Epinephrine in Cardiac arrest : Saves lives but not brain

G.D. Perkins, C. Ji, C.D. Deakin, T. Quinn et el  published a trial of epinephrine in out of hospital cardiac arrest in NEJM ( PARAMEDIC2 Collaborators ).

BACKGROUND

Epinephrine  causes constriction of arterioles mediated by α-adrenergic receptors. Such constriction increases aortic diastolic pressure during CPR, thereby augmenting coronary blood flow and increasing the chance of a return of spontaneous circulation.  It has been used for last 50 years but there was limited evidence to support its use.

It also causes β-adrenergic stimulation, which causes dysrhythmias and increased myocardial oxygen demand . Its effect on  α-adrenergic receptors causes platelet activation  which can eventually lead to cerebral ischemia.

Previous randomized trials did not show benefit of its use in out of hospital cardiac arrest.   Previous trials that have compared standarddose epinephrine (1 mg) with high-dose epinephrine (5 to 10 mg), with epinephrine and vasopressin, or with placebo .

WHEN AND WHERE

From December 2014 through October 2017, the multicenter, randomized, double-blind, placebocontrolled PARAMEDIC2 trial was conducted by five National Health Service ambulance services  in the United Kingdom.  The process of obtaining written informed consent was deferred until after the emergency had passed.

FUNDING

By University of Warwick

PATIENTS

Adult patients who had sustained an out-of-hospital cardiac arrest .

Total of 10623 patients were assessed, 2520 excluded.  Out of these, 3995 were in placebo and 4015 were in epi group in final analysis.

EXCLUSIONS

Age less than 16 yrs, pregnancy,  cardiac arrest from anaphylaxis or asthma, or the administration of epinephrine before the arrival of the trial-trained paramedic.  In one ambulance service, trauma patients were also excluded.

METHODS

If initial attempts at resuscitation (CPR and defibrillation) were unsuccessful, the patient was randomly assigned to receive either parenteral epinephrine(1 mg.) or saline placebo.

OUTCOMES

Primary outcome was rate of survival at 30 days.

The secondary outcomes were the rate of survival until hospital admission, the lengths of stay in the hospital and in the intensive care unit (ICU), the rates of survival at hospital discharge and at 3 months, and the neurologic outcomes at hospital discharge (Modified Rankin Score in a binary fashion- 0-3 = good , 4-6= poor)and at 3 months.

RESULTS

  1. Median time from emergency call to ambulance arrival was 6.6 minutes
  2. The proportion of patients who had a return of spontaneous circulation during the prehospital resuscitation phase was higher in the epinephrine group than in the placebo group (36.3% vs. 11.7% )
  3. Proportion who were transported to the hospital were also higher in epinephrine group (50.8% vs. 30.7%)
  4. In the epinephrine group, 130 patients (3.2%) were alive at 30 days, as compared with 94 patients
    (2.4%) in the placebo group. 
  5. Number needed to treat to prevent 1 death was 112.
  6. There was no evidence of a significant difference between the epinephrine group and the placebo group in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] and 74 of 3994 patients [1.9%], respectively .
  7. Severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) was more common among survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%])
  8. The results with respect to survival at 3 months and neurologic outcomes at 3 months were similar in the two groups.

LIMITATIONS

Patient’s baseline neurologic status was not documented.  The original protocol anticipated a higher survival rate than the one that was observed.   Information about the quality of CPR was limited to the first 5 minutes of cardiac arrest and involved fewer than 5% of the enrolled patients.

POSSIBLE EXPLANATION FOR POOR NEUROLOGICAL OUTCOMES

Epinephrine may paradoxically impair cerebral micro vascular blood flow.  Alternatively, brain is more sensitive to ischemia and reperfusion injury.  Heart may recover but brain may not.

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