Callaway, Clifton W.
Cardiac arrest is the sudden cessation of cardiac mechanical activity because of dysrhythmia or electromechanical dissociation. Unless reversed within minutes, cardiac arrest results in lethal brain and other end-organ damage. Meaningful patient outcomes require not only restoration of effective cardiac activity but also reversal and mitigation of whole-body ischaemia and reperfusion.
Better outcomes result with rapid initiation of chest compressions, rapid electrical defibrillation of ventricular dysrhythmias and induction of mild hypothermia for 12–24 h after restoration of pulses . However, only weak evidence is available for all other interventions, including all drug therapy during cardiac arrest. Epinephrine is the primary drug advocated for patients who are receiving chest compressions during cardiac arrest .
Recent clinical data suggest that epinephrine administered during cardiac arrest may actually be harmful for subsets of patients. This review highlights recent data and proposes that there is an urgent need to reassess how and to whom we administer epinephrine.
MECHANISMS OF ACTION
Epinephrine augments coronary blood flow generated by chest compressions during cardiopulmonary resuscitation (CPR). Coronary perfusion pressure, operationally defined as the difference between aortic blood pressure and the right atrial pressure, is the major determinant of coronary blood flow. When CPR does not generate coronary perfusion pressure of more than 15–20 mmHg, return of spontaneous circulation (ROSC) rarely or never occurs . After more than a few minutes of cardiac arrest, arterial tone collapses and epinephrine or another vasoconstrictor is essential for restoration of cardiac activity [3–5].
Epinephrine increases aortic pressure during chest compressions via alpha-adrenergic constriction of arterioles, which increases pressure in the proximal aorta . Increased aortic pressure may shunt more blood into the coronary arteries and increase the probability of ROSC.
POTENTIAL DETRIMENTAL EFFECTS OF EPINEPHRINE
Beta-adrenergic effects of epinephrine are generally undesirable for cardiac arrest patients. Beta-adrenergic stimulation causes tachycardia, tachydysrhythmias and increased myocardial oxygen demand. Epinephrine can promote thrombogenesis and platelet activation . Acute coronary syndromes are the most common cause of sudden cardiac arrest in a series of resuscitated out-of-hospital cardiac arrest patients . Increased platelet activity might worsen this acute coronary ischaemia.
Epinephrine impairs myocardial function despite increasing coronary perfusion pressures. After 10 min of CPR in dogs, myocardial ATP depletion and lactate accumulation increased after epinephrine administration despite an increase in coronary blood flow . This effect was attributed to beta-adrenergic inotropic and chronotropic increases in myocardial oxygen demand. Epinephrine also exacerbates rat myocardial dysfunction after 4 or 8 min of cardiac arrest . Epinephrine-induced post-CPR myocardial dysfunction is temperature dependent . When rat temperature was lowered to 34°C, epinephrine reduced post-CPR myocardial dysfunction. These data support the idea that epinephrine produces a mismatch between oxygen delivery and consumption, because temperature reductions will slow metabolism and oxygen demand.
Vasoconstriction induced by epinephrine prolongs ischaemia in some tissue beds during and after CPR . In particular, epinephrine reduces capillary blood flow in swine brain [13,14]. Direct visualization of brain capillaries demonstrated that epinephrine constricted microvessels, with little or no perfusion of the tissue despite increased pressure in the large arteries. Confirming this hypoperfusion, brain tissue pO2 declined and pCO2 increased, and carotid blood flow increased minimally. Cerebral hypoperfusion was attributable to the alpha-1 agonist effects of epinephrine. Epinephrine-induced hypoperfusion persisted during CPR and for at least 10 min after ROSC. Therefore, epinephrine treatment more than doubled the total duration of cerebral ischaemia during a brief cardiac arrest.
After more prolonged cardiac arrest in swine, epinephrine administered after 6 min of untreated cardiac arrest and 3 min of CPR increased carotid artery pressure, but reduced carotid artery blood flow [15▪]. This study focused only on cerebral perfusion during CPR. However, the previous results suggest that reductions in microvascular blood flow persist after ROSC.
Clinically, persistent signs of hypoperfusion after ROSC have been related to the total dose of epinephrine administered during CPR in observational studies . These observations about epinephrine effects are not limited to cardiac arrest patients. A recent study compared epinephrine infusion with norepinephrine-dobutamine infusions in patients with cardiogenic shock . Epinephrine prolonged lactic acidaemia and reduced gastric mucosal perfusion assessed with gastric tonometry.
PRIOR CLINICAL EXPERIENCE
There are no convincing dose–response data for epinephrine use during cardiac arrest and long-term outcome. The original studies in 20–30 kg dogs used a 1-mg dose of epinephrine, which has been the standard for adult patients ever since. [3,4]. Recognizing that adult humans were larger than dogs, multiple clinical trials examined the efficacy of doses of epinephrine above 1 mg [18–21]. These studies were consistent in showing no incremental increase in survival, even when higher doses increased the rate of ROSC [18,19].
Epinephrine has been compared with several vasoactive medications that might increase coronary perfusion pressure in clinical trials [19,22,23]. In particular, studies have found no consistent superiority of epinephrine over other alpha-adrenergic agonists or more recently vasopressin. None of these studies included placebo-treated groups that received no vasopressor.
ASSESSING THE HARM–BENEFIT RATIO
Interpretations of the net effect of epinephrine vary depending on when patient outcomes are assessed (Fig. 1). Adverse effects of epinephrine on cardiac function or perfusion may occur hours after CPR and effects on neurological or other organ function may become evident over days.
If beneficial effects outweigh harmful effects, increased ROSC will be accompanied by increased survival and favourable outcome. If harmful effects outweigh beneficial effects, increased ROSC will be followed by greater in-hospital mortality and lower favourable outcome. A third possibility, ‘futility’, would occur if epinephrine increased ROSC only in patients in whom brain injury or other disease had already progressed to a lethal state, or if the detrimental and beneficial effects of epinephrine were exactly balanced. In this ‘futile’ scenario, temporary ROSC in some patients who are too sick to survive will not cause any net change in survival or favourable outcome.
RANDOMIZED CONTROLLED TRIALS
Two randomized clinical trials provide no support for a beneficial effect of epinephrine on patient-oriented outcomes. The final sample sizes for both studies lacked power to make definitive statements about functional outcomes.
In Oslo, adult, out-of hospital cardiac arrest patients were randomly allocated to have intravenous drugs versus no intravenous drugs [24,25▪]. Allocation was achieved by opening a sealed envelope immediately after emergency responders confirmed cardiac arrest. In one group of patients, an intravenous line was started and drugs were allowed during CPR. In the other group of patients, no intravenous line was started until after ROSC. Blinding of the emergency responders to group allocation was impossible.
Among 1183 patients assessed for eligibility, 916 were successfully randomized. Investigators excluded 65 randomized patients who did not meet a-priori inclusion criteria, leaving 851 patients in the primary analysis: 433 with no intravenous access and 418 with intravenous access. In 45 patients (10%) assigned to no intravenous line, an intravenous drug administration did occur later in the resuscitation (n = 40) or due to breach of protocol (n = 5). In 74 patients (17%) assigned to have an intravenous line, no line could be established prior to the end of resuscitation.
Patients with an intravenous line had a higher rate of return of pulses (40 versus 25%) and admission to the ICU (30 versus 20%). However, the proportion discharged from the hospital (10.5 versus 9.2%) or alive at 1 year (10 versus 8%) did not differ. The most common intravenous drug administered was epinephrine (79% of patients).
A post-hoc analysis compared outcomes between patients who received epinephrine and those who did not receive epinephrine [25▪]. The comparison groups align very closely with the randomized treatment groups. For patients who received epinephrine (n = 367) versus those who did not receive epinephrine (n = 481), rates of admission to the ICU increased (28 versus 23%). However, smaller proportions were discharged from the hospital (7 versus 13%), recovered functionally (5 versus 11%) or survived to 1 year (6 versus 12%).
In Australia, investigators compared survival when adult, out-of-hospital cardiac arrest patients received standard 1-mg boluses of epinephrine versus placebo [26▪▪]. Random allocation and blinding were achieved by supplying paramedics with identical vials that contained either 1 mg/ml epinephrine or saline placebo. Among 1586 patients with resuscitation attempted by paramedics, 602 were randomized. After exclusion of 67 patients (11%) who did not meet inclusion criteria, 535 patents were included in the primary analysis: 273 receiving epinephrine and 262 receiving placebo.
Patients who received epinephrine had higher rates of return of pulses (30 versus 11%) and admission to the hospital (25 versus 13%). However, the proportion discharged from the hospital (4.1 versus 1.9%) or with a favourable recovery (3.3 versus 1.9%) did not differ. Unfortunately, this study did not continue to its intended enrolment because of funding and loss of support from the participating paramedics.
Receiving epinephrine and increasing epinephrine dosage are associated with worse survival and neurological outcome after cardiac arrest [27,28]. These observational studies are confounded by the fact that epinephrine is only administered when initial CPR or defibrillation is unsuccessful. In addition, the total dose of epinephrine administered is proportional to how long a patient remains in cardiac arrest, resulting in higher doses for patients who fail to respond to initial treatment. Therefore, adverse relationship between epinephrine dose and outcome is largely attributed to systematic bias in study design.
In several countries, detailed data were collected spanning the time period when regulations or protocols introduced epinephrine into clinical practice for paramedics or out-of-hospital providers. These before–after studies have the advantage that control patients exist who would have received epinephrine prior to the administrative changes. In Norway, introduction of epinephrine increased ROSC but was not associated with any large increase in survival . Neurological outcomes were not assessed. In Singapore, the introduction of epinephrine did not alter ROSC, survival or neurological outcome . However, overall rates of survival were very low in that system.
An extremely large and well-controlled observational study from Japan suggests that epinephrine drug therapy during cardiac arrest is associated with lower long-term survival and worse neurological outcome despite its short-term benefit [31▪▪]. Using a database of all persons in Japan treated for out-of-hospital cardiac arrest over 4 years (n = 417 188), investigators compared outcomes for patients who were treated with epinephrine (n = 15 030) with those who received no prehospital epinephrine (n = 402 158). Patients only received epinephrine after a change in scope of practice in 2006 that allowed emergency responders to administer drugs. Different regions implemented epinephrine use at different times, providing concurrent controls for the study.
In the unadjusted analysis of the Japanese data, epinephrine administration was associated with higher rates of return of pulses [18.5 versus 5.7%; odds ratio (OR) 3.75; 3.59–3.91] and 1-month survival (5.4 versus 4.7%; OR 1.15; 1.07–1.23). However, neurologically favourable survival was significantly less in the epinephrine group (1.4 versus 2.2%; OR 0.63; 0.55–0.73). There were some baseline differences between the groups that actually should have biased this study towards better outcomes in the epinephrine group. The epinephrine group had higher rates of witnessed collapse, bystander CPR and initial ventricular fibrillation (VF) rhythm. Even after adjustment for these covariates, epinephrine was associated with higher rates of return of pulses (OR 3.06; 2.93–3.21), but lower 1-month survival (OR 0.43; 0.39–0.46) and neurologically favourable survival (OR 0.21; 0.18–0.24).
A carefully matched comparison took advantage of the large number of available observations. Patients who received epinephrine (n = 13 401) were matched with control patients who did not receive epinephrine (n = 13 401) using a propensity score. This process resulted in two groups with very similar baseline characteristics. Again, epinephrine use was associated with increased rates of return of pulses (18.3 versus 10.5%, OR 1.91; 1.76–2.05), but decreased rates of 1-month survival (5.1 versus 7.0%; OR 0.71; 0.64–0.79) and neurologically favourable survival (1.3 versus 3.1%; OR 0.41; 0.34–0.49). These results confirm the overall comparison.
Finally, these authors addressed the concern that patients who did not receive epinephrine in the prehospital setting might have received epinephrine later at the hospital. Patients with return of pulses in the field would have no reason to receive in-hospital epinephrine. Among these patients, 1-month survival was lower in the epinephrine group (18.0 versus 46.8%), as was neurologically favourable survival (4.7 versus 25.0%). Therefore, the pattern of results is consistent across all analyses and sensitivity analyses, adjusting for multiple potential confounding variables.
TIMING OF DRUG ADMINISTRATION AND DIFFERENTIAL EFFECTS IN SUBSETS OF PATIENTS
Variable timing of epinephrine administration confounds most clinical studies. Efficacy of epinephrine declines with duration of cardiac arrest. For example, multiple swine studies in a single laboratory suggested that the efficacy for epinephrine is almost essential for ROSC after 5–10 min but declines after 15–20 min . An observational study [33▪] of 3161 cardiac arrests in Osaka, Japan, compared patients who did versus those who did not receive epinephrine and analysed the timing of epinephrine administration. The pattern of results in this subset confirmed the short-term benefit and long-term detriment observed in the national Japanese data [31▪▪]. Interestingly, epinephrine administered within 10 min of cardiac arrest to patients with VF was associated with better functional outcomes. In most clinical studies, the timing of drug administration is not reported, and future trials should measure this important covariate.
Current data do not support administration of epinephrine to all patients with cardiac arrest (Fig. 2). However, there may be subgroups of patients for whom epinephrine does improve outcomes. In observational studies, epinephrine worsened long-term outcomes mostly in patients with VF [31▪▪], though the subset from Osaka also showed long-term detriment in non-VF cardiac arrest [33▪]. This statistical difference may simply result from the fact that overall survival is higher in patients with VF, allowing greater power to see a negative effect. However, patients with VF are most likely to have acute coronary syndromes, which could be exacerbated by vasoconstriction, positive chronotropy and thrombogenesis. Nevertheless, future studies should consider whether differential effects of epinephrine are observed in clinically distinct subsets of patients, such as non-VF cardiac arrest, or at distinct times after cardiac arrest.
POTENTIAL FUTURE DIRECTIONS
Novel pharmacological strategies have been explored to ameliorate the potential detrimental effects of epinephrine. For example, microvascular hypoperfusion might be ameliorated by concurrent administration of vasodilating drugs. In fact, nitroprusside  or nitroglycerin  with epinephrine improves organ perfusion and short-term outcomes in animals. Whether these drugs act primarily via vasoactive properties or have direct cellular effects remains to be determined. Nitrite administration after restoration of pulses also improves outcomes, perhaps via direct action on mitochondria , and is safe in humans . These studies illustrate that future research may centre on promotion of microvascular flow rather than maximizing pressures in large arteries.
Studies of epinephrine do not provide clear evidence for long-term patient benefit with indiscriminate use of 1-mg boluses (0.05–0.1 mg/kg) of epinephrine during CPR. Nonrandomized studies [27–29,31▪▪,33▪] suggest that neurological outcomes may be worse with epinephrine. Basic science provides some possible explanations for this effect, including reductions of microvascular blood flow despite macroscopic increases in perfusion pressures. Until recently, the short-term benefit for restoration of circulation justified continued use of epinephrine despite uncertainty about the long-term effects. Now that studies suggest long-term detrimental effects of this drug, there should be sufficient clinical equipoise to justify prospectively testing lower doses or alternative regimens for epinephrine during cardiac arrest.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 81–82).
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