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

- Rogue Medic

Amiodarone for Cardiac Arrest in the 2010 ACLS – Part III


ResearchBlogging.org

Continuing from Amiodarone for Cardiac Arrest in the 2010 ACLS – Part I and Amiodarone for Cardiac Arrest in the 2010 ACLS – Part II.

Antiarrhythmics
There is no evidence that any antiarrhythmic drug given routinely during human cardiac arrest increases survival to hospital discharge. Amiodarone, however, has been shown to increase short-term survival to hospital admission when compared with placebo or lidocaine.[1]

The research only demonstrates improved survival to admission, as if that does anything more than provide false hope and huge hospital bills. Why do we base the standard of care on such limited research?

Since there is no new amiodarone research, let’s look at the old surrogate endpoint research that compares amiodarone with placebo. Keep in mind that this surrogate endpoint study is the basis for over a decade of still unproven treatment.

Whether the hemodynamic effects of polysorbate 80 are as pronounced or as clinically significant in humans is controversial.35-37[2]

Has the availability of amiodarone without polysorbate 80 affected treatment?

We don’t know.

In interpreting our findings, one should consider factors that may have affected the outcome. The diluent was used as a placebo in this study. Although hemodynamic derangements were less common after the administration of placebo than after amiodarone, it is possible that the diluent aggravated hypotension and bradycardia. The incidence and magnitude of these effects could also have been blunted by the previous administration of epinephrine.[2]

If the polysorbate 80 is not considered to be inactive, as appears to be the case, is it an appropriate placebo?

Why isn’t this variable controlled for?

Amiodarone was administered relatively late in the course of the resuscitation attempt, when significant end-organ damage had probably already resulted from prolonged hypoperfusion. For these reasons, the potential benefit of treatment could have been underestimated.[2]

Which also means that –

For these reasons, the potential benefit harm of treatment could have been underestimated.

Generally, the later a drug is given, the less the effect. There is no reason to assume that the effects of any drug are only beneficial. It is an error to suggest that the effects of any drug are only beneficial. This is the kind of fraud promoted by alternative medicine.

Finally, the treatment of patients after hospitalization was not standardized, nor did we evaluate the effect of care given in the hospital on survival.[2]

Since they were only able to evaluate survival to admission, how much effect would there be from any treatment given in the ED (Emergency Department)?

How much is ED treatment likely to differ from prehospital treatment?

The salient observation in this study is that adding amiodarone to advanced cardiac life-support measures resulted in a net benefit: 1 of every 10 patients treated survived to admission to the hospital. This result does not imply that amiodarone is superior to other antiarrhythmic agents or that pharmacologic therapy is a substitute for expeditious defibrillation.42[2]

The salient observation in this study is that adding amiodarone to advanced cardiac life-support measures resulted in a net benefit.

Survival to admission is a net benefit?

A lot more patients dying in the hospital is a net benefit?

Survival to discharge is a real benefit.

Imagine telling a patient’s family –

She died, but she lived long enough to acquire thousands of dollars in hospital bills. We consider this a net benefit.

A surrogate endpoint is not a real benefit!

Whether the benefits observed in this trial extend to survival to discharge from the hospital merits further investigation.[2]

Where is the further investigation?

Nowhere.

We just got a new standard of care, even though it is not supported by evidence of improved real survival.

Where is the ethics in that?

Where is the responsibility to patients to provide treatments that improve real outcomes, rather than the sleight of hand of a net benefit.

Footnotes:

[1] Amiodarone
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8.2: Management of Cardiac Arrest
Medications for Arrest Rhythms
Antiarrhythmics
Free Full Text Article with links to Free Full Text PDF download

[2] Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation.
Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, Hallstrom AP, Murray WA, Olsufka M, Walsh T.
N Engl J Med. 1999 Sep 16;341(12):871-8.
PMID: 10486418 [PubMed – indexed for MEDLINE]

Free Full Text Article from N Engl J Med with links to Free Full Text PDF download

Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, Hallstrom AP, Murray WA, Olsufka M, & Walsh T (1999). Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. The New England journal of medicine, 341 (12), 871-8 PMID: 10486418

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Comments

  1. I’m surprised the IRB allowed polysorbate-80 to be used as the “placebo”. It would be like using phenol as a placebo…not a particularly good idea for patients.

    Our code meds need studies without confounders like polysorbate-80 or CPR uniformity/quality. Perhaps with a study design with: fake epi/fake amio, real epi/fake amio, fake epi/real amio, real epi/real amio. Pick a decent sized, well performing system and you can probably evaluate any change from baseline within a few months.

    • Christopher,

      I’m surprised the IRB allowed polysorbate-80 to be used as the “placebo”. It would be like using phenol as a placebo…not a particularly good idea for patients.

      I agree.

      I do not have a lot of confidence in IRBs, since they approve so much research that is poorly designed. Why subject anyone to research that is not designed well enough to provide any valuable new information?

      Why approve studies that are too small to be able to provide any useful results, except when someone decides to combine all of these too small studies into a metaanalysis?

      Yet this seems to be the bulk of the studies approved by IRBs.

      Our code meds need studies without confounders like polysorbate-80 or CPR uniformity/quality.

      Absolutely.

      Perhaps with a study design with: fake epi/fake amio, real epi/fake amio, fake epi/real amio, real epi/real amio. Pick a decent sized, well performing system and you can probably evaluate any change from baseline within a few months.

      There are many possible study designs. I described some ways to do this in How to Study Epinephrine in Cardiac Arrest.

      According to Blair Bigham, 15,000 cardiac arrest patients would be needed to produce meaningful results for survival to discharge (or past discharge) with good brain function.

      One thing that we know from the requirements for such a large study –

      The potential benefit is tiny, otherwise it could be demonstrated in much smaller studies.

      We need to stop throwing treatments at patients because of small surrogate endpoint studies.

      We need to eliminate our bias toward treatment, since we know that this bias will probably lead us to harm patients.

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