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?

This trial tests different doses of epinephrine, a medicine used during emergencies to restart the heart, in people who have experienced cardiac arrest (when the heart suddenly stops). The goal is to determine if a lower dose of epinephrine works better or as well as the regular dose when the heart rhythm is out of sync. Potential participants include those who have had a cardiac arrest outside of a hospital, with specific heart rhythm issues identified by emergency responders. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment can benefit more 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.

What is the safety track record for epinephrine?

Research has shown that epinephrine, used during cardiac arrest, is generally safe. Studies have found that it helps restart the heart and increases short-term survival. Both low and standard doses of epinephrine are well-documented for emergency use.

The low dose, up to 2mg total, improves blood flow during resuscitation. The standard dose, up to 6mg, is more commonly used and has been extensively studied. Both doses aim to improve survival chances during cardiac arrest. However, no clear evidence indicates that higher doses lead to better long-term outcomes.

Trials have demonstrated that while epinephrine aids immediate survival, its benefits for long-term survival or brain function remain uncertain. Overall, epinephrine is well-tolerated, especially since it is already approved for use in cardiac emergencies. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about exploring different dosing strategies for epinephrine in cardiac arrest situations. Current treatments typically use a standard dose approach, but this trial is looking at both low dose and standard dose epinephrine to see if varying the amount can improve outcomes. The hope is that by fine-tuning the dosage, patients might have better chances of survival and recovery without increasing the risk of side effects. This trial could lead to a more tailored approach in emergency care, potentially setting a new standard for how epinephrine is administered during cardiac arrest.

What evidence suggests that this trial's treatments could be effective for cardiac arrest?

Research has shown that using epinephrine during cardiac arrest can help restart the heart and improve short-term survival. In this trial, participants will receive either a low dose or a standard dose of epinephrine. One study found that a lower dose does not affect the chances of surviving long enough to reach the hospital. However, the standard dose has been shown to improve survival until hospital discharge compared to not using it at all. Studies also suggest that while the standard dose is effective, using more than that does not lead to better results. Overall, epinephrine benefits survival rates after cardiac arrest. ^{1 2 4 6 7}

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 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]

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]

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]

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 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]

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 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]

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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11596809/

Use of Epinephrine in Cardiac Arrest: Advances and Future ... This study aims to evaluate the literature describing the efficacy, timing, and dosing of epinephrine use in cardiac arrest.

2. ccforum.biomedcentral.com ccforum.biomedcentral.com/articles/10.1186/s13054-025-05417-4

Association of epinephrine and outcome in cardiac arrest with ... Among the 3163 patients with refractory shockable arrest, 2572 (81%) received epinephrine. Primary outcome was achieved in 270 patients (11%) ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0300957218300042

Lower-dose epinephrine administration and out-of-hospital ... Conclusion. Reducing the dose of epinephrine administered during out-of-hospital cardiac arrest was not associated with a change in survival to hospital ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1806842

A Randomized Trial of Epinephrine in Out-of-Hospital ... In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo.

5. journals.lww.com journals.lww.com/co-cardiology/fulltext/2013/01000/epinephrine_for_cardiac_arrest.7.aspx

Epinephrine for cardiac arrest : Current Opinion in Cardiology The available clinical data confirm that epinephrine administration during CPR can increase short-term survival (return of pulses), but point towards either no ...

6. ahajournals.org ahajournals.org/doi/10.1161/circ.102.suppl_1.i-129

Part 6: Advanced Cardiovascular Life Support | Circulation But 8 randomized clinical studies involving more than 9000 cardiac arrest patients have found no improvement in survival to hospital discharge or neurological ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0012369223001654

Epinephrine in Out-of-Hospital Cardiac Arrest: A Network ... Compared with placebo or no treatment, standard-dose epinephrine improved survival to discharge among patients with nonshockable rhythm (OR, 2.10; 95% CI, 1.21- ...