All other post
arrest critical care management will follow recent ERC
guidelines and other generally accepted approaches
[3,6,7,26].
Since the official initiation of the study, all patients
resuscitated by Prague EMS not fulfilling eligibility criteria
for this study will also be followed for outcome
assessment and will constitute the third comparative
group, “Prague OHCA study registry” patients (see the
outline of the study).
Devices used
LUCAS (Lund University Cardiac Arrest System, PhysioControl
Inc./Jolife AB, Lund, Sweden) device for mechanical
chest compressions, http://www.physio-control.
com/LUCAS.
RhinoChill device (BeneChill, Inc., San Diego, Calif,
USA) device for intraarrest intranasal evaporative
cooling, http://www.benechill.com/wp/rhinochill-trade/
rhinochill-device.
For ECLS, MAQUET PLS console (MAQUET Cardiopulmonary
AG, Hirrlingen, Germany) and Rotaflow
RF 32 centrifugal pump with Quadrox PLS hollow fibre
BIOLINEW
coated membrane oxygenator (MAQUET
Cardiopulmonary AG, Hirrlingen, Germany) or alternatively
MAQUET custom made tubing set and Eurosets
ECMO oxygenator A.L.ONE (EUROSETS s.r.l., Medolla,
Italy) and a mechanical gas blender (Sechrist, Anaheim,
CA, USA) will be used. Edwards cannulae (Fem-Flex
Cannulae, Edwards Lifesciences Research Medical Inc.,
Midvale, UT, USA) or alternatively MAGUET cannulae
will be used for femoro-femoral cannulation. Surgical
standby will be available to assist in case of any cannulation
difficulties. Ultrasound guided antegrade perfusion
cannula will be implanted whenever limb ischemia is
being detected clinically or by regional oxygen saturation
decrease (see below). Patients on ECLS will be continuously
anticoagulated with heparin until contraindicated,
targeted to ACT (activated clotting time) of 180–220 sec
or aPTT of 50–80 sec.
For regional oxygen saturation (neuromonitoring and
lower extremities´ perfusion), an INVOS device (INVOS
Cerebral/Somatic Oximeter, Covidien, Boulder, CO, USA)
will be used for near infrared spectroscopy measurement
during both prehospital and inhospital phase. During
prehospital phase, only brain regional saturations will be
measured. During inhospital phase, in standard arm,
brain saturations will be further measured, in hyperinvasive
arm, 4 channels will be used to measure both
hemispheres and also lower extremities´ saturations for
early detection and further monitoring of possible lower
limb ischemia due to ECMO cannula femoral artery
obstruction.
Ethics, safety and registration
The study has been approved by the Institutional Review
Board of the General University Hospital and First
Faculty of Medicine, Charles University in Prague.
Ethical considerations for treating subjects without their
expressed consent are in accordance with the Helsinki
Declaration of 1964, revised in 2008. The subject’s legal
representative will be informed of the subject’s study participation
as soon as practical, and patients who regain
normal neurological function will be asked to provide
their consent for use of the data. The study has been registered
under ClinicalTrials.gov identifier: NCT01511666.
Data safety monitoring board (DSMB) and data
monitoring
An independent DSMB consisting of experts in the field
of cardiac arrest will follow the overall study progression
and integrity. DSMB will meet after inclusion of every
30 patients or every 6 months, whatever comes first, to
evaluate the progress in the study and review all adverse
events. Study data will be monitored by a professional
contracted CRO (contract research organization).
Outcomes
Primary outcome
Composite endpoint of 6 months survival with good
neurological outcome (CPC 1–2).
Secondary outcomes
1/30 day neurological recovery - defined as no or minimal
neurological impairment (CPC 1 or 2) at any timepoint
within first 30 days after initial cardiac arrest. Neurological
status will be evaluated by determining CPC value
every day on ICU and on ICU discharge, on hospital discharge
and/or on day 7, 14 ± 2 days, 30 ± 2 days, 90 ±
3 days and 180 ± 3 days. Neurological assessment on hospital
discharge will be provided by a neurologist blinded
to study protocol and the treatment assignment. Neurological
status on ECLS will follow the same timeline as
stated above, brain death determination will respect the
valid laws of the country.
2/30 day cardiac recovery - defined as no need for
pharmacological or mechanical cardiac support. Cardiac
status will be evaluated every day on ICU and on ICU
discharge. Systolic function will be measured by echocardiography
on day 1 on ICU, before hospital discharge
and on day 180 ± 3 days.
Tertiary outcomes
Early outcome will also be monitored by means of ROSC
achievement, defined as a palpable puls and measurable
blood pressure without ECLS and ROSB (return of
spontaneous beating) on ECLS, defined as palpable pulse
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or pulsatile flow on arterial invasive blood pressure
curve. ECLS weaning will be considered when cardiac
function starts to improve, meaning that spontaneous
pulsatile flow will be achieved and stable or decreasing
doses of inotropes and vasopressors will be used for
more than 24 hours. Stable circulation for more than
24 hours after stopping ECLS will be considered to be
a weaning success. In case of failed ECLS weaning due
to a persistent heart dysfunction and good neurological
and overall recovery, patients will be considered for ventricle
assist device (VAD) implantation or heart transplantation.
In nonweanable ECLS situation and poor
neurological outcome, the patient will be considered to
become a nonbeating heart donor. For patients not suitable
for VAD/heart transplantation nor for nonbeating
heart donorship consideration, ECLS will be withdrawn.
All survivors will be followed until discharge home or to
a long term care or rehabilitation center and thereafter in
an Outpatient Heart Failure Clinic of the coordinating
center. Quality of life will be assessed using SF-36 questionnaire
on discharge and during the 6 months visit.
Safety of the invasive methods will be monitored by adverse
events occurrence in survivors and organ damage
will be assessed on autopsies in nonsurvivors. Costeffectiveness
will be evaluated by determination of QALY
(Quality Adjusted Life Year). Patients who die, will
undergo autopsy at the Department of Forensic Medicine
and Toxicology, General University Hospital and First
Faculty of Medicine.
Timeline
During the initial months of 2012 we expect a development
of web based randomization and database system
including CRF (case report form). EMS personnel has
been trained in all necessary procedures and methods
(i.e. LUCAS and RhinoChill device) during 2011 (3 seminars
per 4 hours) and routinely uses LUCAS device in
cardiac arrest setting. A simulation study is planned for
the first half of 2012, i.e. 3–5 patients will be “randomized”
to hyperinvasive arm, to be sure, that the protocol
is feasible, all procedures are well trained and ECLS team
is able to meet quickly and connect the patient to ECLS
as per scheduled outline. Only thereafter and following
DSMB recommendation a real randomized study phase
will be initiated. We expect approximately 40 patients to
be enrolled yearly until planned number of patients
according to power analysis, or DSMB stops the study.
Statistical considerations
Initial statistical analysis was performed taking into account
three proposed groups of patients. First, patients
who will not be randomized, i.e. Prague OHCA study
registry patients (see study outline on Figure 1). These
patients will not fulfill inclusion/exclusion criteria mainly
by means of not having “refractory” cardiac arrest, ie,
successful ROSC will be reached within 5–10 minutes of
ACLS provided by EMS physician staffed team. According
to Prague EMS study assessing overall outcome of
all CPRs in Prague in 2008 [4] with 15% overall short
term survival with favourable neurological outcome (discharged
home), we expect better, approximately 20–30%
of “primary outcome” occurrence in this comparative
group of patients. The other two groups in randomized
part of the study will yield standard and hyperinvasive
arm patients with rather worse outcomes. We expect
90% mortality in standard arm, or alternatively stated,
10% six-month survival with favourable neurological
outcome. The characteristics of patients and their procedures
not included in randomization process will be
tracked and treated as possible confounding factors
and included in statistical analysis as cofactors when
necessary.
The power analysis of the study
The power analysis was computed for superiority of
hyperinvasive approach over standard approach, i.e. using
two tailed test with the α = 0.05 and desired power 0.9. In
the standard arm 10% six-month survival with favourable
neurological outcome (primary outcome) is assumed and
15% increase in primary outcome occurrence (6 month
survival with favourable neurological outcome) is considered
as clinically relevant. Three scenarios with 10%,
15% and 20% increase of primary outcome were computed.
The analysis was computed using ADDPLAN
BASE version 6.0 (Aptiv Solutions, Cologne, Germany,
2011).
Scenario 1: standard (10%) vs. hyperinvasive (20%)
groups with allocation ratio 1; two tailed test with α =
0.05 and power = 0.9.
A design with a maximum of K = 4 stages was chosen.
The critical values and the test characteristics of the
group sequential test design were calculated for a Pampallona
and Tsiatis design with boundary shape parameter
Delta0 = 0.00 to reject H0, and boundary shape
parameter Delta1 = 0.00 to reject H1.
This yields a total of 285.7 + 285.7 = 571.4 observations.
For comparison, the sample size in a fixed sample
size design is n1 = 265.9, n2 = 265.9. The expected (average)
total sample size under the alternative hypothesis is
404.1, under a value midway between H0 and H1 it is
444.3, and under the null hypothesis it is 403.1, see
Figure 2.
Scenario 2: standard (10%) vs. hyperinvasive (25%)
groups with allocation ratio 1; two tailed test with α =
0.05 and power = 0.9.
A design with a maximum of K = 4 stages was chosen.
The critical values and the test characteristics of the
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group sequential test design were calculated for a Pampallona
and Tsiatis design with boundary shape parameter
Delta0 = 0.00 to reject H0, and boundary shape parameter
Delta1 = 0.00 to reject H1.
This yields a total of 142.7 + 142.7 = 285.4 observations.
For comparison, the sample size in a fixed sample size design
is n1 = 132.8, n2 = 132.8. The expected (average) total
sample size under the alternative hypothesis is 201.8,
under a value midway between H0 and H1 it is 221.9,
and under the null hypothesis it is 201.3, see Figure 3.
Scenario 3: standard (10%) vs. hyperinvasive (30%)
groups with allocation ratio 1; two tailed test with α =
0.05 and power = 0.9.
A design with a maximum of K = 4 stages was chosen.
The critical values and the test characteristics of the
group sequential test design were calculated for a Pampallona
and Tsiatis design with boundary shape parameter
Delta0 = 0.00 to reject H0, and boundary shape
parameter Delta1 = 0.00 to reject H1.
This yields a total of 88.1 + 88.1 = 176.2 observations.
For comparison, the sample size in a fixed sample size
design is n1 = 82.0, n2 = 82.0. The expected (average)
total sample size under the alternative hypothesis is
124.6, under a value midway between H0 and H1 it is
137.0, and under the null hypothesis it is 124.3002, see
Figure 4.
Figure 2 Graphical delineation for scenario 1, estimated 10% increase of primary outcome in hyperinvasive (20%) vs. standard (10%)
groups.
Figure 3 Graphical delineation for scenario 2, estimated 15% increase of primary outcome in hyperinvasive (25%) vs. standard (10%)
groups.
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Cooperation
The project will be executed in a close cooperation of
Complex Cardiac Center of General University Hospital
with Prague Emergency Medical Service. Both institutions
cooperate on a day by day basis during the routine
care for cardiac arrest patients including admissions during
ongoing CPR. In these occasions the cardiac center
is alerted early and the catheterization and ECLS team is
prepared at the cathlab. The decision on ECLS initiation
is always reached consensually within the ECMO team
members [47].
Readiness of cooperating institutions
Complex Cardiac Center of General Teaching Hospital,
Charles University in Prague admits approximately 100
patients after cardiac arrest yearly. Approximately 20
patients per year are treated by ECLS under ECMO team
guidance, coordinated by principal investigator of this
project (JB). Until now, 67 patients have been treated by
ECMO and both clinical [47-50] and experimental [51]
results and experiences have been published. Cardiac
center is located within the city center.
Prague EMS provides a prehospital urgent care within
the capitol Prague by a rendezvous system with rapid response
vehicles (RRV) staffed by emergency physicians
and ambulance cars staffed by paramedics and intensive
care nurses. Necessary devices, i.e. LUCAS for mechanical
chest compressions and RhinoChill for intranasal
evaporative cooling are currently available for all RRVs.
An INVOS device (INVOS Cerebral/Somatic Oximeter,
Covidien, Boulder, CO, USA) for NIRS monitoring is also
available, however only for one inspector car. This car is
alerted routinely in every resuscitated OHCA in Prague
for CPR assistance, however, inclusion into the study is
possible without INVOS availability. An analysis of cardiac
arrest occurrence in Prague in 2007–2010 confirms
a frequent occurrence in the center of the city, which is a
favourable precondition to reach short transport times to
cardiac center (personal communication with OF – data
not published).
Discussion
This complex and logistically demanding project has
been designed to collect a clear result stating whether
the combination of modern sophisticated methods
improves or not the unfavourable prognosis of cardiac
arrest patients. The project differs from other already
performed studies by randomizing the patients to a combination
of potentially beneficial methods used in cardiac
arrest. Such a combination or “hyperinvasive” approach
has not been performed so far, as per our knowledge.
The underlying “all in one” concept is to maximize the
beneficial effect on outcome of cardiac arrest patients,
i.e. to keep the end-organ perfusion by mechanical chest
compression, to avoid neurological damage by early
intraarrest intranasal evaporative cooling and to bridge
to ECLS with further invasive evaluation to identify and
immediately treat the cause of refractory arrest by means
of percutaneous techniques, if cause is identified. Of
course, we may also expect untreatable causes of sudden
refractory arrest like aortic aneurysmal rupture, intracranial
bleeding with occipital conus, unidentified trauma
with severe inner organ damage, initially unrecognizable
poisoning etc. However, we also expect a significant
proportion of potentially treatable causes, mainly the
ongoing ischemia due to acute coronary obstruction
Figure 4 Graphical delineation for scenario 3, estimated 20% increase of primary outcome in hyperinvasive (30%) vs. standard (10%)
groups.
Belohlavek et al. Journal of Translational Medicine 2012, 10:163 Page 10 of 13
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and massive pulmonary embolism with severe right
ventricle failure. As per available data [3] and our own
experience (Smid, Belohlavek – data not published yet),
in 80% of OHCA victims, cardiac etiology can be identified
with diagnostic accuracy in prehospital phase of approximately
75% [52]. Two thirds of these patients suffer
either acute coronary syndrome or pulmonary embolism.
In remaining one third of patients, complications of
chronic heart failure is the the most frequent cause.
A key prerequisite for successful result is strict compliance
with proposed timeline (see the outline of the study
on Figure 1) and adequate use of all devices. Therefore,
study preparation phase lasted over one year. All RRV
crews had to become perfectly familiar with LUCAS
device and were repeatedly trained in application of this
device. The same applies for prehospital RhinoChill
device use and also for an acute implantantion of ECLS
by ECMO team in cathlab. All study investigators, cathlab
and ICU personnel have also been repeatedly trained in
study protocol. Moreover, initially we plan at least 3–5
patients to be “randomized” to hyper invasive approach
(simulation phase) before real randomized study starts,
to prove the concept and feasibility of the protocol. This
allows us to recognize potential logistic barriers or any
other misconceptions. Further on, the pilot phase of the
study will be performed only within working hours, ie,
8 AM to 4 PM and only when principal investigator is
present, to optimize for personal and organizational
demands. Based on initial result and feasibility of the
whole concept, after randomization of 30 patients, DSMB
will decide whether to continue the study or not.
We also seriously considered the definition of
“refractory” cardiac arrest, as this definition varies in
available studies [31,33]. We expect the average time to
randomization in our proposed study to be around
20 minutes, considering following time intervals: 9 minutes
is an average response time for a RRV to reach the
patient with OHCA in Prague [4]; a minimum of 5 minutes
of ACLS by the EMS team on scene including performance
of all necessary procedures (defibrillation or
defibrillations, airway management, intravenous access establishment),
we actually expect this interval to last longer,
ie, approximately 10 minutes and 1–2 minutes of
randomization phone call with cardiac center coordinator.
The protocol is opened for sharing by other cardiac
centers with available ECLS and cathlab teams trained to
admit patients with refractory cardiac arrest under ongoing
CPR. A prove of concept study will be started
soon. The aim of the authors is to establish a net of centers
for a multicenter trial initiation in future.
Contribution of the project and clinical consequences
Potential contribution is crucial taking into account the
socio-economic consequences of cardiac arrest. Cardiac
arrest often affects relatively young fully active persons
and portends high mortality mainly due to severe neurological
damage causing both personal tragedies to
patients and to their relatives and increases in health care
costs. If the beneficial effect of proposed combination of
therapeutical methods were proved, it might have a profound
influence on logistics of emergency care for cardiac
arrest patients, mainly in cities and urban agglomerations
similar to Prague, i.e. in cities with well organized prehospital
care, short arrival times and within city center
located cardiac center with emergently available ECLS
and cathlab team capacity.
Conclusion
Authors introduce and offer a protocol of a proposed randomized
study enrolling patients with witnessed OHCA
presumably of cardiac origin planned to be initiated in
Prague in 2012. Study will compare hyperinvasive approach
encompassing prehospital intraarrest cooling,
mechanical chest compression, veno-arterial ECLS and
immediate invasive diagnostics in all patients compared
to a standard of care. The protocol is opened for sharing
by other cardiac centers with readily available ECLS and
cathlab teams used to cooperate with emergency medical
services to admit patients with refractory cardiac arrest
under ongoing CPR to establish a net of centers for a
multicenter trial realization in future.
Abbreviations
ACLS: Advanced cardiac life support; AG: Angiography; AoG: Aortography;
ASAP: As soon as possible; BLS: Basic life support; CA: Cardiac arrest;
CPC: Cerebral performance category; CPR: Cardiopulmonary resuscitation;
CRF: Case report form; CT: Computed tomography; DSMB: Data safety
monitoring board; ECMO: Extracorporeal membrane oxygenation;
ECLS: Extracorporeal life support; EMS: Emergency medical service;
ICU: Intensive care unit; I/E: Inclusion/exclusion; IHCA: In hospital cardiac
arrest; LUCAS: Lund University Cardiac Arrest System; NIRS: Near infrared
spectroscopy; OHCA: Out of hospital cardiac arrest; PCI: Percutaneous
coronary intervention; QALY: Quality Adjusted Life Year; RRV: Rapid response
vehicle; ROSC: Return of spontaneous circulation; STEMI: ST elevation acute
myocardial infarction; TTE: Transthoracic echocardiography; V-A: Veno-arterial.
Competing interests
A Puroklima a.s. company, a distributor for Czech Republic for Benechill
provided eight Rhinochill devices and for the purpose of the study will also
provide the application sets and evaporative liquid per substantially reduced
cost. Likewise, a Physio-Control, division of Medtronic Czechia s.r.o. company
provided eight LUCAS devices for the purpose of the study. Both device will
be provided to Prague EMS to equip all RRVs. Maquet company provided
the MAQUET PLS device for ECLS. Covidien company provided the INVOS
devices for NIRS measurement. The main author (JB) has received two
lecture honoraria from Maquet company, Czech Republic.
Authors’ contribution
JB is a main author, concepted and designed the study and prepared the
manuscript. JJ and VK prepared the statistical power analysis, will assist in
data management. KK, OF, MP, JD, RS, JV and ZS substantially contributed to
conception and design and will be responsible for acquisition, verification
and interpretation of prehospital data. OS, JH, MB and AL participated on
conception and design and will be responsible for acquisition, verification
and interpretation of inhospital data. VM and AL obtained research funding
and AL has also given a final approval of the version to be published. All
authors read and approved the final manuscript.
Belohlavek et al. Journal of Translational Medicine 2012, 10:163 Page 11 of 13
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Acknowledgement
The design and preparation of the study has been supported by a research
grants from Internal Grant Agency Ministry of Health, Czech Republic NS
9770-4/2008 and NT 13225-4/2012 and partially supported by a grant from
Czech Society of Cardiology “Follow-up of the cardiac arrest victims with an
impact on early invasive investigation and organ support initiation”.
Author details
1
2nd Department of Medicine - Department of Cardiovascular Medicine, 1st
Faculty of Medicine, Charles University in Prague and General University
Hospital in Prague, U Nemocnice 2, Prague 2 128 00, Czech Republic.
2
Emergency Medical Service Prague, Korunni 98, 101 00, Prague 10, Czech
Republic. 3
Institute for biostatistics and analysis, Masaryk University Brno,
Kotlářská 2, Brno, Czech Republic. 4
Department of anesthesiology,
resuscitation and intensive medicine, 1st Faculty of Medicine, Charles
University in Prague and General University Hospital in Prague, U Nemocnice
2, Prague 2 128 00, Czech Republic.
Received: 6 July 2012 Accepted: 6 July 2012
Published: 10 August 2012
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doi:10.1186/1479-5876-10-163
Cite this article as: Belohlavek et al.: Hyperinvasive approach to out-of
hospital cardiac arrest using mechanical chest compression device,
prehospital intraarrest cooling, extracorporeal life support and early
invasive assessment compared to standard of care. A randomized
parallel groups comparative study proposal. “Prague OHCA study”.
Journal of Translational Medicine 2012 10:163.
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