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Severe pain + 2mg of Morphine = severe pain.

- Rogue Medic

Are We Killing People With ROSC?

Wed, 05 Jun 2013 19:00:27 +0000 by 5 Comments

 

Why do we keep paying attention to studies that only look at ROSC (Return Of Spontaneous Circulation)?

It is true that ROSC is associated with survival to discharge, but as we use treatments to increase ROSC, we only seem to increase the rate of death in the hospital.

We do not increase the rate of survival.
 

Epinephrine (Adrenaline) produces a lot more ROSC, but appears to produce worse survival.

What is it about epinephrine that causes so many more people to die before they wake up from a coma?

Why do we keep trying to put people in short-term comas, before admitting that they are dead?

Why are we still using a treatment that only causes a brief pulse, when what we want is a treatment that increases the rate of survival to discharge with a working brain?
 

Even ventilations seem to dramatically decrease survival.
 


Click on images to make them larger.
 

Patients had dramatically better survival without ventilations.[1]
 

Don’t change the subject. What about the epi?
 

This is comparing three different treatments HDE (High-Dose Epinephrine), SDE (Standard-Dose Epinephrine), and NE (NorEpinephrine). The lines for the HDE and NE are so close to each other, that you may not be able to see the gold line.[2]
 

Compare that chart of HDE, SDE, and NE with this chart comparing Epinephrine and No Epinephrine.[3]
 


 

More ROSC, but fewer survivors.

Shouldn’t the standard of care improve outcomes?
 

 

Even the patients who only received the minimum dose – 1 mg – had worse outcomes.[4]

It is possible that there is a subgroup that does benefit from epinephrine – perhaps patients who have ROSC, but remain very bradycardic and lose pulses again. However, there appears to be no attempt to identify any patients who actually may benefit.

This binary, all or nothing, approach is dangerous and nothing new. Five centuries ago Paracelsus gave important advice that we continue to ignore.
 

All things are poison and nothing is without poison, only the dose permits something not to be poisonous. – Paracelsus.

Dr. David Newman at The NNT reviewed ACLS medications and concluded that there is no evidence of benefit.[5]
 


 

The patients who receive epinephrine are those who remain dead long enough to be treated with epinephrine.

Why do we assume that their outcomes would be any worse without epinephrine?

This is the arrogance of ignorance. We don’t know and we don’t want to know.

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Footnotes:

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[1] Cardiocerebral resuscitation is associated with improved survival and neurologic outcome from out-of-hospital cardiac arrest in elders.
Mosier J, Itty A, Sanders A, Mohler J, Wendel C, Poulsen J, Shellenberger J, Clark L, Bobrow B.
Acad Emerg Med. 2010 Mar;17(3):269-75.
PMID: 20370759 [PubMed - indexed for MEDLINE]

Free Full Text from Academic Emergency Medicine.

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[2] A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest.
Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J.
JAMA. 1992 Nov 18;268(19):2667-72.
PMID: 1433686 [PubMed - indexed for MEDLINE]

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[3] 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.

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[4] 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; the Resuscitation Outcomes Consortium Investigators.
Resuscitation. 2012 Jul 31. [Epub ahead of print]
PMID: 22858552 [PubMed - as supplied by publisher]

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[5] NIPPV for CHF Works, ACLS Algorithms Do Not
by David Newman, MD
September 26, 2012
Emergency Physicians Monthly
Article

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Filed Under: ACLS, Epinephrine, Evidence, Heresy, Research

Some Excellent New Medical-Research Sites

Fri, 24 May 2013 08:00:22 +0000 by 2 Comments
 

Where are the best new places to get emergency medical research?

First, an older place, which gathers a lot of research together.
 


 

Life in the Fast Lane has its Research Review (the most recent is #104), which provides links to what people are writing about emergency medicine and critical care research as well as great writing by their own authors.
 

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But what about the newer sites?
 


Image credit.
 

The Lit Whisperers
 

The new blog of Brandon Oto to go along with The EMSB Digital Research Library by Brandon with Vince DiGiulio as the Head Librarian and Master of Evidence-Based Codices. .
 

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Skeptical Medicine
 

Dr. John Byrne tries to explain about the medical mistakes we make in being too cynical or too gullible, rather than appropriately skeptical of claims made by researchers, or those who do not even care if their treatments work.
 

Where do we fall on this spectrum?

Too many of us seem to be fond of the idea of using what some fan of physiology claims works, even though this approach frequently does not even work as well as placebo. We need less of that textbook gullibility that is regularly disproved by research.
 

** It is logically contradictory – and therefore forbidden – to embrace science and logic when they support an idea, but then to reject them when they do not.

 

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Mill Hill Ave Command
 

Dr. Brooks Walsh examines recent research with a lot of visual aids that take what could be dense material and makes it very educational and fun. There is otherwise a shortage of paramedic/medical directors out there writing about research.
 

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EMS Patient Perspective

Bob Sullivan writes about the way our treatments affect patients, for good and for bad.
 

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Then some of the older sites –
 


 

Street Watch: Notes of a Paramedic
 

Peter Canning writes about what works in patient care from the street level and from the administrator level in one of the first EMS blogs.
 

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A Day in the Life of an Ambulance Driver
 

Perhaps the most hated blog name in EMS, because We’re too good to be called ambulance drivers. Those critics may not even deserve to be called taxi drivers.

Kelly Grayson writes about all aspects of EMS, but he has a series with Gene Gandy that looks at the EMS mythology that just does not seem to go away, such as the recent More Oxygen Can’t Hurt…Can It?
 

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EMS 12 Lead
 

Tom Bouthillet, Christopher Watford, and David Baumrind write about all things electrical in the heart.
 

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SMART EM

Dr. David Newman, and sometimes Dr. Ashley Shreves, write and podcast about research and emergency medicine. There is an excellent deconstruction of the ACLS (Advanced Cardiac Life Support) guidelines and the lack of evidence for the drugs recommended in the guidelines.

The NNT is another excellent site that is here, too.
 

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EM Crit
 

Dr. Scott Weingart podcasting on bringing ICU medicine to the ED, so why shouldn’t we continue that by taking ED medicine to the street?
&nbsp

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Emergency Medicine Literature of Note
 

Dr. Ryan Radecki writes a couple of paragraphs that get to the heart of recent research – the important points, including the flaws. His criticism of the only partially disclosed biases of the cherry-picked research misrepresented as a comprehensive research review by JAMA (Journal of the American Medical Association) was posted on his site, rather than trying to get it published in JAMA. It probably received more attention this way. Go read it.

Are blogs the future of peer review, because the journals do not seem to do an adequate job. If they did, I would not have so many badly written papers to criticize.
 

These sites are not examples of gullibility in medicine.
 

I am sure I am missing some important sites, but I am too tired to focus. Going to bed.
 

What sites do you recommend?
 

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Filed Under: Heresy, Research

Too Much Oxygen, Too Many Backboards

Fri, 17 May 2013 08:00:13 +0000 by
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This week on EMS Office Hours, Jim Hoffman, Josh Knapp, and I discuss a variety of topics – quality in EMS, respect for EMS, the value of research and whether we should teach people to use research in EMS.
 

Too Much Oxygen, Too Many Backboards
 

Spinal immobilization can be done in many different ways. Strapping a curved spine to a flat piece of lumber/plastic is not the only way to do it and not even the only way that it is done in the US, nor in the rest of the world.
 


 

Long spine board immobilization is continuing to be replaced by the lateral trauma position in Norway.[1],[2]
 

What about in America?

Going back to 2008 (the earliest protocols available on line, all of Pennsylvania has had spinal clearance.
 

Immobilize the entire spine3,4 in any trauma patient who sustains an injury with a
mechanism having the potential for causing spinal injury and who has at least one of
these clinical criteria:5
a. Altered mental status (including any patient that is not completely alert and oriented)
b. Evidence of intoxication with alcohol or drugs
c. A distracting painful injury (including any suspected extremity fracture)
d. Neurologic deficit (including extremity numbness or weakness- even if resolved)
e. Spinal pain or tenderness (in the neck or back)[3]

 

Without altered mental status, evidence of intoxication, a distracting painful injury, neurologic deficit, and/or spinal pain or tenderness spinal immobilization is a violation of protocol in Pennsylvania.

Alameda County, California; Xenia, Ohio; and all of Connecticut are doing away with backboards.

Spinal clearance has been in place in many more places in various forms for years, or even for decades.

Don’t let local attitudes fool you. this is not new or limited to isolated areas.
 

Spinal immobilization is witchcraft. There is no evidence of benefit.
 

Oxygen was also discussed.

There is a lot to discuss about the absence of good evidence that supplemental oxygen improves outcomes when there is no known hypoxia.
For heart attack patients, why do we want to give a drug (oxygen) that causes vasoconstriction, when our goal is vasodilation?

If the goal is to improve blood supply, and oxygen decreases blood supply, then why are we giving oxygen in the absence of evidence of hypoxia?

Supplemental oxygen without evidence of hypoxia is also witchcraft.

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Footnotes:

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[1] The lateral trauma position: what do we know about it and how do we use it? A cross-sectional survey of all Norwegian emergency medical services.
Fattah S, Ekås GR, Hyldmo PK, Wisborg T.
Scand J Trauma Resusc Emerg Med. 2011 Aug 4;19:45.
PMID: 21816059 [PubMed - in process]

Free Full Text from PubMed Central with links to PDF Download

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[2] The Lateral Trauma Position: What do we know about it and how do we use it
Sun, 04 Dec 2011
Rogue Medic
Article

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[3] Spinal Immobilzation – 261
2008 Pennsylvania Protocols
PEHSC
Page with links to protocols in PDF format.

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[4] More Oxygen Can’t Hurt…Can It?
by William E. “Gene” Gandy, JD, LP and Steven “Kelly” Grayson, NREMT-P, CCEMT-P
Created: MAY 1, 2013
EMS World
Article

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Filed Under: EMS Office Hours, Heresy, Oxygen, Research, Spinal Immobilization

With Conflicting Evidence, What Should We Do? – Oxygen

Sun, 21 Apr 2013 08:00:17 +0000 by
 

Dr. Brooks Walsh writes about a recent paper on the amount of oxygen in the blood of resuscitated.[1] This paper appears to show benefit from high oxygen concentrations.[2] This is contrary to almost all the previous papers looking at the effects of supplemental oxygen.

How do we decide what to believe?

Does this paper mean that the people who claim that science constantly reverses itself are right?

Let me answer the second question first.

No. Science does not constantly reverse itself. The media does report oversimplified mistaken explanations of the results of research. When that media-reported inaccuracy is corrected, that does not mean that the original research made any of the claims the media reported. A reversal of a media misrepresentation is not a scientific reversal.

Science does continually modify previous understanding, but that is how we learn. We do not learn by making exaggerated claims on limited evidence.

So, how do we decide what to believe?

First, we need to understand what conclusions are actually being stated in the research. Reading a news article is not the same as understanding the original paper.

Second, we need to understand how the conclusions were arrived at and how the acknowledged limitations affect the results, as well as the effects of limitations that even the authors may not be aware of.

One limitation is the intervention and how the authors decide what the intervention is.

The intervention is the treatment that must be demonstrated to be safer and more effective than providing a placebo or even safer and more effective than doing nothing.

In these studies of supplemental oxygen, the intervention is supplemental oxygen. If we think of the intervention as withholding supplemental oxygen, we are looking at things backwards.

As with any drug, and oxygen certainly is a drug, the dose should also be taken into consideration. We should not administer unproven treatments in the highest dose possible, just because we can. We should have evidence that the intervention is beneficial and that the dose is safe and effective.

Where is that evidence?

The evidence against supplemental oxygen is the stronger evidence.

Stressing the hearts of cardiac patients leads to slower recovery and evidence of more ischemia with supplemental oxygen than with room air. Ischemia is supposed to be prevented by supplemental oxygen.[3]

This study was tiny, but it was prospective, double-blinded. The new study reviewed by Dr. Walsh has larger numbers, but everything else about the study is too poorly controlled to be considered good science. Over 60 years have gone by and we still do not have any studies that provide good evidence that supplemental oxygen is safe and improves outcomes for patients who are not hypoxic.

Dr. Walsh writes –

 

As the authors note, “Reasons for the benefit of higher oxygen tensions during CPR can more easily be hypothesized than explained.” Given the conflicting data, it might behoove us to proceed cautiously in modifying the targets for oxygen delivery in cardiac arrest.[1]

 

But which caution is appropriate?

Should we be cautious about giving too much of an unproven treatment?

Or –

Should we be cautious of evidence that we are harming patients with an unproven treatment?

Dr. Walsh is not telling us that there is clear evidence of benefit.

This is the history of a lot of medical treatment is that we harm patients with unproven traditional treatments.
 


Image credit.
 

How well do we understand the pathophysiology on which we base our treatment decisions?

We think we understand the way the body works. We start to use a treatment based on that misunderstanding. Somebody eventually studies the treatment. We admit that our misunderstanding misled us to harm patients. We still do not admit that we should have studied the treatment before making it a standard of care.
 

Until there is good evidence that supplemental oxygen improves outcomes, we should not be aggressive with this unproven traditional treatment.

Will we ever have good evidence of benefit? History continually provides more evidence that traditional treatments are harmful – not evidence that these traditional treatments have been neglected.

Oxygen is a drug. Drugs should be used when indicated by our assessment. Drugs should not be used out of a belief that drugs cannot hurt.

The intervention is the risk, the danger, the threat to the patient until there is evidence of safety and benefit.

It is rare that we ever have that evidence, because we keep unreasonably expecting each treatment to be magically beneficial.

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Footnotes:

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[1] Hyperoxia during CPR associated with improved survival
Wednesday, April 3, 2013
Mill Hill Ave Command
Article

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[2] Increasing arterial oxygen partial pressure during cardiopulmonary resuscitation is associated with improved rates of hospital admission.
Spindelboeck W, Schindler O, Moser A, Hausler F, Wallner S, Strasser C, Haas J, Gemes G, Prause G.
Resuscitation. 2013 Jan 17. doi:pii: S0300-9572(13)00042-7. 10.1016/j.resuscitation.2013.01.012. [Epub ahead of print]
PMID: 23333452 [PubMed - as supplied by publisher]

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[3] One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris.
RUSSEK HI, REGAN FD, NAEGELE CF.
J Am Med Assoc. 1950 Sep 30;144(5):373-5. No abstract available.
PMID: 14774103 [PubMed - indexed for MEDLINE]
 

In five patients with angina pectoris the administration of 100 per cent oxygen did not favorably influence the onset or duration of pain or the electrocardiographic alterations induced by standard exercise. On the contrary, oxygen therapy actually appeared responsible for more pronounced and persistent electrocardiographic changes in several patients.

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Filed Under: Evidence, Heresy, Oxygen, Research

The Parachute Study as an Objection to Studying Ventilations in Cardiac Arrest

Mon, 08 Apr 2013 08:00:42 +0000 by
 
The use of ventilations in cardiac arrest is an example of a treatment that some of us defend by reference to the parachute study.

We assume that we understand all we need to know about physiology, thus we overestimate our ability to understand what we are doing.

Is it impractical to compare the effects of compression-only CPR with standard CPR?
 

It doesn’t take a PhD physiologist to know that at SOME point you have to provide some ventilation, or 02 sats will decrease, CO2 will increase, etc., to unsurvivable levels. Before you buy the “never been researched ergo must be bad,” you have to read http://www.bmj.com/content/327/7429/1459.full

No, there has never been a prospective, randomized trial of the parachute, but does that make the use of parachutes any less valid?

 

Is compression-only CPR the same as throwing the patient from a plane without a parachute?

Of course not, but suggesting that traditional treatments are not essential does seem to encourage the use of logical fallacies in otherwise intelligent people, even those trained to the doctorate level especially those trained to the doctorate level.

How much bias is necessary to jump to the conclusion that the criticism of our evidence-free traditional treatments is the same as claiming that the treatment must be bad?

The decision to continue to use treatments of unknown benefit and unknown harm is what is bad.

The list of treatments we have abandoned after we finally examined the treatments, and found out the traditional treatments were harmful, is not short.

We killed a lot of people with ignorance and appeals to common sense.

We still do.
 


 

The decision to remain ignorant is a bad decision for us, but a much worse decision for our patients.

What evidence do we have that ventilations improve survival from cardiac arrest?

None.

We assume this.

Is any ventilation provided by continuous chest compressions?

The comment above suggests that there is no ventilation, or that the ventilation is completely inadequate for the physiologic needs of a dead patient.

Is it reasonable to treat patients based on those assumptions?

Is it ethical to treat patients based on those assumptions?
 

It doesn’t take a PhD physiologist to know that at SOME point you have to provide some ventilation, or 02 sats will decrease, CO2 will increase, etc., to unsurvivable levels.

Is that point at any time before ROSC (Return Of Spontaneous Circulation)?

Maybe.

Maybe not.
 

Conclusions
This report demonstrates that if powerful cardiac compressions are started early, in this case less than two minutes after normothermic arrest, it is possible to maintain circulation and a sort of spontaneous respiratory movements resulting in gas exchange for more than 25 minutes. For this patient, this kind of respiration was sufficient for survival without neurological damage.

Favourable outcome after 26 minutes of “Compression only” resuscitation: a case report.
Steen-Hansen JE.
Scand J Trauma Resusc Emerg Med. 2010 Apr 16;18:19.
PMID: 20398354 [PubMed - indexed for MEDLINE]

Free Full Text from PubMed Central

 

Unless there is evidence of benefit, an intervention should not be presumed to be benign.

 

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Filed Under: 2010 AHA Guidelines, Heresy, Research, Unicorn Medicine

Common Sense vs. Evidence

Thu, 28 Mar 2013 19:00:08 +0000 by
 

Too Old To Work, Too Young To Retire challenges me to respond to his recent discovery of the parachute study.[1] The parachute study is from a decade ago, when Too Old was just a charming young curmudgeon.

What is common sense?

It is easier to describe what common sense is not.

What is common only appears to make sense.

What makes sense – to an individual who really understands what he is doing – is not common.

Con men rely on our belief in common sense to scam us. Maybe we should call it con man sense.

I have already written about the parachute study.[2]

The authors of the parachute study make it clear that their paper is a satire. It appears in the Christmas issue, which is the most comedic of the BMJ (British Medical Journal) issues.
 

Notes
Contributors: GCSS had the original idea. JPP tried to talk him out of it. JPP did the first literature search but GCSS lost it. GCSS drafted the manuscript but JPP deleted all the best jokes. GCSS is the guarantor, and JPP says it serves him right.
Funding: None.
Competing interests: None declared.
Ethical approval: Not required.[3]

 

This is why actually reading the full paper, and understanding it, is important in evaluating research. When we read, and understand what we are reading, we are able to see the strengths and weaknesses of the paper.

This is why what I write about research papers tends to be much longer than what I write about everything else.

EM Literature of Note has much shorter analyses of papers. Dr. Radecki would probably respond to, and dismiss, what Too Old wrote in a short paragraph, but I am less concise.

Reading, and understanding, the whole paper is why I do not post just the abstract and some unwarranted conclusions.

That would be foolish, but that seems to be what we get from most of science reporting, including the material written by doctors for medical web sites. I am not suggesting that I am perfect. I miss stuff, too, but I will not hide it when I miss stuff.[4],[5],[6]

Perfection is the realm of the quack.

Perfection is not real, but quacks are very real and all too common.

While the parachute study points out some of the weaknesses of basing treatments on evidence (or science), nobody claims that evidence is perfect. The critics act as if evidence is supposed to be perfect, and since evidence is not perfect, then our only alternative is to fall for whatever quackery they are pushing.

Evidence is not expected to be perfect.

Evidence is still the best way we have of finding what works.
 


Download Video from YouTube | Convert YouTube to MP3
 

 

You can use the anecdote-based parachute provided by the ACME Alternative Parachute Company, Ltd.

There was this one time that . . . yada yada . . . twice . . . yada yada yada . . . and then he . . . I swear . . . and it totally worked!

I will use a parachute that is manufactured according to designs that have been well tested and constructed using materials that have been well tested.
 

  • We would still be using common sense and remain ignorant of the effects of H pylori in peptic ulcers if not for evidence.[7]

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  • How many patients did we common sense to death when blood-letting to remove bad humors was the standard of care?[8]

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  • How many patients did we common sense to death when antiarrhythmics to eliminate PVCs after a heart attack was the standard of care?[9]

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  • How many patients did we common sense to death when giving high-flow oxygen for heart attacks, cardiac arrest, and everything else was the standard of care?[10],[11],[12]

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  • We would still be using the common sense of internal mammary artery ligation to treat heart attacks if not for evidence.[13]

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  • We would still be using the common sense of standing back and letting the medic get the line, or the tube, if not for evidence. How much did your resuscitation rate go up when you made the evidence-based change of focusing on excellent compressions?[14],[15]

 
Most of the links are to what I have written about these examples, because to list all of the research demonstrating the ways we killed people with common sense would take much more room.

You might think that common sense would include an understanding of the benefits of research, but it does not.

Maybe common sense would be more appropriately titled common ignorance.

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Footnotes:

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[1] Common Sense Versus Evidence Based Medicine
March 27, 2013
Too Old To Work, Too Young To Retire
Article

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[2] Does the parachute study prove that research doesn’t matter? Part I
Wed, 22 Aug 2012
Rogue Medic
Article

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[3] Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.
Smith GC, Pell JP.
BMJ. 2003 Dec 20;327(7429):1459-61. Review.
PMID: 14684649 [PubMed - indexed for MEDLINE]

Free Full Text from PubMed Central.

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[4] Corrections of Misleading Charts
Mon, 07 Feb 2011
Rogue Medic
Article

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[5] Is the Difference in Penetrating Trauma Mortality Truly Significant? Part I
Sun, 03 Feb 2013
Rogue Medic
Article

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[6] Advanced Airway vs. BVM During CPR – Which is Worse?
Sun, 10 Feb 2013
Rogue Medic
Article

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[7] Timeline of peptic ulcer disease and Helicobacter pylori
Wikipedia
Article

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[8] Answer to What is this Dangerous Treatment and How Long Did it Take to Stop Using it
Wed, 01 Feb 2012
Rogue Medic
Article

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[9] C A S T and Narrative Fallacy
Mon, 20 Jul 2009
Rogue Medic
Article

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[10] More Oxygen in the New AHA Guidelines
Tue, 26 Oct 2010
Rogue Medic
Article

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[11] One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris
Tue, 19 Jun 2012
Rogue Medic
Article

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[12] Evidence for Oxygen in Cardiac Arrest
Wed, 10 Aug 2011
Rogue Medic
Article

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[13] An evaluation of internal-mammary-artery ligation by a double-blind technic.
COBB LA, THOMAS GI, DILLARD DH, MERENDINO KA, BRUCE RA.
N Engl J Med. 1959 May 28;260(22):1115-8. No abstract available.
PMID: 13657350 [PubMed - indexed for MEDLINE]

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[14] Cardiac Arrest Management is an EMT-Basic Skill
Wed, 07 Dec 2011
Rogue Medic
Article

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[15] Cardiac Arrest Management is an EMT-Basic Skill – The Hands Only Evidence
Fri, 09 Dec 2011
Rogue Medic
Article

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Filed Under: Evidence, Heresy, Research, Science

Giving New Meaning to Carpe Diem

Thu, 21 Mar 2013 20:15:40 +0000 by
 

On facebook, Jon Kuppinger describes the following situation –
 

So what made you decide to call now given your patient has been in full tonic-clonic seizures for over three hours now?

 

Maybe their washing machine was broken.
 


Image credit.
 

The response by the nurse?
 

The nurse was out and we don’t have access to any meds and it just seemed worse than it was earlier and we weren’t sure what to do about it so we decided to wait until she got back to call.

 

Paging Nurse Gilligan! Paging Nurse Gilligan!

The nurse was out for over three hours and . . . .
 

Just sit right back and you’ll hear a tale,
A tale of an endless fit
That started at a nursing home
Then went straight to $#!†.

The patient was a flailing man,
The aide had not a clue.
The patient’s brain was fried that day
In a three hour spaz, a three hour spaz.

The seizure started getting rough,
The patient quaked and tossed,
If not for the callousness of the staff,
The seizure would be stopped.
The seizure would be stopped.

 

Maybe they were engaging in a modern Tuskegee experiment.

Maybe they were using homeopathy or some other form of alternative medicine and were waiting for for the scam treatment to work.

Maybe three hours of seizure was getting boring and they thought that a few more hours of this might be life-threatening. If the patient dies, what will they do for entertainment tomorrow?

Unlike Robin Williams’ character in Dead Poets’ Society, I guess that we can be glad that they did not decide to let the patient seize the whole day. This is not what carpe diem means.

We’ve schedule you for a three hour high colonic tonic/clonic today. Ordering activities using drop down menus can cause some real problems.
 

Out of 205 patients, only 19 died in a study comparing using diazepam (Valium), lorazepam (Ativan), or placebo by EMS to treat seizures.[1]

Most of those who died were in the placebo group, even though the placebo group was only one third of the patients. Over 15% of the placebo group died during their hospitalization.

NNK = 6.4 (for untreated seizures)

NNK = Number Needed to Kill. NNH (Number Needed to Harm) is the actual term. These seizures were only untreated for about 15 minutes – not for three hours.

NNH = 3 1/3 (for untreated seizures).

Even an inadequate dose of benzodiazepine would lower the death rate. None of those received IM (IntraMuscular) medication. All received IV (IntraVenous) medication.

Half of the lorazepam group received only one 2 mg dose of lorazepam. The other half of the lorazepam group was given a second dose of 2 mg of lorazepam.

With such low doses, over 40% of the lorazepam patients were still seizing when they arrived at the ED (Emergency Department).

The FDA (Food and Drug Administration) recommends 4 mg lorazepam as the initial dose for seizures.
 

For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15- minute observation period, an additional 4 mg intravenous dose may be slowly administered.[2]

 

A slightly smaller percentage of the diazepam patients were given a second 5 mg dose of diazepam, so it is not surprising that well over half were still seizing when they arrived at the ED.

A low dose means continuing seizures. My brand new protocols ignored the evidence from the recent IM midazolam (Versed) vs IV lorazepam study and have us continuing to use inadequate doses.[3]
 


 

Only 1 mg – 2 mg lorazepam?

Only 1 mg – 5 mg midazolam?

Holy Continuing Seizures, Batman!

Even the FDA recommends 4 mg.

4 mg was the initial dose in recent study that was safe, but not as effective as 10 mg IM midazolam
 

Does anyone take the adverse effects of seizures seriously?
 

After three hours of seizing, the patient might end up as brain damaged as the staff who decided not to treat him, but maybe not.

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Brooks Walsh asks 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 and Ethics and IRBs, Oh My! is my answer.

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Footnotes:

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[1] 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.

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[2] Lorazepam (lorazepam) Injection, Solution
[Baxter Healthcare Corporation]
DailyMed
NLM
FDA label

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[3] Seizure
7007– ALS – Adult/Peds
Statewide ALS Protocol
Pennsylvania
Page with link to Full Text Download of Full Protocols in PDF format.

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[4] Intramuscular versus intravenous therapy for prehospital status epilepticus.
Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators.
N Engl J Med. 2012 Feb 16;366(7):591-600.
PMID: 22335736 [PubMed - in process]

Free Full Text from N Engl J Med.
 

All adults and those children with an estimated body weight of more than 40 kg received either 10 mg of intramuscular midazolam followed by intravenous placebo or intramuscular placebo followed by 4 mg of intravenous lorazepam.

 

The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.11

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Filed Under: Ethics, Heresy, Malpractice, Research

Methodology of tPA Studies – Comment from Joshua

Wed, 30 Jan 2013 08:00:00 +0000 by
 

In response to my criticism of the ACEP (American College of Emergency Physicians) polict statement on Genentech’s r-tPA (recombinant tissue Plasminogen Activator) – alteplase (Activase®),[1] Joshua responded with these comments on what I cited/quoted. I think this is a first for me. –
 

First of all, IST-3 is a very large trial, involving more than 3000 subjects. Nortin Hadler, in his book Rethinking Aging, wisely suggests that whenever a very large trial is required to show statistical benefit, it means that the purported benefit cannot be clinically important.19 [2]

I disagree. When we are unable isolate a single variable (in this case administration of tPA) a large scale study may be the only way to identify outcomes attributable to the intervention (good or bad). The further from treatment to identifiable outcome and the more variables that can’t be (or simply are not) accounted for the larger the sample size should be.

 

There are several reasons I did not use that quote. I would have used an earlier book[3] as the source of that idea.

You do raise an important point. If few variables have been controlled for, are we measuring what we think we are measuring?

You appear to be making one of the same arguments that Dr. Lyden made. That enough data makes the flawed methods irrelevant.

I do not agree with that.

Dr. Lyden wrote –
 

The study leadership invoke a concept known as “large simple” trials, meaning trials that seek power by simplifying protocols and reducing data collection to a bare minimum in hopes of enhanced recruitment. Large simple trials may be an answer to the continuing difficulty getting clinical trials finished on budget and in time.[4]

 

And –
 

When reorganized, the trial became an unblinded trial with a design that sounds rigorous: “prospective, randomized, open, blinded end point” (PROBE). The investigators have written that their end point is blinded because a centralized researcher, unaware of the patient’s treatment group, contacts the patient or family member 6 months after stroke and attempts to derive a modified Rankin Scale from a questionnaire or telephone call.[4]

 

While this does make things more simple, it does not appear to be capable of producing blinded data, but it may blind some people to the fatal flaws of the study methods.
 

If we have only one variable that is the same among thousands of patients, then we might draw some conclusions, but only tentatively. There could easily be other variables which are not universally present and are not being controlled for, yet may have much greater influence on the outcomes. We would not know what is being measured.

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There’s a lot more that goes into the treatment of stroke patient than just whether or not they received fibrinolytic therapy. How many patients received rehabilitative care? How many were treated for hypertension and if so with what? How was patient weight calculated with an administration dose that’s weight dependent? If you only have 100 patients 1 or 2 nurses screwing up their drug calculations (of course that never happens and it ALWAYS gets reported ;-) ) is a difference of 1-2% when evaluating final outcomes. What about 10 patients receiving anti hypertensive therapy in a sample size of 100? If 8 out of those ten patients have a negative outcome what’s to say that the combination of therapies and not TPA itself is responsible for this 8% increase in patients with increased neurological deficit at the 90 day mark? The larger the sample size the more you can negate the weight of these variables. While it’s not unreasonable to assume that 1 or 2 nurses may inadvertently administer an incorrect dose assuming that 100-200 nurses in a sample size of 1000 would do the same would suggest that tPA is the last thing we should be worried about when evaluating our patient’s outcomes.

 

The variability in competence and variability in methods are some of the problems that become more difficult to address in larger studies, but they may reflect the diversity in treatment that exists across the country, or around the world.
 

The substantial increased rate of symptomatic intracerebral hemorrhage among tPA-treated patients has tempered enthusiasm for the rapid adoption of tPA as routine care, in part because of the concern that treatment may be less safe in routine clinical practice than in the highly monitored setting of a clinical trial.[5]

 

This raises a serious problem.

In theory, there is no difference between theory and practice. But in practice, there is.
― Yogi Berra

If tPA works tolerably only during studies, but does a lot damage in use outside of controlled studies, is tPA too dangerous to use outside of controlled trials?

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Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.

If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.[3] [6]

Why are we suprised that pharmacuetical manufacturers are helping write our clinical guidelines?
(http://www.manhattan-institute.org/html/fda_05.htm)(http://www.sciencebasedmedicine.org/index.php/what-does-a-new-drug-cost/ <– read both parts)

It takes a lot of money to conduct phase 2 and 3 drug trials, though as the second article points out the actual cost is probably significantly skewed intentionally. But even at a conservate estimate of $43.4 million that's a lot of money to be gambling. So it's no wonder that they want the best chance at a possible outcome and hire people to make it happen.

 

Genentech should not have any control over who writes policy statements.

It is not a surprise that a drug company would attempt to influence policy statements, but it should not be so easy for any drug company to succeed.
 

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More so than full financial disclosure (because given the cost there's only one entity that can afford it so it's usually safe to assume who's paying to make it happen) I'd like to see a better explanation of how patients are treated in their entirety. Give me ALL the data and not just what you want me to see or what magical mathematical formula you think justifies what you've written in your abstract and let me be the one to interpret it. It's kind of like EPI in cardiac arrest. We may find that the drug is not beneficial for everyone but should instead be reserved for a particular subset of patients.

 

The quality of the research that is published does leave a lot to be desired. How much would it cost to add an on-line data file supplement, or several file supplements, of the raw data to the paper?

Not much.

How much do some of the researchers want to hide this information?

Probably very much.

Along with requiring registering the study with ClinicalTrials.gov, this is something that should be simple to achieve high compliance on. The reality is only about half of trials were registered prior to enrolling patients.[7] Improvements in research quality take time, even though they seem as if they should be no-brainers.

One of the big problems with NINDS was the refusal of the NINDS investigators to release the raw data.[8],[9]

The biggest problem may be the expectation that we will successfully develop drugs in laboratories, when this is not the way we have historically come up with useful drugs.

We would like a drug better than warfarin (Coumadin), but the designer drugs do not seem to be better. The designer anti-clotting drugs only seem to improve surrogate endpoints over warfarin, but we spend a lot on them and that may increase dramatically.

A lot of patients studied, but no important difference in outcomes. Sometimes, when a very large trial is required to show statistical benefit, it means that the purported benefit cannot be is not clinically important.
 

Image credit.

Where is Waldo?

Is Waldo’s location clinically significant?

Click on the image to make the image larger, but making it larger won’t make Waldo any more clinically significant. ;-)

There he is.
 

Image credit.
 

“Spinal immobilization” is one area where the results will require huge numbers, the number of affected patients will be tiny, but the importance of the outcomes will be very important clinically.

The sad thing is that so many people do not want to know how much harm we may be causing or if we could improve care.

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Footnotes:

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[1] Can we trust drug companies to provide accurate information about their products? Part II
Mon, 28 Jan 2013
Rogue Medic
Article

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[2] How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed - in process]

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[3] Fiction And Fantasy In Medical Research: The large scale randomised trial
By James Penston
Published by London Press, 2003
ISBN 0954463617, 9780954463618
144 pages
GoogleBooks link

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[4] In anticipation of International Stroke Trial-3 (IST-3).
Lyden PD.
Stroke. 2012 Jun;43(6):1691-4. Epub 2012 May 3. No abstract available.
PMID: 22556196 [PubMed - indexed for MEDLINE]

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[5] Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department.
This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the American Academy of Neurology.
Ann Emerg Med. 2013 Feb;61(2):225-43. doi: 10.1016/j.annemergmed.2012.11.005. No abstract available.
PMID: 23331647 [PubMed - in process]

Free Full Text Download in PDF format from Elsevier.

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[6] New ACEP tPA Clinical Policy
Wednesday, January 23, 2013
EM Literature of Note
Article

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[7] Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010.
Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem A.
JAMA. 2012 May 2;307(17):1838-47. doi: 10.1001/jama.2012.3424.
PMID: 22550198 [PubMed - indexed for MEDLINE]

Free Full Text from JAMA.

The proportion of trials registered before beginning participant enrollment increased over the 2 time periods: from 33% (9041/27 667) in October 2004–September 2007 to 48% (19 347/40 333) in October 2007–September 2010.

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[8] Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
[No authors listed]
N Engl J Med. 1995 Dec 14;333(24):1581-7.
PMID: 7477192 [PubMed - indexed for MEDLINE]

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[9] Free Full Text from New England Journal of Medicine.
The raw data of the NINDS trial should be made public
Dr. Jeffrey Mann
BMJ
Rapid response letter

Unfortunately, it has been years since Dr. Mann discontinued his EM Guidemaps site, where he posted the raw data that the NINDS investigators finally sent him in 2003, and I no longer have a copy of what he posted.

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Filed Under: Ethics, FDA, Heresy, Pharmacology, Research
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