Therapeutic Hypothermia Following Out-of-Hospital Cardiac Arrest - A Randomized Trial Comparing Mild and Moderate Therapeutic Hypothermia (CAPITAL CHILL)
Phase: NA
Conditions: Cardiac Arrest
Sponsor: Ottawa Heart Institute Research Corporation

 
 
 
 
 
22 MAR 2013 - FINAL 
 
 Michel Le May, MD 
 
 
 
 
 
 
 
Therapeutic Hypothermia following Out-of-
Hospital Cardiac Arrest – A randomized trial 
comparing mild and moderate therapeutic 
hypothermia 
 
CAPITAL-CHILL 
 
 
 
 
Principal Investigator: Michel Le May, M.D. 
 
Address: 
University of Ottawa Heart Institute 
 
40 Ruskin St.  
Ottawa, Ontario, Canada 
 
 
Telephone Number: 
(613) 761- 4223 
 
Email Contact: 
 
 
mlemay@ottawaheart.ca 
 
Co-Investigators:  
 
Ronnen Maze, Benjamin M Hibbert, Derek Y So, George Wells, Alexander Dick, Christopher 
Glover, Michael Froeschl, J.F. Marquis, Shawn Marshall, Ali Pourdjabbar, Marino Labinaz 
 
 
Research Coordinators:   
Christina Osborne 
 
 
 
         
Melissa Blondeau 
 
 

 
 
 
 
 
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TABLE OF CONTENTS 
 
PAGE 
 
1. 
GLOSSARY OF ABBREVIATIONS ....................................................................................   3 
 
2. 
SYNOPSIS OF THE PROTOCOL .......................................................................................   4 
 
 
3. 
SYNOPSIS OF THE TRIAL ....................................................................................................5 
 
3.1. 
Primary Outcome .......................................................................................................5 
 
3.2. 
Inclusion Criteria ........................................................................................................5 
 
3.3. 
Exclusion Criteria .......................................................................................................5 
 
3.4. 
Study Design ..............................................................................................................6 
 
3.5 
Summary. ...................................................................................................................7 
 
3.6 
Statistical Analyses....................................................................................................7 
 
3.6.1 
Sample Size...............................................................................................................7 
 
 
 
4. 
PROTOCOL ............................................................................................................................8 
 
4.1. 
Background and Rationale.........................................................................................8 
 
4.2 
Study Design .......................................................................................................  ...10 
 
4.2.1 
Study Population .................................................................................................. ...10 
 
4.2.2 
Inclusion Criteria......................................................................................................10 
 
4.2.3 
Exclusion Criteria.....................................................................................................10 
 
4.2.4 
Randomization.........................................................................................................10 
 
4.2.5 
Blinding....................................................................................................................11 
 
4.2.6 
Participant Consent.................................................................................................11  
 
4.3 
Interventions............................................................................................................11 
 
4.4 
Laboratory Assessments.........................................................................................12 
 
4.5 
Discovery of Novel Biomarkers – Blood Samples...................................................12 
 
4.6 
Follow-up.................................................................................................................13 
 
4.7 
Pre-specified subgroups..........................................................................................13 
 
5. 
STUDY OUTCOMES .......................................................................................................... .13 
 
5.1 
Primary Outcomes...............................................................................................13 
 
5.2 
Secondary Outcomes..........................................................................................14 
 
6. 
DEFINITION OF STUDY OUTCOMES ............................................................................... 14 
 
6.1. 
Poor Neurological outcome..................................................................................... 14 
 
6.2 
Bleeding............................................................................................................... ..14 
 
6.3 
Stroke......................................................................................................................14 
 
6.4 
Cardiogenic Shock..................................................................................................14 
 
6.5 
Stent Thrombosis According to Academic Research Consortium (ARC)................15 
 
6.6 
PCI Procedural Success..........................................................................................15 
 
 
7. 
STATISTICAL AND ANALYTICAL METHODS .................................................................. 15 
 
7.1. 
Hypothesis Testing ................................................................................................. 15 
 
7.2. 
Efficacy Analysis ..................................................................................................... 16 
 
7.3. 
Comparability of Patient Groups ............................................................................. 16 
 
 
8. 
SAMPLE SIZE .................................................................................................................  ...16 
 
8.1        Sample Size............................................................................................................16 
 
9.  
DATA QUALITY ASSURANCE .......................................................................................... 16 
 
10. 
STUDY COMMITTEES ........................................................................................................ 16 
10.1 Steering Committee ............................................................................................................. 16 
10.2 Clinical Event Adjudication Committee ................................................................................ 16 
   10.3 
Data and Safety Monitoring Committee (DSMC).....................................................17 
 

 
 
 
 
 
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11. 
ANALYSIS OF DATA .......................................................................................................... 17 
 
 
12. 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS ............................................. 17 
 
12.1 
Definition of an Adverse Event (AE) ....................................................................... 17 
 
12.2 
Definition of Serious Adverse Events (SAE) ........................................................... 17 
 
12.3 
Expedited Reporting of Serious Adverse Events .................................................... 17 
 
12.4 
Reporting of Subject Death ..................................................................................... 18 
 
 
13. 
APPENDICES ...................................................................................................................... 19 
 
13.1      APPENDIX 1: Investigators.....................................................................................19 
 
13.2      APPENDIX 2: Eligibility Screening Form.................................................................20 
 
13.3      APPENDIX 3: The Steering Committee...................................................................21 
 
13.4      APPENDIX 4: Safety and Laboratory Tests.............................................................22 
 
13.5      APPENDIX 5: Ethical Aspects.................................................................................23 
 
13.6      APPENDIX 6: Schedule of Assessments and Procedures......................................24 
 
13.7      APPENDIX 7: TIMI Bleeding Definition....................................................................25 
 
13.8      APPENDIX 8: The Disability Rating Scale (DRS)....................................................27 
 
13.9      APPENDIX 9: The University of Ottawa and The Ottawa Hospital  
                                              Therapeutic Hypothermia Protocol...................................................29 
 
 
14.    REFERENCE  ................................................................................................................ ......30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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1. GLOSSARY OF ABBREVIATIONS 
 
AEs 
Adverse Events 
ARC 
Academic Research Consortium 
CABG 
Coronary Artery Bypass Grafting 
CCU 
Coronary Care Unit 
CHF 
Congestive Heart Failure 
CK 
Creatinine Kinase 
CRF 
Case Report Form 
DRS 
Disability Ratings Scale 
DSMC 
Data and Safety Monitoring Committee 
EAC 
Event Adjudication Committee 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
ESF 
Eligibility Screening Form 
GCS 
Glasgow Coma Score 
IV 
Intravenous 
LV 
Left Ventricular 
mL 
Millilitre 
µmmol/L 
Micromoles per litre 
OHCA 
Out-of-Hospital Cardiac Arrest 
PCI 
Percutaneous Coronary Intervention 
ROSC 
Return Of Spontaneous Circulation 
SAE 
Serious Adverse Event 
STEMI 
ST-Elevation Myocardial Infarction 
TH 
Therapeutic Hypothermia 
UOHI 
University of Ottawa Heart Institute 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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2. SYNOPSIS OF PROTOCOL 
 
Title 
Therapeutic Hypothermia following Out-of-Hospital Cardiac Arrest 
– A randomized trial comparing mild and moderate therapeutic 
hypothermia 
Sponsors 
None 
Clinical phase 
III 
Indication 
Therapeutic Hypothermia  
Objectives  
Cooling with moderate hypothermia to a goal temperature of 31C 
will result in improved neurologic outcomes compared to mild 
hypothermia with a goal of 34C in comatose survivors of OHCA.   
Trial design 
Single center, randomized, double blinded, parallel group design. 
Number of subjects 
340 
Target population 
Out-of-hospital cardiac arrest   
Length of study  
6 months 
Investigational product(s) 
None  
Comparator “drug” 
None 
The primary outcome 
Death or poor neurologic outcome at 6 months  
Event adjudication committee 
The following events will be adjudicated by a masked Event 
Adjudication Committee (EAC): neurologic outcome; death, stroke, 
and stent thrombosis 
Data safety monitoring committee  
The DSMC will give advice to the Steering Committee on the 
safety aspects of the study. 
 
 
 

 
 
 
 
 
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3. SYNOPSIS OF THE TRIAL 
3.1 Primary Outcome 
The primary outcome of the study will be death or poor neurologic outcome at six months.  Neurologic 
outcome will be assessed using the Disability Ratings Scale (DRS), an 8-item ordinal scale that evaluates 
functional dependence (See Appendix 8).1  Neurologic outcome will be assessed by a specialist in rehabilitation 
medicine at six months.  Patients will be judged to have had a poor neurological outcome if the score on the DRS 
scale is >5 i.e. cannot live independently. 
 
3.2 Inclusion Criteria 
Any patient >18 years of age who is comatose (Glasgow Coma Score 8) following out-of-hospital 
cardiac arrest (OHCA) in whom the treatment plan includes therapeutic hypothermia (TH).  The University of 
Ottawa Heart Institute Therapeutic Hypothermia protocol will guide in patient selection.  However, patients will be 
recruited, irrespective of initial rhythm. 
 
3.3 Exclusion Criteria 
1. Patients residing in a Nursing Home or patients unable to reside independently,  
2. Intracranial bleed responsible for the cardiac arrest,  
3. Severe coagulopathy with clinical evidence of major bleeding,  
4. Coma that is not attributable to cardiac arrest,  
5. Pregnancy, 
6. Life expectancy of < one year due to any cause unrelated to the cardiac arrest, 
7. Known coagulation disorder (i.e. INR >2.0, platelets <100,000 / mm3), 
8. Participation in a study with another investigational device or drug < four weeks,  
9. The Endovascular cooling (ZOLL Thermogard XP) device is not available. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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3.4 Study Design                
 
 
 
             CAPITAL CHILL
Out-of-Hospital Cardiac Arrest
Resuscitated with ROSC
Glasgow Coma Score ≤ 8
Initial Rhythm 
VT / VFib
Not VT / VFib
Mild TH
34 C
Randomized 
1:1
Moderate TH
31 C
Mild TH
34 C
Randomized 
1:1
Moderate TH
31 C
 
 
 
 
 
 
 

 
 
 
 
 
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3.5 Summary 
This is a single-center, randomized, double-blind investigator initiated prospective clinical trial to be 
performed at the University of Ottawa Heart Institute (UOHI).  The patients for this study will be recruited amongst 
comatose survivors of OHCA who are admitted at the UOHI.  The aim of this study is to determine whether 
neurologic outcomes at six months are improved with moderate (31C) versus mild (34C) TH following ROSC in 
patients suffering OHCA, with ROSC defined as the resumption of sustained perfusing cardiac activity. 
The primary outcome will be the proportion of patients experiencing death or a poor neurologic outcome at six 
months after out of hospital cardiac arrest. 
 
3.6 Statistical Analyses  
3.6.1 Sample size 
A total of 340 patients will be required to detect an absolute 15% risk reduction (30% relative risk 
reduction) in the primary outcome based on an anticipated event rate of 50% in the mild hypothermia group and 
of 35% in the moderate hypothermia group using a chi-square test for comparing proportions with alpha set of 
0.05 and a power of 80%.   
 
 
 

 
 
 
 
 
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4. PROTOCOL 
4.1 Background and Rationale  
Despite many advances in cardiac care over the past decades, prognosis following out-of-hospital cardiac 
arrest (OHCA) remains poor.  Patients are often left with severe neurologic dysfunction if they survive the index 
hospitalization. 
Two pivotal trials published in the New England Journal of Medicine demonstrated improved neurologic 
outcomes in comatose survivors of OHCA who undergo therapeutic hypothermia (TH).2, 3  Bernard and 
colleagues demonstrated an improvement in neurologic function at hospital discharge, while the Hypothermia 
After Cardiac Arrest group found both favourable neurologic outcomes and a significant improvement in survival 
at 6 months post-discharge. 
Current American Heart Association/International Liaison Committee on Resuscitation guidelines 
incorporate TH as the standard of care for comatose survivors of OHCA.4  Recently, the University of Ottawa 
Heart Institute published a paper in Resuscitation demonstrating a beneficial outcome in patients referred for 
primary percutaneous coronary intervention (PCI) and TH in patients with OHCA following ST-segment elevation 
myocardial infarction.5  The use of TH (to a target temperature of 32-34 degrees) did not delay door-to-balloon 
times and neurologic benefit was seen despite the relatively slow cooling times in our retrospective cohort. 
Therapeutic hypothermia functions to reduce cerebral metabolic demands, thereby reducing both the 
hypoxic insult and suppressing chemical reactions associated with reperfusion injury.  These reactions include 
the production of free radicals, excitatory amino acid release and calcium shifts which can lead to apoptosis.6  In 
the normal brain, hypothermia reduces cerebral metabolic rate for oxygen by 6% for every 1C reduction in brain 
temperatures >28C.7 
 
Despite evidence that TH is beneficial following OHCA, there is a lack of evidence to guide the targeted 
temperature during TH.  In the two aforementioned randomized controlled trials, Bernard et al targeted a core 
temperature of 33 degrees, while the HACA group set a target core temperature of 32-34 degrees.  A recent 
retrospective review showed improved neurologic outcomes with mild hypothermia (32C-34C) compared to 
normothermia (<37.5C).8  Animal evidence suggests that even more aggressive cooling to a target temperature 
of 30C may be associated with greater neuroprotection.8, 9 
A recent pilot study by Lopez-de-Sa published in Circulation randomized 36 comatose survivors of OHCA 
to two distinct goal-cooling temperatures, 34C or 32C.8, 10  The primary outcome was survival free from severe 
dependence (Barthel Index Score ≥ 60) at 6 months.  They found no difference in the primary outcome between 
the two groups.  Subgroup analysis found that in patients with an initial shockable rhythm, those randomized to 
32C had improved outcomes compared to those assigned to the 34C target temperature.  To date, this remains 
the first and only randomized controlled trial comparing two different goal-cooling temperatures in comatose 
survivors of OHCA. Cooling was achieved using the ZOLL endovascular cooling device (ZOLL Medical 
Corporation, Chelmsford, MA USA).  This endovascular cooling device allows the treating physician to cool the 
patient rapidly to a target core body temperature with accuracy and efficiency.  The device can be programmed to 
actively rewarm the patient after the cooling period is completed.   

 
 
 
 
 
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Despite advances in cooling mechanisms and comprehensive coronary care, patients surviving OHCA 
continue to experience poor outcomes from a neurologic perspective.  The importance of TH is paramount in this 
high-risk population, and despite evidence of benefit with TH, the optimal goal temperature continues to remain 
unknown.  
Our center is the single regional cardiac referral center for Eastern Ontario – servicing a population of 
approximately 1.2 million residents.  In 2011, we established a CODE ROSC program to manage patients who 
suffer OHCA in a coordinated and timely fashion.  All patients referred to the UOHI who are comatose following 
OHCA with no identifiable etiology are candidates for TH in our coronary care unit to preserve neurologic 
function.   
 
Herein, we propose a randomized controlled trial to determine whether TH with cooling to a lower goal 
temperature is associated with improved outcomes.  We hypothesize that cooling with moderate hypothermia to a 
goal temperature of 31C will result in improved neurologic outcomes compared to mild hypothermia with a goal 
of 34C in comatose survivors of OHCA. 
Therapeutic hypothermia has been shown to improve neurologic outcomes and survival in comatose 
survivors of OHCA.  Nevertheless, outcomes remain poor with as many as 60% of patients either dying or 
surviving with significant neurologic impairment.  Despite many advances in cardiac care, these patients still 
suffer significant mortality and morbidity as a result of cardiac arrest.  Our center has a particular interest in 
cardiac arrest and the use of TH to provide neuroprotection for these patients.  In 2011, we established a “CODE 
ROSC” program in an attempt to streamline and centralize care for these patients (abstact at 2012 CCC in 
Toronto). 
Current American Heart Association/International Liaison Committee on Resuscitation guidelines 
incorporate TH as the standard of care for comatose survivors of OHCA.  These guidelines recommend a target 
temperature of 32C-34C to provide neuroprotection following cardiac arrest.  This degree of therapeutic 
hypothermia is an effective therapy (compared to placebo), improving neurologic outcomes at six months in 
comatose survivors of out-of-hospital cardiac arrest.  However, the optimal goal temperature for therapeutic 
hypothermia in these patients has not been investigated in large randomized trial.  It is possible that a further 
reduction in metabolic demand that is associated with cooler temperatures may lead to a clinically significant 
improvement in patient outcomes.  
The proposed study is designed to test the hypothesis that more profound cooling by achieving moderate 
TH will result in improved neurologic outcomes.  Our aim is to answer a clinically important question in a 
randomized, double-blinded fashion.  The trial design respects evidence from previous trials and current 
international guidelines.  We have chosen a design that is inclusive of all patients with cardiac arrest (unless 
attributable to a proven intracranial bleed) for whom the treating physician wishes to incorporate therapeutic 
hypothermia as part of the patient’s treatment plan.  While previous trials have excluded patients who presented 
with an initial rhythm of asystole or pulseless electrical activity, we have chosen to include these patients in our 
study as they are routinely treated with TH in most clinical settings.  Although there is no data on the use of TH in 
patients with an initial rhythm of asystole, we believe that these patients should be offered TH and a randomized 
trial to address the utility of this strategy in these patients.  Lastly, our protocol design allows for discontinuation of 
Commented [c1]: Reference? 

 
 
 
 
 
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cooling in patients in whom TH may be contributing to worsening clinical condition – however, data from our 
ROSC database and from the literature suggests this is an infrequent event2, 4. 
We believe that this randomized study will provide valuable clinical information for the physician and 
health care team treating comatose survivors of OHCA. 
 
4.2. Study Design  
4.2.1 Study Population  
Our proposed study is a single-center, randomized, double-blind investigator initiated prospective clinical 
trial performed at the University of Ottawa Heart Institute (UOHI).  The patients for this study will be recruited 
amongst comatose survivors of OHCA who are admitted at the UOHI.  The aim of this study is to determine 
whether neurologic outcomes at six months are improved with moderate (31C) versus mild (34C) TH following 
ROSC in patients suffering OHCA, with return of spontaneous circulation (ROSC) defined as the resumption of 
sustained perfusing cardiac activity. 
 
4.2.2 Inclusion Criteria 
Inclusion criteria will be any patient >18 years of age who is comatose (Glasgow Coma Score [GCS] 8) 
following OHCA in whom the treatment plan includes TH.  The UOHI and The Ottawa Hospital Therapeutic 
Hypothermia protocol (See Appendix 9) will guide in patient selection.  However patients will be recruited, 
irrespective of initial rhythm found at the time of the cardiac arrest. 
 
4.2.3 Exclusion Criteria 
1. Patients residing in a Nursing Home or patients unable to reside independently,  
2. Intracranial bleed responsible for the cardiac arrest,  
3. Severe coagulopathy with clinical evidence of major bleeding,  
4. Coma that is not attributable to cardiac arrest,  
5. Pregnancy, 
6. Life expectancy of < one year due to any cause unrelated to the cardiac arrest, 
7. Known coagulation disorder (i.e. INR >2.0, platelets <100,000 / mm3), 
8. Participation in a study with another investigational device or drug < four weeks,  
9. The Endovascular cooling (ZOLL) device is not available. 
 
4.2.4 Randomization 
Randomization will be performed in a 1:1 fashion by sealed opaque envelopes and treatment assigned 
by random number generation done in blocks.  Patients will be randomized immediately following insertion of the 
endovascular cooling catheter.  Because patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) 
have better survival than other rhythms10 patients will be stratified based on their initial rhythm. Patients with an 
initial rhythm of either VT or VF will be randomized from a different series of envelopes than patients with an 
initial rhythm of asystole or pulseless electrical activity (PEA). The two different series of randomization 

 
 
 
 
 
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envelopes will be identifiable and differentiable by coding (ie. VT/VF randomization codes will begin by the 
number 1, while randomization codes for asystole/PEA will begin by the number 2). This will ensure balancing in 
the groups in this important prognostic factor. 
 
4.2.5 Blinding 
The treating physician and patient will be blinded to group allocation.  The only member of the health 
care team who is not blinded will be the treating nurse as temperature adjustments on the cooling catheter will be 
performed by the nurse as per protocol. Nurses will chart temperature in a separate log, as per usual. This log, 
however, will be kept in the patient’s room and will not be a part of the medical records that the physician has 
routine access to. Randomization documents will be collected by nurses and or the study coordinator to ensure 
blinding.  
Outcomes will be adjudicated by an independent, blinded committee.  Cardiologists performing the 
follow-up assessments will be blinded.  Rehabilitation physicians performing the cognitive assessments will be 
blinded to group allocation. 
 
4.2.6 Participation Consent 
This study, complies with the Tri-Council Policy Statement 2 (TCPS 2) guidelines from Chapter 3, 
Sections 3.8, 3.9 and 3.10. for obtaining proper consent from the participants and or from their authorized third 
party. 
 
4.3 Interventions 
Eligible patients will be randomized to mild TH (goal cooling temperature of 34C) or moderate TH (goal 
cooling temperature of 31C).  The rate of cooling to the signed temperature after randomization will be on the 
basis of as fast as technically feasible by the device.  Cooling will be performed via an endovascular cooling 
device (ZOLL Medical Corporation, Chelmsford, MA) inserted via the femoral vein into the inferior vena cava 
either in the cardiac catheterization laboratory or in the coronary care unit.  Our current practice is to target 33C 
with the identical protocol.  Paramedics and transferring facilities will be encouraged to initiate hypothermia with 
ice packs as soon as possible (prior to arrival at the University of Ottawa Heart Institute).  This is done by placing 
ice packs to the neck, groin and axilla.  
Upon presentation to the University of Ottawa Heart Institute, patients may be taken to the cardiac 
catheterization laboratory at the discretion of the treating team for coronary angiography and/or insertion of a 
mechanical support device (intra-aortic balloon pump).  
All patients will be sedated, intubated and ventilated.  The University of Ottawa Heart Institute standard 
cooling protocol will be used to implement sedation, analgesia and neuromuscular blockade.  Paralytic agents will 
be used during the cooling process to inhibit shivering.  All of these medications and monitoring are currently the 
standard of care.  The temperature will be recorded via the ZOLL catheter.  Patients will have nasopharyngeal 
and bladder temperature probes inserted to correlate with temperatures monitored intravascularly.   

 
 
 
 
 
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Patients who present to the Ottawa Heart Institute with body temperatures <34C can still be randomized 
to one of the groups.  The temperature will be adjusted with the endovascular cooling device according to the 
randomly assigned temperature.  Note that the device is capable at cooling or warming to the set target 
temperature.   
Patients will be maintained at their assigned cooling temperature for a duration of 24 hours after reaching 
target temperature.  Following the mandated 24-hour cooling period, patients will be actively re-warmed at a rate 
of 0.25C/hour until normothermia (36.5C) is reached.  Normothermia will be maintained for 48 hours from the 
time of initiation of re-warming with active management of the temperature via the ZOLL catheter.  This is the 
current standard of practice at the University of Ottawa Heart Institute.  
If, in the opinion of the blinded treating physician, cooling is contributing to intractable arrhythmia, or 
hypotension refractory to vasopressor use, then the treating physician may choose to abandon cooling.  In this 
situation the temperature of the patient will be increased by 3C (i.e. from 31C to 34C or from 34C to 37C).  
The treating physician will remain blinded to group allocation.  If, despite the increased temperature, it is believed 
that cooling is still contributing to significant  adverse events, the physician can request to raise the temperature 
again (34 to 37C and if at 37C then no change will be made).  Blinding will be maintained. 
The patient’s dedicated nurse will perform all temperature changes on the ZOLL machine.  The nurse is 
the only member of the health care team that is unblinded to group allocation – for logistical reasons, blinding of 
the nurse is not feasible. 
Aside from the difference in cooling temperatures, management in the coronary care unit and 
subsequently on the cardiology wards will be standard of care.  Again, both the treating physicians and the 
patient will be blinded to treatment allocation to ensure assessment of outcomes remains unbiased. 
 
4.4 Laboratory Assessments 
Total creatinine kinase (CK) and troponins will be assessed on admission and q8h x 24 hrs.  A complete 
blood count (CBC) will be obtained immediately upon admission and repeated daily x3, and thereafter as 
indicated.  A CBC will be repeated anytime that there is evidence of overt bleeding.  Initial blood work will include 
electrolytes and serum creatinine and repeated daily x3.  An ECG will be done immediately after a PCI, and daily 
x3.  An ejection fraction will be obtained within 1 week of admission and at 90 days.  This can be obtained by 
echocardiography, radionuclear imaging (LV Gated scan) or by magnetic resonance imaging (MRI).  The imaging 
at 90 days should be the same imaging modality as was used initially. 
 
4.5 Discovery of Novel Biomarkers - Blood Samples 
The purpose of the blood samples is to screen for potential biomarkers of prognosis in patients 
presenting with ROSC undergoing TH. To screen for identification of potential biomarkers 50 patients will be 
enrolled. Because of the need to process blood samples promptly, the first 50 patients presenting during regular 
working hours will be selected. Blood samples will be drawn at baseline, 12hrs, 24hrs, 48 hrs and 72hrs for a total 
of 5 samples. Each sample will be 5cc's and they will be drawn by the patient’s nurse from the established 
cooling catheter thus requiring no additional venipuncture. Study co-investigators will be responsible for obtaining 

 
 
 
 
 
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blood samples from the nurses and processing the blood samples. In total, 25 cc's of blood will be drawn per 
patient. Therefore, a total of 1250 cc’s of blood will be drawn in the context of this study.   
 
Samples will be stored in the designated locked laboratory at the University of Ottawa Heart Institute for a 
period of one year at -80 degrees celsius. Samples will be de-identified by a number and linked to a password 
protected master list maintained on the University of Ottawa Heart Institute server and or secure network server.  
  
Once samples from 50 patients have been collected we will screen for biomarkers of poor neurologic 
outcome (the primary outcome of the study) using unbiased screening technology. Specifically, we will screen 
serum levels of proteins using proteomics techniques which enable us to identify proteins with distinctly different 
levels between the groups. Secondarily, we will screen for levels of circulating microRNA which may predict poor 
neurologic outcome. No genetic testing will be performed on the samples. 
  
The goal of these studies is to identify previously unidentified markers of poor prognosis in ROSC 
patients which are needed to prognosticate outcomes at an early stage of their presentation. 
 
4.6 Follow-up 
Patients will be assessed by a cardiologist at the following time intervals – 1, 3, 6 months after the 
cardiac arrest.  Patients will be seen by the rehabilitation specialist at 6 months after the cardiac arrest.  Current 
standard of care for follow-ups for this population is for patients to be seen by a cardiologist at 1 and 6 months. 
However, if deemed to be necessary the cardiologist may decide to see a patient at a higher frequency. Follow-
up with the rehabilitation specialist is likely to be done at 6 months but is determined on a case by case basis.  
 
4.7 Pre-specified subgroups 
The following pre-specified subgroups will be analyzed at the end of the study: 
1. Ventricular tachycardia or ventricular fibrillation as initial rhythm 
2. ST segment elevation myocardial infarction as index event 
3. Patients taken to the cardiac catheterization laboratory  within 12 hrs of the cardiac arrest event 
4. Patients undergoing percutaneous coronary intervention 
5. Patients age >75yrs 
 
5. STUDY OUTCOMES 
5.1 Primary Outcome 
The primary outcome of the study will be death or poor neurologic outcome at six months.  Neurologic 
outcome will be assessed using the Disability Ratings Scale (DRS), an 8-item ordinal scale that evaluates 
functional dependence.11  The DRS has both reliability and validity in the assessment of neurologic function 
following traumatic and acquired brain injury.1, 8  Neurologic outcome will be assessed by a specialist in 
rehabilitation medicine.  Patients will be judged to have had a poor neurologic outcome if the score on the DRS 
scale is >5. 
 

 
 
 
 
 
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5.2 Secondary Outcomes 
1) Death during the initial hospitalization, at 30 days and at 6 months  
2) Stroke during the initial hospitalization, and at 6 months 
3) TIMI minor/major bleeding during first hospitalization (+7 days) 
4) Length of stay in the unit 
5) Length of stay in the hospital 
6) Cardiogenic shock during the initial hospitalization 
7) Repeat circulatory arrest requiring cardiopulmonary resuscitation (CPR) 
8) Arrhythmia requiring anti-arrhythmic medication (aside from beta blocker) 
9) Presence of seizures 
10) Renal failure requiring renal replacement therapy  
11) Ventilator associated pneumonia 
12) LV function assessed by echo done on day 3 and at 90 days 
13) CK release within first 48 hrs: 
14) Frequency of Stent thrombosis 
15) Discharged home. 
 
All clinical events will be adjudicated by a committee utilizing the abovementioned definitions in a blinded manner. 
As noted, rehabilitation physicians performing the neurologic assessments will be blinded to group allocation. 
 
6. DEFINITION OF STUDY OUTCOMES 
6.1 Poor Neurological outcome 
Defined as a DRS score > 5 (See Appendix 8). 
 
6.2 Bleeding 
Defined as TIMI minor or major (See Appendix 7). 
 
6.3 Stroke 
A neurologic injury occurring as a result of a disease process involving one or more of the blood vessels 
of the brain, i.e. atherosclerosis, dissection, thrombus, embolism, decreased perfusion pressure resulting in 
inadequate blood flow, vessel rupture associated with intracranial haemorrhage.  Strokes will be classified as 
hemorrhagic or non-hemorrhagic with duration > 24 hrs. 
 
6.4 Cardiogenic Shock 
Systolic blood pressure < 80 mm Hg not responding to fluid expansion, and requiring the use of 
intravenous inotropic support or the use of intra-aortic balloon counterpulsation. 
 
 

 
 
 
 
 
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6.5 Stent Thrombosis According to Academic Research Consortium (ARC) 
The Academic Research Consortium (ARC) of academic investigators, regulators, and industry 
representatives has proposed definitions to serve as standard criteria for stent thrombosis for the comparison of 
event rates across different trials and studies. 11  
 
Stent thrombosis was classified as:  
 
1) Acute if it occurred within 24 hours after the index procedure,  
2) Subacute if it occurred between 1 and 30 days after,  
3) Late if it occurred between 31 days and 1 year after, and  
4) Very late if it occurred more than 1 year after the procedure.  
 
Stent thrombosis was then classified as definite, probable, or possible.  
 
Definite stent thrombosis required the presence of an acute coronary syndrome with angiographic or 
autopsy evidence of thrombus or occlusion.  
 
 
Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute 
myocardial infarction involving the target-vessel territory without angiographic confirmation.  
 
Possible stent thrombosis included all unexplained deaths occurring at least 30 days after the procedure.  
 
Intervening target lesion revascularization was defined as any repeated percutaneous revascularization 
of the stented segment, including the 5-mm proximal and distal margins that preceded stent thrombosis.  
 
6.6 PCI Procedural Success 
PCI procedural success is defined as the achievement of TIMI grade 3 flow with < 30% residual stenosis 
by visual estimate. 
 
7. STATISTICAL AND ANALYTICAL METHODS 
All analyses on the primary outcome and its components will be performed on an intention-to-treat. The 
primary outcome will be compared between treatment arms using a significance level of 5% and a power of 80%.  
Secondary outcomes will be examined using parametric or non-parametric statistics as appropriate for the scale 
of measurement of the dependent variables.  Analyses will be conducted using SAS. 
 
7.1 Hypothesis Testing 
Primary and secondary efficacy parameters will be evaluated for treatment-associated differences 
between the two groups.  The null hypothesis states that there will be no between treatment difference.  The 

 
 
 
 
 
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alternate hypothesis states that moderate TH will be significantly more effective than the mild TH at reducing the 
number of primary outcome events at six months. 
 
7.2 Efficacy Analysis 
All participants, who receive study treatment, will be included in the analyses according to their initial 
randomization group, i.e. intention to treat analysis.  No interim analysis is planned. 
 
7.3 Comparability of Patient Groups 
Descriptive statistics will be used to evaluate the comparability of patients randomized to either group 
with respect to age, gender, cardiovascular history, functional capacity, medications and interventions 
administered in hospital, and course in hospital. 
 
8. SAMPLE SIZE 
8.1 Sample Size 
Outcome measures for all randomized patients will be analyzed in an intention-to-treat analysis.  The 
primary outcome of our study will be a composite of 1) death or 2) poor neurologic outcome, at 6 months.  Based 
on our review of the literature and our own cardiac arrest database we estimate an event rate of 50% in the mild 
TH group.  To detect a 30% relative risk reduction with 80% power and a type I error of 5% will require a sample 
size of 340 patients (170 per temperature group). 
 
9. DATA QUALITY ASSURANCE 
The DSMC will consist of one chairperson and two members, all external and not directly involved with 
the study.  One member will be a qualified biostatistician/methodologist.  The DSMC will review the data from the 
study at regular intervals and determine if it is safe to continue the study according to the protocol.  The DSMC 
will have access to all available data from the study throughout the study duration. All Serious Adverse Events 
(SAEs), including deaths, will be reported immediately to the DSMC.  The purpose of the DSMC will be primarily 
safety and no formal analysis will be done on major outcomes. 
 
10. STUDY COMMITTEES 
10.1 Steering Committee  
The steering committee, chaired by the principal investigator, will have the responsibility of overseeing 
the scientific conduct of the study.  Members are listed in Appendix 3. 
 
10.2 Clinical Event Adjudication Committee 
The adjudication committee will consist of a chairperson and two members.  Members will not be 
investigators or co-investigators.  The committee will adjudicate the following events on a regular basis: 1) death, 
2) 6 month neurological outcome results according to the DRS, 3) stroke, and 4) stent thrombosis.  Members will 
be provided with relevant physician and nurses' notes, ECGs and laboratory test results.  The research 

 
 
 
 
 
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coordinator will mask the treatment group before providing documentation.  The adjudication committee will 
perform the verification of clinical outcomes in a blinded manner and the statistician will perform a blinded 
analysis. 
 
10.3 Data and Safety Monitoring Committee (DSMC) 
The DSMC will consist of one chairperson and two members, all external and not directly involved with 
the study.  One member will be a qualified biostatistician/methodologist.  The DSMC will review the data from the 
study at regular intervals and determine if it is safe to continue the study according to the protocol.  The DSMC 
will have access to all available data from the study throughout the study duration.  All Serious Adverse Events 
(SAEs), including deaths, will be reported immediately to the DSMC.  The purpose of the DSMC will be safety.  
 
11. ANALYSIS OF DATA 
Statistical analysis will be performed under the supervision of Dr. George Wells in the Methods Center at 
the University of Ottawa Heart Institute. 
 
12. ASSESSMENT AND REPORTING OF ADVERSE EVENTS 
12.1 Definition of an Adverse Event (AE) 
An adverse event is any untoward medical occurrence or unfavourable and unintended sign in a subject 
administered a pharmaceutical product/biologic (at any dose), or medical device, whether or not considered 
related to the use of that product. Additionally, any event that is associated with or observed in conjunction with a 
product overdose (whether accidental or intentional) or a product abuse and/or withdrawal is also considered an 
adverse event. 
 
12.2 Definition of Serious Adverse Events (SAE) 
A serious adverse event is any adverse drug or biologic or device experience occurring at any dose that results in 
any of the following outcomes: 
1) Death 
2) life-threatening adverse event (i.e., one that places the subject, in the view of the initial reporter, at 
immediate risk of death from the adverse event as it occurs) 
3) persistent or significant disability/incapacity 
4) required in-patient hospitalization, or prolonged hospitalization 
5) congenital anomaly or birth defect 
 
12.3 Expedited Reporting of Serious Adverse Events 
All serious adverse events, whether or not deemed drug-related or expected, must be reported by the 
principal investigator or designee to the Human Research Ethics Board and to the Data and Safety Monitoring 
Committee (DSMC) within 24 hours (one working day) of first becoming aware of the event.  Serious adverse 
events that occur at any time after the inclusion of the subject in the study (defined as the time when the subject 
Commented [c2]: Specify 

 
 
 
 
 
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signs the informed consent) up to 6 months after the subject completed or discontinued the study must be 
reported.  The subject is considered to have completed the study either after the completion of the last visit or 
contact (e.g., phone contact with the investigator or designee), OR after the last dose of the study medication, 
whichever is later.  The date of discontinuation is when a subject and/or investigator determines that the subject 
can no longer comply with the requirements for any further study visits or evaluations.  
 
12.4 Reporting of Subject Death 
The death of any subject during the study regardless of the cause will be reported to the Data and Safety 
Monitoring Committee (DSMC) within 24 hours of first becoming aware of the death.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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13.1     APPENDIX 1: INVESTIGATORS 
 
 
University of Ottawa Heart Institute       
 
 
Principal Investigator 
 
Michel Le May, MD 
 
 
Co-Investigators 
 
Ronnen Maze, MD 
 
Benjamin M Hibbert, MD  
 
Marino Labinaz, MD  
 
Alexander Dick, M.D. 
 
 
Jean-François Marquis, M.D.  
 
 
 
 
Christopher Glover, MD 
 
Michael Froeschl, MD  
 
 
 
 
Derek So MD  
 
Shawn Marshall, MD 
 
Ali Pourdjabbar, MD 
 
George Wells, Ph.D (Statistical Analyst) 
 
 
 
Research Coordinator 
 
       
Christina Osborne, B.Sc. 
 
 
 
 

 
 
 
 
 
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13.2     APPENDIX 2: ELIGIBILITY SCREENING FORM 
 
 
SCREENING DATE: _______________ 
 
 
ELIGIBILITY SCREENING FORM 
 
Before entering a subject into the study, all of the following items must be completed.  If any of the items are 
indicated “No”, the subject is not eligible for enrolment. 
INCLUSION CRITERIA 
Yes 
No 
 
Out of Hospital Cardiac Arrest,  
 
 [   ] 
[   ] 
 
 
 
and 
Glasgow Coma Score   8 
 
 
 
 
 
 
 
[   ] 
[   ] 
 
 
 
 
and 
Return of Spontaneous Circulation 
 
 
 
 
 
 
[   ] 
[   ] 
 
Before entering a subject into the study, all of the following items must be completed.  If any of the items are 
indicated “Yes”, the subject is not eligible for enrolment. 
 
EXCLUSION CRITERIA 
 
 
 
 
 
 
 
YES 
NO 
 
1. Age <18 years   
 
 
 
 
 
 
 
[   ] 
[   ] 
 
2. Pregnancy   
 
 
 
 
 
 
 
 
[   ] 
[   ] 
 
3. Patients residing in a Nursing Home or patients unable to reside independently    [   ] 
[   ] 
 
4. Intracranial bleed responsible for the cardiac arrest   
 
 
 
[   ] 
[   ] 
 
5. Severe coagulopathy with clinical evidence of major bleeding 
 
 
[   ] 
[   ] 
 
6. Coma that is not attributable to cardiac arrest 
 
 
 
 
[   ] 
[   ] 
 
7. Life expectancy < one year due to cause unrelated to the cardiac arrest.  
[   ] 
[   ] 
 
8. Known coagulation disorder (i.e. INR >2.0, platelets <100,000 / mm3) 
  
[   ] 
[   ] 
 
9. Participation in a study with another investigational device or drug < four weeks  [   ] 
[   ] 
 
10. The Endovascular cooling (ZOLL) device is not available  
 
 
[   ] 
[   ] 
 
 
 
 
Will the subject participate in this trial? 
Yes [   ]    Randomization Number:  
 
 
  
 
 
 
 
No   [   ]   Reason: 
 
 
 
Investigator’s Signature:                            Date:  ____/____/____    (yr    mo    day)      

 
 
 
 
 
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13.3     APPENDIX 3: THE STEERING COMMITTEE 
 
Michel Le May (Chairman)  
University of Ottawa Heart Institute  
George Wells 
 
 
University of Ottawa Heart Institute 
Ronnen Maze   
 
University of Ottawa Heart Institute  
Ben Hibbert  
 
 
 
University of Ottawa Heart Institute 
Shawn Marshall   
 
 
Ottawa Hospital 
 
 
 
 

 
 
 
 
 
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13.4     APPENDIX 4: SAFETY AND LABORATORY TESTS 
 
Adverse Events and Laboratory Abnormalities 
Clinical Adverse Events 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.  An Adverse Event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  Pre-existing conditions that worsen during a study 
are to be reported as Adverse Events.  
All clinical adverse events (AEs) encountered during the clinical study will be reported on the AE page of 
the Case Report Form (CRF).  Intensity of adverse events will be graded on a four -point scale (mild, moderate, 
severe, life-threatening) and reported as indicated on the CRF.  Relationship of the adverse event to the 
treatment should also be assessed.  
 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the CRF.  Laboratory test value 
abnormalities as such should not be reported on the AE page of the CRF as adverse events unless they result in 
a clinically relevant condition. 
 
Serious Adverse Events (SAE) 
Please refer to Section 12 of the Protocol. 
 
Treatment and Follow-up of Adverse Events  
Adverse events will be followed up until they have returned to baseline status or stabilized. 
   
 
 
 
 
 
 
 

 
 
 
 
 
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13.5     APPENDIX 5: ETHICAL ASPECTS 
 
Independent Ethics Committees/Institutional Review Board   
Approval from the committee will be obtained before starting the study, and will be documented in a letter 
to the investigator specifying the date on which the committee met and granted the approval.  Any modifications 
made to the protocol after receipt of the Independent Ethics Committee approval will also be submitted by the 
investigator to the Committee in accordance with local procedures and regulatory requirements. 
 
Investigator's Files / Retention of Documents 
For each patient enrolled, a CRF must be completed and signed by the principal investigator or 
authorized delegate from the study staff.  This also applies to records for those patients who fail to complete the 
study.  If a patient withdraws from the study, the reason must be noted on the CRF.  If a patient is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.  The investigator should ensure the accuracy, completeness, legibility and timeliness of the data in the 
CRFs and in all required reports. 
Documents will be kept for a period of 25 years after the study has been completed. This is in 
accordance to Health Canada. At the end of the retention period, all paper records will be disposed of in 
confidential waste or shredded, and all electronic records will be deleted. 
 
Confidentiality of Trial Documents and Subject Records 
Patients will be randomly assigned to treatment according to a prepared randomization schedule. The 
subject randomization numbers will be generated by the Investigator and will include balanced blocks for each 
study center.  Sets of patient numbers and associated treatment(s) will be provided to the investigators in sealed 
opaque envelopes.  The patient randomization numbers/envelopes are to be allocated sequentially in the order in 
which the subjects are enrolled. 
 
 
 
 
 
 

 
 
 
 
 
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13.6     APPENDIX 6: SCHEDULE OF ASSESSMENTS AND PROCEDURES  
 
Boxes marked with an X show what will happen at each visit. 
 
Visit
Screening/
Randomization
Day 1
In-Hospital 
Day 2
In-Hospital
Day 3
Cardiologist
Visit 1
(1 month)
Cardiologist
Visit 2
(3 month)
Cardiologist
Visit 3
(6 month)
Rehabilitation 
Specialist
(6 month)
Length of time 
needed
30 minutes
N/A
N/A
1 hour
1 hour
1 hour
1 hour
Written informed 
consent
x
Medical History
x
x
x
x
x
Vital Signs
x
x
x
x
x
Physical 
examination
x
x
x
x
x
Routine 
Hematology
x
x
x
Routine Blood 
Chemistry
x
ECG
x
x
x
LV Function Test
x
x
Endovascular 
Cooling Device
x
x
x
Study Blood 
Sample Collection
x
x
x
Review of 
Medications
x
x
x
x
x
Neuro-
Psychological 
Assessment
(Disability Rating 
Scale)
x
Clinical 
Outcomes/ 
Endpoints
x
x
x
x
 
 
 
 
 

 
 
 
 
 
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13.7     APPENDIX 7: TIMI BLEEDING DEFINITION 
 
Types of TIMI Bleeding 
1. Major:  
• 
Any intracranial bleeding or;  
• 
Clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥ 5 g/dL. (or, 
when Hgb is not available, an absolute drop in hematocrit (Hct) of ≥15%). 
2.  Minor: 
• 
Any clinically overt signs of hemorrhage (including imaging) that is associated with a fall in Hgb of 3 
to < 5 g/dL (or, when Hgb is not available, a fall in Hct of 9 to b15%). 
3. Needing medical attention 
• 
Any overt sign of hemorrhage that requires medical evaluation, medical treatment (including 
discontinuation of medications), or surgical treatment, and that does not meet criteria for a major or 
minor bleeding event, as defined above.  
4. Minimal 
• 
Any overt bleeding event that does not meet the criteria above 
NOTE: To account for transfusions, Hgb measurements will be adjusted for any packed red blood cells (PRBCs) 
or whole blood given between baseline and post-transfusion measurements.  A transfusion of one unit of blood 
will be assumed to result in an increase by 1 gm/dL in Hgb.  Thus, to calculate the true change in hemoglobin, if 
there has been an intervening transfusion between two blood measurements, the following calculations should be 
performed: ∆ Hgb = [Baseline Hgb – Post transfusion Hgb] + [# transfused units]. 
 
TIMI Clinically Significant Bleeding: 
The presence of either TIMI major or TIMI minor bleeding, or bleeding requiring medical attention. 
For patients experiencing a hemorrhage that occurs as a result of CABG, the following criteria will be used: 
 
5. Bleeding in the Setting of Coronary Artery Bypass Graft Surgery (CABG) 
Minor and minimal bleeding are not adjudicated in the setting of CABG 
As a drop in hemoglobin and transfusions are commonplace in routine CABG cases, one of the following 
criteria must be met to qualify for major bleeding in any of the preceding definitions:  
• 
Fatal bleeding (i.e., bleeding that directly results in death)  
• 
Perioperative intracranial bleeding*  
• 
Reoperation following closure of the sternotomy incision for the purpose of controlling bleeding  
• 
Transfusion of ≥ 5 units of packed red blood cells (PRBCs) or whole blood within a 48 hour period. 
Cell saver transfusion will not be counted in calculations of blood products  
• 
Chest tube output > 2 L within a 24 hour period  

 
 
 
 
 
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*In light of the increased sensitivity of brain imaging for microhemorrhages of uncertain clinical significance, brain 
imaging with an incidental finding of microhemorrage in the absence of associated clinical symptoms/ findings will 
not be considered to meet the protocol definition of intracranial hemorrhage. 
 
Relationship of Bleeding to Death 
Fatal Bleeding 
Death in which a bleeding event directly led to death within 7 days. Examples of fatal bleeding events are an 
intracranial hemorrhage that led to herniation of the brain and death within 24 hours, and a massive 
gastrointestinal hemorrhage that results in shock, hemodynamic collapse, and death. If a bleeding event is 
considered fatal, then the cause of death must be either intracranial or non-intracranial bleeding.  
 
Bleeding Contributed to Death 
Death in which a bleeding event was part of a causal chain of medical events that ultimately led to death within 
30 days of the bleed, but bleeding was not directly and/or immediately related to the subject’s death. An example 
of bleeding contributing to death is a large retroperitoneal bleed that leads to surgical evacuation, development of 
a subsequent abscess in the area of bleeding that leads to sepsis, multiorgan failure, and death 10 days after the 
onset of bleeding. If bleeding has contributed to death (but the bleeding was not categorized as “fatal”), then the 
cause of death must be recorded as something other than intracranial / non-intracranial bleeding.  

 
 
 
 
 
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13.8     APPENDIX 8 – THE DISABILITY RATING SCALE (DRS) 
 

 
 
 
 
 
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13.9     APPENDIX 9 – 
THE UNIVERSITY OF OTTAWA HEART INSTITUTE AND 
THE OTTAWA   HOSPITAL THERAPEUTIC HYPOTHERMIA PROTOCOL 
 
 
 

 
 
 
 
 
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14.     REFERENCES 
 
 
(1)  Gouvier WD, Blanton PD, LaPorte KK, Nepomuceno C. Reliability and validity of the Disability Rating 
Scale and the Levels of Cognitive Functioning Scale in monitoring recovery from severe head injury. Arch 
Phys Med Rehabil 1987 February;68(2):94-7. 
 
(2)  Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002 
February 21;346(8):549-56. 
 
(3)  Bernard SA, Smith K, Cameron P et al. Induction of therapeutic hypothermia by paramedics after 
resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. 
Circulation 2010 August 17;122(7):737-42. 
 
(4)  Peberdy MA, Callaway CW, Neumar RW et al. Part 9: post-cardiac arrest care: 2010 American Heart 
Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. 
Circulation 2010 November 2;122(18 Suppl 3):S768-S786. 
 
(5)  Maze R, Le May MR, Hibbert B et al. The impact of therapeutic hypothermia as adjunctive therapy in a 
regional primary PCI program. Resuscitation 2012 August 21. 
 
(6)  Colbourne F, Sutherland G, Corbett D. Postischemic hypothermia. A critical appraisal with implications 
for clinical treatment. Mol Neurobiol 1997 June;14(3):171-201. 
 
(7)  Steen PA, Newberg L, Milde JH, Michenfelder JD. Hypothermia and barbiturates: individual and 
combined effects on canine cerebral oxygen consumption. Anesthesiology 1983 June;58(6):527-32. 
 
(8)  Horburger D, Testori C, Sterz F et al. Mild therapeutic hypothermia improves outcomes compared with 
normothermia in cardiac-arrest patients--a retrospective chart review. Crit Care Med 2012 
August;40(8):2315-9. 
 
(9)  Leonov Y, Sterz F, Safar P, Radovsky A. Moderate hypothermia after cardiac arrest of 17 minutes in 
dogs. Effect on cerebral and cardiac outcome. Stroke 1990 November;21(11):1600-6. 
 (10)  Lopez-de-Sa E, Rey JR, Armada E et al. Hypothermia in comatose survivors from out-of-hospital cardiac 
arrest: pilot trial comparing 2 levels of target temperature. Circulation 2012 December 11;126(24):2826-
33. 
 (11)  Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized 
clinical trials of drug-eluting stents. N Engl J Med 2007 March 8;356(10):1020-9.