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

- Rogue Medic

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest – Part I

 
Also to be posted on ResearchBlogging.org when they relaunch the site.

The results are in from the only completed Adrenaline (Epinephrine in non-Commonwealth countries) vs. Placebo for Cardiac Arrest study.
 


 

Even I overestimated the possibility of benefit of epinephrine.

I had hoped that there would be some evidence to help identify patients who might benefit from epinephrine, but that is not the case.

PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) compared adrenaline (epinephrine) with placebo in a “randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest”.

More people survived for at least 30 days with epinephrine, which is entirely expected. There has not been any controversy about whether giving epinephrine produces pulses more often than not giving epinephrine. As with amiodarone (Nexterone and Pacerone), the question has been whether we are just filling the ICUs and nursing home beds with comatose patients.
 

There was no statistical evidence of a modification in treatment effect by such factors as the patient’s age, whether the cardiac arrest was witnessed, whether CPR was performed by a bystander, initial cardiac rhythm, or response time or time to trial-agent administration (Fig. S7 in the Supplementary Appendix). [1]

 

The secondary outcome is what everyone has been much more interested in – what are the neurological outcomes with adrenaline vs. without adrenaline?

The best outcome was no detectable neurological impairment.
 

the benefits of epinephrine that were identified in our trial are small, since they would result in 1 extra survivor for every 112 patients treated. This number is less than the minimal clinically important difference that has been defined in previous studies.29,30 Among the survivors, almost twice the number in the epinephrine group as in the placebo group had severe neurologic impairment.

Our work with patients and the public before starting the trial (as summarized in the Supplementary Appendix) identified survival with a favorable neurologic outcome to be a higher priority than survival alone. [1]

 


Click on the image to make it larger.
 

Are there some patients who will do better with epinephrine than without?

Maybe (I would have written probably, before these results), but we still do not know how to identify those patients.

Is titrating tiny amounts of epinephrine, to observe for response, reasonable? What response would we be looking for? Wat do we do if we observe that response? We have been using epinephrine for over half a century and we still don’t know when to use it, how much to use, or how to identify the patients who might benefit.

I will write more about these results later

We now have evidence that, as with amiodarone, we should only be using epinephrine as part of well controlled trials.

Also see –

How Bad is Epinephrine (Adrenaline) for Cardiac Arrest, According to the PARAMEDIC2 Study?

Footnotes:

[1] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMoa1806842. [Epub ahead of print]
PMID: 30021076

Free Full Text from NEJM

All supplementary material is also available at the end of the article at the NEJM site in PDF format –

Protocol

Supplementary Appendix

Disclosure Forms

There is also an editorial, which I have not yet read, by Clifton W. Callaway, M.D., Ph.D., and Michael W. Donnino, M.D. –

Testing Epinephrine for Out-of-Hospital Cardiac Arrest.
Callaway CW, Donnino MW.
N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMe1808255. [Epub ahead of print] No abstract available.
PMID: 30021078

Free Full Text from NEJM

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The Magical Nonsense of Friday the 13th

ResearchBlogging.org
 

Today we celebrate the fears of those who do not understand that magic does not affect reality. Our fears of magic can affect reality, when we act on those fears. Why should a special day cause more problems than a boring day? Many people believe in magic powers as being more than just the fictional entertainment we see in novels and movies.

Here is another study of the effects of Friday the 13th on emergency medicine/EMS that I have not written about. It is no surprise that they did not find what is not there – an influence of this magic date on the type or volume of patients in the emergency department.
 

CONCLUSIONS:
Although the fear of Friday the 13th may exist, there is no worry that an increase in volume occurs on Friday the 13th compared with the other days studies. Of 13 different conditions evaluated, only penetrating traumas were seen more often on Friday the 13th. For those providers who work in the ED, working on Friday the 13th should not be any different than any other day.
[1]

 

When measuring of a large number of variables, it is expected that one, or more, will appear to be statistically significant. This is why the p value of outcomes should be adjusted when there are multiple outcomes being measured. The p value is just a measure of how likely it is that the result occurred by chance (and thus meaningless), so the more chances, the more likely that the meaningless is considered significant.
 

Fear of Friday the 13th is mistakenly attributing some magical power to a day, to a number, to the calendar, and/or to some other variation of belief in the magic of numbers.

Numbers are important and can provide us with useful information about the risks in our lives. The risks we take confidently, cautiously, or those we don’t take. Often our decisions about risk are based on faulty information, such as the fear of a date. Mathematical literacy is necessary to understand the ways that we can use numbers to obtain valid information. John Allen Paulos created the term innumeracy to describe our lack of literacy in the language of numbers. He explained this in 1988 in his book Innumeracy: Mathematical Illiteracy and its Consequences.[2]
 

Innumeracy cover
 


 

Oh! But what about Lies, damned lies, and statistics?

Doesn’t using math make it easier for people to lie to us?

No. Ignorance of math makes it easier for people to lie to us with math.

People do not often lie with numbers. People lie with words. Maybe they lie with the salesman smile. Maybe they lie with the fear monger frown. Maybe they lie unintentionally, because they don’t know what they are talking about. They lie with words. Our ignorance of logic, not our understanding of math, is what allows us to fall victim to most lies.

Today is another Friday that is no more exciting than any other Friday.

Luck works in our favor when we are prepared for the results of our actions, but that is not the kind of luck many people want to understand.
 

Happy Friday the 13th – New and Improved with Space Debris – Fri, 13 Nov 2015

Friday the 13th and full-moon – the ‘worst case scenario’ or only superstition? – Fri, 13 Jun 2014

Blue Moon 2012 – Except parts of Oceanea – Fri, 31 Aug 2012

2009’s Top Threat To Science In Medicine – Fri, 01 Jan 2010

T G I Friday the 13th – Fri, 13 Nov 2009

Happy Equinox! – Thu, 20 Mar 2008

Footnotes:

[1] Answering the myth: use of emergency services on Friday the 13th.
Lo BM, Visintainer CM, Best HA, Beydoun HA.
Am J Emerg Med. 2012 Jul;30(6):886-9. doi: 10.1016/j.ajem.2011.06.008. Epub 2011 Aug 19.
PMID: 21855260

[2] Innumeracy: Mathematical Illiteracy and its Consequences
Wikipedia
Page on Wikipedia

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Happy Friday the 13th – New and Improved with Space Debris


 

This is not your regular scary old Friday the 13th. This one is new and improved with Death from the Skies! Not the great book by Phil Plait, just the fear and anxiety of the What if . . . ?

This debris will not cause any harm to anyone, but the whole idea of superstition is to fear the unknown and come up with other superstitions to provide a feeling of control over the unknown. But look at the bones name!

WT1190F

It’s got to mean something!

It couldn’t just be a coincidence!

Those phrases are the basis of a lot of superstition and conspiracy theories.

For example, psychics aren’t going to be completely wrong all of the time, so they claim that their vague prediction, that is almost right if you ignore most of what really happened, is proof of their abilities, when it is only to be expected that nobody will be completely wrong all of the time unless they make very few predictions. Psychics make a lot of predictions in order to be able to say they got something right. Nostradamus was given credit for this for centuries, but he is just another one who makes vague predictions that cannot all be completely wrong.

Sylvia Browne is one of the most famous people to take advantage of this. She gets everything wrong, but spins it so that those who want to believe can ignore reality and continue to believe pay her millions of dollars.

Is a bunch of WTF debris on Friday the 13th something to worry about? No.

Our lack of understanding of probability is what we should really worry about. People do lie with statistics, but people lie much more often with words. How often do people claim that we should not understand English, because people lie with English? Why should we choose willful ignorance of probability and statistics, when the same argument would be ridiculed if it were made for something we like?

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EMS Volunteers, Patient Stress and 200,000 Downloads for EMS Office Hours


 

Last week on EMS Office Hours, Jim Hoffman, Josh Knapp, and Dave Brenner discussed a variety of topics before I got on the show. We ended up discussing a question Josh had posted on the WANTYNU Facebook page.
 

EMS Volunteers, Patient Stress and 200,000
 

I do not have a link to the original question, but it was along the lines of If you are 99% sure that your patient is having a heart attack, do you tell the patient?

My original comment was along the lines of

1. How did I develop so much certainty about this actually being a heart attack?

2. What is the benefit of telling the patient You are having a heart attack?
 

1.

A. Do we track all of our heart attack patients and compare their final diagnoses with our diagnoses?

Would only STEMIs (ST segment Elevation Myocardial Infarctions) be considered for the You are having a heart attack, with 99% accuracy claim?

Does we have the statistics to back up that claim?

Are we overly confident of our diagnoses and unaware of the difference between our accuracy and reality?

Even if we do track our precision (when we state that it is a heart attack, it truly is a heart attack), do we assume that means that we avoid false negatives(when we do not state that it is a heart attack, there is no heart attack)?

Do we track false negatives?

How do we know if we miss false negatives?

How does awareness of these false negatives affect our confidence in claiming You are having a heart attack?
 

Do our misses count?

Is it a miss, if the machine analysis states ***STEMI***, we disagree, but it turns out to be a STEMI?

Is it a miss, if the machine analysis does not state ***STEMI***, we disagree, and it turns out to not be a STEMI?

Is it a miss, if the machine analysis does not state ***STEMI***, we disagree, but it turns out to be a STEMI? The machine was wrong, but we were right.

All of these affect our diagnosis of STEMI, but how much do we pay attention to any of them?

Is the excuse, Most doctors would have missed that, a valid excuse? We are wrong, but we are as wrong as another group of people would be expected to be.
 

appropriate-cath-lab-activation-1
 

If the goal is to be wrong less than 5% of the time, what evidence do we have that we are wrong less than 1% of the time?
 

In summary, broad awareness should exist regarding evidence-based triggers for appropriate Cath Lab activation. A diverse group of frontline clinicians making these time-pressured decisions need a comprehensive list of precise criteria, because not all “acute MIs” have classic ST-elevation on ECG (eg, STEMI-equivalents and certain OCHA scenarios), not all ST-elevation patterns represent “true STEMI” (ie, STE-mimics), and some “true STEMI” patients are not reasonable candidates for an aggressive treatment strategy involving PPCI. Optimal ECG interpretation proficiency by all clinicians in identifying both classic STEMI and STEMI-equivalents constitutes a major cornerstone of ongoing efforts to maximize STEMI system efficiency.[1]

 

And the most important question may be How much do we know about what we don’t know?

Am I 99% certain, or just convincing myself that I am much more certain than I have any right to claim?

Why should we assume that we do not need to know our limitations?
 

Go listen to the podcast.
 

Also see Tom Bouthillet’s slides from his presentation –

STEMI Mimics and STEMI Equivalents
EMS 12 Lead
Slide presentation.

Footnotes:

[1] Appropriate cardiac cath lab activation: optimizing electrocardiogram interpretation and clinical decision-making for acute ST-elevation myocardial infarction.
Rokos IC, French WJ, Mattu A, Nichol G, Farkouh ME, Reiffel J, Stone GW.
Am Heart J. 2010 Dec;160(6):995-1003, 1003.e1-8. doi: 10.1016/j.ahj.2010.08.011. Review.
PMID:21146650[PubMed – indexed for MEDLINE]

Free Full Text from Am Heart J.

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Equipoise and Ethics and IRBs, Oh My!

ResearchBlogging.org
 

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.

 

Equipoise?

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 A?

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.

Footnotes:

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

[2] Clinical equipoise
Wikipedia
Article

[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

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