Epinephrine in cardiac arrest: systematic review and meta-analysis

abstract Objective: evaluate the effectiveness of epinephrine used during cardiac arrest and its effect on the survival rates and neurological condition. Method: systematic review of scientific literature with meta-analysis, using a random effects model. The following databases were used to research clinical trials and observational studies: Medline, Embase and Cochrane, from 2005 to 2015. Results: when the Return of Spontaneous Circulation (ROSC) with administration of epinephrine was compared with ROSC without administration, increased rates were found with administration (OR 2.02. 95% CI 1.49 to 2.75; I2 = 95%). Meta-analysis showed an increase in survival to discharge or 30 days after administration of epinephrine (OR 1.23; 95% IC 1.05-1.44; I2=83%). Stratification by shockable and non-shockable rhythms showed an increase in survival for non-shockable rhythm (OR 1.52; 95% IC 1.29-1.78; I2=42%). When compared with delayed administration, the administration of epinephrine within 10 minutes showed an increased survival rate (OR 2.03; 95% IC 1.77-2.32; I2=0%). Conclusion: administration of epinephrine appears to increase the rate of ROSC, but when compared with other therapies, no positive effect was found on survival rates of patients with favorable neurological status.


Introduction
Cardiorespiratory arrest is the sudden and unexpected cessation of breathing and spontaneous circulation, that can be restored to a previous status, in those in whom a fatal outcome was not expected at that time (1) . This is a major problem worldwide because the incidence is estimated at around 55 out-of-hospital cardiac arrests in adults per 100,000 people, of whom only 7% survive (2) .
As regards in-hospital cardiac arrests, relevant findings in the literature were scarce, but estimates indicate that the incidence could be between 1 and 5 cases per 1.000 admissions per year, and the overall survival varies between 10% and 42% (3) . With the present evidence, the use of epinephrine in cardiac arrest is recommended as class IIb (4) . This should be considered, as the benefits may outweigh the risks; therefore both organizations recommend the use of 1 mg of epinephrine every 3-5 min. However AHA has indicated that 40UI of vasopressin may replace the first or second dose of epinephrine (5)(6)(7)(8)(9) .
Epinephrine is one of three natural catecholamines, along with norepinephrine and dopamine, that has a potent stimulatory action on α and β receptors distributed throughout the body; in the heart increases the flow speed, the heart rate and the force of contraction (chronotropic and inotropic effects on the heart) therefore increases the volume per minute, the systolic blood pressure and simultaneously the myocardial oxygen consumption. High doses produce extrasystoles and cardiac arrhythmias; they (high doses) also produce a rise in blood pressure (especially diastolic) that facilitates venous return and ventricular filling during diastole by stimulating α and β receptors. This increases total peripheral resistance, thus causing an increase in differential tension and tachycardia. If hypertension is high it can cause reflex bradycardia.
Excessive and prolonged activation of the myocardium is dangerous; this could cause improper increased oxygen consumption and micro injuries that may appear in the vessels and myofibrils (10) .
Based on the foregoing discourse, the question arises about the effect of epinephrine on survival of patients suffering cardiac arrest and on the neurological status of survivors of these cardiac events.
The objective of the review was to investigate the scientific production and evaluate the effectiveness of epinephrine in treatment of cardiac arrest in terms of survival and neurological status.

Method
A systematic review of the scientific literature was performed, with meta-analysis of the results. The search was conducted in Medline, Embase and Cochrane databases, between 01/01/2005 and 02/28/2015, using free-text terms and MeSH terms: "Heart arrest", "Outof-Hospital Cardiac Arrest", "Death, Sudden, Cardiac", "Ventricular Fibrillation", "Pulseless Electrical Activity" plus the Boolean operator "AND" with the terms "epinephrine", "adrenaline" (Figure 1). This search strategy was adapted to other databases. The full search strategy can be provided by the authors.

Outcome measures
The main outcome measure was survival to discharge/30 days. Secondary outcome measures were: survival to discharge/30 days with favorable neurologic status, one year survival, and one year survival with

Descriptive and thematic analysis
The STROBE questionnaire was used to assess the quality of observational studies, and the CONSORT questionnaire to evaluate clinical trials (13)(14) .
Data on clinical outcomes were grouped into short term and long term -the most common forms in cardiac arrest studies. The outcome measures were defined as follows: 1) return of spontaneous circulation, as an outcome measure in the short term and 2) survival to discharge/30 days, as an outcome measure in the long term. In the latter, the patient survived ≥30 days after cardiac arrest or left the hospital alive with favorable neurological function, obtaining a score in the categories of Glasgow-Pittsburgh brain performance of 1 (good cerebral performance) or 2 (moderate cerebral disability).

Meta-analysis
Due to the heterogeneity of the effects contained in the studies included, data were analyzed using the

Subgroup analysis
Interventions and outcome measures (when stratified data by initial heart rhythm were found) were stratified by initial rate of cardiac arrest: shockable rhythm (ventricular fibrillation and pulseless ventricular tachycardia) and non-shockable rhythm (pulseless electrical activity and asystole).

Characteristics of studies included
After eliminating duplicate citations, 2239 references were identified. Of these, 9 randomized clinical trials and 17 observational studies were included.
Details of studies selected are shown in Figure 2.       Only one observational study (37)

Epinephrine vs. Epinephrine + vasopressin + nitroglycerin
A randomized clinical trial compared the administration of epinephrine with epinephrine combined with vasopressin and nitroglycerin. In this study there was no significant difference between the combination and epinephrine alone (19) .

Early administration of epinephrine vs. late administration of epinephrine
Two observational studies (n=49.851 patients included in these studies) compared early administration of epinephrine (before 10 minutes) with late administration (after 10 minutes) (27,33) .
The meta-analysis showed an increase in survival to hospital discharge/30 days for early administration (before 10 minutes) when compared with late administration (OR 2.03; 95% IC 1.77-2.32; I 2 =0%).
An observational study (18) showed a decrease in survival to hospital discharge/30 days, when epinephrine was administered in more than 9 minutes (OR 0.63; 95% IC 0.52-0.76).

Time between doses of epinephrine
An observational study that compared the time between doses of epinephrine during cardiac arrest (40) observed that when doses far apart (more than 5 minutes) were compared with administration every 1-5 minutes, the former decreases the survival rate (OR 2.17; 95% IC 1.62-2.92).
The summary of results is shown in Table 1.

Discussion
In this systematic review and meta-analysis, a comparison was evaluated of epinephrine effectiveness during cardiac arrest with the use of other therapeutic options.
We did not find other comprehensive reviews and meta-analysis evaluating doses of epinephrine, time between doses, cumulative doses and short-term and long-term effects, especially in terms of neurological status. Instead we found systematic reviews and meta-analysis, in which the effect of epinephrine was compared with the use of other therapies for cardiac arrest.
Regarding the survival to hospital discharge/30 days when epinephrine was administered in comparison with no administration of the drug, we found contradictory outcomes. The administration of epinephrine improved the rate of survival to hospital discharge/30 days (37) .
However, another research (21) stated otherwise; however, when the results were stratified by initial non-shockable rhythm the two findings coincided.
Ong et al. (38) stated that there were no clear benefits administering epinephrine or not, thus this author was in agreement with Dumas et al. (20) , who supported better outcomes when epinephrine was not administered. In their randomized clinical trial (39) the combination of epinephrine and vasopressin did not increase the longterm survival rates, but they noted an increase in the number of patients arriving at the hospital admission with spontaneous circulation. On the contrary (23) , they established favorable results for the group of patients who received epinephrine as a single therapy, but the difference in comparison with the combination of epinephrine and vasopressin, was not significant.
Our findings suggested that epinephrine increased the achievement of the return of spontaneous circulation, especially when epinephrine was administered in a short period of time. This result was corroborated by other systematic reviews and meta-analysis that support the benefit of epinephrine in terms of shortterm survival (42)(43)(44)(45)(46)(47)(48) .
As regards the neurological status, we found no significant differences, but the results seemed Rev. Latino-Am. Enfermagem 2016;24:e2821 to show a decrease in rates of favorable neurological status when epinephrine was used, especially when doses were higher; However an increase in rates of favorable neurological status was found when combined vasopressin and epinephrine were administered, which was in disagreement with the systematic review with meta-analysis (45) . The authors stated that the increase in rates of favorable neurological status were higher in patients receiving standard doses of epinephrine.
We assumed that this decline in survival rates might be due to variations in heart rhythm induced by epinephrine in patients with reversed cardiac arrest, since this drug caused more instability in heart rhythm and complicated the patient's treatment (35)(36) .
We could also assume that epinephrine tended to decrease the long-term survival rates, since it caused cardiac damage and increased consumption of oxygen in myocardial tissue.
Researchers found that patients treated with epinephrine for cardiac arrest and died, suffered subendocardial hemorrhage; this aspect was observed in forensic studies.
Our systematic review and meta-analysis had limitations. Firstly, most of the articles included were observational studies; therefore these uncontrolled studies included more bias in the results of the review.

Conclusion
The scientific evidence on the use of epinephrine in cardiorespiratory arrest was contradictory. We found epinephrine administration to be beneficial for the return of spontaneous circulation during resuscitation maneuvers; however, we did not find this benefit in the survival rate up to the time of discharge from hospital, in the long-term and on the neurological status of patients.
We believe it is necessary to conduct highquality studies that take into account confounding variables, such as the quality of resuscitation, route of administration and numbers of doses, with the purpose of confirming the findings based on sufficient evidence.