Introduction
Survival after out-of-hospital cardiac arrest is poor. Studies in animal models of cardiac arrest demonstrate enhanced myocardial perfusion and vital organ blood flow when using the ITD. Studies in humans with out-of-hospital cardiac arrest demonstrated that the ITD increased systolic blood pressure and tended to improve short-term clinical outcomes without any adverse effects. A large trial is required to demonstrate whether ITD significantly improves survival and functional status. Evaluation of the effect of ITD requires monitoring whether CPR process is consistent with currently recommended methods of resuscitation.

The most treatable arrhythmias immediately following cardiac arrest are VF and PVT. Current ACLS algorithms emphasize the importance of immediate defibrillation attempts in these patients. While it has been recognized for many years that chest compressions on Out-of Hospital Cardiac Arrest (OOH-CA) patients who received "bystander CPR" result in positive outcomes,(66) this impact has been relegated to a secondary or even tertiary role in resuscitation sequencing. Small randomized or observational studies suggest that CPR before defibrillation may increase survival but the results to date are inconclusive. Although there is some evidence that favors immediate defibrillation in cases where the response time is < 2 minutes, such response times are rare and the frequent delay in recognition of the OOH-CA and calling 911, as well as the complexity of the resuscitation protocol, convince us that response time should not be used as an intervention modifier. We believe that there is clinical equipoise with regard to the competing strategies of Analyze Early vs. Analyze Later. A large, randomized clinical trial is needed to examine the impact of delayed defibrillation on survival to hospital discharge in patients who are presumed to be without circulation for several minutes. Since the only cost of the intervention is training or retraining providers, the proposed study has the potential to have substantial impact upon prevention of premature cardiac death at comparatively little cost.

Aims of Study
The main aims of this trial are to compare survival to hospital discharge with an acceptable neurological status, between standard CPR plus active impedance threshold valve/device (ITD) compared to standard CPR plus sham (non-active) ITD in patients with out-of-hospital cardiac arrest. These same comparisons will be made using a strategy of Analyze Later versus a strategy of Analyze Early.

ITD
For the active ITD vs. the sham ITD, the null hypothesis is that survival to hospital discharge with modified Rankin score <3 is identically distributed with use of standard CPR plus active ITD versus standard CPR plus sham ITD in patients with cardiac arrest. The secondary null hypotheses are that survival to discharge, functional status at discharge and at 1, 3 and 6 months after discharge as well as depression at 3 and 6 months will be identically distributed with use of standard CPR plus active ITD versus standard CPR plus sham ITD in patients with cardiac arrest.

Analyze Early vs Analyze Later
For the Analyze Early vs. Analyze Later arm, the null hypothesis is that survival to hospital discharge with modified Rankin score < 3 is identically distributed between Analyze Later versus Analyze Early in patients with cardiac arrest. The secondary null hypotheses are that survival to discharge, functional status at discharge and at 1, 3 months and 6 months as well as depression at 6 months will be identically distributed between Analyze Later versus Analyze Early in patients with cardiac arrest.

Study Design
The trial will be factorial with one intervention based on a double-blind randomization of individuals through the use of an active versus a sham ITD (identical to the user), and the other intervention based on non-blinded randomized clusters.

ITD
This randomized trial will evaluate manual CPR with either an active or sham ITD in adult patients with out-of-hospital cardiac arrest. Randomization will occur through use of a study ITD that is constructed such that the sham and active valves are indistinguishable. The intervention will be implemented by the first qualified provider to arrive at the scene of cardiac arrest and continued by subsequent providers in all ROC sites. The first qualified providers will most often be EMT-certified responders but will also include responders able to mechanically ventilate the patient using either a bag-mask or an advanced airway. Ventilation rates will be consistent with AHA guidelines.

Analyze Early VS Analyze Later
This protocol will be a single-blinded (i.e. blinded to data management team) cluster randomized controlled trial with two intervention groups: a) an Analyze Early group, and b) Analyze Later group. Subjects in the Analyze Early group will be assigned to receive 50 (or more) compressions of CPR prior to early ECG analysis and defibrillation shocks if indicated and those in the Analyze Later group will receive compressions equivalent to approximately 3 minutes of CPR prior to ECG analysis and rescue defibrillation. The intervention will be implemented by the first qualified provider to arrive at the scene of cardiac arrest and continued by subsequent providers in all sites ROC sites. Qualified providers are defibrillation-capable first-responders, emergency medical technicians (EMTs), and paramedics.

We will include all out-of-hospital locations within the participating study communities within the Resuscitation Outcomes Consortium. Outcomes will be assessed in the field and at the receiving hospitals.

Inclusion/Exclusion Criteria
Persons aged 18 years or more (or local age of consent) who suffer non-traumatic cardiopulmonary arrest outside of the hospital in the study communities who receive defibrillation and/or chest compressions by EMS providers dispatched to the scene and do not meet any of the exclusion criteria below. Note: The etiology will be presumed to be nontraumatic in origin unless the apparent cause is due to trauma, drowning, electrocution, or exsanguination.

Patients enrolled in the ITD portion of the study must also meet the following criteria:

• Not have experienced cardiac arrest secondary to drowning, electrocution, or strangulation;
• Have a response time (time from 911 call to time of arrival of ROC EMS providers at scene) less than 15 minutes, and
• Have the device actually applied.

Common Exclusion Criteria

• Do not attempt resuscitation (DNAR) orders;
• Blunt, penetrating, or burn-related injury;
• Patients with exsanguinations;
• Known prisoners;
• Known pregnancy.

ITD Exclusion Criteria

• Tracheostomy present.
• CPR performed with any mechanical compression device (e.g. AutoPulse, Thumper, ACD-CPR).
• Ventilated with a mechanical device (e.g. automated transport ventilator). Note: a bag-mask is not considered a mechanical ventilator device.
• A non-ROC EMS agency/provider, for whom time call received at dispatch cannot be obtained, began CPR or placed pads.

Analyze Later Exclusion Criteria

• EMS witnessed arrests;
• Non-EMS rhythm analysis (AED placed by police or lay responder);
• Non-ROC EMS agency/provider on scene and began CPR or placed pads.

Informed Consent & Information Sheet
This study qualifies for exception from informed consent required for emergency research as outlined in FDA regulation 21CFR50.24 and tri-council policy article 2.8. The study intervention needs to be administered quickly following the onset of cardiac arrest. In this uncontrolled setting the patient is unconscious. As a result, the patient is unable to provide consent for study enrollment. Legal next-of-kin are often not immediately available at the scene, nor is it practical for the prehospital provider to explain the study and receive consent while caring for a patient in cardiac arrest. Taken together, these issues provide sufficient support for an exception from consent in order to evaluate an intervention that may have significant outcome benefits to this patient population. We shall notify patients enrolled under waiver of consent for emergency research as quickly as feasible, and seek consent from those who survive to discharge for ongoing participation.

• ROC PRIMED Training Video (37 MB WMV)
• ROC Cardiac Arrest protocol - amended 28-Dec-2008
• CPR Process Measures
• Salient CPR References
  • Influence of Cardiopulmonary Resuscitation Prior to Defibrillation in Patients with Out-of-Hospital Ventricular Fibrillation, Cobb, et al. JAMA 1999, Apr 7;281(13):1182-8.
  • Combination Pharmacotherapy with Delayed Countershock vs Standard Advanced Cardiac Life Support after Prolonged Ventricular Fibrillation, Menegazzi et al. Prehosp Emerg Care 2000 Jan-Mar;4(1):31-7.
  • Interruption of Cardiopulmonary Resuscitation with the Use of the Automated External Defibrillator in Out-of-Hospital Cardiac Arrest, van Alem et al. Ann Emerg Med 2003 Oct;42(4):449-57.
  • Delaying Defibrillation to Give Basic Cardiopulmonary Resuscitation to Patients with Out-of-Hospital Ventricular Fibrillation, Wik et al. JAMA 2003 Mar 19;289(11):1389-95.

OHRI members:

Cathy Clement
Jane Banek
Jennifer Brinkhurst
Ghislaine Lepage
Stan Morrow
Connor Sheehan