Epinephrine has been a key treatment of advanced cardiac life support (ACLS) since cardiopulmonary resuscitation (CPR) guidelines were first published in early 1960s.  Epinephrine’s alpha-agonist effect causes increased aortic diastolic pressure, thereby augmenting coronary blood flow and cerebral blood flow.  Various studies have shown that Epinephrine is associated with increased return of spontaneous circulation (ROSC) rates, owing to the alpha-agonistic effects. [2, 3] However, there is uncertainty about its effect on survival to hospital discharge and neurologic recovery. [4, 5, 6] On the other hand, Epinephrine may produce a mismatch between oxygen demand and delivery which results in lactic acidosis. Moreover, the vasoconstrictor effects may prolong ischemia in some tissues. This has been seen particularly in Swine brain. [7, 8] In fact, direct visualization of brain capillaries reveal constricted microvessels, with little or no perfusion to brain tissue. This effect was attributable to the alpha-1 agonist effects of Epinephrine. [1, 7, 8]
Goto et al, looked at the pre-hospital use of intravenous Epinephrine and its effect on return of spontaneous circulation and neurological outcomes. When given within 9-minutes of cardiac arrest, Epinephrine is associated with higher rates of return of spontaneous circulation (ROSC), when compared with patients not receiving Epinephrine. Neurologic outcomes, however were poorer in patients receiving Epinephrine at any given time during cardiac arrest. 
The American Heart Association (AHA) recommends administering Epinephrine as early as feasibly possible and thereafter, every 3–5 minutes.  Various trials suggest a time-dependent effect of Epinephrine on outcomes of CPR; earlier administration of intravenous Epinephrine may improve outcomes. [10, 11] However, previous studies have shown delays in the administration of epinephrine are common in clinical practice, and thus found to be associated with worse outcomes in both adults and children. [12, 13]
A study in 2014 showed that earlier administration of epinephrine in patients with non-shockable cardiac arrest rhythms are associated with increased ROSC and survival. Moreover, a stepwise decrease in survival with every increase in interval of time to epinephrine.  Another study in 2016 found that there were improvements in ROSC and survival with functional recovery with timely administration of Epinephrine.  Recently, in 2019 a study revealed that delays in intravenous epinephrine administration was associated with lower survival. 
The lack of rigorous experimental studies on the clinical outcomes associated with epinephrine has led the resuscitation community to continue to recommend its use in cardiac arrest. However, the PARAMEDIC-2 trial might change the way clinicians think about Epinephrine. The study, conducted by Perkins et al. in the United Kingdom, included 8,014 patients with out-of-hospital cardiac arrest. Patients were randomized to receive either epinephrine (n = 4,015) or placebo (n = 3,999). Primary outcome was 30-day survival, and secondary outcomes included survival to hospital discharge and neurologically intact status. The authors found that administration of epinephrine increased 30-day survival rates (3.2% in the epinephrine group, compared to 2.4% in the placebo group). However, a larger proportion of patients in the epinephrine group were neurologically devastated, with modified Rankin scores of 4–5 (31% in the epinephrine group, compared to 17.8% in the placebo group). This result explains the lack of overall improvement in neurologically intact survival in the epinephrine group, despite the higher rate of overall survival. [16, 17] The authors postulate that, despite improving macrovascular cerebral perfusion pressures, epinephrine may cause microvascular ischemia in the brain, thereby worsening anoxic brain injury. A key finding of the PARAMEDIC-2 trial is that the mean time to Epinephrine administration was 21.5 minutes. This dramatic different time frame precludes generalizability to the in-hospital setting.
Although Epinephrine can increase the likelihood of achieving ROSC, the optimal time of Epinephrine is still uncertain.  It seems intuitive that immediate administration of epinephrine in combination with cardiopulmonary resuscitation will maintain perfusion and therefore, reduce bad outcomes. Our primary objective is to compare the association of immediate administration of epinephrine (within 1-minute) with early administration of epinephrine (≥ 2-minutes) with sustained ROSC (≥ 20-minutes – 24-hours) and ROSC for more than 24-hours in non-shockable in-hospital cardiopulmonary arrest.