Dr. Minh LeCong has been a proponent of epinephrine in cardiac arrest, but he is now realizing that the evidence in favor of epinephrine is weak, old, and limited to animal studies. In humans, the evidence for epinephrine is based on an unreasonable infatuation with the temporary production of a pulse.
 

I would like to believe that epinephrine/adrenaline is not harmful in cardiac arrest or other critical states. I have given so much of it over the years and on occasion believed it has saved lives. Certainly in anaphylaxis I have not doubt it saves lives. For cardiac arrest, cardiogenic shock, septic shock, what of those states?^[1]

However, the evidence against epinephrine keeps accumulating.
 

Anesthetized rats received a single intravenous injection of epinephrine (25, 50, or 100 mcg/kg);^[2]

What is the dose of epinephrine in pediatric cardiac arrest?

10 μg/kg (up to 1,000 μg, which is just the 1 mg dose in micrograms [mcg or μg]).

What would be the adult weight equivalent to 25 μg/kg?

40 kg (88 pounds).

This is less than one single dose of epinephrine in cardiac arrest, but we don’t stop at one dose any more than a junkie stops at one dose of heroin. 2 1/2 doses would be the equivalent for pediatric patients. 2 1/2 doses would also be the equivalent for a 100 kg (220 pound) adult.
 

Epinephrine injection in the intact animal caused hypoxemia, hypercapnia, and acidosis at all doses. Arterial oxygen tension was reduced within 1 min of injection. Hyperlactatemia occurred by 10 min after 50 and 100 mcg/kg.^[2]

The patients we treat are already dead, so some people claim that we cannot make them any worse off, but we can.

Whatever chance they have at resuscitation can be decreased, or eliminated, by using the wrong treatment – anything other than continuous chest compressions and defibrillation. Nothing else has been shown to improve survival.

I know what some people are thinking –

We don’t usually give that much. When we do give that much, it is because the patient needed it. So what?

The problem with that approach is assuming a lack of harm because of a lack of explicit evidence of harm.

The authors did not test less than 25 μg/kg of epinephrine, so this does not provide clear evidence of harm, but it does add more evidence to the ever increasing list of studies showing that epinephrine (all catecholamines) can be very bad for the heart.
 

CONCLUSIONS:: Bolus injection of epinephrine in the intact, anesthetized rat impairs pulmonary oxygen exchange within 1 min of treatment. . . . These results potentially argue against using traditional doses of epinephrine for resuscitation, particularly in the anesthetized patient.^[2]

Why is this being posted by someone who supported epinephrine use in cardiac arrest? Because Dr. Minh LeCong is using a scientific approach. He is not looking for evidence to support his biases, and we all have biases. He is looking for the truth, which does not care what we want the truth to be. That is the importance of evidence, which no amount of wishful thinking can overcome.
 

This is a turn around to my previous stance and reflects that one must follow the literature and read the patterns of where science and clinical practice are heading for the care of our critical patients.^[1]

I agree, but I would not limit that to critical patients.

Harmful effects of treatments will be most noticeable with patients who are already critically ill, but can still harmful to healthy people.

For a nice short presentation on the use of catecholamines (epinephrine, dopamine, norepinephrine, dobutamine, et cetera), there is a recording of a presentation by Dr. Mervyn Singer at the 2009 Manchester Critical Care Conference. This is a free download and should be required listening for anyone who uses catecholamines in patient care.^[3]

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Footnotes:

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^[1] Epinephrine/Adrenaline is RAT POISON
PHARM – PreHospital And Retrieval Medicine
by rfdsdoc
September 22, 2012
Article

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^[2] Epinephrine Induces Rapid Deterioration in Pulmonary Oxygen Exchange in Intact, Anesthetized Rats: A Flow and Pulmonary Capillary Pressure-dependent Phenomenon.
Krishnamoorthy V, Hiller DB, Ripper R, Lin B, Vogel SM, Feinstein DL, Oswald S, Rothschild L, Hensel P, Rubinstein I, Minshall R, Weinberg GL.
Anesthesiology. 2012 Oct;117(4):745-754.
PMID: 22902967 [PubMed - as supplied by publisher]

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^[3] Catecholamines Should Be Banned
Mervyn Singer
2009-04-24-1545
6th Annual Critical Care Symposium
Manchester, UK
Page with link to free mp3 download from Free Emergency Medicine Talks

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Krishnamoorthy V, Hiller DB, Ripper R, Lin B, Vogel SM, Feinstein DL, Oswald S, Rothschild L, Hensel P, Rubinstein I, Minshall R, & Weinberg GL (2012). Epinephrine Induces Rapid Deterioration in Pulmonary Oxygen Exchange in Intact, Anesthetized Rats: A Flow and Pulmonary Capillary Pressure-dependent Phenomenon. Anesthesiology, 117 (4), 745-754 PMID: 22902967

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Only low dose epinephrine was shown to improve ROSC (Return Of Spontaneous Circulation) in this study, but even low dose epinephrine dramatically decreased survival. I looked at that in Part I. Here I look at some of what the authors have to say about this in the discussion.

What seems most surprising is how bad the results were for epinephrine.
 

There was an inverse association between epinephrine dose and survival to discharge (Fig. 3). This relationship persisted after adjusting for age, gender, EMS witnessed arrest, bystander witnessed arrest, bystander CPR, shockable initial rhythm, time from 911 to EMS arrival, the duration of OHCA and study site.^[1]

There appears to be only one thing that is relevant that was not controlled for – quality of CPR. The much worse quality of the Accentuate the ALS pre-2005 guidelines vs. the newer emphasis on compressions.

Here is a graph that shows the trend a bit differently from the graphs I included in Part I. Patients who received even 1 mg epinephrine had significantly worse survival to discharge.
 

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

Everything, no matter how natural, is poisonous.

Epinephrine naturally occurs in the body, but that does not make it safe to add more? Potassium occurs naturally in the body and potassium is used to execute people. Are we doing the same with some doses of epinephrine?

The graph seems to make it clear that the more epinephrine we give, the worse the outcomes. If any of us are still in favor of using epinephrine routinely in cardiac arrest, why aren’t we studying lower doses to see if we can find some dose that is less poisonous?
 

Despite the publication of guidelines designed to help standardize the management of OHCA there is substantial variability in the administration of drugs.^[1]

The people who keep claiming that epinephrine (and other standards of care) should not be studied would be disappointed to find out that there is not universal use of their standards.

Is there any evidence that the EMS organizations that do not use these standards of care are sued at a higher rate than the EMS organizations that slavishly require that every ALS suggestion from the ACLS (Advanced Cardiac Life Support) guidelines be considered a standard of care?
 

The overall lack of evidence in favour of any pharmacological agent administered during CPR may result in different interpretations of the guidelines.^[1]

Yes, these are guidelines and they are open to interpretation.

This is not shocking. What is shocking is that so many people do not understand that medical treatment is not about blindly following ancient ideas at the expense of our patients.
 

The early benefits of many of these drugs may be offset by later detrimental effects following resuscitation.^[1]

I would word that differently.

The early appearance of benefits of many of these drugs may be offset by later detrimental effects following resuscitation.

ROSC is a surrogate endpoint and therefore only useful until larger studies can be done to find out if there is any benefit from the drug and whether that benefit may lead to improved outcomes.

A change in vital signs is not an improved outcome.
 

Relatively small benefits of drugs, especially among the minority of patients with VT/VF, may require very large sample sizes to be demonstrated.^{2 [1]}

Yet we keep being told that it is unethical to study these treatments that have never been subjected to even the same requirements as thalidomide.
 

In addition, there are no Class I indications for any pharmacological agents during ALS which likely results in a substantial variability in the incorporation of guidelines into agency protocols.^[1]

What class is epinephrine in cardiac arrest?
 

Class I
Benefit >>> Risk
Procedure/treatment or diagnostic test/assessment should be performed/administered.
 

Not Class I.
 

Class IIa
Benefit >> Risk
It is reasonable to perform procedure/administer treatment or perform diagnostic test/ assessment.
 

Not even Class IIa.
 

Class IIb
Benefit ≥ Risk
Procedure/treatment or diagnostic test/assessment may be considered.
 

There it is epinephrine is just above Class III – the category for things we should not do.
 

Class III
Risk ≥ Benefit
Procedure/treatment or diagnostic test/assessment should not be performed/administered. It is not helpful and may be harmful.
 

Ideally all CPR and ECC recommendations should be based on large prospective randomized controlled clinical trials that find substantial treatment effects on long-term survival and carry a Class I or Class IIa label.^[2]

Epinephrine is not even Class IIa.

Perhaps Class IIb should be represented this way –

Wishful Thinking >>> Evidence
 

Drug Therapy in VF/Pulseless VT
When VF/pulseless VT persists after at least 1 shock and a 2-minute CPR period, a vasopressor can be given with the primary goal of increasing myocardial blood flow during CPR and achieving ROSC (see “Medications for Arrest Rhythms” below for dosing) (Class IIb, LOE A).^[3]

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.

When do we admit that we have been fooling ourselves?

Why does this long shot remain the routine treatment in most places?

Looking at the graph of the different doses of epinephrine, maybe we should be interpreting the results as 3 mg = time to terminate resuscitation.

Epinephrine.

Cause of death, or just an indicator?

Either way, epinephrine not supported by evidence.
 

Expert recommendations must come with an expiration date.

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Footnotes:

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^[1] 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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^[2] Guidelines and Treatment Recommendations
2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 1: Introduction
Free Full Text

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^[3] 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
Part 8.2: Management of Cardiac Arrest
Free Full Text from Circulation

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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 (2012). Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium. Resuscitation PMID: 22858552

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Here is some more research looking at the use of medications in cardiac arrest. In this part, I will look at the outcomes for patients treated with epinephrine. In Part II I will look at the authors’ discussion of their results.

Maybe this time epinephrine will produce a good outcome.

Despite the publication and widespread application of international Advanced Cardiac Life Support (ALS) guidelines² survival rates remain extremely low. The aim of the ALS guidelines is to help standardize the provision of basic and advanced level care based on the available evidence and expert opinion.^[1]

The lack of evidence of improved outcomes has resulted in an excessive dependence on anything that some experts agree might be helpful, or just meets some surrogate endpoint. We need evidence of improved outcomes, not evidence of temporarily improved vital signs. Surrogate endpoints are notorious for consistently failing to predict improved outcomes, so we should not base guidelines on surrogate endpoints.

There has even been opposition to obtaining evidence about the effects of these standards of mediocrity.^[2]

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The 2010 guidelines have removed atropine from the current treatment guidelines for OHCA and the accompanying 2010 Consensus on Science document suggested that placebo trials are needed to evaluate antiarrhythmic and vasopressor use in OHCA.^{5 [1]}

Atropine was removed, because of a lack of evidence of benefit, but the other drugs remain.

The aim of this study was to describe the variability of drug administration for OHCA between EMS agencies across North America in a large multicentre registry of cardiac arrests and examine whether there was an association between administration of individual drugs and the presence of a pulse at emergency department (ED) admission as well as survival to hospital discharge.^[1]

This study has a lot of variables and is not definitive, but if there is some actual benefit from the the wonder drug, epinephrine, this study should show some benefit. The ROC (Resuscitation Outcomes Consortium) registry had relevant data for 16,221 cardiac arrest patients treated from December 2005 to June 2007. Many, maybe even most, of these patients may not have been treated according to the 2005 ACLS (Advanced Cardiac Life Support) guidelines due to the delays some agencies had in implementing the new guidelines.

Epinephrine, amiodarone, lidocaine, vasopressin, atropine, and sodium bicarbonate were examined, but the doses were only documented for epinephrine in the registry. Documenting the use of vasopressin was not part of the registry requirements, so patients might have received a pressor, yet not had any documentation of pressor use if they received vasopressin, rather than epinephrine.

In the multivariable logistic regression model, dose of epinephrine was grouped into none, low (1–2 mg), moderate (3–5 mg), and high (>5 mg).^[1]

Finding out the different results at various doses is a good idea.

Is more better?

If epinephrine is harmful, more epinephrine could show progressively increasing harm.
 

Amiodarone, lidocaine, and epinephrine all look as if they may be beneficial.

Epinephrine was administered in approximately 80% of ALS treated cardiac arrests (range 57–98% among agencies). All agencies used epinephrine in some cardiac arrests. The mean dose administered was 3.5 mg (±2.0 mg). Epinephrine dose varied widely across agencies, with a range in the mean epinephrine dose of 1.9–5.5 mg (p < 0.001). There was an inverse association between epinephrine dose and survival to discharge (Fig. 3). This relationship persisted after adjusting for age, gender, EMS witnessed arrest, bystander witnessed arrest, bystander CPR, shockable initial rhythm, time from 911 to EMS arrival, the duration of OHCA and study site.^[1]

Low dose epinephrine did improve ROSC, but how import is ROSC (Return Of Spontaneous Circulation)?
 

 

Lidocaine and amiodarone, while not producing statistically significant results, don’t look that much worse for survival than they were for ROSC.

But epinephrine, even at low doses, looks like a good way to guarantee death.

ROSC would be important if there were a positive relationship with regaining pulses, but there isn’t.

Patients who do not have ROSC are not going to be resuscitated, but that does not mean that any means of obtaining ROSC will improve survival.

This is just more evidence that -

epinephrine increases ROSC, but decreases survival.

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Continued in Part II.

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Footnotes:

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^[1] 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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^[2] Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial
Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL.
Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.
PMID: 21745533 [PubMed - in process]

Free Full Text PDF Download of In Press Uncorrected Proof from xa.yming.com

This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.

In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.

This is just one of many examples.

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Delayed prehospital implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiac care.
Bigham BL, Koprowicz K, Aufderheide TP, Davis DP, Donn S, Powell J, Suffoletto B, Nafziger S, Stouffer J, Idris A, Morrison LJ; ROC Investigators.
Prehosp Emerg Care. 2010 Jul-Sep;14(3):355-60.
PMID: 20388032 [PubMed - indexed for MEDLINE]

Free Full Text from PubMed Central.

On December 13, 2005, the AHA published “Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care”

ROC EMS agencies required an average of 416 days to implement the 2005 AHA guidelines for OHCA. Small EMS agencies, BLS-only agencies, and nontransport agencies took longer than large agencies, agencies providing ALS care, and transport agencies, respectively, to implement the guidelines.

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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 (2012). Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium. Resuscitation PMID: 22858552

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Bigham BL, Koprowicz K, Aufderheide TP, Davis DP, Donn S, Powell J, Suffoletto B, Nafziger S, Stouffer J, Idris A, Morrison LJ, & ROC Investigators (2010). Delayed prehospital implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiac care. Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors, 14 (3), 355-60 PMID: 20388032

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Jacobs IG, Finn JC, Jelinek GA, Oxer HF, & Thompson PL (2011). Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation, 82 (9), 1138-43 PMID: 21745533

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