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InFocus: Epinephrine in Cardiac Arrest A Therapeutic Dinosaur?

Roberts, James R. MD

doi: 10.1097/01.EEM.0000432260.80545.12

Dr. Roberts is the chairman of emergency medicine and the director of the division of toxicology at Mercy Catholic Medical Center, and a professor of emergency medicine and toxicology at the Drexel University College of Medicine, both in Philadelphia.

It would be akin to medical heresy to question the use of epinephrine in all cases of cardiac arrest, but the American Heart Association states that no drug favorably influences the outcome of sudden cardiac death or is associated with an increased rate of survival with a good neurologic outcome

It would be akin to medical heresy to question the use of epinephrine in all cases of cardiac arrest, but the American Heart Association states that no drug favorably influences the outcome of sudden cardiac death or is associated with an increased rate of survival with a good neurologic outcome

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Every patient with cardiac arrest, regardless of the cause, has been treated with intravenous epinephrine. Doses may have changed, and alternate routes of administration have been explored, but the bottom line is that cardiac arrest has always been treated with epinephrine. This drug became a staple in our armamentarium against cardiac arrest based on a few anecdotal reports and some animal studies, but it simply would be malpractice to eschew its use in any code.

All clinicians have observed that cardiac activity was often stimulated by epinephrine, making the EP feel better and seemingly giving some hope for the patient, but overall survival rates were still quite dismal, and legitimate survival, when carefully investigated, did not appear to be augmented by epinephrine. Nonetheless, the drug was and still is probably used in every code.

Imagine our surprise and dismay when this dogma was questioned. The value of epinephrine in cardiac arrest is now under intense scrutiny, and it has even been suggested that it is not only useless, but may be harmful in the long run. The American Heart Association has been slow to change, and still recommends epinephrine for cardiac arrest, but I suspect that axiom might change in the next iteration of the guidelines. The concern is that epinephrine has no proven value in cardiac arrest and may, in fact, be detrimental to a favorable outcome.

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Epinephrine for Cardiac Arrest

Callaway CW

Curr Opin Cardiol


This is a nifty review article in the current opinion section of a popular cardiology journal written by an emergency physician. The author states that better outcomes from cardiac arrest are currently thought to be possible via rapid institution of chest compressions (note that airway/ventilation are not required initially), rapid electrical defibrillation, and the induction of hypothermia after restoration of pulses. One wonders if these sacred cows will also be put out to pasture with further rigorous investigation. The author notes that recent clinical data suggest that epinephrine administered during cardiac arrest has been an omnipresent intervention, but routine epinephrine may actually be harmful for some patients. The author reviews the current data, and highlights the urgent need to reassess how and when to administer epinephrine in cardiac arrest.

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The pharmacology of epinephrine would appear beneficial to a recently dead heart. Epinephrine certainly has been proven to augment coronary blood flow generated by chest compressions during CPR. The increase in coronary perfusion pressure is thought to be the major determinant of coronary blood flow and hence spontaneous return of cardiac activity. Epinephrine restores peripheral vasomotor arterial tone, also believed to be useful in restoring cardiac activity via increased coronary flow. It is generally universally agreed that epinephrine augments the likelihood of the return of spontaneous circulation during CPR. Increased aortic pressure may also result in better coronary circulation following epinephrine injection.

Now for the bad news. Epinephrine has seemingly beneficial alpha-adrenergic effects but also potentially undesirable beta-agonism. Beta stimulation causes tachycardia, dysrhythmias, and increased myocardial oxygen demand, and epinephrine can promote thrombogenesis via platelet activation, and most importantly, decrease cerebral blood flow post-resuscitation. Such physiologic effects may worsen acute coronary and brain ischemia. Pharmacologically speaking, epinephrine actually impairs overall myocardial function despite an increase in coronary perfusion pressure and coronary blood flow, causing a depletion of myocardial ATP, and enhances lactate accumulation. These effects are thought to be caused by epinephrine's adverse beta-adrenergic-mediated inotropic and chronotropic increases in myocardial oxygen demand.

Animal studies showed that epinephrine causes enough vasoconstriction to impair capillary blood flow in the brain. Even though there is an increased blood pressure in large arteries, there does not appear to be a concomitant epinephrine-induced increase in the micro-circulation of the brain. In fact, the opposite ensues, so alpha-1 epinephrine effects result in decreased cerebral perfusion and decreased brain oxygenation during CPR and following return of circulation. Epinephrine treatment more than doubles the total duration of cerebral ischemia after a brief cardiac arrest, according to this author.

Actual clinical experience with epinephrine during cardiac arrest, particularly for long-term outcome, is rather obtuse and essentially anecdotal. Even the standard 1 mg bolus dose was derived from dog studies in the 1960s. One must consider whether short-term benefits, such as an initial return of circulation, are better than the overall long-term detriments of epinephrine administration when assessing the harm-benefit ratio of epinephrine in out-of-hospital arrest. Presumably this also applies to ED or in-hospital cardiac arrest.

Prospective randomized controlled trials are lacking, but two recent relevant observational reports were reviewed by the author. These studies provide no support for routine epinephrine administration in cardiac arrest and no beneficial effect of epinephrine on long-term patient-oriented outcomes. The studies lacked great scientific clarity to make definitive statements about functional outcome, but the results are rather ominous. Importantly, the overall conclusions of recent reports have been consistent for years. One randomized Scandinavian study of out-of-hospital cardiac arrest found that patients receiving IV epinephrine (and other ACLS medications) did have a higher rate of return of pulses than those who did not have IV access (40% vs. 25%). (JAMA 2009;302[20]:2222.) Patients given epinephrine likewise better survived initial resuscitation to be admitted to the ICU (30% vs. 20%). Importantly, a post-hoc analysis found that the proportion of patients given epinephrine who were discharged from the hospital was seven percent compared with 13 percent for those not given the drug. (Resuscitation 2012;83[3]:327.) A smaller portion of patients given epinephrine experienced functional recovery or survived to one year in the final analysis. Epinephrine use was associated with an overall worse final outcome.

An Australian study of out-of-hospital cardiac arrest comparing the randomized variable of 1 mg bolus doses of epinephrine with placebo reported similar discouraging findings. (Resuscitation 2011;82[9]:1138.) Patients who received the epinephrine had a higher initial rate of return of circulation (30% versus 11%) as well as increased admission to the hospital (25% versus 13%), but the proportion of patients discharged from the hospital or those with a favorable neurologic recovery did not differ statistically. The conclusion was that epinephrine use did not improve survival to hospital discharge after out-of-hospital cardiac arrest.

The final prospective randomized trial has not yet been accomplished, but a large observational study from Japan also suggests epinephrine use during cardiac arrest is associated with a lower long-term survival rate and a worsened neurological outcome. (JAMA 2012;307[11]:1161.) Previous data and this study show a short-term benefit, but the initial positive effects of epinephrine disappear in the final evaluation that measures survival to discharge. In fact, a neurologically favorable final outcome was significantly less in the epinephrine-treated group. The detrimental effects of epinephrine were evident despite a higher rate of witnessed arrest, bystander CPR, and early defibrillation in the epinephrine group.

It is difficult to adjust for multiple potential compounding variables, but this Japanese study of more than 400,000 patients failed to confirm a long-term benefit of epinephrine for patients who did experience spontaneous circulation with epinephrine in the field. The one-month survival rate was 18 percent vs. 46.8 percent without epinephrine. Favorable neurologic outcome with epinephrine was 4.7 percent versus 25 percent without epinephrine. Further confounding the interpretation of this study was the inability to confirm the cause of the cardiac arrest, the timing of epinephrine, and variables in dosing.

It may be anathema and a tough clinical pill to swallow, but studies of the routine use of epinephrine for out-of-hospital patients undergoing CPR do not provide clear evidence of long-term benefit. There is a nagging suggestion — and some very scary statistics — that neurological outcome actually may be worse with epinephrine use. Epinephrine may have greater downsides pharmacologically. This author calls for further study to justify the use of epinephrine in ACLS and into alternative regimens for cardiac arrest.

Comment: It is certainly nearly impossible to have strict scientific controls in any cardiac arrest. The downtime, underlying pathology, and numerous variables in post-resuscitative care make comparing a single intervention difficult if not impossible. This is not the first author to call into question the universal and routine use of epinephrine as a beneficial routine intervention in cardiac arrest.

I can remember when 5-15 mg of epinephrine was considered the appropriate intervention, and those mega-doses appeared to create a marked increase in spontaneous circulation. Like many other seemingly wonderful interventions for cardiac arrest, high-dose epinephrine had only transient benefit, it fell into disuse, and is no longer recommended.

The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Arrest state that no medication has proven beneficial to cardiac arrest yet, and the AHA still recommends epinephrine, either IV or intraosseous, in a dose of 1 mg every three to five minutes for ventricular fibrillation and asystole/PEA. Alternatively, vasopressin can be used in place of epinephrine. Interestingly, atropine has been deleted as an AHA recommendation to routinely managing PEA/asystole. Calcium and sodium bicarbonate, other prior stalwarts of cardiac arrest, have not been recommended for years, even though the acidosis of cardiac arrest may be severe. These erstwhile favorites are a perfect example of something that seemingly should work and were used for decades but had no proven benefits. Epinephrine has, so far, missed the cut, and is still recommended in the AHA guidelines as of this writing.

Questioning the benefit of epinephrine for patient-oriented outcome is not a novel concept. One wonders how this drug has remained in its unquestioned exalted status for so many years. At least two studies in the 1990s failed to support a beneficial effect. (New Engl J Med 1998;339[22]:1595; JAMA 1992;268[19]:2667.) These studies were not randomized, but two recent randomized trials failing to show an increase in long-term survival rate with epinephrine for out-of-hospital cardiac arrest raise serious questions about current ACLS cardiac arrest recommendations. Interestingly, EMS personnel were reluctant to withhold traditional drugs, especially epinephrine, during cardiac arrest in both studies, and therefore, many patients could not be randomized. It is indeed difficult to forgo a drug that will likely give the patient a blood pressure and pulse, if only transiently, especially when the initial caregivers do not provide long-term care or are not aware of ultimate outcome.

The best available observational evidence suggests that epinephrine is harmful to patients during cardiac arrest, but a causal relationship has yet to be proven. Clearly more research is required. The entire concept of withholding epinephrine during cardiac arrest was previously branded as unethical, but that is currently not the case.

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Prehospital Epinephrine Use and Survival among Patients with Out-of-Hospital Cardiac Arrest

Hagihara A, Hasegawa M, et al



This landmark Japanese article prompted a re-evaluation of the routine use of epinephrine in out-of-hospital cardiac arrest. It included an evaluation of 417,000 patients who received prehospital cardiac arrest by EMS. The authors of this gargantuan study attempted to evaluate return of spontaneous circulation before hospital arrival, survival at one month after cardiac arrest, survival with good or moderate cerebral function, and survival with no mild or moderate neurological disability. This was a massive study that was clearly a statistical nightmare.

As with other studies, the return of spontaneous circulation in patients given epinephrine was far more likely than in the non-epinephrine group, 18.5 percent versus 5.7 percent, respectively (P=.01). In fact, all investigations of the ability of epinephrine to prompt an initial return of circulation have yielded the same conclusion: epinephrine will often flog the heart to return a heartbeat and pulse, at least initially. The chance for one-month survival with a good or moderate cerebral outcome, however, was statistically and significantly poorer for those patients who received epinephrine in this study. Overall survival fell by about half post-epinephrine, and survival with a good or only mildly impaired cerebral function fell by more than two-thirds if epinephrine was given. In short, a significant negative association was observed between prehospital epinephrine and long-term outcome measures in all patients. The results were statistically significant in all categories. The authors concluded that patients had a decreased chance of survival with a good outcome one month after cardiac arrest if epinephrine was administered by EMS.

Comment: Epinephrine reduces cerebral perfusion during CPR, increasing the severity of brain ischemia, at least in pigs. (Crit Care Med 2009;37[4]:1408.) This month's article clearly shows that intravenous epinephrine administered by EMS for cardiac arrest using traditional criteria and doses is independently associated with a reduced one-month survival rate. In fact, epinephrine given before hospital arrival was a significant predictor of an overall poor long-term outcome in cardiac arrest subjects. These authors emphasize the previously described adverse effects of epinephrine, including decreased myocardial function, impaired cerebral microcirculation, and ventricular arrhythmias during the post-resuscitation period. The short-term benefit of return of spontaneous circulation has been attributed to the pharmacological effects of epinephrine, but these same pharmacological effects worsen long-term survival and ultimate outcome.

It is interesting the way data became available for this study. EMS technicians in Japan were permitted to administer intravenous epinephrine in the field after April 2006. Apparently, the Japanese paramedics loved epinephrine because only 190 patients received intravenous epinephrine in the field in 2005 before the change took effect. This study clearly shows that epinephrine may temporarily save the heart, but it doesn't save the brain in the long run.

This observational study was not randomized, and post-cardiac arrest care was not included in the analysis. The actual cause of the cardiac arrest was not clarified in many cases, and the actual number of doses of epinephrine could not be ferreted out. Nonetheless, the authors believe that their results are strong and consistent, and they contend that their data show that intravenous epinephrine administered for prehospital cardiac arrest was detrimental to the final outcome.

Before epinephrine joins the brontosaurus in the tarpits of clinical antiquity, we need to know if lower doses would be helpful, if a time cut-off that prohibits epinephrine in all patients is useful, and if hypothermia or other drugs may short-circuit the adverse pharmacologic effects of epinephrine but not totally negate the drug benefit on initial resuscitation. And to be fair, early epinephrine as opposed to late epinephrine may improve neurologic outcome in prehospital cardiac arrest, so time of administration may be critical. (Circ J 2012;76[7]:1639.)

Giving epinephrine in asystole or after a prolonged downtime without CPR seems illogical in most cases, and it risks an initial return of circulation in someone with no chance of long-term survival and a high chance for a vegetative state.

One wonders what currently acceptable and advocated axioms for treating acute cardiac arrest will be debunked or discredited next. The use of high-flow oxygen for cardiac arrest has now been questioned; who would ever question the use of lots of oxygen for cardiac arrest? Also, even immediately breathing for the dead patient has taken a back seat to chest compressions.

It's amazing how sentiments change. I can remember a colleague who lost a malpractice case when he responded to a code inside the hospital in a manner that was termed untimely and delayed, resulting in the delayed use of epinephrine. Being called to the floor from the ED to treat a cardiac arrest is lunacy enough, but one now can assume my colleague's patient may have had a better chance of survival if epinephrine had been totally withheld.

Finally, a word of caution and a discouraging reality: before you adopt the latest craze that limits the use of epinephrine in cardiac arrest, remember that the 2010 AHA as well as our current medicolegal system may not agree with your enthusiasm.

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