Adrenaline in cardiopulmonary resuscitation: time to rethink?

 

The potential efficacy of adrenaline in cardiac arrest was first highlighted by Criley and Dolley in 1901.(1) In a study of anesthetic agent or asphyxiation induced-cardiac arrest in dogs, the infusion of a therapeutic dose of adrenaline resulted in improved aortic blood pressures and enabled resuscitation. Subsequent animal studies by Redding et al. further emphasized the administration of adrenaline as a critical intervention for resuscitation from cardiac arrest.(2) The guidelines of the American Heart Association recommend intravenous administration of 1 mg adrenaline for every 3–5 minutes of cardiopulmonary resuscitation (CPR).(3)

Currently, there is strong evidence that early defibrillation and rapid initiation of effective chest compressions are important predictors of favorable clinical outcomes after cardiac arrest. However, there is considerable debate on whether the administration of boluses of adrenaline during CPR improves outcomes. In cardiac arrest, adrenaline is considered to cause alpha adrenergic receptor-mediated vasoconstriction with an increase the aortic diastolic pressure. An increase in the aortic diastolic pressure is believed to improve coronary blood flow during chest compressions and improve the overall likelihood of successful resuscitation.

However, adrenaline may exert deleterious effects during CPR through its beta-adrenergic receptor-mediated effects. Beta stimulation leads to increased myocardial oxygen demand, tachycardia, and tachyarrhythmias. The increase in oxygen demand may be particularly harmful in cardiac arrest provoked by ischemic heart disease. Besides, adrenaline is known to cause thrombogenesis and platelet activation, adversely affecting blood flow to vital organs, including the brain, and may lead to poor neurological outcomes.

Three randomized controlled studies (RCTs) have been carried out to evaluate the efficacy of adrenaline during CPR. Patients who suffered out of hospital cardiac arrest and received advanced cardiac life support by the Oslo Emergency Medical System were randomized to receive intravenous medication or no intravenous access.(4) Hospital admission with ROSC was significantly higher with intravenous medication; however, survival to hospital discharge, the primary outcome, was no different between groups. Furthermore, there was no difference in survival to a favorable neurological outcome nor the 1-y survival. Adrenaline was used in 79% of patients randomized to receive intravenous medication in this study. Patients who received adrenaline had a higher rate of ROSC; however, long term survival and functional recovery were significantly lower.(5)Another placebo-controlled RCT among out of hospital cardiac arrests attended by paramedics in Western Australia revealed very similar findings.(6) Pre-hospital ROSC was significantly higher with adrenaline administration; however, survival to hospital discharge was no different with adrenaline compared to placebo. A large, propensity-matched observational study was conducted in Japan to assess the effect of adrenaline in out of hospital cardiac arrest. The findings of this study were similar to the RCTs mentioned above. There was a significantly higher incidence of ROSC, with adrenaline use; however, survival to 1 month and neurological recovery were significantly lower.(7) These studies clearly demonstrate that though adrenaline may facilitate ROSC, survival to hospital discharge and neurological outcomes are unchanged or even worse.

The most recent and the largest randomized controlled trial that tested the efficacy of adrenaline in cardiac arrest was conducted by the ambulance services of the National Health Services in the UK.(8) As in previous studies, survival to hospital discharge was significantly higher with adrenaline compared to placebo (23.8 vs. 8%). Survival at 30 days, the primary outcome which the study was powered for, was poor in both arms, but significantly higher with adrenaline (3.2 vs. 2.4%). The number of patients who needed to be treated with adrenaline to save one life was 112. A favorable neurological outcome at hospital discharge was no different between groups; importantly, patients with a poor neurological outcome (a score of 4 or 5 on the Modified Rankin Scale) was much higher with adrenaline use (31.0% vs. 17.8%). This study strengthens the evidence that pre-hospital adrenaline administration as currently recommended may improve survival at the expense of poor neurological outcomes. The median time to administration of the study drug was about 21 minutes; hence the finding of this study are not extrapolatable to in-hospital cardiac arrests.

A 3-phase model has been proposed to postulate the physiological changes during CPR.(9) This model involves an early electrical phase extending from the onset of cardiac arrest to approximately 4 min, during which defibrillation and compressions are crucial. This is followed by the circulatory phase, between 4–10 min after cardiac arrest, during which interventions that improve tissue oxygen delivery are important, including adrenaline and continued compressions. Finally, the metabolic phase ensues after 10 min. Adrenaline may worsen outcomes during this phase by increasing the oxygen demand, thus worsening myocardial ischemia, and may also lead to thrombogenesis and an increase in lactate levels. The observational study from Osaka seems to support this hypothesis.(7)

Does the time-honoured dose of 1 mg of adrenaline, based mainly on older animal models need to be modified? Intuitively, it would seem to be a mega-dose, especially if one considers the physiological effect of such a large bolus. Perhaps a smaller dose, delivered as an infusion, may be more appropriate and needs investigation.(10) Besides, a dosing interval of longer than 5 min may be more optimal.(11)

Summary

• Adrenaline improves coronary blood flow by increasing the aortic diastolic pressure; however, it increases the myocardial oxygen demand. Platelet activation and propensity to thrombogenesis may lead to poor outcomes.
• There is robust evidence that adrenaline administration facilitates ROSC; however, neurological outcomes are unchanged or even worse.
• Adrenaline administration later during CPR may not be effective.
• Future research should focus on the timing and a lower dose of adrenaline, possibly as an infusion compared to bolus doses.

 

References

1. Crile G, Dolley DH. An experimental research into the resuscitation of dogs killed by anesthetics and asphyxia. J Exp Med. 1906 Dec 21;8(6):713–25.
2. Redding JS. Resuscitation from ventricular fibrillation. Drug therapy. JAMA J Am Med Assoc. 1968 Jan 22;203(4):255–60.
3. Neumar Robert W., Shuster Michael, Callaway Clifton W., Gent Lana M., Atkins Dianne L., Bhanji Farhan, et al. Part 1: Executive Summary. Circulation. 2015 Nov 3;132(18_suppl_2):S315–67.
4. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous Drug Administration During Out-of-Hospital Cardiac Arrest. :8.
5. Olasveengen TM, Wik L, Sunde K, Steen PA. Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial. Resuscitation. 2012 Mar;83(3):327–32.
6. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011 Sep;82(9):1138–43.
7. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012 Mar 21;307(11):1161–8.
8. Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018 Aug 23;379(8):711–21.
9. Weisfeldt ML, Becker LB. Resuscitation After Cardiac Arrest: A 3-Phase Time-Sensitive Model. JAMA. 2002 Dec 18;288(23):3035.
10. Arrich J, Sterz F, Herkner H, Testori C, Behringer W. Total epinephrine dose during asystole and pulseless electrical activity cardiac arrests is associated with unfavourable functional outcome and increased in-hospital mortality. Resuscitation. 2012 Mar;83(3):333–7.
11. Warren SA, Huszti E, Bradley SM, Chan PS, Bryson CL, Fitzpatrick AL, et al. Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation. 2014 Mar;85(3):350–8.