Epinephrine in Cardiac Arrest

Anand Swaminathan, MD, MPH (@EMSwami) is an assistant professor and assistant program director at the NYU/Bellevue Department of Emergency Medicine in New York City.

Clinical Question

Does epinephrine increase the rate of survival with good neurologic outcome in patients with out-of-hospital cardiac arrest (OHCA)?

Background

Sudden cardiac arrest is common and, obviously, very bad. In the US, there are about 500,000 cardiac arrests each year. About half of these cardiac arrests are OHCA and the survival rate is pretty poor. The most recent survival estimates put it at 7 – 9.5% in most communities. About 10-12 years ago, the American Heart Association built the 4-step “chain-of-survival.”

• Step One – Early access to emergency care
• Step Two – Early CPR
• Step Three – Early defibrillation

In fact, in communities with high layperson BLS training and AEDs in the community, the rate of survival after OHCA is higher.

The 4^th step in the chain, however is slightly more controversial; early advanced care. This basically means rapid access to ACLS type resuscitation skills.

The ACLS package of therapies has minimal evidence to defend it and yet, it is the standard care patients receive. The real question, though is does it improve outcomes? Specifically, does the application of ACLS decrease mortality and increase the rate of good neurologic outcomes after OHCA?

As always, we also have to ask if we are doing harm. Does the ACLS algorithm harm patients by bringing back more people with severe neurologic disabilities?

This question was answered 10 years ago in the Ottawa Prehospital Advanced Life Support (OPALS) Study. Follow this link to the Skeptics Guide to Emergency Medicine blog/podcast for a detailed review of this study with Ken Milne (@TheSGEM). Here’s a quick review:

OPALS was a prospective before and after study. They collected data on OHCA for 12 months before adoption of ACLS (paramedics did CPR and defibrillation only) and for 36 months after adoption of ACLS. They found a significant increase in ROSC and admission to hospital but no significant increase in survival to discharge. Additionally, neurologic outcomes of the survivors to discharge were worse in the ACLS group. Overall, this study demonstrated harm from incorporation of ACLS.

Can we separate out parts of the ACLS bundle that would be helpful? Doing a study like this is difficult as ACLS is the accepted standard care but there are some studies delving into the utility of epinephrine in OHCA.

The pathophysiologic basis behind epinephrine being beneficial comes mainly from animal models. Here are three of those efforts (courtesy of Bryan Hayes – @PharmERToxGuy):

1. ‘Beneficial’ effects come primarily from alpha-adrenergic stimulation induced vasoconstriction [dog study, Yakaitis RW, Crit Care Med 1979]
2. This effect increases CPP and myocardial perfusion during CPR [dog study, Michael JR, Circulation 1984]
3. The potential problem is that the beta-agonist effects may increase myocardial work and reduce subendocardial perfusion [dog study, Ditchey RV, Circulation 1988]

What about the argument against epinephrine?

1. Beta-adrenergic effects are undesirable in arrest patients – tachycardia, tachydysrhythmias, and increased myocardial oxygen
2. Can promote thrombogenesis and platelet activation
3. Impairs myocardial function in spite of increased coronary perfusion pressure (in animal studies)
4. Reduces microvascular perfusion – particularly brain perfusion. What good is saving the heart if the brain is dead?

Let’s look at some studies. There are a number of observational studies (usually before and after) that show increased ROSC without increased good neurologic survival.

Hagihara A et al. Prehospital Epinephrine Use and Survival among Patients with OHCA. JAMA 2012; 307(11): 1161-68

• Observational study. Database of all cardiac arrests over 4 years (415,000). 15,000 got epinephrine and the rest did not.
• Higher rate of ROSC (OR = 3.75)
• Higher rate of survival at 1 month 5.4% vs. 4.7% (OR 1.15)
• Good neuro outcome was significantly less 1.4% vs. 2.2%
  Of note, differences in groups favored epi (more witnessed arrest, more initial VF)

Nakahara S et al. Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study. BMJ December 2013

• VF/VT Arrest
  • Overall survival: 17% vs. 13.4% (favored epinephrine group)
  • Neurologically intact survival: 6.6% vs. 6.6%

• Non-VF/VT Arrest
  • Overall survival: 4.0% vs. 2.4% (favored epinephrine group)
  • Neurologically intact survival: 0.7% vs. 0.4%

Olasveengen TM, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009;302:2222–2229.

This was an RCT (not blinded) looking at whether giving epinephrine improved outcomes in OHCA. Basically, they either did ACLS without drugs or ACLS with drugs.

• ROSC 40% (IV drugs) vs 25%
• ROSC and Admission 32% (IV drugs) vs. 21% (p<.001)
• Survival to discharge 10.5% (IV drugs) vs. 9.2% (no IV drugs) (p = .61)
• Survival with good neurologic outcome 10% vs. 8% (p = .53)

Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation 2011; 82:1138–1143.

This was an RDCT with placebo that unfortunately lost funding before full enrollment. They were able to randomize 600 patients and had complete data on 534.

• ROSC 23.5% (epinephrine) vs. 8.4% OR = 3.4
• Survival to hospital discharge: 4.0% (epinephrine) vs. 1.9% – not statistically different

Bottom line

Epinephrine and other ACLS drugs lead to more patients with ROSC but no increase in the number of patients with good neurologic outcomes after OHCA.

Something that’s very interesting is the actual ACLS recommendation for epinephrine. It reads, “it is reasonable to consider administering a 1 mg dose of IV/IO epinephrine every 3 to 5 minutes during adult cardiac arrest.” This actually leaves room to not give the medication if the physician thinks it should be withheld.

OPALS was a pretty robust study and little has changed in the last 10 years. The literature that has come out has been quite clear, thus it’s time to re-examine this recommendation.

Further Reading / Resources