First, it was calcium. Then, it was bicarbonate. Then, high-dose epinephrine. Next came atropine. Now, it's standard-dose epinephrine under criticism as unhelpful and even possibly detrimental when administered to patients with cardiac arrest. Epinephrine is still recommended by the American Heart Association, but over the past years has garnered a somewhat sullied reputation for therapeutic benefit in cardiac arrest. (“2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science,” Circulation 2010;122[18 Suppl 3]; http://bit.ly/1DJBho3.)
Last month, I discussed the observed downside or lack of benefit of all ACLS drugs in prehospital cardiac arrest. This month, I focus solely on epinephrine. It should be noted that prior to adoption and incorporation into guidelines, no ACLS drug was ever the subject of randomized controlled human evaluations. Drugs were chosen on animal studies, and proposed benefit was based on pharmacology.
It seemed reasonable, for example, to include bicarbonate because of the acidosis associated with cardiac arrest. That medication has long been considered useless. Epinephrine has stood the test of time for some reason, although it is currently under close scrutiny and likely will be reconsidered in the list of empiric drugs for cardiac arrest. International resuscitation guidelines still recommend administration of epinephrine every three to five minutes during cardiac arrest, regardless of the initial rhythm, but a long-term benefit is questionable. More importantly, a worsened final outcome has been posited after the use of epinephrine.
Is Epinephrine during Cardiac Arrest Associated with Worse Outcomes in Resuscitated Patients?
Dumas F, Bougouin W, et al.
J Am Coll Cardiol
These authors, primarily from France, note that the alpha-adrenergic/vasopressive effects of epinephrine can initially increase coronary and cerebral perfusion pressure early during the resuscitation period. Whenever studied, epinephrine augments the initial return of spontaneous circulation (ROSC); this is temporary, however, and subsequent adverse effects can occur, such as myocardial dysfunction, increased oxygen requirements, and cerebral microcirculatory abnormalities. Basically, any long-term benefits of epinephrine and better long-term survival remain uncertain, at least according to these authors.
The authors are still somewhat ambiguous in their conclusions even though they note that a recent study also found no overall survival benefit of epinephrine and an association with a lower likelihood of long-term survival. It was admitted, however, that the initial ROSC is clearly enhanced by epinephrine. Unfortunately, ROSC does not seem to prognosticate a better final outcome nor does that early benefit translate into better long-term survival. In fact, epinephrine-treated patients had a worse outcome compared with those who were not given that intervention.
The object of this study was to investigate the relationship between the prehospital use of epinephrine and functional survival among patients who achieved ROSC following use of the still-recommended ACLS drug. The authors studied all patients admitted to the hospital over a 12-year period who had received epinephrine, and compared them with those who did not receive epinephrine. Doses of 1, 2 to 5, or more milligrams were evaluated. A favorable or unfavorable discharge outcome was coded.
A total of 1556 eligible patients were in the study, and 73 percent received epinephrine. Seventeen percent had a good outcome, and 83 percent had a bad outcome. Twenty-seven percent in the comparison group were not given epinephrine, and a good outcome was found in an amazing 63 percent; a bad outcome was seen in 37 percent. This final outcome was statistically significant. Adverse effects associated with epinephrine were observed regardless of the length of resuscitation or other in-hospital interventions. The adjusted odds ratio of survival decreased as the amount of epinephrine increased. A delay in administration of epinephrine was also associated with a worse outcome. Blood lactate and post-cardiac arrest shock were also statistically higher with the use of epinephrine.
Out-of-hospital cardiac arrest involved intervention by an emergency resuscitation team that included at least one emergency physician trained according to international guidelines. Epinephrine was administered promptly at the beginning of ACLS or later if it subsequently was thought to be required. Patients who failed resuscitation were not transported to the hospital. Post-resuscitation procedures in both groups included targeted temperature management and early coronary reperfusion as being the most important components of post-resuscitation care. Coronary artery angiography was performed in 63 percent of patients and PCI in 44 percent. About 70 percent underwent therapeutic hypothermia.
The majority, about three-quarters of the patients, received epinephrine as part of the resuscitation protocol. Survival with a good neurological outcome was significantly less likely among those who received epinephrine compared with those who did not: 17 percent versus 63 percent, respectively. Analysis confirmed that ACLS delays were similar in both groups. EMS treatment was rather long: 16 +/- 10.6 minutes after collapse. This is a relatively long delay, but it did not change the overall benefit or lack of benefit for epinephrine. Interestingly, a better outcome was seen when epinephrine was given within the first nine minutes after cardiac arrest compared with those who received epinephrine between 10 and 15 minutes later. The adverse outcome association between epinephrine and survival was independent of initial rhythm, length of resuscitation, or post-resuscitation care. Increasing doses of epinephrine were associated with decreasing odds of survival. Epinephrine during resuscitation was also associated with the worse neurological outcome after adjustment for other compounding variables.
Epinephrine was associated with a decreased likelihood of neurologically intact survival among patients who achieved ROSC. This was thought to be because of post-resuscitation harm of epinephrine. The use of PCI or hypothermia did not alter the adverse outcomes of epinephrine. The authors did state that there may be a potential benefit of early-dose epinephrine, but even this requires more study. They did conclude that patients receiving later or higher doses of epinephrine had little or low chance of survival, possibly from epinephrine use.
Comment: These authors (and others) observed an inverse association between epinephrine and neurologically intact survival, but they suggest that additional investigations are still required. It apparently takes more data to remove epinephrine from guidelines than it did to initially recommend it initially. One wonders how these authors can still waffle on epinephrine based on their current data. One also wonders when the American Heart Association, an organization that recognizes this phenomenon, will concede that epinephrine has no proven benefit, but, in fact, has proven harm for patients administered the drug during cardiac arrest.
Many studies looking at any prehospital intervention have many variables and parameters, particularly time intervals, that could affect outcome. More than 1500 patients were included, so one would think that this would not be an issue, and the authors failed to uncover any variables other than epinephrine. The prehospital use of epinephrine was consistently associated with a lower chance of survival despite post-resuscitation interventions.
It's understandable why physicians would be unwilling to withhold epinephrine, a current ACLS recommendation, from any resuscitation protocol in today's medicolegal environment. I could not find a single study that supported the use of epinephrine in human cardiac arrest, either prehospital or inhospital. Granted some studies have methodological problems, and no study that evaluated the outcome of ACLS found that epinephrine improves long-term survival. Of course, one has to affect ROSC before any long-term benefit can be evaluated. And epinephrine does increase initial ROSC. One may be initially pleased by achieving ROSC, but such an early victory does not equate to a better long-term outcome. Simply stated, the subsequent adverse effects of this drug are quite suspect.
Epinephrine for Cardiac Arrest
Curr Opin Cardiol
This recent article from the department of emergency medicine at the University of Pittsburgh reviews the value of epinephrine in cardiac arrest. The single author notes that better outcomes in cardiac arrest result from the early initiation of chest compressions, early electrical defibrillation of ventricular dysrhythmias, or the induction of post-arrest hypothermia. The evidence supporting any other intervention, especially drugs, is relatively weak or absent, and no conclusive evidence shows any benefit from ACLS drug therapy, including epinephrine. Epinephrine is still the primary ACLS drug advocated in patients who are receiving CPR. This article is a review of recent data that suggest an urgent need to reassess how and to whom one administers epinephrine.
Physiologically, it is known that epinephrine augments coronary blood flow generated by CPR. This is enhanced by the vasoconstrictive properties of epinephrine that augment arterial, especially aortic, vascular tone following cardiac arrest. Enhanced vasoconstriction is considered essential to restore cardiac activity from the generation of adequate coronary artery perfusion pressures. It is generally assumed that the increased aortic pressure secondary to epinephrine sends more oxygenated blood into coronary arteries and increases the probability of ROSC via increased coronary perfusion. In fact, most studies do show that epinephrine will initially increase coronary blood flow and enhance ROSC compared with no epinephrine.
Epinephrine has alpha and beta effects, and the beta-adrenergic effects are generally undesirable for cardiac arrest patients. Beta-agonism stimulates tachycardia, and increases myocardial oxygen demand. Epinephrine can also promote platelet activation, potentially worsening acute coronary ischemia. Despite an initial increase in coronary perfusion pressure, epinephrine subsequently impairs myocardial function, thought to be due to beta-adrenergic-caused increases in myocardial oxygen in demand. Probably more importantly, epinephrine decreases capillary blood flow and constricts the cerebral micro vessels and brain capillaries, resulting in decreased CNS perfusion pressure, despite producing an increased pressure in large arteries. Overall, epinephrine increases the duration of cerebral ischemia during cardiac arrest. It is brain death that forecasts ultimate survival parameters.
One of the problems complicating an evaluation of epinephrine in cardiac arrest is that adverse effects on cardiac function or cerebral perfusion can occur many hours after CPR has been successful, and may not become clinically evident for a number of days. The author states that two recent randomized clinical trials provide no support for any true beneficial effect of epinephrine or enhanced patient-oriented outcomes in cardiac arrest. (JAMA 2009;302:2222; Resuscitation 2011;82:1138.) ROSC was higher for patients receiving epinephrine in both controlled trials, but the long-term outcome was much worse. Observational studies have also suggested that epinephrine, or increasing the epinephrine dose, is associated with worse survival rates and worse neurological outcome after cardiac arrest.
The author does hold out hope that pharmacological studies may identify ways to ameliorate the potential detrimental effect of epinephrine, including the use of nitroprusside or nitroglycerine. Theoretically, post-arrest vasodilation might improve cerebral perfusion, rescue brain, and promote better long-term outcome. Better initial resuscitation, then cerebral protection from adverse effects of epinephrine, is an intriguing concept that has not yet been explored in any detail.
Comment: This is one of the few articles on the use of epinephrine and cardiac arrest written by an emergency physician. It is generally a fine overview that brings home most of the important issues. Note that it was written before the Dumas article reviewed above. This author's conclusion is that the long-term detrimental effects of epinephrine during cardiac arrest are enough to justify using lower doses, none at all, or alternative regimens ameliorating epinephrine's effects post-cardiac arrest. I could not find a single article in the past three years that has proved a benefit of epinephrine in the long-term outcome of patients with cardiac arrest.
The issue of time of arrest versus time of epinephrine use requires some comment. There certainly appears to be no advantage of providing epinephrine in the ED, and likely no other intervention will help a patient with asystole after EMS intervention or someone who has had more than 10 to 15 minutes of cardiac arrest before ROSC or unknown downtime. These patients in the United States will have received epinephrine during their prehospital care. If out-of-hospital spontaneous circulation is not restored with CPR, intubation, or epinephrine, the outcome is likely obvious. Continuing to resuscitate an asystolic patient who has had current standard prehospital interventions, with or without epinephrine, is fruitless.
When one adds up the use of multiple hospital resources and personnel, false hope to family members, and the increased burgeoning cost of medical care, what we do post-arrest without proven benefit and potential harm seems illogical. Unfortunately, medicolegal action used to be nonexistent in the 80-year-old who arrived to the hospital in extremis, but this has changed. It seems to me that much of the hesitation to believe data and common sense is based on the fact that the American Heart Association still recommends epinephrine for cardiac arrest, so it is deemed standard of care. Given the numerous investigations, both randomized and observational of the subject, it is now time for this recommendation to be revisited.
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De-emphasis on Devices and ACLS Drugs during Cardiac Arrest
“At the time of the 2010 International Consensus Conference, there were still insufficient data to demonstrate that any drugs or mechanical CPR devices improve long-term outcome after cardiac arrest. Clearly further studies, adequately powered to detect clinically important outcome differences with these interventions, are needed.”
Source: Circulation 2010;122(18 Suppl 3):S640.
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Dr. Roberts: IV, O2, monitor is the mantra of emergency medicine. Now one of them is possibly going by the wayside. (“Supplemental Oxygen Can Worsen Outcome for STEMI Patients,” EMN 2015;37:10; http://bit.ly/1Jnjqbd.)
It has already been damned in CPR. In light of an article I read fairly recently, I have started putting my headache patients (tension, migraine, etc.) on high-flow oxygen for 15 to 30 minutes. (Am J Emerg Med 2012;30:1760.)
When do you think oxygen toxicity starts? From your article, it sounds like it can happen fairly quickly. Should I consider abandoning this practice? Do you think it does more harm than good? Thank you in advance. — Scott Goldstein, DO, Philadelphia
Dr. Roberts responds: There are no absolute answers to your excellent questions; the subject just has not been rigorously studied. I don't think 30 minutes of high-flow oxygen is harmful, although its value for headaches is questionable. Most ED patients, even those with acute MI, are not on 8 L/min for prolonged periods, which has been identified as the seemingly dangerous long-term oxygen concentration. The most logical tactic is to routinely limit oxygen concentration in the ED, restricting nasal flow rates to about 2-4 L/min, and continuing to lower that and the ventilator settings to keep oxygen saturation at about 95%. Most interesting is the potential for harm of 100% oxygen for the newborn, even those with low-oxygen saturations at birth; it's best to wait about eight to 10 minutes before expecting oxygen saturations in the mid- to high 90 percentiles. For some reason, we want to see all sick patients with saturations near 100%, and that for certain is not necessary.
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