Immediate Intravenous Epinephrine Versus Early Intravenous Epinephrine for Inhospital Cardiopulmonary Arrest

Abdullah Bakhsh; Maha Safhi; Ashwaq Alghamdi; Amjad Alharazi; Bedoor Alshabibi; Rajwa Alobaidi; Maryam Alnashri


BMC Anesthesiol. 2021;21(147) 

In This Article

Abstract and Introduction


Background: Intravenous epinephrine has been a key treatment in cardiopulmonary arrest since the early 1960s. The ideal timing for the first dose of epinephrinee is uncertain. We aimed to investigate the association of immediate epinephrine administration (within 1-min of recognition of cardiac arrest) with return of spontaneous circulation (ROSC) up to 24-h.

Methods: This was a multicenter retrospective analysis of patients who underwent cardiopulmonary resuscitation. We included the following patients: 1) ≥18 years-old, 2) non-shockable rhythms, 3) received intravenous epinephrine during cardiopulmonary resuscitation, 4) witnessed in-hospital arrest and 5) first resuscitation attempt (for patients requiring more than one resuscitation attempt). We excluded patients who suffered from traumatic arrest, were pregnant, had shockable rhythms, arrested in the operating room, with Do-Not-Resuscitate (DNR) order, and patient aged 17 years-old or less.

Results: A total of 360 patients were included in the analysis. Median age was 62 years old and median epinephrine administration time was two minutes. We found that immediate epinephrine administration (within 1-min) is associated with higher rates of ROSC up to 24-h (OR = 1.25, 95% CI; [1.01–1.56]), compared with early epinephrine (≥2-min) administration. After adjusting for confounding covariates, earlier administration of epinephrine predicted higher rates of ROSC sustained for up to 24-h (OR 1.33 95%CI [1.13–1.55]).

Conclusions: Immediate administration of epinephrine in conjunction with high-quality CPR is associated with higher rates of ROSC.


Epinephrine has been a key treatment in advanced cardiac life support (ACLS) since cardiopulmonary resuscitation (CPR) guidelines were first published in early 1960s.[1] The alpha-agonist effect of epinephrine causes increase in aortic diastolic pressure, augmenting the coronary and cerebral blood flow.[1] Various studies have shown that the use of epinephrine is associated with increase in return of spontaneous circulation (ROSC) rates because of its alpha-agonistic effects.[2,3] However, there is uncertainty about its effect on survival to hospital discharge and neurologic recovery.[4–6] Epinephrine may produce a mismatch between oxygen demand and delivery which could result 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 reveals constricted microvessels, with little or no perfusion to brain tissue. This effect is due to the alpha-1 agonist effects of epinephrine.[1,7,8]

Goto et al investigated the pre-hospital use of intravenous epinephrine and its effect on ROSC and neurological outcomes in large Japanese database. When given within 9-min of cardiac arrest, epinephrine is associated with higher rates of ROSC compared to patients who did not receive epinephrine. However, neurologic outcomes were poorer in patients receiving epinephrine at any given time during cardiac arrest.[5]

The American Heart Association (AHA) recommends giving epinephrine as early as possible then every 3–5 min thereafter.[9] 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 that delays in the administration of epinephrine are common in clinical practice. Thus, this is -found to be associated with worse outcomes in both adults and children.[12,13]

A study in 2014 utilized the AHA's Get With The Guidelines-Resuscitation (GWTG-R) database which included in-hospital arrest across 570 American hospitals. This study showed that earlier administration of epinephrine in patients with non-shockable cardiac arrest rhythms was associated with increased ROSC and survival. Moreover, a stepwise decrease in survival with every increase in interval of time to epinephrine.[12] Another study in 2016 also including in-hospital cardiac arrest from the GWTG-R database in US hospitals found improvements in ROSC and survival with functional recovery with timely administration of epinephrine.[14] A recent study in 2019 which examined the GWTG-R database in US hospitals revealed that delays in intravenous epinephrine administration was associated with lower survival.[15]

The lack of rigorous experimental studies on the clinical outcomes associated with epinephrine has led the resuscitation community to continue recommending epinephrine 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 8014 patients who underwent out-of-hospital cardiac arrest. Patients were randomized to receive either epinephrine (n = 4015) or placebo (n = 3999). Primary outcome was 30-day survival, and secondary outcomes were survival to hospital discharge and neurologically intact status. The authors found that the 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 demonstrated a lack of overall improvement neurologically in the epinephrine group, despite the higher rate of overall survival.[16,17] The authors postulate that despite the improvement in the 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 min. The significant difference in time frame precludes the generalizability to the in-hospital setting.

Although epinephrine can increase the likelihood of achieving ROSC, the optimal time of epinephrine is still uncertain.[17] It seems intuitive that immediate administration of epinephrine 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-min) with early administration of epinephrine (≥2-min) in sustained ROSC (≥20-min – 24-h) in non-shockable in-hospital cardiopulmonary arrest.