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

- Rogue Medic

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

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

Do we have to stop using epinephrine (adrenaline in Commonwealth countries) for cardiac arrest?
 


 

PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) compared adrenaline (epinephrine) with placebo in a “randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest”.[1]

The results showed that 1 mg of epinephrine every 3 – 5 minutes is even worse than I expected, but a lot of the more literate doctors have not been using epinephrine that way. What does this research tell us about their various methods? The podcast REBEL Cast (Rational Evidence Based Evaluation of Literature in Emergency Medicine) has a discussion of this question in REBEL Cast Ep56 – PARAMEDIC-2: Time to Abandon Epinephrine in OHCA?.[2]

The current ACLS/ILCOR (Advanced Cardiac Life Support/International Liaison Committee on Resuscitation) advice on epinephrine does not state that epinephrine is a good idea, or even require that you give epinephrine to follow their protocol –
 

The major changes in the 2015 ACLS guidelines include recommendations about prognostication during CPR based on exhaled CO2 measurements, timing of epinephrine administration stratified by shockable or nonshockable rhythms, and the possibility of bundling treatment of steroids, vasopressin, and epinephrine for treatment of in-hospital arrests. In addition, the administration of vasopressin as the sole vasoactive drug during CPR has been removed from the algorithm.[3]

 

What was the ACLS/ILCOR advice in the 2010 guidelines?
 

The 2010 Guidelines stated that it is reasonable to consider administering a 1-mg dose of IV/IO epinephrine every 3 to 5 minutes during adult cardiac arrest.[4]

 

This is in a paragraph that links to the PICO (Population-Intervention-Comparator-Outcomes) question that has been an open question for over half a century – In cardiac arrest, is giving epinephrine better than not giving epinephrine?[5]

They only considered it reasonable, based on low quality evidence.

What was the ACLS/ILCOR advice in the 2015 guidelines?
 

Standard-dose epinephrine (1 mg every 3 to 5 minutes) may be reasonable for patients in cardiac arrest (Class IIb, LOE B-R).[6]

 

Again, ACLS/ILCOR only considered a dose of epinephrine to be reasonable. Again, this was based on low quality evidence. I am not criticizing the efforts of those who worked on the Jacobs study of adrenaline vs. placebo, because they were stopped by the willfully ignorant opponents of science.[7]

What about the method of attempting to titrate an infusion to the hemodynamic response, which Dr. Swaminathan and Dr. Rezaie alluded to?

There is a lot of anecdotal enthusiasm from doctors who use this method, but I do not know of any research that has been published comparing outcomes using this method with anything else. How do we know that the positive reports from doctors are anything other than confirmation bias? We don’t.

This year is the 200th anniversary of the publication of the very first horror novel – Frankenstein; or, The Modern Prometheus. The doctor in the novel used electricity to raise the dead (and the subjects were very dead). There were no chest compressions in the novel, but it is interesting that we have barely made progress from the fiction imagined by an 18 year old with no medical training, although she did have the opportunity to listen to many of the smartest people in England discuss science. Mary Godwin (later Mary Wollstonecraft Shelley by marriage) was 16 when she started writing the novel.[8]

We have barely made more progress at resuscitation than a teenager did 200 years ago in a novel. Most of our progress has been in finally admitting that the treatments we have been using have been producing more harm than benefit. Many of us are not even that honest about the harm we continue to cause.

We dramatically improved resuscitation in one giant leap – when we focused on high quality chest compressions and ignoring the medical theater of advanced life support.

There are two treatments that work during cardiac arrest – high quality chest compressions and rapid defibrillation.

Why haven’t we made more progress?

We have been too busty making excuses for remaining ignorant.

We need to stop being so proud of our ignorance.

We now know that amiodarone doesn’t work for cardiac arrest (and is more dangerous than beneficial for ventricular tachycardia – even adenosine appears to be better for VTach), atropine doesn’t work for cardiac arrest, calcium chloride doesn’t work for cardiac arrest (unless it is due to hyperkalemia/rhabdomyolysis), vasopressin doesn’t work for cardiac arrest, high dose epinephrine doesn’t work for cardiac arrest, standard dose epinephrine doesn’t work for cardiac arrest – in other words, we have tried all sorts of drugs, based on hunches and the weakest of evidence, but we still haven’t learned that there isn’t a magic resuscitation drug.

Should anyone be using any epinephrine to treat cardiac arrest outside of a well controlled study?

No.

Also –

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

Footnotes:

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

Free Full Text from NEJM

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

Protocol

Supplementary Appendix

Disclosure Forms

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

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

Free Full Text from NEJM

[2] REBEL Cast Ep56 – PARAMEDIC-2: Time to Abandon Epinephrine in OHCA?
Anand Swaminathan, MD and Salim Rezaie, MD, FACEP
July 20, 2018
Episode 56 and show notes

[3] Introduction
Part 7: Adult Advanced Cardiovascular Life Support
2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Mark S. Link, Lauren C. Berkow, Peter J. Kudenchuk, Henry R. Halperin, Erik P. Hess, Vivek K. Moitra, Robert W. Neumar, Brian J. O’Neil, James H. Paxton, Scott M. Silvers, Roger D. White, Demetris Yannopoulos, Michael W. Donnino
Circulation. 2015;132:S444-S464, originally published October 14, 2015
https://doi.org/10.1161/CIR.0000000000000261
Introduction – scroll down to the last paragraph

[4] Vasopressors in Cardiac Arrest: Standard-Dose Epinephrine
Part 7: Adult Advanced Cardiovascular Life Support
2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Mark S. Link, Lauren C. Berkow, Peter J. Kudenchuk, Henry R. Halperin, Erik P. Hess, Vivek K. Moitra, Robert W. Neumar, Brian J. O’Neil, James H. Paxton, Scott M. Silvers, Roger D. White, Demetris Yannopoulos, Michael W. Donnino
Circulation. 2015;132:S444-S464, originally published October 14, 2015
https://doi.org/10.1161/CIR.0000000000000261
2010 epinephrine advice

[5] Epinephrine Versus Placebo
ILCOR Scientific Evidence Evaluation and Review
Epinephrine Versus Placebo

 

Among adults who are in cardiac arrest in any setting (P), does does the use of epinephrine (I), compared with 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)?

 

[6] 2015 Recommendation—Updated
Part 7: Adult Advanced Cardiovascular Life Support
2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Mark S. Link, Lauren C. Berkow, Peter J. Kudenchuk, Henry R. Halperin, Erik P. Hess, Vivek K. Moitra, Robert W. Neumar, Brian J. O’Neil, James H. Paxton, Scott M. Silvers, Roger D. White, Demetris Yannopoulos, Michael W. Donnino
Circulation. 2015;132:S444-S464, originally published October 14, 2015
https://doi.org/10.1161/CIR.0000000000000261
2015 Recommendation—Updated

[7] 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 from reanimacion.net
 

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.

 

[8] Frankenstein
Wikipedia
Article

.

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

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

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


 

Even I overestimated the possibility of benefit of epinephrine.

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

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

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

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

 

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

The best outcome was no detectable neurological impairment.
 

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

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

 


Click on the image to make it larger.
 

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

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

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

I will write more about these results later

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

Also see –

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

Footnotes:

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

Free Full Text from NEJM

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

Protocol

Supplementary Appendix

Disclosure Forms

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

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

Free Full Text from NEJM

.

New Illinois state law will allow basic EMTs to inject epinephrine

 
EpiPen 1 from Bloomberg dot com
Image from Bloomberg.com.
 

0.15 mg (0.15 ml of 1 mg/ml epinephrine) for a child.
0.3 mg (0.3 ml of 1 mg/ml epinephrine) for an adult.
Inject deep into the side of the thigh.
This should not be complicated, but . . . .

Paramedics have generally been able to give epinephrine injections for anaphylaxis in Illinois and elsewhere. As of January 1, 2017, basic EMTs (Emergency Medical Technicians) in Illinois, who have been able to use the EpiPen autoinjector, will be able to give epinephrine injections the same way paramedics give epinephrine for anaphylaxis.[1],[2]

Why? The cost of the autoinjector has increased from around $100 to around $600 since 2007, when Mylan bought the EpiPen as part of a group of products from Merck. During that time, the packaging has gone from a single EpiPen to two EpiPens, so that may be one part of the increase.

The EpiPen, which is currently only made by Mylan, used to have competition from Sanofi. On October 30, 2015, Sanofi recalled their Auvi-Q autoinjectors due to the possibility of dosage inaccuracies.[3] Some people are claiming that the increase in cost is due to the withdrawal of this competitor from the market, but I was able to locate two other competitors in the US, so there is competition.

Explanations exist; they have existed for all time; there is always a well-known solution to every human problem — neat, plausible, and wrong. H.L. Mencken.

If only the Sanofi recall caused the price increase, the price would not have been increasing for the past 10 years, but only for the past 10 months. Here is a graph of the price increase before the Sanofi recall.
 

EpiPen 2 from Bloomberg dot com
Graph from September 2015 – before the Sanofi recall – from Bloomberg.com.[4]
 

There are other competitors out there. Adrenaclick by Amedra Pharmaceuticals LLC,[5] and epinephrine injection, USP auto-injector by Lineage Therapeutics Inc.[6] – both located in Horsham, PA and the web sites have the same design, so they may be manufactured in the same facility.
 

The problems with having basic EMTs giving epinephrine injections are that the education has to be very good and the oversight has to be aggressive. As with naloxone (Narcan), doctors, nurses, and paramedics often give the drug inappropriately, so we know that there is a lot of potential for error.

The closest children’s hospital only uses autoinjectors, because they do not allow the nurses to draw up epinephrine for anaphylaxis. They probably do not allow the doctors to either, but I did not ask.

How bad are doctors at diagnosing and treating anaphylaxis?
 

Senior house officers (SHOs) (n=78) at the start of their accident and emergency (A&E) post were given an anonymous five case history questionnaire, containing one case of true anaphylaxis, and asked to complete the medication they would prescribe. In the case of anaphylaxis, 100% would administer adrenaline (epinephrine) but 55% would do so by the incorrect route. In the remaining cases, 10%–56% would be prepared to administer adrenaline inappropriately. Only 5% were able to indicate the correct route and dose of adrenaline according to Resuscitation Council guidelines (UK). This has implications for training as the survey took place before the start of the A&E posting. Anaphylaxis is over-diagnosed and poorly treated despite Resuscitation Council guidelines.[7]

 

That was in 2002. Have things improved?
 

RESULTS:
68 of 107 (64%) junior doctors completed the questionnaire. All recognised the need for adrenaline in anaphylaxis, but only 74% selected the correct intramuscular route, and 34% the correct route and dose. 82% of junior doctors would inappropriately give adrenaline to the patient who had inhaled a foreign body (case 2). A higher percentage of the 2013 cohort indicated the correct route and dose of adrenaline in anaphylaxis than their 2002 colleagues. However, a greater percentage also selected adrenaline treatment inappropriately in non-anaphylactic case scenarios.

CONCLUSIONS:
Despite updated guidelines, junior doctors continue to have poor knowledge about the recognition and management of anaphylaxis, with some still considering inappropriate intravenous adrenaline. More effort should be given to the recognition of anaphylaxis in early medical training.
[8]

 

Other research on doctors shows similar inability to come up with the right diagnosis, the right dose, and/or the right route of administration.[9],[10],[11] There are more. My anecdotal experience is that this is also a problem in the US with experienced paramedics and experienced physicians.

What about the King County epinephrine kit for basic EMTs?
 

King County epinephrine program to replace epipens 1 from Seattle Times
Image from the Seattle Times.
 

With training, EMTs in the program have learned to administer epinephrine efficiently and safely, he said. An EpiPen takes about 45 seconds to administer, start to finish. With the vial and syringe, it’s about 2 minutes, Duren said.[12]

 

As a paramedic, I am not going to be much faster.
 

“That sounds reasonable,” Reiter said. “For all but the most severe cases of anaphylaxis, a one-minute time lag is unlikely to make a difference.”[12]

 

The article suggests that King County is tracking their results carefully, which does not appear to be the case for EMS systems that have first responders giving naloxone. I would still like to see something published in a peer reviewed journal.

Footnotes:

[1] New state law will allow EMTs to inject epinephrine
Dan Petrella
The Southern Springfield Bureau
The Southern Illinoisan
Updated 22 hrs ago
Article

[2] New Ill. law to allow all EMTs to use syringes to administer epinephrine – The new law will allow EMTs with basic-level training to use a syringe to administer epinephrine
By EMS1 Staff
EMS1.com
Yesterday at 12:59 PM
Article

[3] UPDATED: Sanofi US Issues Voluntary Nationwide Recall of All Auvi-Q® Due to Potential Inaccurate Dosage Delivery
FDA (Food and Drug Administration – US)
For Immediate Release
October 30, 2015
Recall notice

[4] How Marketing Turned the EpiPen Into a Billion-Dollar Business – Mylan’s marketing turned the allergy device into a must-have.
Cynthia Koons and Robert Langreth
Bloomberg Businessweek
September 23, 2015 — 10:00 AM EDT
Article

[5] How to use Adrenaclick (epinephrine injection, USP auto-injector)
Adrenaclick by Amedra Pharmaceuticals LLC, Horsham, PA
Web site

[6] epinephrine injection, USP auto-injector
Lineage Therapeutics Inc., Horsham, PA
Web site

[7] Proposed use of adrenaline (epinephrine) in anaphylaxis and related conditions: a study of senior house officers starting accident and emergency posts.
Gompels LL, Bethune C, Johnston SL, Gompels MM.
Postgrad Med J. 2002 Jul;78(921):416-8.
PMID: 12151658

Free Full Text from PubMed Central.

[8] Correct recognition and management of anaphylaxis: not much change over a decade.
Plumb B, Bright P, Gompels MM, Unsworth DJ.
Postgrad Med J. 2015 Jan;91(1071):3-7. doi: 10.1136/postgradmedj-2013-132181.
PMID: 25573132

Free Full Text from Postgrad Med J.

[9] Survey of the use of epinephrine (adrenaline) for anaphylaxis by junior hospital doctors.
Jose R, Clesham GJ.
Postgrad Med J. 2007 Sep;83(983):610-1.
PMID: 17823230

Free Full Text from PubMed Central

[10] Anaphylaxis: lack of hospital doctors’ knowledge of adrenaline (epinephrine) administration in adults could endanger patients’ safety.
Droste J, Narayan N.
Eur Ann Allergy Clin Immunol. 2012 Jun;44(3):122-7.
PMID: 22905594

[11] Treatment of a simulated child with anaphylaxis: an in situ two-arm study.
O’Leary FM, Hokin B, Enright K, Campbell DE.
J Paediatr Child Health. 2013 Jul;49(7):541-7. doi: 10.1111/jpc.12276. Epub 2013 Jun 12.
PMID: 23758136

Free Full Text from J Paediatr Child Health.

 

RESULTS:
Fifty-six junior medical staff participated (90% participation rate). Only 50% of participants administered adrenaline in scenarios of definite anaphylaxis. Adrenaline was more likely to be administered if the scenario included hypotension, where the junior medical officer had previous formal resuscitation training (Advanced Paediatric Life Support) and by medical officers with more years of training.

CONCLUSION:
Anaphylaxis is a life-threatening presentation and requires prompt recognition and appropriate adrenaline administration. Junior medical staff may require more emphasis on recognition and prompt adrenaline administration in both undergraduate and in hospital training and education. Simulated scenarios may provide a platform to deliver this training to ultimately improve patient care.

 

[12] King County drops EpiPen for cheaper kit with same drug
By JoNel Aleccia
Seattle Times health reporter
Originally published January 14, 2015 at 10:05 pm
Updated January 15, 2015 at 7:00 pm
Seattle Times
Article

.

Natural Alternatives to the EpiPen, Because We Believe in Parachutes

 

The evidence for epinephrine (Adrenaline in Commonwealth countries) in anaphylaxis is not the highest quality available, but that does not mean that the use of epinephrine to treat anaphylaxis is not EBM (Evidence Based Medicine).
 

Evidence Pyramid

Evidence Pyramid


Image credit.
 

The patients are not randomized to placebo vs. epinephrine treatments, but EBM is not limited to placebo studies[1] – unless you believe that the Parachute Study is valid evidence, rather than just satire.[2]

It is entirely appropriate to use logical fallacy for satire, since humor is not expected to be based on valid evidence. It is definitely not appropriate to use logical fallacy as scientific evidence. Logic is essential to science, while logical fallacy and the avoidance of rational analysis are essential to deception.

What does the Parachute study have to do with Natural Alternatives to Epipen?[3] The evidence supporting epinephrine is even weaker than the evidence supporting parachutes, since one of the advantages of parachutes is that their use can be adequately studied without using human subjects. Therefore we actually have excellent evidence that parachutes will deploy as expected (with the obvious error bars that apply to valid science), will slow the descent (again, with the obvious error bars that apply to valid science), et cetera.
 

Even the most dimwitted purveyor of “natural” cures should know that and stay away from “natural” treatments for anaphylaxis, while the smarter snake oil salesmen also know that you can’t afford to mess around with a medical condition that can cause such rapid deterioration from seemingly perfectly health to dead. It’s not good for business.[4]

 

Ignoring the pathetic absence of evidence for alternative medicine, what is the evidence that epinephrine does improve outcomes?

There is an excellent discussion of the evidence in an article available for free at PubMed Central.
 

International guidelines concur that epinephrine (adrenaline) is the medication of first choice in anaphylaxis because it is the only medication that reduces hospitalization and death.[5]

 

There is no reduction of hospitalization and death with Benadryl (diphenhydramine), with any of the steroids, or with any alternative medicine. Go read the full paper.

Also, go read the analysis of the problems in the article advocating the use of Natural Alternatives to Epipen at Respectful Insolence.

Footnotes:

[1] Evidence based medicine: what it is and what it isn’t.
Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS.
BMJ. 1996 Jan 13;312(7023):71-2.
PMID: 8555924 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.
 

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.

 

Maybe the opponents of Evidence Based Medicine do not understand that using judgment to apply the best evidence to the patient is essential to EBM.

[2] 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.

The authors searched the literature for parachute research, but eliminated all studies without control groups, which suggests that EBM has some sort of requirement that all research include a control group. That is one of the logical fallacies employed by the authors for humorous intent.
 

We excluded studies that had no control group.

 

Those who cite the parachute study as valid evidence do not seem to understand this sleight of hand. EBM does not exclude studies that have no control group. EBM even includes expert opinion.

[3] Natural Alternatives to Epipen
Gazette Review
Dec 18, 2015
Adam Trent
Cached article

[4] Worst idea ever: “Natural” alternatives to the Epipen
Respectful Insolence
Posted by Orac
December 22, 2015
Article

[5] 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
Simons FE, Ebisawa M, Sanchez-Borges M, Thong BY, Worm M, Tanno LK, Lockey RF, El-Gamal YM, Brown SG, Park HS, Sheikh A.
World Allergy Organ J. 2015 Oct 28;8(1):32. doi: 10.1186/s40413-015-0080-1. eCollection 2015.
PMID: 26525001

Free Full Text from PubMed Central.

.

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 from reanimacion.net
 

 

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 from reanimacion.net
 

 

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.

.

The Media are Just As Bad at Ethics As They are at Science

 
There is another article about the adrenaline (epinephrine in non-Commonwealth countries) vs. placebo in cardiac arrest trial that is about to start in England.[1] Media sites no longer seem to want to spend money to get valid information on science or ethics. Forbes provides another example of the writer completely missing the obvious.
 

It’s one thing to treat an incapacitated emergency patient without consent, when you’re administering a standard therapy already proven to be beneficial.[2]

 

Nobody is being deprived of anything that has been adequately tested on humans. Why assume that the untested and unknown standard treatment is beneficial?

The active drug (adrenaline) is an unknown. There is no good evidence that adrenaline improves outcomes.

If you disagree, provide some evidence that shows that adrenaline is better than placebo at anything that matters.

Adrenaline is an unknown because it has never been adequately studied. The only study that has tried to compare it to placebo was limited by politicians and the media – the people who know the least about how science works.

This is like being told that you will be put in a room with either a killer or a mannequin. Which one do you want. Except that we do not know if adrenaline is a killer. We do not have enough information. The only way to find out is to study it.

The research so far is negative. Is that because the adrenaline is given too late? Is that because too much adrenaline is given? Is that because we give it to everyone still dead after a few minutes?

We do not know.

We treat adrenaline like snake oil – Able to cure all kinds of cardiac arrest. Step right up and get your magic elixir. Cures baldness, too!
 


Image credit.
 

When the sales pitch is that the drug fixes everything, we should be very suspicious.

Cardiac arrest due to blood loss?   Give adrenaline.

Cardiac arrest due to slow heart rate?   Give adrenaline.

Cardiac arrest due to fast heart rate?   Give adrenaline.

Cardiac arrest due to irritated heart?   Give adrenaline.

Cardiac arrest due to not enough stimulus to the heart?   Give adrenaline.

Cardiac arrest due to drug over-dose?   Give adrenaline.

Cardiac arrest due to drug under-dose?   Give adrenaline.

Cardiac arrest due to diabetes problem?   Give adrenaline.

Cardiac arrest due to infectious disease?   Give adrenaline.

Cardiac arrest due to lightning strike?   Give adrenaline.

Cardiac arrest due to drowning?   Give adrenaline.

Cardiac arrest due to asthma?   Give adrenaline.

Cardiac arrest due to stroke?   Give adrenaline.

Cardiac arrest due to cancer?   Give adrenaline.

Cardiac arrest due to adrenaline overdose?   Give adrenaline.

We do not discriminate. We just give adrenaline. All of the other drugs have failed to produce a benefit, but we still believe in adrenaline without good evidence. We have been using adrenaline for over half a century on unsuspecting people and we still have no evidence that it works.
 

However, the more important issue is what you as a patient think. Should scientists be able to enroll you in a life-or-death medical experiment without your consent?[2]

 

Adrenaline has worked in laboratory animals, but every drug that is tested in humans is supposed to have worked in animals. Why doesn’t adrenaline work in humans? If it does work, where is the evidence?

The standard of care is an experiment that is not controlled and not even acknowledged. The guidelines clearly state that we do not know what works and that we should only consider adrenaline, but that we do not have any good evidence that adrenaline improves outcomes for anyone.

The ethical failure is that we have failed to find out if what we are giving is harmful.
 

We have only improved outcomes when we have ignored the drugs and paid attention to chest compressions and defibrillation.
 

We are lying to patients when we tell them that we know what works in cardiac arrest.

How much worse than placebo is adrenaline? We don’t know. Failing to find out is what is unethical.

Footnotes:

[1] Does a Placebo vs. Adrenaline Study Deprive Patients of Necessary Care According to the Resuscitation Guidelines?
Wed, 27 Aug 2014
Rogue Medic
Article

[2] UK To Experiment on Cardiac Arrest Patients Without Their Consent
8/27/2014 @ 3:55PM
Paul Hsieh – Contributor
Forbes
Article

.

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


 Some in the media have been critical of the upcoming British study of adrenaline (epinephrine) vs. placebo for cardiac arrest.[1] They assume that the guidelines require that we give adrenaline, but that is not true.

The guidelines only state that adrenaline may be considered.

If you are a dog, pig, or rat in a laboratory and you have had an artificially induced cardiac arrest, then adrenaline will help resuscitate you. If you are a human who has a cardiac arrest for any one of a variety of reasons, then there is not a good reason to give this rat resuscitation drug, which has not been adequately studied in humans.

There probably are some human patients who do benefit from adrenaline in cardiac arrest, but we have no idea which patients those are and there probably are humans who are harmed by adrenaline. The most common cause of cardiac arrest is heart attack, but you were having a heart attack while still alive, is there a worse drug we could give you than adrenaline? Does adrenaline suddenly become sugar and spice and everything nice, just because we cannot feel a pulse? Maybe, but should we assume that?

What if you have lost so much blood that your heart is not able to produce a pulse, even though your heart is beating as hard as it can? Adrenaline is indicated according to the same guidelines. Why? Unreasonable optimism.

Which patients benefit from adrenaline? We don’t know.

Which patients are harmed by adrenaline? We don’t know.

How do we find out? Research, such as the upcoming study of adrenaline (epinephrine).

What do the guidelines say about conducting this research?
 

Given the observed benefit in short-term outcomes, the use of epinephrine or vasopressin may be considered in adult cardiac arrest.

Knowledge Gaps

Placebo-controlled trials to evaluate the use of any vasopressor in adult and pediatric cardiac arrest are needed.[2]

 

Vasopressors are adrenaline, vasopressin, norepinephrine, and phenylephrine. We need evidence to find out if any of them work.

When the 2010 guidelines were written there was an inescapable need for placebo studies.

Has anything changed?

No.

There was a placebo study in 2012 that was aborted by pressure from media and politicians before any useful results could be obtained.[3]
 

There is evidence that adrenaline improves the return of a pulse, but that appears to just produce comatose patients who die in the hospital without waking up, so the initial improvement appears to be very misleading.

We could try real medicine, where we find out what the right treatment is and give the right treatment to the right patient, but that seems to be asking too much for some people.
 

The Media are Just As Bad at Ethics As They are at Science

Footnotes:

[1] The Controversy of Admitting ‘We Do Not Know What Works’
Wed, 13 Aug 2014
Rogue Medic
Article

[2] Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.
Morrison LJ, Deakin CD, Morley PT, Callaway CW, Kerber RE, Kronick SL, Lavonas EJ, Link MS, Neumar RW, Otto CW, Parr M, Shuster M, Sunde K, Peberdy MA, Tang W, Hoek TL, Böttiger BW, Drajer S, Lim SH, Nolan JP; Advanced Life Support Chapter Collaborators.
Circulation. 2010 Oct 19;122(16 Suppl 2):S345-421. doi: 10.1161/CIRCULATIONAHA.110.971051. No abstract available.
PMID: 20956256 [PubMed – indexed for MEDLINE]

Free Full Text from Circulation.

[3] 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 from reanimacion.net
 
 

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.

 

.