Learning Objectives
- Explain the ongoing debate between single-dose (SDEP) and multidose (MDEP) epinephrine in out-of-hospital cardiac arrest
- Summarize the design and key findings of this CARES registry secondary analysis
- Describe how patient age modified the association between epinephrine dosing strategy and survival
- Identify the study design limitations that keep these findings hypothesis-generating rather than practice-changing
Why Are We Talking About This?
Epinephrine has been part of the cardiac arrest algorithm for decades, but how much and how often to give it is still an open question. The landmark PARAMEDIC-2 trial found that epinephrine improved return of spontaneous circulation (ROSC) and survival compared to placebo, but the margin was thin. Survival was 3% with epi versus 2% with placebo. And survival with a favorable neurologic outcome actually trended slightly worse in the epinephrine group.
That result opened the door to a harder question. If epinephrine helps a little but might carry some downside, does giving it repeatedly make things better or worse? Stacked doses of epinephrine can drive up myocardial oxygen demand, worsen post-ROSC hemodynamics, and contribute to catecholamine-related harm after the patient comes back.
Two dosing philosophies have emerged:
Multidose (MDEP)
Repeated epinephrine doses given at standard intervals throughout the resuscitation, consistent with traditional ACLS dosing. More circulating epinephrine, and historically associated with higher ROSC rates.
Single-Dose (SDEP)
One dose of epinephrine given, then no additional doses regardless of how long the arrest continues. The theory is less cumulative catecholamine exposure and less post-ROSC toxicity.
In 2018, five counties in North Carolina switched their protocols from MDEP to SDEP. That real-world policy change gave researchers a natural experiment: compare outcomes before and after the switch and see what happened.
What They Did
This was a secondary analysis of registry data, not a randomized trial. Researchers pulled records from the Cardiac Arrest Registry to Enhance Survival (CARES) for adult OHCA patients treated within one year before or after the five North Carolina counties transitioned from MDEP to SDEP.
| Detail | What the Study Did |
|---|---|
| Design | Before-and-after (quasi-experimental), not randomized |
| Data source | CARES registry, 5 North Carolina counties |
| Population | Adults 18+, treated within 1 year of the MDEP-to-SDEP protocol switch |
| Total patients | 1,690 (899 MDEP phase, 791 SDEP phase) |
| Outcomes measured | ROSC and survival to hospital discharge, stratified by age group |
| Analysis | Multivariate logistic regression, adjusted for age, initial rhythm, bystander CPR |
What They Found
| Outcome | MDEP Phase | SDEP Phase |
|---|---|---|
| ROSC (overall) | 45% | 35% |
| Survival to discharge (overall) | Baseline | ~5% higher |
| Survival, age >65 (unadjusted) | 6% | 12% |
| Survival, age >65 (adjusted OR) | 1.87 (95% CI, 1.36–2.56) | |
| Survival, age 18–64 (adjusted OR) | ~0.8 (not statistically significant) | |
The age split is the headline finding here. In patients over 65, SDEP was associated with roughly double the odds of surviving to discharge compared to MDEP. In younger and middle-aged adults, the direction actually flipped. Unadjusted survival was slightly lower in the SDEP phase, and the adjusted odds ratio trended below 1, though it didn't reach statistical significance.
What This Actually Means
This is a before-and-after registry study, not a randomized controlled trial. That distinction matters more here than in most modules you'll see on this platform.
On top of that, remember that actual epinephrine dosing wasn't confirmed. Whether a specific patient got one dose or five was inferred from the calendar, not from the chart. And this data comes from five counties covering about 850,000 people. That's a small, specific population, and it's not clear how well these findings would generalize to a different EMS system with different call volumes, response times, or crew configurations.
The younger-patient finding deserves its own caveat too. Fewer younger patients arrest and get enrolled in a study like this, so that subgroup may simply have been underpowered to detect a true effect, rather than showing a genuinely neutral or harmful signal.
What This Study Supports
A hypothesis worth testing further: that older adults in cardiac arrest may fare better with a single dose of epinephrine rather than repeated dosing.
What This Study Doesn't Prove
That single-dose epinephrine should replace current multidose protocols. The design can't rule out confounding, and the authors themselves call this hypothesis-generating.
Apply What You Know
You arrive to find a 78-year-old male in cardiac arrest. Family witnessed the collapse and started CPR immediately. Your monitor shows an initially shockable rhythm. You defibrillate, continue high-quality compressions, and establish IV access. Your protocol calls for standard ACLS epinephrine dosing every 3 to 5 minutes.
You give your first dose of epinephrine per protocol. The patient remains in a shockable rhythm through several cycles.
Based on this study, what should guide your next move?
This paper raises two important questions for us to think about: how much epi, and to who? It's pointing us in an interesting direction, but not enough to change practice. Keep following your agency's ACLS-based dosing until real trial data says otherwise. Let this one make you curious, not make you improvise.
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