Podcast #105 - PARAMEDIC2: It's Time to Call the Code on Epinephrine (Adrenaline)

Epinephrine (adrenaline) has been a hallmark of cardiac arrest management as an attempt to obtain a return of spontaneous circulation (ROSC).  However, the evidence for epinephrine in out-of-hospital cardiac arrest (OHCA) as well as in the hospital (IHCA) has been conflicting.  We review the largest trial to date just recently published in the New England Journal of Medicine (NEJM).

Title:
Perkins, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest NEJM July 18, 2018 
 
Case:
You are called to the home of a 64 y/o female who suddenly collapsed after reporting chest pain to her spouse.  Family called 911 and initiated bystander CPR while waiting for fire and EMS to arrive approximately 8 minutes later.  After providing high-quality CPR and defibrillating for ventricular fibrillation, ROSC has not yet been achieved.  As the team leader, you start considering if epinephrine should be administered after this initial shock.
 
Background:
There has been a lot of debate on the potential risks and benefits of epinephrine for cardiac arrest, but there has been a demand for a large RCT to help answer the question.  Epinephrine has been a part of cardiac arrest protocols since the 1960s.  Its alpha-adrenergic effects of constriction increases aortic diastolic pressure (what is needed for increasing coronary blood flow) to help increase the chances of ROSC but at the cost of impairing microvascular blood flow including to the cerebral cortex.  Also, the beta-adrenergic effects of epinephrine can cause dysrhythmias, increased myocardial oxygen demand, and increases the risk of recurrent cardiac arrest.
 
Clinical Question:
Is epinephrine beneficial in the treatment of out-of-hospital cardiac arrest?
 
Reference:

• Population: Adult patients who had sustained an out-of-hospital cardiac arrest for which advanced life support was provided by trial trained paramedics.      
  • Exclusion Criteria: Patients with known or apparent pregnancy, age less than 16 years, cardiac arrest from anaphylaxis or asthma, or administration of epinephrine prior to arrival of a trial-trained paramedic.  Additionally, London Ambulance Service also excluded traumatic cardiac arrests.
• Intervention: 1mg of epinephrine given every 3-5 minutes with a total of 10 prefilled syringes possible for delivery. 
• Comparison: Placebo of 0.9% normal saline with a total of 10 prefilled and identical appearing syringes possible for delivery.
• Outcome: The primary outcome was the rate of survival at 30 days.

 
Author’s Conclusions:
In adults with OHCA, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group different in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.
 
Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the ED. Not directly as all patient may not have been transported, but this was an EMS study and still very important
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. Yes
4. The patients were analyzed in the groups to which they were randomized. Yes
5. The study patients were recruited consecutively (i.e. no selection bias). Yes, but a large set of patients were excluded because they achieved ROSC prior to enrollment
6. The patients in both groups were similar with respect to prognostic factors. Yes
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
8. All groups were treated equally except for the intervention. Yes
9. Follow-up was complete (i.e. at least 80% for both groups). Yes
10. All patient-important outcomes were considered. Yes, but it was not the primary outcome
11. The treatment effect was large enough and precise enough to be clinically significant. No

 
Key Results:
A total of 10,623 patients were screened for eligibility for which 8103 were randomized (trial pack opened) and 8016 were enrolled in the trial (pack opened and drug administered).  4015 patients received epinephrine while 3999 received placebo.  Only 7 total patients (3 from the epinephrine group and 4 from the placebo group) were excluded from the primary outcome.  130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive at 30 days (unadjusted odds ratio for survival 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02) with a fragility index of 6.  In regards to discharge from the hospital with a favorable neurological outcome (modified Rankin scale [mRS] of 3 or less) was 87 of 4007 patients (2.2%) in the epinephrine group) and 74 of 3994 (1.9%) in the placebo group  but was not statistically significant (unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61).  A mRS of 4 or 5 was considered severe neurological impairment and at hospital discharge 39 of the 126 patient (31.0%) in the epinephrine group had this versus only 16 of 90 (17.8%) in the placebo group.

Key Points of Debate:

• This was a well done study in another country, but guidelines are slightly different.
  • With the study being in the United Kingdom, the European Resuscitation Council's (ERC) guidelines are being followed versus ACLS.
  • In the event of shockable rhythms, ERC recommends epinephrine only after the third shock versus ACLS which encourages this use earlier no matter if it is shockable or not a shockable rhythm.
  • Given that there has been evidence that earlier epinephrine administration has improved rates of ROSC, we should consider that there could be a potential difference.
  • However, the ERC guidelines have some basis in evidence published in the BMJ that earlier epinephrine after the first defibrillation had decreased odds of survival.
  • The average time to administration of the trial agent was approximately 21 minutes which is most likely delayed enough that epinephrine may not be as beneficial.
  • There has been the suggestion that there are three phases of cardiac arrest and the circulatory phase may extend out to 15 minutes.
    • Electrical phase: most likely phase where defibrillation may have best chance in achieving ROSC (often though at the first four minutes of arrest)
    • Circulatory phase: usually thought of as first 4-10 minutes but could be longer as is the stage where epinephrine may be the most beneficial given that the heart is globally ischemic and a combination of high-quality CPR and epinephrine could improves odds of successful defibrillation.
    • Metabolic phase: often thought of as after 10 minutes, this phase is where there is significant metabolic derangement  and the likelihood of survival decreases significantly.
• This trial is specifically designed for OHCA which has its unique challenges.
  • It is not accurate to exactly extrapolate the results to IHCA (at least in a monitored setting) where patients are often reached in much shorter periods.
  • That said, patients 11.5% of patients had a witnessed cardiac arrest by a paramedic.
  • It would have been nice to have further data on those who had a witnessed arrest by a paramedic to know those patients exact survival rates as this could have played a role in the survival amounts.
• Is it more appropriate to start calling OHCA non-witnessed by medical professional (NBMP) for those cases when patients arrest away from a medical professional?
  • When patients have immediate access to advanced life support, odds of survival will increase.
  • This is primarily to the effect of high-quality CPR and early defibrillation, but reversal of causes and medications may also help survival.
  • Rather than refer to all OHCA as the same (given its wide spectrum), should we start differentiating IHCA versus OHCA as those that were witnessed by a medical professional (more specifically one who has the capabilities needed to treat cardiac arrest in an advanced form) versus those not witnessed?
  • The witnessed by medical professional (WBMP) is not always the case in IHCA given the possibility that patients may go unmonitored for prolonged periods such as regular floor patients.
• It was not controlled how patients were managed once in the hospital.
  • Most likely, patients were treated the same way in both groups.
  • However, epinephrine may have been administered in those who may have initially received the placebo.
  • This leads us to ask if some of the survival in the placebo group could be attributed to them receiving epinephrine.
  • Given the rest of the trial results though, this most likely did not have a major impact since epinephrine would have been given much later in the arrest.
• Overall survival rates were low for those included in the study.
  • This may seem like a major negative portion of the study and it has been frequently pointed out in discussions.
  • However, 637 of the 2607 patients excluded (24.4%) achieved ROSC prior to enrollment in the study.  
  • This means that 6% of the total patients in the trial obtained ROSC prior to the study enrollment which when combined with those from the rest of the trial actually leads to rates of ROSC similar to other well-run EMS agencies. 
• There was a low rate of shockable rhythms in this study.
  • Only 770 (19.2%) in the epinephrine arm and 748 (18.7%) in the placebo arm had a shockable rhythm with almost all being ventricular fibrillation.
  • This again makes sense with the population that was enrolled given that there was a significant amount of patients who were not enrolled because ROSC was achieved prior to their enrollment.
  • Like the overall survival being low, this should be attributed to the method of enrollment and not a true limitation to the study itself.
• A modified Rankin Scale (mRS) was used in this study for neurological outcomes.
  • We have talked previously about the issues with mRS in regards to its potential inaccuracy and subjectivity.
  • There is potential for bias between a 2 and a 3.
  • This study used 3 as the cutoff but other studies (such as in the stroke literature) go between 2 and 3.
  • This subtle difference matters because with the 3 epinephrine had a slightly better outcome (87 at 2.2% versus 74 at 1.9%) but if the cutoff was 2  epinephrine was worse at 52 (1.3%) versus 54 (1.4%).
  • Some have argued for a trend toward epinephrine having better outcomes, but it is all in relation to the cutoff used.
  • Either way, the statistical significance is not present and neurological outcomes overall were worse in the epinephrine group.

• Although patients found neurologically intact survival as the most outcome, this was not the primary focus on the study.
  • Instead, authors investigated something that has already been demonstrated before: epinephrine will increase ROSC, but not neurologically intact survival.
  • However, this was already the largest study performed and to get the power needed to investigate survival with a good neurological outcome would have required far more patients.
  • This could have led to a statistically significant difference, but with such low numbers of patients and with the use of mRS to test such an outcome it would still be far from a perfect study.
• Epinephrine may not be the best drug or other maybe there could be a better dosing.
  • Bolus dosing of epinephrine physiologically does not make sense.
  • Continuous dosing is more physiological and others have advocated for this method in resuscitation (most commonly in conjunction with an arterial line).
  • Other medications such as norepinephrine may make more sense given its mostly alpha-adrenergic effects with less beta-adrenergic effects.
  • Dosing for such medications is less clear, but further studies could be attempted.
• There are far more important parts of resuscitation.
  • The number needed to treat (NNT) with epinephrine was 112.
  • Other treatments have demonstrated far better NNTs:
    • CPR performed by a bystander (NNT of 15)
    • Early recognition of cardiac arrest (NNT of 11)
    • Early defibrillation (NNT of 5)
  • We may debate epinephrine, but we must recognize that it is not the most important factor in resuscitation.

 
Comparing Conclusions:
Although more patients will achieve ROSC with epinephrine in OHCA, it does not lead to a significant increase in neurologically intact survival.
 
Our Bottom Line:
Epinephrine for OHCA should not be routinely used in cardiac arrest unless higher level evidence can demonstrate its benefits for improving a neurologically intact survival.  Resuscitation efforts should still focus on high-quality CPR and early defibrillation.  The recognition and correction of reversible causes is also important.  Further studies could investigate other medications or dosings, but the focus must be on neurologically intact survival.
 
Case Resolution:
After a quick discussion with your team, you all agree to focus on high quality CPR and continued attempts at defibrillation.  On the rhythm check, you see an organized rhythm and have a palpable pulse.  Your team immediately starts post-resuscitation care and transfers to the closest facility. 
 
Clinical Application:
At this time, multiple studies have demonstrated that epinephrine may improve ROSC but not neurologically intact survival in OHCA.  You can see an extensive list at REBEL EM where they also have a recent review of this trial.  Although guidelines still have epinephrine listed in their protocols we must seriously consider limiting its use (if at all) and work to help change guidelines.
 
What do I tell my patient?
With your patient in cardiac arrest, you will not be able to talk to them directly but can talk to their family.  You explain to the family present that you are working on saving their loved one and that you are using the current best evidence to make that happen.  In that time you explain the importance of high-quality CPR and early defibrillation whenever possible.  You also explain that sometimes other treatments can be performed which may help but that this is very much on a case-by-case basis.
 
Conclusion:
As one my expect, there has been quite a bit of reporting on this topic.  In addition to the REBEL EM post mentioned above EMNerd, St. Emlyn's, and First10EM have all made posts.   Check these out but make sure to read the article yourself! 

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