We are there for the good of the patient, not for the good of the protocol, not for the good of the medical director, and not for the good of the company.

- Rogue Medic

Dextrose in Cardiac Arrest – More Kitchen Sink Medicine

 
Should we treat hypoglycemia in a dead person?

How do we determine hypoglycemia in a dead person?

Is there any evidence that giving dextrose, in any concentration, will help to resuscitate a dead person?

Should we treat patients based on the philosophy of Who knows? Maybe it could work? Bleach enemas are currently in fashion among the alternative to medicine crowd,[1] so we could use the same reasoning to give bleach enemas in cardiac arrest. Who knows? Maybe it could work.

Is Kitchen Sink Medicine significantly different from any other alternative to medicine?

The dead person is not breathing, so we have to provide ventilations.[2], [3], [4]

The dead person is dead, so we have to do something.

We do compressions and (when indicated) defibrillation, because those are the only treatments that have been demonstrated to work.

 


 
 

The foundation of successful ACLS is high-quality CPR, and, for VF/pulseless VT, attempted defibrillation within minutes of collapse. For victims of witnessed VF arrest, early CPR and rapid defibrillation can significantly increase the chance for survival to hospital discharge.128–133 In comparison, other ACLS therapies such as some medications and advanced airways, although associated with an increased rate of ROSC, have not been shown to increase the rate of survival to hospital discharge.31,33,134–138 [5]

 

Ventilations are only a part of high-quality CPR for children and people who have a respiratory cause of cardiac arrest.

But what about dextrose for hypoglycemic cardiac arrest?

We may already be raising the blood sugar with epinephrine.
 

Epinephrine causes a prompt increase in blood glucose concentration in the postabsorptive state. This effect is mediated by a transient increase in hepatic glucose production and an inhibition of glucose disposal by insulin-dependent tissues.[6]

 

We seem to have trouble understanding that dead people do not respond to treatments the same way that living people do.
 

Pharmacologic insults are just so massive and normal metabolism and physiology so deranged that no mere mortal can make a meaningful intervention. The seriously poisoned who maintain vital signs in the ED have the best, albeit never guaranteed, chance of rescue from a modicum of antidotes and intensive supportive care.[7]

 

Maybe we should find out what we are doing and not blindly throw kitchen sinks at dead people based on hunches.

Dr. Brooks Walsh gave a good review of the evidence in his article written three years ago.[8]
 

What about my original questions?

Should we treat hypoglycemia in a dead person?

There is no evidence that giving dextrose is safe or effective for any cardiac arrest patients.

How do we determine hypoglycemia in a dead person?

We guess or check a capillary blood sugar, which is not reliable.

Is there any evidence that giving dextrose, in any concentration, resuscitates a dead person?

No.
 

Go read Using Dextrose in Cardiac Arrest at Mill Hill Ave Command.
 

Footnotes:

[1] Bleaching away what ails you
Science-Based Medicine
David Gorski
May 28, 2012
Article

[2] Cardiocerebral Resuscitation: An Approach to Improving Survival of Patients With Primary Cardiac Arrest.
Ewy GA, Bobrow BJ.
J Intensive Care Med. 2014 Jul 30. pii: 0885066614544450. [Epub ahead of print]
PMID: 25077491 [PubMed – as supplied by publisher]

[3] 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.

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

[5] Management of Cardiac Arrest
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science
Part 8.2: Management of Cardiac Arrest
Overview
Free Full Text from Circulation.

[6] Effect of epinephrine on glucose metabolism in humans: contribution of the liver.
Sherwin RS, Saccà L.
Am J Physiol. 1984 Aug;247(2 Pt 1):E157-65.
PMID: 6380304 [PubMed – indexed for MEDLINE]

[7] Dissecting the ACLS Guidelines on Cardiac Arrest from Toxic Ingestions
Emergency Medicine News:
October 2011 – Volume 33 – Issue 10 – pp 16-18
doi: 10.1097/01.EEM.0000406945.05619.ca
InFocus
Roberts, James R. MD
Article

[8] Using Dextrose in Cardiac Arrest
Wednesday, March 14, 2012
Mill Hill Ave Command
Dr. Brooks Walsh
Article

.

Proposed 2015 ACLS Chest compression only CPR vs conventional CPR Recommendation


 
The AHA (American Heart Association) and ILCOR (International Liaison Committee On Resuscitation) 2015 resuscitation guidelines evidence reviews appear to be merely justifications for continuing to use treatments that do not improve survival with good neurological function, which is the only outcome that matters. What do the AHA and ILCOR intend to recommend for ventilation of patients who appear to be adults and pulseless due to non-respiratory conditions?
 

Full Question:
Among adults who are in cardiac arrest outside of a hospital (P), does provision of chest compressions (without ventilation) by untrained/trained laypersons (I), compared with chest compressions with ventilation (C), change Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year, ROSC, bystander CPR performance, CPR quality (O)?
[1]

 

Do we really want to increase the rate of survival of permanently comatose patients?
 


Image credit.
 

That is not a goal. That is only a first step if we can do something to change the outcome for this comatose patient. There is no reason to believe that ventilations during CPR will do anything to improve the neurological outcome of these patients. We want to improve the survival of neurologically intact patients, not fill nursing homes with comatose patients until sepsis finishes them off.
 

We suggest performing chest compressions alone for trained laypersons if they are incapable of delivering airway and breathing manoeuvres to cardiac arrest victims (weak recommendation, very low quality of evidence).[1]

 

The AHA and ILCOR want us to provide this intervention that is based on tradition and disproven pathophysiology, rather than based on any valid evidence, except if we are incapable of providing the intervention.

Ventilations do not improve outcomes. However, ventilations may be harmful, so we should avoid using them in all cases where ventilations are not supported by valid evidence. Ventilations are not supported by valid evidence for non-respiratory causes of adult cardiac arrest.
 

We suggest the addition of ventilations for trained laypersons who are capable of giving CPR with ventilations to cardiac arrest victims and willing to do so (weak recommendation, very low quality of evidence).[1]

 

Each study cited to support ventilations showed no significant difference between compression only and standard CPR according to the AHA/ILCOR evidence review. That is the way to imitate Rube Goldberg. That is not support for any kind of medical intervention.
 

This recommendation places a relatively high value in [1] harm avoidance (not performing CPR or performing ineffective chest compressions and ventilations) and [2] simplifying resuscitation logistics, than potential benefit of an intervention of routine ventilations and compressions.[1]

 

That statement misrepresents harm avoidance and simplification of resuscitation logistics, since it encourages the potentially harmful treatment that has no valid evidence that the intervention increases any benefit that matters. How does adding ventilations simplify resuscitation logistics?

There is no evidence that passive ventilation provides inadequate oxygenation during chest compressions.

There is no evidence that passive ventilation provides inadequate removal of carbon dioxide during chest compressions.

Where is the need for any positive pressure ventilation to decrease blood return to the heart and increase the likelihood of vomiting?

Why continue to recommend doing something harmful for no benefit to the patient?

Footnotes:

[1] Chest compression only CPR vs conventional CPR
ILCOR Scientific Evidence Evaluation and Review System
Questions Open for Public Comment
Closing Date – February 28, 2015
Question page

.

The Kitchen Sink Approach to Cardiac Arrest

 
When faced with death, we can become desperate, stop thinking clearly, and just try anything.

Alternative medicine thrives on the desperation of people who are not thinking clearly. We should be better than that, but are we?

A recent comment on The Myth that Narcan Reverses Cardiac Arrest[1] proposes that I would suddenly give kitchen sink medicine a try, if I really care about the patient.

Kitchen sink medicine? It’s better to do something and harm the patient, than to limit treatment to what works. Throw everything, including the kitchen sink, at the patient.

Mike Karras writes –
 

I will leave you with this question sir and I am interested to hear your answer. You walk in to find your 14 year old daughter that intentionally overdosed on morphine in a suicide attempt and she is in cardiac arrest. How would you treat her? Would you give her Narcan? I think you would.[2]

 

Mike, I am thrilled to read that you do not think that I care about the outcomes of my patients, unless the patient happens to be my daughter. I am even more thrilled that you made my imaginary daughter suicidal.

No, I would not use naloxone (Narcan).

I would also not use homeopathy, acupuncture, sodium bicarbonate, incantations, or magic spells to treat my daughter during cardiac arrest. Voodoo only works on believers, because voodoo is just a placebo/nocebo.[3]
 


Image credit.
 

Does really wanting something to be true make it true? If you believe in magic, the answer is Yes, believing makes it true. If you examine the evidence for that belief, you have several choices. You can acknowledge your mistake, or you can employ a bit of cognitive dissonance, or . . . . Cognitive dissonance is the way our minds copes with the conflict, when reality and belief do not agree, and we choose to reject reality.[4]

According to the ACLS (Advanced Cardiac Life Support) guidelines –
 

Naloxone has no role in the management of cardiac arrest.[5]

 

If the patient is suspected of having a cardiac arrest because of an opioid overdose (overdose of heroin, fentanyl, morphine, . . . ), the treatments should include ventilation and chest compressions. If those do not provide a response, epinephrine (Adrenaline in Commonwealth countries) is added.

An opioid overdose can produce respiratory depression and/or vasodilation. I can counter both of those with chest compressions, ventilation, and maybe epinephrine. Naloxone works on opioid receptors. What does naloxone add?

Does naloxone’s stimulation of an opioid receptor produce more ventilation than bagging/intubating?

Does naloxone’s stimulation of an opioid receptor produce more oxygenation than bagging/intubating?

Does naloxone’s stimulation of an opioid receptor produce more vasoconstriction than chest compressions and epinephrine?*

Also –
 

Don’t confuse post- or pre–arrest toxicologic interventions with the actual cardiac arrest event.[6]

 

Dead people do not respond to treatments the same way living people do.
 
 

See also –
 

Dissecting the ACLS Guidelines on Cardiac Arrest from Toxic Ingestions – Tue, 01 Nov 2011

Naloxone in cardiac arrest with suspected opioid overdoses – Thu, 05 Apr 2012

The Myth that Narcan Reverses Cardiac Arrest – Wed, 12 Dec 2012

Resuscitation characteristics and outcomes in suspected drug overdose-related out-of-hospital cardiac arrest – Sun, 03 Aug 2014
 

* Late edit – 02/17/2015 10:52 – added the word naloxone’s to the three sentences about the relative amount of stimulus provided by standard ACLS and by the addition of naloxone. Thanks to Brian Behn for pointing out the lack of clarity.

Footnotes:

[1] The Myth that Narcan Reverses Cardiac Arrest
Wed, 12 Dec 2012
Rogue Medic
Article

[2] Comment by Mike Karras
The Myth that Narcan Reverses Cardiac Arrest by Rogue Medic
Mon, 16 Feb 2015
Article

[3] Nocebo
Wikipedia
Article

A nocebo is an inert agent that produces negative effects. What this means is that nocebo effects are adverse placebo effects. There is no reason to believe that placebos only produce positive effects or no effects at all.

[4] Cognitive dissonance
Wikipedia
Article

[5] Opioid Toxicity
2010 ACLS
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 12.7: Cardiac Arrest Associated With Toxic Ingestions
Free Full Text from Circulation

[6] Dissecting the ACLS Guidelines on Cardiac Arrest from Toxic Ingestions
Emergency Medicine News:
October 2011 – Volume 33 – Issue 10 – pp 16-18
doi: 10.1097/01.EEM.0000406945.05619.ca
InFocus
Roberts, James R. MD
Article

Read the whole article about antidotes and cardiac arrest.

.

Should ACLS Recommend the Unknown Based on Weak Evidence?


 
The AHA (American Heart Association) and ILCOR (International Liaison Committee on Resuscitation) will be meeting tomorrow to finalize the recommendations for the 2015 ACLS (Advanced Cardiac Life Support) guidelines. Here is the comment I submitted on the proposed recommendation for epinephrine (Adrenaline in Commonwealth countries) in cardiac arrest.

I have not received any information about where to submit SEERS comments, so I am sending this to you. Please forward it to whomever is supposed to receive comments.

Vasopressors for cardiac arrest (1. Epi v Placebo)
 

Consensus on Science:
For all four long term (critical) and short term (important) outcomes, we found one underpowered trial that provided low quality evidence comparing SDE to placebo (Jacobs, 2001, 1138).
[1]

 

As a trial that is stated to be underpowered (through no fault of Dr. Jacobs),[2] is there any valid reason the Jacobs study should be considered to be superior to observational studies?
 

Among 534 subjects, there was uncertain benefit or harm of SDE over placebo for the critical outcomes of survival to discharge [RR 2.12, 95% CI 0.75-6.02, p=0.16] and good neurological outcome defined as CPC of 1-2 [RR 1.73, 95% CI 0.59-5.11, p=0.32].[1]

 

We do not have good evidence to tell us if this is harmful or beneficial and we do not have any way of determining which patients will be harmed or helped by administration of epinephrine.


 

However, patients who received SDE had higher rates of the two important outcomes of survival to admission [RR 1.95, 95% CI, 1.34-2.84, p=0.0004] and ROSC in the prehospital setting [RR 2.80, 95% CI 1.78-4.41, p<0.00001] compared to those who received placebo.[1]

 

Are these surrogate endpoints important?

How do we know?

If these surrogate endpoints are important, why is there no valid evidence to support this claim?

We have a history of being misled by surrogate endpoints. We used to bleed patients and that produced a number of clear benefits in surrogate endpoints.
 

Physicians observed of old, and continued to observe for many centuries, the following facts concerning blood-letting.

1. It gave relief to pain. . . . .

2. It diminished swelling. . . . .

3. It diminished local redness or congestion. . . . .

4. For a short time after bleeding, either local or general, abnormal heat was sensibly diminished.

5. After bleeding, spasms ceased, . . . .

6. If the blood could be made to run, patients were roused up suddenly from the apparent death of coma. (This was puzzling to those who regarded spasm and paralysis as opposite states; but it showed the catholic applicability of the remedy.)

7. Natural (wrongly termed ” accidental”) hacmorrhages were observed sometimes to end disease. . . . .

8. . . . venesection would cause hamorrhages to cease.[3]

 

We don’t do that any more, because medicine is not supposed to just create a superficial improvement.

We should not be making any recommendation to treat based on such weak evidence.
 

The evidence for the routine use of adrenaline is perceived to be at equipoise within the international community of resuscitation scientists requiring re-evaluation19 as suggested by this comprehensive systematic review and meta-analysis. There is a need for well-designed, placebo-controlled, and adequately powered RCTs to evaluate the efficacy of adrenaline and to determine its optimal dosing.11,16,54 The question as to the efficacy of adrenaline for OHCA remains unanswered.[4]

 

Since the question as to the efficacy of adrenaline for OHCA remains unanswered, we should avoid substituting a bad answer for We don’t know.

Maybe we should bring back the indeterminate class for these unanswerable questions.
 

Treatment Recommendation
Given the observed benefit in short term outcomes, we suggest Standard Dose Epinephrine be administered to patients in cardiac arrest.(weak recommendation, low quality)
[1]

 

The benefit is considered important, but that is just an expert opinion, which is the lowest level of evidence.

A weak recommendation to give a treatment of unknown benefit and unknown harm, based on evidence that is admitted to be of low quality, should not set the standard of care. Even if the guidelines are explicitly stated to not be standards of care, they are adopted as standards of care by the emergency medicine community and by the EMS community.

We don’t know enough to make a recommendation about epinephrine, or most other treatments, in cardiac arrest.

We do not need to keep making the same recommendation just because we have made it before. We can leave it up to the treating physician or to the medical director writing the protocols for EMS.
 
 

See also – Proposed 2015 ACLS Epinephrine Recommendation – Vasopressors for cardiac arrest (1. Epi v Placebo)

Footnotes:

[1] Vasopressors for cardiac arrest (1. Epi v Placebo)
ILCOR Scientific Evidence Evaluation and Review System
Questions Open for Public Comment
Closing Date – February 28, 2015
Question page

[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.

 

[3] Blood-Letting
Br Med J.
1871 March 18; 1(533): 283–291.
PMCID: PMC2260507

[4] Adrenaline for out-of-hospital cardiac arrest resuscitation: a systematic review and meta-analysis of randomized controlled trials.
Lin S, Callaway CW, Shah PS, Wagner JD, Beyene J, Ziegler CP, Morrison LJ.
Resuscitation. 2014 Jun;85(6):732-40. doi: 10.1016/j.resuscitation.2014.03.008. Epub 2014 Mar 15.
PMID: 24642404 [PubMed – in process]

.

Proposed 2015 ACLS Epinephrine Recommendation – Vasopressors for cardiac arrest (1. Epi v Placebo)


 
What do the AHA (American Heart Association) and ILCOR (International Liaison Committee on Resuscitation) plan to make their recommendation on use of epinephrine (Adrenaline in Commonwealth countries) in cardiac arrest (ACLS – Advanced Cardiac Life Support)?
 

Full Question:
Among adults who are in cardiac arrest in any setting (P), does does use of epinephrine (I), compared with placebo or not using epinephrine (C), change Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year, ROSC (O)?

The information provided is currently in DRAFT format and is NOT a FINAL version[1]

 

Unless you are familiar with the way AHA/ILCOR ask questions, this may not seem to be a helpful way of addressing the question. Here is the format being used –

PICO:

Population/Patient/Problem

Intervention

Comparison/Control

Outcome
 

The Patients are adults who are in cardiac arrest in any setting.

The Intervention is use of epinephrine.

The Comparison is placebo or not using epinephrine.

The Outcome is a bit complicated – Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year, ROSC. ROSC is Return Of Spontaneous Circulation.

Everything is reasonable – until they get to the outcome. Does anyone still think that it is really an improvement to get pulses back, be transported to the hospital, never wake up, and die in the ED (Emergency Department) or ICU (Intensive Care Unit)? What if the coma lasts for 30 days, 60 days, 180 days AND/OR 1 year. If you think that is an improvement, you may not have considered the cost. How much is it worth to give a family false hope? $10,000? Who pays for this deception?

Should we also try putting the patient in a helicopter to see if the magic rotor blades make the family feel that everything possible was done to deceive them?

These are considered to be important, because we do not seem to know what is important.

Why are ROSC and survival to admission considered important?

Where is the evidence that these measurements lead to better outcomes?
 

 

Studies that look at these outcomes show that real world patients treated with epinephrine are more likely to die in the hospital – and those who do not die in the hospital are more likely to have severe neurological impairment.
 

Click on image to make it larger.[2] The studies are in the footnotes.[3],[4],[5],[6],[7],[8],[9],[10]
 

Is Adrenaline beneficial in cardiac arrest?

Probably, but only for some patients and we do not know which patients benefit.

Is Adrenaline harmful in cardiac arrest?

Probably, but only for some patients and we do not know which patients are harmed.

The evidence evaluation focused on the Jacobs study,[8] which is randomized and placebo controlled, but only reaches the level of fair according to the analysis of all of the evidence. The reason is that politicians and the media combined to sabotage the study. Most of the ambulance services dropped out of the Jacobs study because of this interference. This is not the fault of Dr. Ian G. Jacobs, who deserves credit for setting up the first randomized placebo controlled study of this important topic.
 

For all four long term (critical) and short term (important) outcomes, we found one underpowered trial that provided low quality evidence comparing SDE to placebo (Jacobs, 2001, 1138).[1]

 

We need to bring back the Indeterminate class of recommendation for ACLS, because that is the best that we can come up with for epinephrine, unless we ignore the evidence or we just don’t understand the evidence.
 

Table 3.
Applying Classification of Recommendations and Level of Evidence

. . .

Class Indeterminate.
• Research just getting started
• Continuing area of research
• No recommendations until further research (eg, cannot recommend for or against)[11]

 

Does the proposed ACLS recommendation on epinephrine makes sense?

Consider that we do not know which patients benefit from epinephrine. The treatment for every cause of cardiac arrest includes epinephrine as the first drug, even if the cause of cardiac arrest is known to be an overdose of epinephrine.

Is epinephrine better than nothing for some patients in cardiac arrest? Yes.

Is epinephrine worse than nothing for some patients in cardiac arrest? Yes.

We do not know which patients we are harming with epinephrine and we don’t seem to want to stop harming those patients.

Footnotes:

[1] Vasopressors for cardiac arrest (1. Epi v Placebo)
ILCOR Scientific Evidence Evaluation and Review System
Questions Open for Public Comment
Closing Date – February 28, 2015
Question page

[2] Vasopressors in cardiac arrest: a systematic review.
Larabee TM, Liu KY, Campbell JA, Little CM.
Resuscitation. 2012 Aug;83(8):932-9. Epub 2012 Mar 15.
PMID: 22425731 [PubMed – in process]
 

CONCLUSION: There are few studies that compare vasopressors to placebo in resuscitation from cardiac arrest. Epinephrine is associated with improvement in short term survival outcomes as compared to placebo, but no long-term survival benefit has been demonstrated. Vasopressin is equivalent for use as an initial vasopressor when compared to epinephrine during resuscitation from cardiac arrest. There is a short-term, but no long-term, survival benefit when using high dose vs. standard dose epinephrine during resuscitation from cardiac arrest. There are no alternative vasopressors that provide a long-term survival benefit when compared to epinephrine. There is limited data on the use of vasopressors in the pediatric population.

[3] High dose and standard dose adrenaline do not alter survival, compared with placebo, in cardiac arrest.
Woodhouse SP, Cox S, Boyd P, Case C, Weber M.
Resuscitation. 1995 Dec;30(3):243-9.
PMID: 8867714 [PubMed – indexed for MEDLINE]

[4] Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference?
Herlitz J, Ekström L, Wennerblom B, Axelsson A, Bång A, Holmberg S.
Resuscitation. 1995 Jun;29(3):195-201.
PMID: 7667549 [PubMed – indexed for MEDLINE]

[5] Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest.
Ong ME, Tan EH, Ng FS, Panchalingham A, Lim SH, Manning PG, Ong VY, Lim SH, Yap S, Tham LP, Ng KS, Venkataraman A; Cardiac Arrest and Resuscitation Epidemiology Study Group.
Ann Emerg Med. 2007 Dec;50(6):635-42. Epub 2007 May 23.
PMID: 17509730 [PubMed – indexed for MEDLINE]

Free Full Text Download in PDF format from prdupl02.ynet.co.il

[6] Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L.
JAMA. 2009 Nov 25;302(20):2222-9.
PMID: 19934423 [PubMed – indexed for MEDLINE]

Free Full Text from JAMA

[7] Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial.
Olasveengen TM, Wik L, Sunde K, Steen PA.
Resuscitation. 2011 Nov 22. [Epub ahead of print]
PMID: 22115931 [PubMed – as supplied by publisher]

[8] 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.

 

[9] 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.

[10] Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest.
Hayashi Y, Iwami T, Kitamura T, Nishiuchi T, Kajino K, Sakai T, Nishiyama C, Nitta M, Hiraide A, Kai T.
Circ J. 2012;76(7):1639-45. Epub 2012 Apr 5.
PMID: 22481099 [PubMed – indexed for MEDLINE]

Free Full Text from Circulation Japan.

[11] Table 3. Applying Classification of Recommendations and Level of Evidence
2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 1: Introduction
Table 3

I have modified this table solely for the purpose of clarity of presentation, by modifying color and font. None of the words have been changed.

.

Narcan in Cardiac Arrest – Safe as Long as I Don’t Understand Safety


 
How can I justify exposing patients to the risks of a treatment that has no known benefit?

Here is one way –
 

I give Narcan in arrest. You might not. Neither of us are wrong. Yet.
 

Narcan (naloxone) is one of the safer drugs we use. Suppose that I give a drug in a way that has not been found to be beneficial because I think it is safe as long as I can’t think of a specific problem I can cause. Does that make the inappropriate drug administration safe? Or is it just an example of my ignorance?

If a lack of knowledge were a good thing, we should not teach anything about pharmacology.

The less I know, the safer it is. Ignorance is safety.

We should not teach about the adverse effects of drugs, because as long as I don’t know about the danger, there is no danger. It is only after the danger is known that the danger is real, so don’t tell me about any dangers.
 

In the ACLS (Advanced Cardiac Life Support) guidelines, the American Heart Association tells us that it is wrong to give Narcan during cardiac arrest.
 

Naloxone is a potent antagonist of the binding of opioid medications to their receptors in the brain and spinal cord. Administration of naloxone can reverse central nervous system and respiratory depression caused by opioid overdose. Naloxone has no role in the management of cardiac arrest.[1]

 

Naloxone has no role in the management of cardiac arrest.
 

Why did I give Narcan? Because ACLS told me not to.

Don’t think, just do something. If I do not know of a danger, there is no danger. If I have been told that it is wrong, do it anyway.
 


Image credits – 123
 

Repeat the mindless sequence as often as necessary, until the desire to understand patient care has been destroyed.
 


 

But Narcan reverses respiratory depression and apnea.

Narcan can reverses respiratory depression or apnea in a living patient. A patient in cardiac arrest due to a heroin overdose should be treated for a respiratory cause of cardiac arrest. Children and patients with respiratory causes of cardiac arrest should be ventilated and oxygenated. These patients will also be receiving epinephrine (Adrenaline in Commonwealth countries) in the early part of the standard treatment of cardiac arrest. Narcan does not add anything to these treatments the patient is already receiving.
 

But Narcan is safe – and I can’t make the patient any worse.
 

Naloxone is one of the safer drugs we can give to a patient when there is an indication to give naloxone. Even when given inappropriately, naloxone is not very likely to cause harm.

There are several problems.

If I am pushing drugs because I don’t know what to do, I should be trying to figure out what treatments I can give that might actually help the patient. There is no reason to believe that naloxone might actually help the patient. If I am giving drugs that provide no benefit, I am distracting myself from assessment, which might provide information that can help me resuscitate the patient.
 

As long as I don’t know what I’m doing, I am not wrong.
 

No.

As long as I don’t know what I’m doing, I am both wrong and dangerous.
 
 

See also –
 

Dissecting the ACLS Guidelines on Cardiac Arrest from Toxic Ingestions – Tue, 01 Nov 2011

Naloxone in cardiac arrest with suspected opioid overdoses – Thu, 05 Apr 2012

The Myth that Narcan Reverses Cardiac Arrest – Wed, 12 Dec 2012

Resuscitation characteristics and outcomes in suspected drug overdose-related out-of-hospital cardiac arrest – Sun, 03 Aug 2014

Footnotes:

[1] Opioid Toxicity
2010 ACLS
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 12.7: Cardiac Arrest Associated With Toxic Ingestions
Free Full Text from Circulation

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Opponents of EBM Now Have More Evidence to Justify Their Rejection of Evidence


 

Those scientists clearly can’t get it right. They are constantly changing the guidelines to correct their mistakes. Why don’t they just do it right the first time.

Finally, somebody is recognizing that a treatment should only be eliminated when there is clear evidence that it harms patients – and only when we have run out of excuses to ignore the irrefutable evidence.
 

The 2015 American Heart Organization (AHO) Cardiovascular Care Guidelines will introduce three new levels of evidence in addition to the current existing levels of evidence
In addition to the current levels of evidence classes the AHO’s 2015 guidelines will include Class IVa (Anecdotal Evidence), Class V (Provider Opinion) and Class XI (Treatments Not Proven to Not Work)
[1]

 

When I was in paramedic school we were told the rules. Intubation is the most important treatment, because the airway is the most important part of patient care, because Airway begins with A, Breathing begins with B, and Circulation begins with C. A comes before B and B comes before C.

Do you think that is a coincidence? No. There’s a reason for that. We are supposed to treat the airway first – no matter what. A paramedic can only have one thought in his head at a time, so it has to be the one best thought. Airway always comes first. Did you ever try to live without an airway? Well, did you? It just doesn’t happen. The Gold Standard of Airway is intubation, so we have to intubate people or they will be dropping like flies. You don’t hear about people surviving in places where medics don’t intubate. Dead! All of ‘em. Dead! It’s a fact.

This is serious business people. Every second counts, but there are a lot of seconds, so we don’t count seconds. We count minutes. So every minute counts, but only with an Airway. Without an Airway, you are dead, but you are only dead after we race your cadaver to the hospital and a doctor pronounces you dead and mutters something under his breath about us being straight out of the Dark Ages. We do respect the classics. We have to honor our roots. We can’t be eliminating traditional treatments just because they seem to harm patients.
 

AHO includes the following in the new guidelines, section IVa (Anecdotal Evidence): “Many people have seem something work or they know of someone who has seen something work, or perhaps have heard of someone who knows someone that has seem something work. If a treatment has been said to work in the past then it stands to reason that it will work again. The AHA now accepts anecdotal evidence as equivalent to and just as valid as a Class I intervention provided that the evidence is no more than 4 degrees of separation from the person.”[1]

 

They shouldn’t have left out treatments based on animal research. We have to include everything. It doesn’t matter that people do not do as well with these treatments as animals do. Don’t you love dogs and cats, or are you some kind of monster? If a treatment can bring a dog back to life then that is good enough for grandpa. If cancer can be cured in animals, but we don’t give the treatments to people we are killing people. It is a Big Pharma conspiracy to find cures and then hide them from everyone, because that is why these scientists do all of this research – so they can have the cures for themselves and watch us die. If it works in animals, there is no reason to not use it in people.

All of this research is just too expensive.

We need to just use what we know works.
 

Go read the full article.

Footnotes:

[1] Heart Organization Endorses New Level of Evidence Guildlines
Call The Cops
Posted by: RJ Beam
8/20/2014
Article

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The Controversy of Admitting ‘We Do Not Know What Works’

ResearchBlogging.org

 

There are several news articles today criticizing a study because the patients might be deprived of a drug that has not been adequately studied in humans. This criticism is coming from journalists – the people who publicized the fraudulent vaccines research by Andrew Wakefield, who was trying to sell his competing vaccine and was being paid to produce negative research by lawyers suing the vaccine companies.[1]

The real controversy is that this untested drug became the standard of care with no evidence that it improves outcomes that matter.

Is it controversial to give a placebo, rather than a drug not yet adequately tested in humans?

No.

We are not informing patients that there is no evidence that the standard treatment is effective. We are not obtaining consent to give the unproven drug – epinephrine (Adrenaline in Commonwealth countries). How are the ethics different when we substitute a placebo for a mystery medicine?

What is less ethical than continuing the tradition of giving an inadequately studied drug to people who cannot consent to treatment?

Are we depriving patients of effective medicine or are we depriving them of witchcraft?

If you think that epinephrine is effective medicine at improving survival to discharge, provide the evidence and stop this study. The reason the study is being done is that evidence of benefit does not exist.
 

Click on image to make it larger.[2] The studies are in the footnotes.[3],[4],[5],[6],[7],[8],[9],[10]
 

Is Adrenaline beneficial in cardiac arrest?

Probably, but only for some patients and we do not know which patients benefit.

Is Adrenaline harmful in cardiac arrest?

Probably, but only for some patients and we do not know which patients are harmed.

What is the right dose of Adrenaline in cardiac arrest?

Pick a number – any number. We do not know the right dose.
 

 

Even the patients who only received the minimum dose – 1 mg – had worse outcomes.[11]

Wrong timing? Wrong dose? Wrong drug?

We do not know.
 

We have used this untested treatment for half a century and not bothered to find out if it works. A recent study shows that epinephrine produces worse outcomes when given by EMS later,[12] but that does not mean that the outcomes are good when epinephrine is given early. The study had no placebo group, so like a study comparing different doses of cyanide, just because one dose is not as bad as another dose, the results do not suggest that cyanide is beneficial.
 


 

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.[13] Other studies produce similar results.[3],[14],[15],[16],[17] Only one study showed better ROSC with standard dose epinephrine.[18]
 

Epinephrine does produce more ROSC (Return Of Spontaneous Circulation – at least a temporary pulse) than placebo, but high dose epinephrine produces even more ROSC than standard dose epinephrine, so why do we give the standard dose that only produces middling ROSC?

Is ROSC the goal? No.

For the guidelines (ACLS and ILCOR), ROSC is the basis for giving standard dose epinephrine, but it would make more sense to give high dose epinephrine if the goal is ROSC. More ROSC, but no more survivors leaving the hospital. If all we want is put the patient in a coma long enough to run up a big hospital bill, then the drugs are great.

If we want people to leave the hospital alive, then We Do Not Know What Works.
 

The guidelines are based on wishful thinking and rationalization. They are not based on improved survival. A lot of research is cited (hundreds of papers), but the research does not show improved survival with any drug(s).

Will the guidelines be revised to remove epinephrine? Maybe.
 

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.[19]

 

Some cocktails have produced better results than epinephrine in tiny studies. It is too probably too early to tell if these are just statistical aberrations. I will write about them later.

Continued in Does a Placebo vs. Adrenaline Study Deprive Patients of Necessary Care According to the Resuscitation Guidelines?

Footnotes:

[1] “Piltdown medicine” and Andrew Wakefield’s MMR vaccine fraud
Science-Based Medicine
Posted by David Gorski
January 6, 2011
Article
 

In a mere decade and a half, several decades of progress in controlling this scourge had been unravelled like a thread hanging off a cheap dress, all thanks to Andrew Wakefield and scandal mongers in the British press.

[2] Vasopressors in cardiac arrest: a systematic review.
Larabee TM, Liu KY, Campbell JA, Little CM.
Resuscitation. 2012 Aug;83(8):932-9. Epub 2012 Mar 15.
PMID: 22425731 [PubMed – in process]
 

CONCLUSION: There are few studies that compare vasopressors to placebo in resuscitation from cardiac arrest. Epinephrine is associated with improvement in short term survival outcomes as compared to placebo, but no long-term survival benefit has been demonstrated. Vasopressin is equivalent for use as an initial vasopressor when compared to epinephrine during resuscitation from cardiac arrest. There is a short-term, but no long-term, survival benefit when using high dose vs. standard dose epinephrine during resuscitation from cardiac arrest. There are no alternative vasopressors that provide a long-term survival benefit when compared to epinephrine. There is limited data on the use of vasopressors in the pediatric population.

[3] High dose and standard dose adrenaline do not alter survival, compared with placebo, in cardiac arrest.
Woodhouse SP, Cox S, Boyd P, Case C, Weber M.
Resuscitation. 1995 Dec;30(3):243-9.
PMID: 8867714 [PubMed – indexed for MEDLINE]

[4] Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference?
Herlitz J, Ekström L, Wennerblom B, Axelsson A, Bång A, Holmberg S.
Resuscitation. 1995 Jun;29(3):195-201.
PMID: 7667549 [PubMed – indexed for MEDLINE]

[5] Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest.
Ong ME, Tan EH, Ng FS, Panchalingham A, Lim SH, Manning PG, Ong VY, Lim SH, Yap S, Tham LP, Ng KS, Venkataraman A; Cardiac Arrest and Resuscitation Epidemiology Study Group.
Ann Emerg Med. 2007 Dec;50(6):635-42. Epub 2007 May 23.
PMID: 17509730 [PubMed – indexed for MEDLINE]

Free Full Text Download in PDF format from prdupl02.ynet.co.il

[6] Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L.
JAMA. 2009 Nov 25;302(20):2222-9.
PMID: 19934423 [PubMed – indexed for MEDLINE]

Free Full Text from JAMA

[7] Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial.
Olasveengen TM, Wik L, Sunde K, Steen PA.
Resuscitation. 2011 Nov 22. [Epub ahead of print]
PMID: 22115931 [PubMed – as supplied by publisher]

[8] 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.

 

[9] 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.

[10] Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest.
Hayashi Y, Iwami T, Kitamura T, Nishiuchi T, Kajino K, Sakai T, Nishiyama C, Nitta M, Hiraide A, Kai T.
Circ J. 2012;76(7):1639-45. Epub 2012 Apr 5.
PMID: 22481099 [PubMed – indexed for MEDLINE]

Free Full Text from Circulation Japan.

[11] 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; Resuscitation Outcomes Consortium Investigators.
Resuscitation. 2012 Nov;83(11):1324-30. doi: 10.1016/j.resuscitation.2012.07.008. Epub 2012 Jul 31.
PMID: 22858552 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

[12] Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry.
Donnino MW, Salciccioli JD, Howell MD, Cocchi MN, Giberson B, Berg K, Gautam S, Callaway C; American Heart Association’s Get With The Guidelines-Resuscitation Investigators.
BMJ. 2014 May 20;348:g3028. doi: 10.1136/bmj.g3028.
PMID: 24846323 [PubMed – in process]

Free Full Text from BMJ.

[13] 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]

[14] A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group.
Brown CG, Martin DR, Pepe PE, Stueven H, Cummins RO, Gonzalez E, Jastremski M.
N Engl J Med. 1992 Oct 8;327(15):1051-5.
PMID: 1522841 [PubMed – indexed for MEDLINE]

Free Full Text from NEJM.

[15] Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital.
Choux C, Gueugniaud PY, Barbieux A, Pham E, Lae C, Dubien PY, Petit P.
Resuscitation. 1995 Feb;29(1):3-9.
PMID: 7784720 [PubMed – indexed for MEDLINE]

[16] A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group.
Gueugniaud PY, Mols P, Goldstein P, Pham E, Dubien PY, Deweerdt C, Vergnion M, Petit P, Carli P.
N Engl J Med. 1998 Nov 26;339(22):1595-601.
PMID: 9828247 [PubMed – indexed for MEDLINE]

Free Full Text from NEJM.

[17] High dose versus standard dose epinephrine in cardiac arrest – a meta-analysis.
Vandycke C, Martens P.
Resuscitation. 2000 Aug 1;45(3):161-6.
PMID: 10959014 [PubMed – indexed for MEDLINE]

[18] High-dose epinephrine in adult cardiac arrest.
Stiell IG, Hebert PC, Weitzman BN, Wells GA, Raman S, Stark RM, Higginson LA, Ahuja J, Dickinson GE.
N Engl J Med. 1992 Oct 8;327(15):1045-50.
PMID: 1522840 [PubMed – indexed for MEDLINE]

Free Full Text from NEJM.

[19] 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.

The interview with Dr. Callaway is definitely worth listening to.

Larabee TM, Liu KY, Campbell JA, & Little CM (2012). Vasopressors in cardiac arrest: a systematic review. Resuscitation, 83 (8), 932-9 PMID: 22425731

Woodhouse SP, Cox S, Boyd P, Case C, & Weber M (1995). High dose and standard dose adrenaline do not alter survival, compared with placebo, in cardiac arrest. Resuscitation, 30 (3), 243-9 PMID: 8867714

Herlitz J, Ekström L, Wennerblom B, Axelsson A, Bång A, & Holmberg S (1995). Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference? Resuscitation, 29 (3), 195-201 PMID: 7667549

Ong ME, Tan EH, Ng FS, Panchalingham A, Lim SH, Manning PG, Ong VY, Lim SH, Yap S, Tham LP, Ng KS, Venkataraman A, & Cardiac Arrest and Resuscitation Epidemiology Study Group (2007). Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest. Annals of emergency medicine, 50 (6), 635-42 PMID: 17509730

Olasveengen, T., Sunde, K., Brunborg, C., Thowsen, J., Steen, P., & Wik, L. (2009). Intravenous Drug Administration During Out-of-Hospital Cardiac Arrest: A Randomized Trial JAMA: The Journal of the American Medical Association, 302 (20), 2222-2229 DOI: 10.1001/jama.2009.1729

Olasveengen TM, Wik L, Sunde K, & Steen PA (2011). Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial. Resuscitation PMID: 22115931

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

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), 1161-8 PMID: 22436956

Hayashi Y, Iwami T, Kitamura T, Nishiuchi T, Kajino K, Sakai T, Nishiyama C, Nitta M, Hiraide A, & Kai T (2012). Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest. Circulation journal : official journal of the Japanese Circulation Society, 76 (7), 1639-45 PMID: 22481099

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

Donnino, M., Salciccioli, J., Howell, M., Cocchi, M., Giberson, B., Berg, K., Gautam, S., Callaway, C., & , . (2014). Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry BMJ, 348 (may20 2) DOI: 10.1136/bmj.g3028

Callaham M, Madsen CD, Barton CW, Saunders CE, & Pointer J (1992). A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA : the journal of the American Medical Association, 268 (19), 2667-72 PMID: 1433686

Brown CG, Martin DR, Pepe PE, Stueven H, Cummins RO, Gonzalez E, & Jastremski M (1992). A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. The New England journal of medicine, 327 (15), 1051-5 PMID: 1522841

Choux C, Gueugniaud PY, Barbieux A, Pham E, Lae C, Dubien PY, & Petit P (1995). Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital. Resuscitation, 29 (1), 3-9 PMID: 7784720

Gueugniaud PY, Mols P, Goldstein P, Pham E, Dubien PY, Deweerdt C, Vergnion M, Petit P, & Carli P (1998). A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group. The New England journal of medicine, 339 (22), 1595-601 PMID: 9828247

Vandycke C, & Martens P (2000). High dose versus standard dose epinephrine in cardiac arrest – a meta-analysis. Resuscitation, 45 (3), 161-6 PMID: 10959014

Stiell IG, Hebert PC, Weitzman BN, Wells GA, Raman S, Stark RM, Higginson LA, Ahuja J, & Dickinson GE (1992). High-dose epinephrine in adult cardiac arrest. The New England journal of medicine, 327 (15), 1045-50 PMID: 1522840

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

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