Epinephrine Dosing for Cardiac Arrest

(EpiDOSE Trial)

Recruiting at 2 trial locations

Overseen By Theresa Aves, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Unity Health Toronto

Disqualifiers: Age <18, Non-cardiac arrest, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Immediate

3790 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The objective of this randomized controlled trial is to evaluate the effectiveness of a low cumulative dose of epinephrine compared to a standard cumulative dose of epinephrine during resuscitation from ventricular fibrillation (VF) or ventricular tachycardia (VT) in adult out-of-hospital cardiac arrest (OHCA) patients.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

Is epinephrine generally safe for use in humans?

Epinephrine is generally safe for use in humans, but incorrect dosing can lead to serious complications. For example, giving a high dose meant for cardiac arrest to someone with an allergic reaction can cause severe heart problems. Proper labeling and packaging can help prevent these errors. ^{1 2 3 4 5}

How is the drug epinephrine unique in treating cardiac arrest?

Epinephrine is unique in treating cardiac arrest because it is administered intravenously every 3-5 minutes to improve blood flow to the heart and brain, and there is ongoing research to determine the optimal dosing period and amount, which may vary based on the duration of the cardiac arrest. ^{1 6 7 8 9}

What data supports the effectiveness of the drug epinephrine for cardiac arrest?

Research suggests that higher doses of epinephrine may improve blood flow to the heart and brain during cardiac arrest, potentially leading to better survival rates. However, the traditional dose has little scientific basis, and more studies are needed to confirm the benefits of higher doses in humans. ^{1 2 6 9 10}

Who Is on the Research Team?

Steve Lin, MD, MSc

Principal Investigator

St. Michael&#39;s Hospital

Paul Dorian, MD, MSc

Principal Investigator

St. Michael&#39;s Hospital

Are You a Good Fit for This Trial?

This trial is for adults who've had a cardiac arrest outside of the hospital with specific heart rhythms (VF or pulseless VT) and were treated by paramedics. They must have IV access established. It's not for those under 18, non-cardiac caused arrests, prisoners, people allergic to epinephrine, or if they've already received epinephrine.

Inclusion Criteria

I was treated by paramedics for a cardiac arrest that happened outside of a hospital.

Established intravenous vascular access

My first heart rhythm issue was treated or seen by emergency services.

Exclusion Criteria

I am under 18 years old.

Your heart stopped beating at the beginning of the emergency.

People who are in jail or being held by the police.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Immediate

Treatment

Eligible OHCA patients receive either a low or standard cumulative dose of epinephrine during resuscitation

Immediate

On-site during emergency response

Follow-up

Participants are monitored for survival to hospital discharge and other outcomes using administrative databases and telephone interviews

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Epinephrine

Trial Overview The study tests whether a lower total dose of epinephrine is as effective as the standard dose during resuscitation from certain types of cardiac arrest. Participants are randomly assigned to receive either the low or standard dose.

How Is the Trial Designed?

Group I: Low Dose Epinephrine Active Control 1 Intervention

Epinephrine up to 2mg total

Group II: Standard Dose Epinephrine Active Control 1 Intervention

Epinephrine up to 6mg total

Epinephrine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Approved in United States as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Approved in Canada as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Severe allergic reactions

Who Is Running the Clinical Trial?

Unity Health Toronto

Lead Sponsor

Trials

572

Recruited

470,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

In a study of 20,909 in-hospital cardiac arrest events, administering epinephrine less frequently than the recommended 3-5 minute intervals was associated with higher survival rates to hospital discharge.

Specifically, longer average dosing periods (6-10 minutes) resulted in significantly improved survival odds, suggesting that the traditional dosing guidelines may need reevaluation for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Warren, SA., Huszti, E., Bradley, SM., et al.[2021]

In a study involving 28 male pigs, high-dose adrenaline (HDA) improved the chances of successful resuscitation after 13 minutes of cardiac arrest compared to standard-dose adrenaline (SDA), with all animals in the HDA group being resuscitated.

Despite the initial success in restoring circulation with HDA, there was no significant improvement in long-term survival or neurological outcomes, indicating that higher doses may not enhance overall recovery after cardiac arrest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variable effects of high-dose adrenaline relative to standard-dose adrenaline on resuscitation outcomes according to cardiac arrest duration. Jeung, KW., Ryu, HH., Song, KH., et al.[2013]

In a study of 15,909 patients with out-of-hospital cardiac arrest, shorter average dosing intervals of epinephrine (less than 3 minutes) were linked to better survival rates with favorable neurological outcomes at hospital discharge.

Longer dosing intervals (3 to 5 minutes or more) significantly decreased the odds of survival with favorable neurologic status, suggesting that administering epinephrine more frequently may improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest. Grunau, B., Kawano, T., Scheuermeyer, FX., et al.[2020]

In a study involving 650 cardiac arrest patients, high-dose epinephrine (7 mg) did not improve survival rates or neurological outcomes compared to the standard dose (1 mg), with survival rates of 18% vs. 23% for one hour and 3% vs. 5% for hospital discharge, respectively.

The research indicated that high-dose epinephrine may not only be ineffective but could potentially lead to worse outcomes for some patients, as no subgroup analysis showed any benefit from the higher dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose epinephrine in adult cardiac arrest. Stiell, IG., Hebert, PC., Weitzman, BN., et al.[2022]

The standard recommended dose of epinephrine (1 mg) for cardiopulmonary resuscitation lacks strong scientific support, as evidence suggests that higher doses (0.1 to 0.2 mg/kg) may be more effective in improving blood flow and resuscitation rates based on animal studies.

Limited human data indicate a dose-dependent response to epinephrine, suggesting that higher doses could enhance immediate survival during resuscitation, highlighting the need for further randomized controlled trials to explore this potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epinephrine in cardiopulmonary resuscitation. Hebert, P., Weitzman, BN., Stiell, IG., et al.[2019]

In a study involving 1,280 adult patients experiencing cardiac arrest, there was no significant difference in the rate of return of spontaneous circulation or survival outcomes between those receiving standard-dose (0.02 mg/kg) and high-dose (0.2 mg/kg) intravenous epinephrine.

Both dosing regimens resulted in similar survival rates to hospital discharge and neurologic outcomes, indicating that higher doses of epinephrine may not provide additional benefits in treating cardiac arrest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. Brown, CG., Martin, DR., Pepe, PE., et al.[2013]

Inappropriate administration of high doses of epinephrine intravenously for anaphylaxis can lead to severe cardiac complications, as seen in multiple patients, highlighting the critical need for proper dosing and route of administration.

To prevent these potentially lethal errors, the introduction of prefilled and clearly labeled intramuscular epinephrine syringes in emergency settings is recommended, as many hospitals currently lack these essential supplies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution. Kanwar, M., Irvin, CB., Frank, JJ., et al.[2022]

In a study analyzing 685 cardiac arrest patients, it was found that the dosage of epinephrine needed to achieve return of spontaneous circulation (ROSC) increased with the duration of cardiac arrest, indicating that longer arrest times require higher doses for effectiveness.

The research suggests an escalating dosage approach for epinephrine in CPR, which could optimize treatment by preventing overdose in patients with shorter arrest durations while ensuring adequate dosing for those with longer arrest times, ultimately improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Which dosage concept for adrenaline is correct in cardiopulmonary resuscitation? A data analysis of preclinical resuscitations]. Fischer, M., Fischer, N., Schüttler, J.[2013]

In a study of 2255 patients with out-of-hospital cardiac arrest (OHCA), reducing the dose of intravenous epinephrine from 1 mg to 0.5 mg did not significantly affect survival rates to hospital discharge for either shockable or non-shockable rhythms.

The study found no significant difference in favorable neurological outcomes at discharge between the higher and lower epinephrine doses, suggesting that lower dosing may be safe without compromising patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes. Fisk, CA., Olsufka, M., Yin, L., et al.[2018]

Adrenaline has been a key treatment for cardiac arrest since the late 1800s, with a standard practice of administering 1 mg intravenously every 5 minutes during resuscitation.

Despite some animal studies and case reports suggesting that higher doses of adrenaline might be beneficial, large clinical trials have shown no significant improvement in survival rates compared to the standard 1 mg dose, confirming its continued use as the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adrenaline dosage during cardiopulmonary resuscitation: a critical review. Hubloue, I., Lauwaert, I., Corne, L.[2013]

Citations

1. Ireland pubmed.ncbi.nlm.nih.gov

Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. [2021]

2. Ireland pubmed.ncbi.nlm.nih.gov

Variable effects of high-dose adrenaline relative to standard-dose adrenaline on resuscitation outcomes according to cardiac arrest duration. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

High-dose epinephrine in adult cardiac arrest. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Epinephrine in cardiopulmonary resuscitation. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

[Which dosage concept for adrenaline is correct in cardiopulmonary resuscitation? A data analysis of preclinical resuscitations]. [2013]

9. Ireland pubmed.ncbi.nlm.nih.gov

Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Adrenaline dosage during cardiopulmonary resuscitation: a critical review. [2013]