Epinephrine in cardiac arrest: the past, the present and the (im)possible future. Reflections after PARAMEDIC 2 trial.

23 Lug

The past (a brief history of epinephrine use in cardiac arrest)

19489_eb_adrenaline_molecule

In 1901 Jokichi Takamine (1854-1922) isolated the pure form of adrenaline, also known as epinephrine.

Routine use of adrenaline for cardiac arrest was first proposed in the 1960’s. Its inclusion within cardiac arrest management was based upon an understanding of the physiological role of adrenaline, and experimental data from animal research which showed that ROSC was more likely when the drug was used.

Epinephrine was not included in cardiac arrest protocols on the basis of evidence of benefit in humans.

Epinephrine remained, since today, a significant component of advanced life support despite minimal human data indicating beneficial effect .

The rationale for use of epinephrine in cardiac arrest was that, in animal studies, increases aortic blood pressure and thus coronary perfusion pressure during chest compressions.

IMPORTANT, brief reminder on epinephrine effect and Coronary Perfusion Pressure.
  • Coronary vessels are contained in epicardium and their flow is possible in the diastole when they are not compressed by myocardium during systolic contraction.coro-vessels
  • Coronary flow depends from the gradient between aortic diastolic (Ao) pressure and diastolic left ventricular (LV) pressure.acls3_3-1
  • Higher is the coronary pressure perfusion (CPP), greater is the chance of ROSC.

circ1

  • Epinephrine is a key determinant factor in maintaining diastolic aortic pressure in cardiac arrest; thanks to its interaction with alpha receptors, located on the endothelium of the arteries, produce generalized peripheral arterial vasoconstriction maintaining aortic diastolic pressure to a high level even during chest compressions.
  • The cut off value for ROSC is 15 mmHg of CPP, but more is better (at least 40 mmHg9.

Many and strong recent evidences demonstrates that “Among patients with OHCA, use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes Screen-Shot-2015-03-11-at-8.38.35-PM

The Present: PARAMEDIC 2 trial.

G.D. Perkins, C. Ji, C.D. Deakin, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. 

What kind of study is this:

Randomized, double-blind, multicentric.

Population

8014 patients with out-of-hospital cardiac arrest in the United Kingdom

  • Inclusion Criteria

Adult (>16 years) patients, transported by five National Health Service ambulance services in the United Kingdom, who had sustained an out-of-hospital cardiac arrest for which advanced life support was provided by trial-trained paramedics.

  • Exclusion criteria

Apparent pregnancy, age of less than 16 years, cardiac arrest from anaphylaxis or asthma, administration of epinephrine before the arrival of the trial-trained paramedic.

Intervention

Paramedics administered either IV epinephrine 1mg every 3 – 5min + standard care  or IV 0.9% normal saline bolus + standard care.

Comparison

Placebo (IV 0.9% normal saline bolus) + standard care

Outcome

Primary outcome:
  • Rate of survival at 30 days.
Secondary outcomes:
  • Rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale. 
  • Lengths of stay in the hospital and in the intensive care unit
  • Rates of survival at hospital discharge and at 3 months
  • Neurologic outcomes at hospital discharge and at 3 months
Description-of-the-modified-Rankin-Scale.ppm

Results

  • Patients who received epinephrine had a higher rate of 30-day survival than those who received placebo.
  • No clear improvement in functional recovery among the survivors in the epinephrine group.
  • The proportion of survivors with severe neurologic impairment was higher in the epinephrine group (31.0% vs. 17.8%)
  • Epinephrine NNT of 112 patients to prevent 1 death at 30-days (Early defibrillation NNT = 5, CPR performed by a bystander NNT = 15 )
PARAMEDIC-2-Results-1024x255

Image attribution: REBEL Cast Ep56 – PARAMEDIC-2: Time to Abandon Epinephrine in OHCA?

Conclusions

In adults with out-of-hospital cardiac arrest, 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 difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.

Strengths

  • Randomized, multicenter, double blind, placebo controlled
  • 8014 patients randomised.
  • Well balanced characteristics at baseline of the two groups
  • Concurrent treatments were similar
  • Median time from the emergency call to ambulance arrival was 6.6 minutes
  • Patient oriented outcomes

Paramedic

Limitations

  • Overall survival rate in this trial was disappointingly small (3.2% and 2.4%, respectively)
    • 615 patients where excluded because had return of spontaneous circulation before paramedics can open the trial pack. Of these 615 patients of which we don’t know the clinical outcome but including the survivors overall survival rate is similar to other EMS in Europe.
  • Median time from the emergency call until administration of the trial agent 21 min and we know (according the other studies) that cardiac arrest has 3 phases (Electrical Phase, first 5 min (Defib), Circulatory Phase next 10 – 15min (Chest compressions), Metabolic Phase 10-20min) and epinephrin is effective if administered in the first 20 min of the cardiac arrest.
  • Information about the quality of CPR was limited to the first 5 minutes of cardiac arrest and involved <5% of enrolled patients 
  • The protocol neither controlled nor measured in-hospital treatments and we know that the most common cause of in-hospital death is iatrogenic limitation of life support, which may result in the death of potentially viable patients.

What we know till today

  • Epinephrine in cardiac arrest improve ROSC and patients alive.
  • The improved survival is mostly due to patients with bad (<3 MRS) neurological outcome.

What that means

  • Administering the current recommended dose of Epinephrine we have to choose between numbers and quality of life.
  • Patients clearly said quality of life is more important
  • Epinephrine is anyway important because having bigger numbers of ROSC give the chance to improve neurological outcomes.

Future challenges

  • Understanding why epinephrine doesn’t work and can be detrimental on long term neurological outcome.
  • Obtaining more ROSC and better neurological outcomes in Cardiac Arrest

The (im)possible future

I think there are two key factors, in the actual way to use Epinephrine, that determine its failure:

The wrong administration route

When epinephrine is administered intravenously in a low flow state patient (as is a patient during cardiac arrest, even if proper chest compressions are performed), the amount of drug that arrives to perform the “local” alpha effect on arteries is just a minimal quantity of the (high!!!) dose. The major part rely in the venous circulation and is mobilized in great quantity only when ROSC happens determining a widespread vasoconstriction and a consequent “overdose” effect (think just at the “stunned” myocardium that has to overwhelm such ha great post-load work).

The wrong dose to the wrong patient

From the coronary perfusion pressure (CPP) point of view, every cardiac arrest patient is different: some patients have a (relative) good aortic pressure and a (relative) good  coronary perfusione comparing to others.

When we administer the same amount of epinephrine to each of them this takes to an underdose in some patients (with low flow state) and an overdose in others (with good or high flow state).

So now what?

The right administration route

Probably the best route to administer epinephrine is not the vein but the artery.

It allows, even in a low flow state patient, a better chance to reach the vasoconstrictor effect maintaining a good aortic diastolic pressure and a consequent good coronary flow.

The right dose to the right patient

Giving epinephrine (standard dose) to a patient who has a low flow state (patients who need it more) make epinephrine usefulness (underdose) because just a little part of it circulate.

Giving  epinephrine to patients in a good or high flow state (patients that need it less or don’t need epi at all) is detrimental and can cause overdose effect.

We need to know wich is the circulatory state of the patients to administer the right dose avoiding the “overdose” effect.

The only way to do this is monitoring aortic diastolic pressure through an arterial catheter. We can target Epinephrine dosage to reach a good aortic pressure maintaining a good CPP (achieving ROSC) and avoiding overdose.

evolution

Take home messages for future improvements in cardiac arrest management 

  1. Obtain an arterial line

  2. Give Adrenaline intrarterially

  3. Check blood pressure via arterial line

  4. Target Adrenaline (doses and times) to maintain at least 40 mmHg of diastolic arterial pressure

References

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