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

- Rogue Medic

Should ACLS Recommend the Unknown Based on Weak Evidence?


 
The AHA (American Heart Association) and ILCOR (International Liaison Committee on Resuscitation) will be meeting tomorrow to finalize the recommendations for the 2015 ACLS (Advanced Cardiac Life Support) guidelines. Here is the comment I submitted on the proposed recommendation for epinephrine (Adrenaline in Commonwealth countries) in cardiac arrest.

I have not received any information about where to submit SEERS comments, so I am sending this to you. Please forward it to whomever is supposed to receive comments.

Vasopressors for cardiac arrest (1. Epi v Placebo)
 

Consensus on Science:
For all four long term (critical) and short term (important) outcomes, we found one underpowered trial that provided low quality evidence comparing SDE to placebo (Jacobs, 2001, 1138).
[1]

 

As a trial that is stated to be underpowered (through no fault of Dr. Jacobs),[2] is there any valid reason the Jacobs study should be considered to be superior to observational studies?
 

Among 534 subjects, there was uncertain benefit or harm of SDE over placebo for the critical outcomes of survival to discharge [RR 2.12, 95% CI 0.75-6.02, p=0.16] and good neurological outcome defined as CPC of 1-2 [RR 1.73, 95% CI 0.59-5.11, p=0.32].[1]

 

We do not have good evidence to tell us if this is harmful or beneficial and we do not have any way of determining which patients will be harmed or helped by administration of epinephrine.


 

However, patients who received SDE had higher rates of the two important outcomes of survival to admission [RR 1.95, 95% CI, 1.34-2.84, p=0.0004] and ROSC in the prehospital setting [RR 2.80, 95% CI 1.78-4.41, p<0.00001] compared to those who received placebo.[1]

 

Are these surrogate endpoints important?

How do we know?

If these surrogate endpoints are important, why is there no valid evidence to support this claim?

We have a history of being misled by surrogate endpoints. We used to bleed patients and that produced a number of clear benefits in surrogate endpoints.
 

Physicians observed of old, and continued to observe for many centuries, the following facts concerning blood-letting.

1. It gave relief to pain. . . . .

2. It diminished swelling. . . . .

3. It diminished local redness or congestion. . . . .

4. For a short time after bleeding, either local or general, abnormal heat was sensibly diminished.

5. After bleeding, spasms ceased, . . . .

6. If the blood could be made to run, patients were roused up suddenly from the apparent death of coma. (This was puzzling to those who regarded spasm and paralysis as opposite states; but it showed the catholic applicability of the remedy.)

7. Natural (wrongly termed ” accidental”) hacmorrhages were observed sometimes to end disease. . . . .

8. . . . venesection would cause hamorrhages to cease.[3]

 

We don’t do that any more, because medicine is not supposed to just create a superficial improvement.

We should not be making any recommendation to treat based on such weak evidence.
 

The evidence for the routine use of adrenaline is perceived to be at equipoise within the international community of resuscitation scientists requiring re-evaluation19 as suggested by this comprehensive systematic review and meta-analysis. There is a need for well-designed, placebo-controlled, and adequately powered RCTs to evaluate the efficacy of adrenaline and to determine its optimal dosing.11,16,54 The question as to the efficacy of adrenaline for OHCA remains unanswered.[4]

 

Since the question as to the efficacy of adrenaline for OHCA remains unanswered, we should avoid substituting a bad answer for We don’t know.

Maybe we should bring back the indeterminate class for these unanswerable questions.
 

Treatment Recommendation
Given the observed benefit in short term outcomes, we suggest Standard Dose Epinephrine be administered to patients in cardiac arrest.(weak recommendation, low quality)
[1]

 

The benefit is considered important, but that is just an expert opinion, which is the lowest level of evidence.

A weak recommendation to give a treatment of unknown benefit and unknown harm, based on evidence that is admitted to be of low quality, should not set the standard of care. Even if the guidelines are explicitly stated to not be standards of care, they are adopted as standards of care by the emergency medicine community and by the EMS community.

We don’t know enough to make a recommendation about epinephrine, or most other treatments, in cardiac arrest.

We do not need to keep making the same recommendation just because we have made it before. We can leave it up to the treating physician or to the medical director writing the protocols for EMS.
 
 

See also – Proposed 2015 ACLS Epinephrine Recommendation – Vasopressors for cardiac arrest (1. Epi v Placebo)

Footnotes:

[1] Vasopressors for cardiac arrest (1. Epi v Placebo)
ILCOR Scientific Evidence Evaluation and Review System
Questions Open for Public Comment
Closing Date – February 28, 2015
Question page

[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.

 

[3] Blood-Letting
Br Med J.
1871 March 18; 1(533): 283–291.
PMCID: PMC2260507

[4] Adrenaline for out-of-hospital cardiac arrest resuscitation: a systematic review and meta-analysis of randomized controlled trials.
Lin S, Callaway CW, Shah PS, Wagner JD, Beyene J, Ziegler CP, Morrison LJ.
Resuscitation. 2014 Jun;85(6):732-40. doi: 10.1016/j.resuscitation.2014.03.008. Epub 2014 Mar 15.
PMID: 24642404 [PubMed – in process]

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Comments

  1. Love your articles even though some medical terms are a bit beyond me. I live in Australia so was interested that this study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand. Thanks

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