Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

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Does Faster Epinephrine Administration Produce Better Outcomes from PEA-Asystole?

ResearchBlogging.org
 

If we are going to give epinephrine (Adrenaline in Commonwealth countries) to patients with rhythms that are not shockable (PEA [Pulseless Electrical Activity] or Asystole), it appears that patients receiving epinephrine earlier have better outcomes than patients who receive epinephrine later in the hospital in the less acute care settings.

Does this mean that patients who receive epinephrine have better outcomes than patients who do not receive epinephrine?

We remain willfully ignorant of the answer to that question.
 

Apart from cardiopulmonary resuscitation, no intervention has been shown to be efficacious in patients with non-shockable cardiac arrest.[1]

 

Would a placebo group have had better outcomes than the patients who received epinephrine the earliest? We have no way of knowing, because we discourage asking about what we take for granted.

 

We excluded patients with cardiac arrest in the emergency department, intensive care unit, or surgical or other specialty care or procedure areas,[1]

 


 

This does show an impressive association between giving epinephrine earlier and improved outcomes.

Does this mean that we should avoid giving epinephrine (a drug not yet adequately tested in humans) after a certain amount of time?

Does this mean that we should prioritize giving epinephrine (a drug not yet adequately tested in humans) before a certain amount of time?

Until we find out how harmful/beneficial epinephrine is compared to placebo, we do not know if we are helping with epinephrine, harming with epinephrine, or which patients we might be helping and which patients we might be harming. We have a half a century of I don’t know and I don’t care.
 

Despite a strong physiologic rationale and anecdotal reports of efficacy, there are no well controlled trials of epinephrine to assess endpoints such as improved survival and neurologically intact survival. A randomized trial failed to show efficacy for advanced cardiac life support drugs, and extrapolation to the potential lack of efficacy of epinephrine has been suggested; the dose, timing, and even use of epinephrine remains controversial.15-16 [1]

 

But some of the anecdotes are really good anecdotes!

Anecdote-based treatment is just ignorance-based treatment. We assume that we know what we are doing, but we are only imitating Skinner’s pigeons in our reaction to stimuli.
 


 

We have fancier uniforms than the pigeons, but we are just as unaware of the source of our stimuli.
 

The data was prospectively obtained using specifically defined variables, but the study was a retrospective analysis of that data.
 

Because data were used primarily as the local site for quality improvement, sites were granted a waiver of informed consent under the common rule.[1]

 

Because of the way the data are entered, any errors are likely to be at time of entry and may not be capable of being detected at the time of analysis for research. The numbers are very large – 25,095 patients – so that should correct for idiosyncratic errors, but what about cultural errors?

 

In the sensitivity analyses with adjustment for delays in initiation of cardiopulmonary resuscitation, time to epinephrine administration remained independently associated with survival to hospital discharge after multivariable adjustments.[1]

 

In the context of our findings, future investigations should consider timing of epinephrine administration in design and interpretation.[1]

 

We should also consider that epinephrine, if it is beneficial, is probably only beneficial to some patients. We need to try to identify those patients. Our current method of give epinephrine to everybody and let the emergency department sort them out is not reasonable.

This study ran from 2000 to 2009, so the improvements due to the focus on chest compressions might only affect a tiny portion of patients.[2]

Does epinephrine administration – at any time – produce better outcomes from PEA-asystole?

We still have no idea.

Footnotes:

[1] Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry.
Donnino MW, Salciccioli JD, Howell MD, Cocchi MN, Giberson B, Berg K, Gautam S, Callaway C; American Heart Association’s Get With The Guidelines-Resuscitation Investigators.
BMJ. 2014 May 20;348:g3028. doi: 10.1136/bmj.g3028.
PMID: 24846323 [PubMed – in process]

Free Full Text from BMJ.

[2] Delayed prehospital implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiac care.
Bigham BL, Koprowicz K, Aufderheide TP, Davis DP, Donn S, Powell J, Suffoletto B, Nafziger S, Stouffer J, Idris A, Morrison LJ; ROC Investigators.
Prehosp Emerg Care. 2010 Jul-Sep;14(3):355-60.
PMID: 20388032 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

On December 13, 2005, the AHA published “Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care”

ROC EMS agencies required an average of 416 days to implement the 2005 AHA guidelines for OHCA. Small EMS agencies, BLS-only agencies, and nontransport agencies took longer than large agencies, agencies providing ALS care, and transport agencies, respectively, to implement the guidelines.

How relevant is that to implementation in the less acute care settings studied in these hospitalized patients?

Bigham BL, Koprowicz K, Aufderheide TP, Davis DP, Donn S, Powell J, Suffoletto B, Nafziger S, Stouffer J, Idris A, Morrison LJ, & ROC Investigators (2010). Delayed prehospital implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiac care. Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors, 14 (3), 355-60 PMID: 20388032

Donnino, M., Salciccioli, J., Howell, M., Cocchi, M., Giberson, B., Berg, K., Gautam, S., Callaway, C., & , . (2014). Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry BMJ, 348 (may20 2) DOI: 10.1136/bmj.g3028

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Comments

  1. It seems that people are jumping on/off bandwagons based upon a single study. A local EMS Medical Director is now pushing that epi be given within the first minute of the ALS provider’s arrival at the patient (via IO).

    This reminds me of another medication (or two, or three) which is given with minimal supportive research behind it…

    • One study that confirms a bias can cause us to ignore everything else.

      Selective reinforcement is what gets gamblers, athletes, and doctors/nurses/medics to believe in things that do not really work.

      This study is an analysis of information that is available, so there is no opportunity to make this placebo controlled.

      Without knowing if epinephrine is as good as placebo, are we timing when epinephrine is most dangerous or when epinephrine is most beneficial?

      We do not know.

      We assume that epinephrine is beneficial because that is our bias.

      .

  2. Here’s a recent review and meta-analysis of several epinephrine RCT’s (fourteen; only one compared “standard dose adrenaline (SDA)” to placebo, the others compared SDA to high dose (HDA) or to vasopressin (with or without epi), if you haven’t seen it yet. Their conclusion?

    There was no benefit of adrenaline in survival to discharge or neurological outcomes. There were improved rates of survival to admission and ROSC with SDA over placebo and HDA over SDA.

    I don’t have access beyond the abstract, but I thought you might find it interesting.

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