I began with Ethics, Research, and IRBs – Part I. Then, in Ethics, Research, and IRBs – Part II, I was pointing out this problem with the evidence –
Class IIb, so the Size of the treatment effect is tiny.
LOE A (Level Of Evidence A), so the Estimate of certainty (precision) of the treatment effect is large.
There is a large certainty that the treatment effect is tiny.
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Should epinephrine be Class IIb?
There is still no evidence of any improved survival to discharge with epinephrine, or any other pressor. Why limit this to pressors? There is still no evidence of any improved survival to discharge with anything other than excellent compressions and defibrillation.
We can get a pulse back more often with epinephrine, but does that improve survival?
Does epinephrine cause some harm that decreases survival?
Is epinephrine beneficial for some patients and harmful for others?
The chart from Part II does not really help answer these questions.
We do know that whatever the effect of epinephrine on survival, it is a tiny effect, because none of the research on epinephrine has included enough patients to be able to show a statistically significant difference in outcomes.
With the new guidelines, Class Indeterminate has been removed. Epinephrine would be more appropriately classified as indeterminate, but how do we choose between Class III (not helpful, possibly harmful) and Class IIb (maybe helpful, maybe harmful) for a drug like epinephrine?
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Should epinephrine be LOE A?
When looking at the research, we want to determine the quality of the research. LOE A is the highest quality of research. Data derived from multiple randomized clinical trials or meta-analyses. Unfortunately, due to the tiny size of the effect of epinephrine, huge studies are needed.
No single study has been large enough to determine among improved survival, no effect on survival, and worse survival.
No combination of the studies (meta-analysis) has been large enough to determine among improved survival, no effect on survival, and worse survival.
In other words, the research is not good enough to determine if there is any reason to use epinephrine.
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The AHA states –
The optimal timing of vasopressor administration during the 2-minute period of uninterrupted CPR has not been established.[1]
We don’t even have good evidence that vasopressors should be given to any cardiac arrest patients, but they are acting as if the question is only a matter of something as insignificant as the optimal timing.
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Farther along –
There are no RCTs that adequately compare epinephrine with placebo in treatment of and outcomes related to out-of-hospital cardiac arrest.[2]
RCTs are Randomized Controlled Trials. The basis for the use of epinephrine is research that they admit is not adequate, yet this is considered LOE A.
Then, in the next paragraph, –
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).[2]
Only reasonable?
Only to consider?
It is reasonable to consider administering epinephrine.
Then it also reasonable to consider not administering epinephrine.
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The combination of Class IIb and LOE A means that there is a lot of evidence that any effect is unimportant.
This is just a demonstration of making unreasonable aggressive treatment decisions based on inadequate evidence.
Or based on –
Wishful Thinking >>> Evidence
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Footnotes:
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[1] Drug Therapy in VF/Pulseless VT
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8: Adult Advanced Cardiovascular Life Support
Rhythm-Based Management of Cardiac Arrest
Free Full Text Article with links to Free Full Text PDF download
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[2] Epinephrine
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8: Adult Advanced Cardiovascular Life Support
Medications for Arrest Rhythms
Vasopressors
Free Full Text Article with links to Free Full Text PDF download
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I heard on EMCrit’s podcast for the new ACLS changes about a technique for the appropriate timing of pressors, which I had never previously heard of, basically titrating pressors to an aortic diastolic pressure of 40mmHg. He went over that you used ETCO2 to evaluate compressions and Aortic Diastolic Pressure to evaluate pressors.
Granted I don’t see many medics dropping a fem line in during an arrest, but perhaps this is the type of intervention most appropriate for studying the efficacy of various dosing schedules for epinephrine.
Christopher,
I think that is a great idea. That is one of the things that I love about Dr. Weingart. He thinks about why he is using a particular treatment. If we have a specific indication for giving epinephrine, that makes much more sense than, Everybody dead gets epi.
Maybe there are some specific indications where epinephrine will lead to improved survival.
The 2 reason epinephrine is still used routinely in cardiac arrest.
1. ROSC (Return Of Spontaneous Circulation). Try telling people that getting a pulse back sooner is a bad idea, even though we can show that it was a bad idea with high-dose epinephrine, which increased ROSC more than standard-dose epinephrine does. Why be consistent?
2. Somebody has to prove that the unproven treatments are dangerous, or that some other treatment is better, in order to remove these unproven treatments from the guidelines.
On the podcast interview with Jamie Davis and Tom Bouthillet, Dr. Monica Kleinman said –
This does more to protect the guidelines than to protect patients.
We will be titrating oxygen to the patients’ needs, but patients will continue to get epinephrine according to the same error that we used to excuse high-flow oxygen for everyone – It can’t hurt and it might help.
It might help, but it also can definitely hurt.
Until we start thinking about ways we can limit epinephrine to patients who might actually benefit from epinephrine, the only improvements in survival are likely to be non-pharmacological.
The other point Dr. Weingart made in his podcast was to NOT slam home your 1mg epi post-defibrillation, but instead to wait maybe a minute or so to see if ROSC was achieved (by ETCO2 signs). That way you don’t make your newly revived person dead again.
I’ve been told, crusty medic story alert, if you give 1mg Epi IV to a conscious patient they scream “MY HEAD IS ON FIRE” or “OH MY GOD I’M GOING TO EXPLODE”. In all likelihood a recently resuscitated person does not want either of those side effects.
Christopher,
The new guidelines state –
This is not accurate –
If a shock fails to generate a perfusing rhythm, then giving a vasopressor soon after the shock
will optimizemay have a greater effect on the potential impact of increased myocardial blood flow before the next shock.Optimize is only accurate if it provides a benefit. If there is harm, then that cannot be described as being optimized. We do not know what the optimal myocardial blood flow is in cardiac arrest. We do not know how much variation there might be in the optimal myocardial blood flow in cardiac arrest. We do not know that epinephrine does not cause more harm than benefit in cardiac arrest.
However, if a shock results in a perfusing rhythm, a bolus dose of vasopressor at any time during the subsequent 2-minute period of CPR (before rhythm check) could theoretically have detrimental effects on cardiovascular stability.
The way they write this, the benefit from epinephrine is certain, when there is no pulse, but the only concern is that epinephrine could theoretically have detrimental effects on cardiovascular stability.
No bias evident here.
The AHA does seem to have the same advice about waveform capnography.
That is a problem with epinephrine – neurological toxicity. Even giving intramuscular anaphylaxis doses of epinephrine will commonly produce a headache. High-dose epinephrine was de-emphasized due to worse neurological outcomes among those treated with high-dose epinephrine vs. standard-dose epinephrine.
I have never given 1 mg epinephrine IV to a conscious patient, so I cannot say, but I would not be surprised.
I don’t think that anyone, no matter how recent their last resuscitation, wants those side-effects.
Your responses to all of the above points were excellent. I have witnessed misdosing of epi on conscious patients both in person and during QA review. 1 mg of epi IV in a patient with a pulse is a bad, bad thing associated with dysrhythmia and profound hypertension. Understandable given that it is 100 x the IV dose when a patient has a pulse. ETCO2 will show you ROSC during compressions, so I try to glance up before pushing that epi dose.
I think the take home from this post is a great one: drugs are not what saves lives in ACLS.
“A1. ROSC (Return Of Spontaneous Circulation). Try telling people that getting a pulse back sooner is a bad idea, even though we can show that it was a bad idea with high-dose epinephrine, which increased ROSC more than standard-dose epinephrine does. Why be consistent?”
Sanjay Gupta, MD, in building a case for hypothermic treatment says (my paraphrase) evidence is showing the lack of good result in aggressive treatment as a whole is caused by what he called “re-perfusion injury” where there is a sort of rebound effect of the body, suddenly denied of circulation and oxygenation it is snapped back too quickly and can’t manage the shock — like whiplash. It would seem to be consistent with the sudden return to heartbeat that Epi causes.
firetender,
Therapeutic hypothermia may work the way you state. Dr. Becker has been one of the prominent researchers of therapeutic hypothermia, but he is less impressed with it than Dr. Gupta. Dr. Gupta is a TV personality, who is overly impressed with anecdotes. Dr. Gupta also does not seem to have a problem with misrepresenting those anecdotes to make it seem that he is correct.
We will know a lot more once we have more good outcomes research, but we still will not have any final answer. Science is a process of learning, not a multiple choice test set in stone. That does not mean that science reverses itself, as you like to claim. Science modifies and buttresses earlier science. The cases of complete reversal are extremely rare, such as Helicobacter pylori.
…and here’s where we, as human beings, are very vulnerable to being manipulated by incomplete science. And paramedics are part of a great experiment.
YOU SAY: “We will know a lot more once we have more good outcomes research”
The way the society that supports the science works is this; all it takes is a high-profile Expert, like Gupta to start pressing for Hypo-T. That will release money for research. That’s us, Roque, we’ll be the Administers of an unproven treatment once again.
…and we’ll do it because sometimes it WILL work and our job is to provide the chance for that to happen.
kill the last sentence. Can’t figure out how to edit post-Post!
Scott,
Thank you.
ETCO2 is one piece of technology I love. I think that we go overboard in applying technology to help ourselves feel good, rather than assessment and critical judgment to help the patient. You find ways of mixing the technology, the assessment, and the critical judgment so that they help the patient.
We may eventually find a drug that clearly improves survival with good neurological function, but I do not see one, yet. Even when we do have a drug, or drugs, that improve outcomes, we still need to provide excellent basic treatment – compressions and defibrillation.