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

- Rogue Medic

Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium – Part I

ResearchBlogging.org
 

Here is some more research looking at the use of medications in cardiac arrest. In this part, I will look at the outcomes for patients treated with epinephrine. In Part II I will look at the authors’ discussion of their results.

Maybe this time epinephrine will produce a good outcome.
 

Despite the publication and widespread application of international Advanced Cardiac Life Support (ALS) guidelines2 survival rates remain extremely low. The aim of the ALS guidelines is to help standardize the provision of basic and advanced level care based on the available evidence and expert opinion.[1]

 

The lack of evidence of improved outcomes has resulted in an excessive dependence on anything that some experts agree might be helpful, or just meets some surrogate endpoint. We need evidence of improved outcomes, not evidence of temporarily improved vital signs. Surrogate endpoints are notorious for consistently failing to predict improved outcomes, so we should not base guidelines on surrogate endpoints.

There has even been opposition to obtaining evidence about the effects of these standards of mediocrity.[2]
 

The 2010 guidelines have removed atropine from the current treatment guidelines for OHCA and the accompanying 2010 Consensus on Science document suggested that placebo trials are needed to evaluate antiarrhythmic and vasopressor use in OHCA.5 [1]

 

Atropine was removed, because of a lack of evidence of benefit, but the other drugs remain.
 

The aim of this study was to describe the variability of drug administration for OHCA between EMS agencies across North America in a large multicentre registry of cardiac arrests and examine whether there was an association between administration of individual drugs and the presence of a pulse at emergency department (ED) admission as well as survival to hospital discharge.[1]

 

This study has a lot of variables and is not definitive, but if there is some actual benefit from the the wonder drug, epinephrine, this study should show some benefit. The ROC (Resuscitation Outcomes Consortium) registry had relevant data for 16,221 cardiac arrest patients treated from December 2005 to June 2007. Many, maybe even most, of these patients may not have been treated according to the 2005 ACLS (Advanced Cardiac Life Support) guidelines due to the delays some agencies had in implementing the new guidelines.

Epinephrine, amiodarone, lidocaine, vasopressin, atropine, and sodium bicarbonate were examined, but the doses were only documented for epinephrine in the registry. Documenting the use of vasopressin was not part of the registry requirements, so patients might have received a pressor, yet not had any documentation of pressor use if they received vasopressin, rather than epinephrine.
 

In the multivariable logistic regression model, dose of epinephrine was grouped into none, low (1–2 mg), moderate (3–5 mg), and high (>5 mg).[1]

 

Finding out the different results at various doses is a good idea.

Is more better?

If epinephrine is harmful, more epinephrine could show progressively increasing harm.
 


 

Amiodarone, lidocaine, and epinephrine all look as if they may be beneficial.
 

Epinephrine was administered in approximately 80% of ALS treated cardiac arrests (range 57–98% among agencies). All agencies used epinephrine in some cardiac arrests. The mean dose administered was 3.5 mg (±2.0 mg). Epinephrine dose varied widely across agencies, with a range in the mean epinephrine dose of 1.9–5.5 mg (p < 0.001). There was an inverse association between epinephrine dose and survival to discharge (Fig. 3). This relationship persisted after adjusting for age, gender, EMS witnessed arrest, bystander witnessed arrest, bystander CPR, shockable initial rhythm, time from 911 to EMS arrival, the duration of OHCA and study site.[1]

 

Low dose epinephrine did improve ROSC, but how import is ROSC (Return Of Spontaneous Circulation)?
 


 

Lidocaine and amiodarone, while not producing statistically significant results, don’t look that much worse for survival than they were for ROSC.

But epinephrine, even at low doses, looks like a good way to guarantee death.

ROSC would be important if there were a positive relationship with regaining pulses, but there isn’t.

Patients who do not have ROSC are not going to be resuscitated, but that does not mean that any means of obtaining ROSC will improve survival.

This is just more evidence that –

epinephrine increases ROSC, but decreases survival.
 

Continued in Part II.

Footnotes:

[1] Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium.
Glover BM, Brown SP, Morrison L, Davis D, Kudenchuk PJ, Van Ottingham L, Vaillancourt C, Cheskes S, Atkins DL, Dorian P; Resuscitation Outcomes Consortium Investigators.
Resuscitation. 2012 Nov;83(11):1324-30. doi: 10.1016/j.resuscitation.2012.07.008. Epub 2012 Jul 31.
PMID: 22858552 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

[2] Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial
Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL.
Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.
PMID: 21745533 [PubMed – in process]

Free Full Text PDF Download from reanimacion.net
 

This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.

In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.

This is just one of many examples.

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.

Glover BM, Brown SP, Morrison L, Davis D, Kudenchuk PJ, Van Ottingham L, Vaillancourt C, Cheskes S, Atkins DL, Dorian P, & the Resuscitation Outcomes Consortium Investigators (2012). Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium. Resuscitation PMID: 22858552

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

Jacobs IG, Finn JC, Jelinek GA, Oxer HF, & Thompson PL (2011). Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation, 82 (9), 1138-43 PMID: 21745533

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Comments

  1. Well, if a picture is worth 1000 words, hopefully these graphs will convince people who weren’t convinced by the multiple numbers and tables of previous studies.

    Very instructive to see no error bars on the higher Epi doses in fig. 2; yes boys and girls, nobody who got at least 3mg of Epi left the hospital alive.

    • mpatk,

      Well, if a picture is worth 1000 words, hopefully these graphs will convince people who weren’t convinced by the multiple numbers and tables of previous studies.

      There is one more graph from this paper. That will be in Part II.

      Very instructive to see no error bars on the higher Epi doses in fig. 2; yes boys and girls, nobody who got at least 3mg of Epi left the hospital alive.

      There are error bars, but they are very small. Some patients did survive to discharge with higher doses of epinephrine, but there were so few of them that they do not significantly change the outcome.

      .

  2. Hey Rogue;

    Great job with these research blog series, and for presenting this paper. My immediate response to this study was that a gut level, it makes sense. However, it’s only been since the 2005 guideline implementations, then 2010 updates implementation, that we have really began to see improvements in the OOHCA survival to discharge rates. What changed? Everything is changing, thus making the snapshot of this study partially obsolete in regards to whether EPI has a role at all in cardiac arret. From a variables perspective, we’ve finally started concentrating on compression ratio’s and effectiveness and minimized postive chest pressure ventilations with improved results. We’ve deemphasized advanced airways with positive results. The next areas for improvements in evidence based medicine are in cardiocerebral protection intraarrest, and what medicines have a positive result during arrest states, and this paper doesn’t add anything we didn’t already know about that snapshot in time. This paper does do a great job of questioning if high doses of EPI (>2mg) offer any benefit, especially since we wouldn’t do this to a person having an MI and wide awake. It also further leads to questions on whether other types of pressor agents to improve CPP and SVR may offer more benefits with less side effects. Look forward to seeing research post 2010 implementations and upgrades. Keep up the research and provocative questions!

    • Andrew DeWolf,

      However, it’s only been since the 2005 guideline implementations, then 2010 updates implementation, that we have really began to see improvements in the OOHCA survival to discharge rates. What changed? Everything is changing, thus making the snapshot of this study partially obsolete in regards to whether EPI has a role at all in cardiac arret.

      That is one of the problems with having treatments seen as essential, even though there is no good evidence that they work.

      As we eliminate other problems with resuscitation, we make excuses for keeping the favorite screwy ideas in the guidelines.

      Epinephrine for cardiac arrest was a good idea half a century ago, but good ideas need evidence to support them. Since there is no evidence that epinephrine improves survival, we need to acknowledge that it should be treated the same as any other unproven experimental idea.

      We should limit epinephrine in cardiac arrest to controlled trials.

      Our patients have nothing to lose by removing epinephrine from the guidelines while we await well done research.

      Our patients do appear to have a lot to lose if we continue to keep epinephrine in the guidelines.

      There is more in Part II.

      .

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