What is cardiac arrest and how is it treated?

Cardiac arrest is the loss of detectable pulses and can be caused by a primary electrical malfunction (ventricular fibrillation or ventricular tachycardia) or be due to other causes. Overall, survival from cardiac arrest nationally is near 10%. For cardiac arrest due to electrical abnormalities in the heart, the heart does not beat normally and a patient is without pulses. In addition to cardiopulmonary resuscitation, rapid defibrillation – a shock from a defibrillator – can restore normal electrical function and as a result, a pulse. However, often these shocks are not initially successful and these electrical abnormalities – the arrythmias ventricular fibrillation of ventricular tachycardia – continue. In these cases of shock-refractory cardiac arrest, in addition to the continuation of CPR and shocks, medications are given as treatment. One, epinephrine, is given after two shocks and another, the antiarrhythmic amiodarone, is given after three shocks.

The Early-Amio study will be conducted across three counties in the Portland, Oregon metropolitan region including Clackamas, Washington, and Multnomah counties. The study will enroll adults who have cardiac arrest with an initial rhythm of ventricular fibrillation or ventricular tachycardia (shockable rhythms) who have persistence or recurrence of these rhythms after an initial shock from EMS. Patient who receive care in the control group will get routine, usual care from EMS no different than if there was not a trial ongoing. Those in the intervention group will be treated under a protocol to give amiodarone with the initial dose of epinephrine after two shocks, one-cycle of CPR sooner than current guidelines. No further care is changed or dictated, whether by EMS or in the hospital, by the study.

Why is this study being done?

Currently guidelines recommend for patients who have persistent or recurrent shockable cardiac arrest, termed shock-refractory cardiac arrest, the administration of the medications epinephrine (after the 2nd shock) and an antiarrhythmic, such as amiodarone (after the 3rd shock). However, it is unclear if administration of amiodarone after the 3rd shock is the best timing to give amiodarone so as to maximize its potential benefit. This purpose of this study is to explore if a change in the cardiac arrest treatment protocol to recommend earlier amiodarone administration, given with epinephrine after the 2nd shock, is safe and effective at improving the timeliness of amiodarone administration in cardiac arrest.

What is amiodarone?

Amiodarone is an FDA approved antiarrhythmic medication used for the treatment of ventricular arrythmias. Amiodarone is a standard medication to treat cardiac arrest due to a ventricular arrythmia and is given via a catheter in the vein (intravenous access) or a needle in the bone marrow (intraosseous access). The EMS treatment guidelines currently recommend amiodarone after the 3rd shock, in-line with national guidelines. These protocols also recommend amiodarone after return of pulses for patients who had ventricular fibrillation or ventricular tachycardia as the cause of their cardiac arrest. Patients in this study who receive cardiac arrest treatment under the modified guidelines may receive amiodarone faster and earlier in their course of treatment.

How long is this study ongoing?

The study aims to enroll patients over the course of 36 months and enroll 800 patients combined, inclusive of an observational cohort of patients treated under current care for the 12 months prior to the study starting. The study intervention is conducted via participating EMS agencies and no in-hospital interventions or study procedures are performed.

What are the risks of the study?

Participation in the study involves routine EMS care (control group) or treatment under a protocol recommending amiodarone be given earlier during treatment, with initial epinephrine (intervention group). The risks from treatment in the control group are no different than the risks of routine care. The risks of treatment in the intervention group include the possibility that a patient would receive amiodarone earlier than under current guidelines. This could mean a patient was given amiodarone when, under usual guidelines, they may not have if their cardiac arrest ended due to return of pulses before the third shock was due. Current EMS protocols in the region are to give amiodarone, if not already given, after return of pulses for patients with a cardiac arrest due to ventricular fibrillation or ventricular tachycardia. As a result, there are no participants in this study who will receive amiodarone who did not otherwise qualify to receive amiodarone per usual care if they were not included in this study.

The risks of amiodarone include:

• Lower blood pressure (hypotension)
• A slower heart rate (bradycardia)
• Cardiac arrythmias including ventricular fibrillation and ventricular tachycardia
• Congestive heart failure
• Abnormal liver function tests
• Nausea

As this study tests a change to the order of drugs in the standard guidelines for cardiac arrest care in the intervention arm (earlier administration of amiodarone), there is the potential risk that this change could delay or otherwise impact the quality of other EMS interventions you received.

Will this study impact any other parts of patient treatment?

No, the only part of this study that changes usual treatment is the timing of the initial administration of amiodarone during cardiac arrest care in the intervention group. No further EMS or in-hospital care is modified by this study.

Ethical standards require that researchers get permission before a person can be included in a study through a process called informed consent. However, cardiac arrest is an emergency condition that must be treated immediately. There will not be enough time to locate and talk to the person’s family, guardian, or legal representative about the study. Patients enrolled in Early-Amio will be enrolled before permission can be given. This is called “Exception from Informed Consent” (EFIC). Patients and/or the legal representative of patient’s enrolled in this study will be notified about enrollment as soon as possible.

What is Exception From Informed Consent (EFIC)?

The U.S. Food and Drug Administration (FDA) is an agency of the federal government that oversees human research protection involving medicines. The FDA has created a set of special rules, called Exception from Informed Consent (EFIC), for clinical trials that apply to critically ill patients who require emergency treatment when obtaining consent in advance is not possible or may put the patient at risk for increased harm by delaying potentially life-saving therapies. Under some circumstances, there may not be time to obtain consent in advance from every eligible patient. In some cases, such as cardiac arrest, discussing a possible option to enroll in a study with family may cause dangerous delays in a person’s care. Nonetheless, many critically ill patients could benefit from enrollment in an appropriate clinical trial. Therefore, to ensure that clinical trials can be conducted for patients in emergencies, the FDA established rules for EFIC that require special safeguards to ensure that most people would consider the study ethical and appropriate. These special rules allow research studies in certain emergencies to be conducted without obtaining consent in advance.

EFIC can only be used when:

• The person’s life is at risk, AND
• The best treatment is not known, AND
• The study might help the person, AND
• It is not possible to get permission:
  • From the person because of their medical condition NOR
  • From the person’s guardian, because there is a very short amount of time required to treat the medical problem

Before researchers start a study using EFIC, they must provide information about the study to the community and get their feedback. If you would like to fill out a short online survey to provide your thoughts about this study, please click https://redcap.link/EarlyAmioCCsurvey

Delays in treating many aspects of cardiac arrest, such as initiating CPR or defibrillation, can lead to longer arrest duration and lower survival to hospital discharge. Although rapid, high-quality CPR and early defibrillation is most critical for improving survival from cardiac arrest due to a shockable rhythm, not uncommonly cardiac arrest due to ventricular arrythmias continues despite shock delivery. In these cases of shock-refractory cardiac arrest, survival is lower and there are few evidence-based treatment. Under current guidelines, epinephrine is given after two shocks and the antiarrhythmic amiodarone after three shocks. However, in practice amiodarone is often given more then 4 minutes after the initial dose of epinephrine and more than 10 minutes after EMS begin treatment on-scene

The Early-Amio study is pilot, pragmatic stepped-wedge randomized trial to compare the current standard treatment to a new protocol where amiodarone is given with the initial dose of epinephrine. No further care from EMS or in-hospital is changed or dictated as part of this protocol. Participants will be enrolled if they suffer a cardiac arrest and are treated by participating agencies in Clackamas, Washington, and Multnomah counties in Oregon. Eligible patients are adults with persistent or recurrent cardiac arrest due to ventricular fibrillation or ventricular tachycardia after one defibrillation attempt. The study is funded by the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH).

This pilot study aims to test our ability to collect all of the data needed and if the protocol change is successful at reducing the time to amiodarone administration.

Because cardiac arrest requires immediate treatment, it will not be possible to obtain informed consent from patients before they are enrolled. Therefore, eligible patients will be enrolled in this trial under the U.S. Food and Drug Administration’s exception from informed consent (EFIC) requirements for emergency research (21 CFR 50.24). These special rules allow research studies in certain emergency situations to be conducted without consent. EFIC can be used only when the person’s life is at risk, the best treatment is not known, the study might help the person, and it is not possible to obtain informed consent from the patient or a legally authorized representative.

The study will not modify the way cardiac arrest is managed by providers in the emergency department or hospital; it will only modify the timing of initial amiodarone for cardiac arrest when managed by EMS before hospital arrival. All hospital-based care will be standard and determined by the treatment team per routine.

We believe that this study may help paramedics optimally treat shock-refractory cardiac in the future by optimizing medication timing.