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

- Rogue Medic

Equipoise and Ethics and IRBs, Oh My!

In the comments to what I wrote yesterday about seizures and a study comparing lorazepam (Ativan), diazepam (Valium), and placebo,[1] Brooks Walsh had the following comment –

Although I’ve read the study before, I am only wondering now how the IRB for Alldredge 2001 thought there was “equipoise” between placebo and benzos.


Not just he race horse mentioned in one of the songs from Guys and Dolls, or a mouse being a raced in Stalag 17. Maybe I should have written this with Nathan Detroit being stranded on Gilligan’s Island, or I could try that for something on ketamine. 😉

In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial.[2]

In many cases, there is equipoise, but we are too biased to realize how little we know about the treatments we are using. Epinephrine in cardiac arrest, ventilations in cardiac arrest, and prehospital use of backboards and EMS collars are a few examples of this kind of bias.

We have been using the treatments for so long that we can’t imagine that we have been doing something useless, or even worse, something harmful.

Our knowledge of the effects of the treatments we use may not be any better than what we see in the video of the the knowledge of the horses that the characters are betting on. Selective memory and wishful thinking are the basis for our choices.

The diazepam vs. lorazepam vs. placebo study is a bit of a different situation. EMS was still largely doing what medical directors felt could safely be moved from the ED (Emergency Department) to the EMS setting, but we did not know if any of it worked as used by EMS. We also worried that the respiratory depression would be common and cause more problems than the potential benefits of stopping the seizures.

The doses were small.

With the doses we used, I felt that the seizures were more likely to stop on their own, rather than because of the small doses of diazepam that I could give – up to 5 mg at a time.

A lot of people (including emergency physicians) do not seem to realize that most seizures are self-limiting. EMS is not treating aggressively for these seizures, which would go away even if treated with homeopathy (or any other placebo treatment).

We are treating all of the patients who might have status epilepticus because the outcome for those who do have status epilepticus is so bad when they are not treated aggressively.

There do not appear to have been any studies that compared EMS administered benzodiazepines with EMS not administering benzodiazepines. There are only two studies that I found published before this study was published, but both were published years after this study began.[3],[4]

Here is what the authors wrote about the state of the evidence before they began the study.

Several randomized trials of drug treatment for status epilepticus in hospitalized patients have been conducted.1,3,4 However, patients with seizures and status epilepticus are commonly encountered outside of the hospital by emergency-medical-services personnel. Traditionally, these patients have been transported quickly to emergency departments for treatment. In recent years, many emergency-medical-services systems have implemented protocols that allow the intravenous administration of benzodiazepines (principally diazepam) by paramedics. However, the risks and benefits of treatment with benzodiazepines outside of the hospital have not been studied. Potential benefits include the prevention of systemic and neurologic sequelae of prolonged convulsive seizures. Potential risks include respiratory depression and cardiovascular compromise associated with benzodiazepines and misdiagnosis leading to inappropriate treatment.2 [5]

It is easy to forget how much things have changed in a couple of decades.

This study began to enroll patients January 4, 1994, so the planning of the study began over twenty years ago.

Because of the emergency nature of status epilepticus and the unconscious state of the patient, enrollment took place under a waiver of informed consent pursuant to federal regulations. The rationale for the waiver was that diazepam, lorazepam, or no benzodiazepines were used by various emergency-medical-services systems for the management of status epilepticus at the time of the study and that insufficient data were available to determine the optimal out-of-hospital treatment for this condition.[5]

In other words, we doid not know what was best.

In another word – equipoise.

The average time from patient contact to arrival in the ED was only 15 minutes.

Click on images to make them larger.
The outcomes showed that waiting until the patient is in the ED to treat the seizure is not a good idea.

Before this study, that was just an opinion.

After the study, it had been demonstrated objectively.
Some people have similar criticism about a lot of other treatments that have never been demonstrated to improve outcomes.

A year ago yesterday, the Hagihara study[6] comparing cardiac arrest outcomes with and without epinephrine was published in JAMA.

In the editorial accompanying that paper, Dr. Clifton Callaway wrote the following about the state of equipoise of epinephrine in cardiac arrest.

The exciting development is that these data create equipoise about the current standard of resuscitation care. The best available observational evidence indicates that epinephrine may be harmful to patients during cardiac arrest, and there are plausible biological reasons to support this observation. However, observational studies cannot establish causal relationships in the way that randomized trials can.[7]

Similarly –

The best available observational evidence indicates that epinephrine ventilation may be harmful to patients during cardiac arrest, and there are plausible biological reasons to support this observation.

or –

The best available observational evidence indicates that epinephrine use of backboards and EMS collars may be harmful to patients during cardiac arrest with unstable injuries of the spine, and there are plausible biological reasons to support this observation.

When we base our treatments on hunches, or expert opinions, we will eventually have to go back and find out if they work.

Or, as a quote attributed to John Wooden puts it –

If You Don’t Have Time to Do It Right, When Will You Have Time to Do It Over?

We expect that our experts will have gotten combinations of treatments just right on the first try, or the second try, or even on the third try, even though there is no good reason to expect this.

Experts have a history of repeated failure and eventual success, not a history of continual success.

An expert is a man who has made all the mistakes which can be made in a very narrow field. – Niels Bohr.

Image credit.
Is it safe to bet on the opinions of experts?

That depends on what they are expressing opinions on, how accurate they have been with previous opinions, and the quality of the information on which they base their opinions.

In this case, the odds are against the experts.

Maybe we think that because an expert has made all of the known mistakes in a field, the expert cannot make any more mistakes in the same field.

We continue to think that ROSC (Return Of Spontaneous Circulation) is the most important factor in resuscitation, but we have proven that to be false.

Norepinephrine and high-dose epinephrine produced more ROSC than standard-dose epinephrine.

If ROSC were the most important factor in resuscitation, we would use these treatments, rather than standard-dose epinephrine.

We do not.

Norepinephrine and high-dose epinephrine produce more brain damage than standard-dose epinephrine.[8]

We know that epinephrine produces brain damage, but we foolishly believe that the doses we use are not toxic.

We need to demonstrate the safety and efficacy of epinephrine in cardiac arrest.

We need to demonstrate the safety and efficacy of ventilations in cardiac arrest.

We need to demonstrate the safety and efficacy of backboards and EMS collars for injuries to the spine.

The stakes are too high to keep playing a hunch – whether Paul Revere, Valentine, Epitaph, epinephrine, ventilation, or backboards and EMS collars.

Look at how we rejected making high-dose epinephrine routine –

A meta-analysis and other studies have found improved ROSC, but none have demonstrated a survival benefit of high-dose epinephrine versus standard-dose epinephrine in cardiac arrest.135,268,–,272 [8]

What do we do with the same, or worse, results when the comparison is between epinephrine and not drug?

There are no RCTs that adequately compare epinephrine with placebo in treatment of and outcomes related to out-of-hospital cardiac arrest. A retrospective study267 compared epinephrine to no epinephrine for sustained VF and PEA/asystole and found improved ROSC with epinephrine but no difference in survival between the treatment groups.[8]

We have to do something.

We rejected high-dose epinephrine, which had improved ROSC, but no improved survival.

We embrace standard-dose epinephrine, which has improved ROSC, but no improved survival.

We might as well be playing the ponies.

It is reasonable to consider administering a 1 mg dose of IV/IO epinephrine every 3 to 5 minutes during adult cardiac arrest (Class IIb, LOE A).[8]


LOE is Level Of Evidence. A is the highest ranking of evidence.

That means that the AHA (American Heart Association) is confident that they have excellent evidence, but that the evidence is not enough to give anything more than their weakest recommendation for use.

This Class IIb recommendation remains unaffected, even though the studies published continue to be neutral or negative.

Epinephrine equipoise is nothing new. what is new is that it is being acknowledged.


[1] Giving New Meaning to Carpe Diem
Thu, 21 Mar 2013
Rogue Medic

[2] Clinical equipoise

[3] Pediatric emergency medicine practice patterns: a comparison of pediatric and general emergency physicians.
Schweich PJ, Smith KM, Dowd MD, Walkley EI.
Pediatr Emerg Care. 1998 Apr;14(2):89-94.
PMID: 9583386 [PubMed – indexed for MEDLINE]

[4] Prehospital management of the seizure patient.
Nicholl JS.
Emerg Med Serv. 1999 May;28(5):71-5; quiz 77.
PMID: 10537415 [PubMed – indexed for MEDLINE]

Free Full Text Download in Word format from angelfire.com.

[5] A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, Lowenstein DH.
N Engl J Med. 2001 Aug 30;345(9):631-7. Erratum in: N Engl J Med 2001 Dec 20;345(25):1860.
PMID: 11547716 [PubMed – indexed for MEDLINE]

Free Full Text from N Engl J Med.

[6] Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest.
Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S.
JAMA. 2012 Mar 21;307(11):1161-8. doi: 10.1001/jama.2012.294.
PMID: 22436956 [PubMed – indexed for MEDLINE]

Free Full Text from JAMA.

[7] Questioning the use of epinephrine to treat cardiac arrest.
Callaway CW.
JAMA. 2012 Mar 21;307(11):1198-200. doi: 10.1001/jama.2012.313. No abstract available.
PMID: 22436961 [PubMed – indexed for MEDLINE]

Link to a free 6 1/2 minute recording of an interview with Dr. Callaway about this paper.

On the right side of the page, to the right of the First Page Preview, is a section with the title Multimedia Related by Topic. Below that is Author Interview. Below that is some information about the edition, . . . , and below that is an embedded recording of the interview. Press on the arrow to play. That has the recording of the interview with Dr. Callaway.

This is definitely worth listening to.

[8] Epinephrine
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science
Part 8: Adult Advanced Cardiovascular Life Support
Part 8.2: Management of Cardiac Arrest
Medications for Arrest Rhythms
Free Full Text from Circulation.

Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, Lowenstein DH. (2001). A Comparison of Lorazepam, Diazepam, and Placebo for the Treatment of Out-of-Hospital Status Epilepticus New England Journal of Medicine, 345 (25), 1860-1860 DOI: 10.1056/NEJM200112203452521

Callaway, C. (2012). Questioning the Use of Epinephrine to Treat Cardiac Arrest JAMA: The Journal of the American Medical Association, 307 (11) DOI: 10.1001/jama.2012.313

Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. (2012). Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest JAMA: The Journal of the American Medical Association, 307 (11) DOI: 10.1001/jama.2012.294



  1. Thanks for the focus on the context of the study. Interesting stuff.

    And, as usual, you combine wonderfully disparate elements, e.g. Bohr and backboards. As for Bohr himself, not only did he make “all the mistakes in a narrow field,” he helped create that field with those errors. Even his “mistakes,” like his model of the hydrogen atom, are still taught (en route to the “correct” model), since there is utility and insight to be had in considering it.