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

.

Cardiac arrest victim Trudy Jones ‘given placebo’ – rather than experimental epinephrine

 

As part of a study to find out if epinephrine (adrenaline in Commonwealth countries) is safe to use in cardiac arrest, a patient was treated with a placebo, rather than the inadequately tested drug. Some people are upset that the patient did not receive the drug they know nothing about.[1]

The critics are trying to make sure that we never learn.

We need to find out how much harm epinephrine causes, rather than make assumptions based on prejudices.

When used in cardiac arrest, does epinephrine produce a pulse more often?

Yes.

When used in cardiac arrest, does epinephrine produce a good outcome more often?

We don’t know.

In over half a century of use in cardiac arrest, we have not bothered to find out.
 


 

We did try to find out one time, but the media and politicians stopped it.[2]

We would rather harm patients with unreasonable hope, than find out how much harm we are causing to patients.

We would rather continue to be part of a huge, uncontrolled, unapproved, undeclared, undocumented, unethical experiment, than find out what works.

Have we given informed consent to that kind of experimentation?

Ignorance is bliss.

The good news is that the enrollment of patients has finished, so the media and politicians will not be able to prevent us from learning the little that we will be able to learn from this research.[3]

Will the results tell us which patients are harmed by epinephrine?

Probably not – that will require a willingness to admit the limits of what we learn and more research.

What EMS treatments have been demonstrated to improve outcomes from cardiac arrest?

1. High quality chest compressions.
2. Defibrillation, when indicated.

Nothing else.

All other treatments, when tested, have failed to be better than nothing (placebo).

Footnotes:

[1] Cardiac arrest victim Trudy Jones ‘given placebo’
BBC News
23 March 2018
Article

[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] Paramedic2 – The Adrenaline Trial
Warwick Medical School
Trial Updates
 

Trial Update – 19 February 2018:
PARAMEDIC2 has finished recruitment and we are therefore no longer issuing ‘No Study’ bracelets. The data collected from the trial is in the process of being analysed and we expect to publish the results in 2018. Once the results have been published, a summary will be provided on the trial website.

 

.

Prehospital cooling to improve successful targeted temperature management after cardiac arrest: A randomized controlled trial

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

This is a nice study, which unfortunately ran into problems with enrollment and funding. There are some things that I think should have been done differently.

The doses of chilled IV (IntraVenous) fluid were not weight-based, while the fluid in the human body is weight-based. If midazolam (Versed) was given, the dose was just a single dose of 5 mg, or 2 doses of 5 mg each. The effects of midazolam are much less weight-based, than fluid, but the appropriate way to administer midazolam is to titrate to effect. Even if administering 10 mg of midazolam produces the desired effect in 80%, or 90%, of patients, that can still leave a significant portion inadequately sedated. The goal of TTM (Targeted Temperature Management) may be defeated by the movement of an even mildly agitated patient.

Would another drug, such as ketamine, be more appropriate? How much does use of midazolam affect the use of pressors to counter the vasodilatory effects of midazolam? Unlike other sedatives, ketamine does not seem to produce vasodilation and/or depress cardiac activity. The midazolam was only mentioned in the description of the study interventions and only described as being given to prevent shivering, so the dose may be adequate, but there is only the one mention in the entire paper.

The fluid administration was shown to be different with a p value of <0.0001. The difference is only 170 ml (5 3/4 oz), so it is a distinction described as significant by p value, but it does not appear to be a significant difference in any way that would affect patients. The SD (Standard Deviation - how much variability exists in about 2/3 of patients) is the same as the amount of fluid given to the control group and 2 3/4 times the amount of the difference. In other words, there was a lot of overlap in the volumes administered to the patients in the two groups. While the p value of <0.0001 suggests confidence in the results being due to change only one time in 10,000, that is misleading.  

Total fluid infused was not documented for 98 (35%) patients who received Prehospital Cooling and 121 (40%) control patients.[1]

 


 

The raw data on the volumes is not included, nor is the shape of the graph of distribution of the volumes, but it looks as if 20%, or 30%, of the control group may have received more fluid that the intervention group – and then there are the more than 35% of patients without documentation of fluid volumes.

Since the amount of difference is small, it does not seem to matter, but the intervention group was forcing the chilled fluid into the patients with pressure bags, so why so little difference between the groups?

How long does it take to administer 170 ml of chilled IV fluid by pressure infusion? Does it take longer than it takes to get from the ambulance to the hospital stretcher?

That is just a statistical oddity that is not going to affect outcomes.

The next may be the true the significant finding of the study.
 

Patients in the prehospital cooling group were more likely to (ever) receive TTM in hospital [190 (68%) vs 170 (56%); RR 1.21, p = 0.003] than patients in the control group.[1]

 


 

TTM (Targeted Temperature Management) is the new term for therapeutic hypothermia, which has been shown to be effective.

If not, why not?
 

Across all studies that used conventional cooling methods rather than no cooling (three studies; 383 participants), we found a 30% survival benefit (RR 1.32, 95% CI 1.10 to 1.65). The quality of the evidence was moderate.[2]

 

With no difference in the rhythms of the control group and the intervention group, why the difference in the rate of TTM in the hospital?

Will this be similar to the case of waveform capnography? EMS ended up pressuring many/some EDs to begin to use EtCO2 on all intubated patients. This was a change from the previous, much too common, ED practice of complaining about and pulling at the EtCO2 tubing, because it was an unknown item that was in the way.

EMS should not need to encourage the ED to provide better care, especially about treatments/assessments that originated as in-hospital treatments/assessments. It should be the reverse.

There is an excellent review of TTM research at Life In The Fast Lane.[3]

Footnotes:

[1] Prehospital cooling to improve successful targeted temperature management after cardiac arrest: A randomized controlled trial.
Scales DC, Cheskes S, Verbeek PR, Pinto R, Austin D, Brooks SC, Dainty KN, Goncharenko K, Mamdani M, Thorpe KE, Morrison LJ; Strategies for Post-Arrest Care SPARC Network.
Resuscitation. 2017 Dec;121:187-194. doi: 10.1016/j.resuscitation.2017.10.002. Epub 2017 Oct 5.
PMID: 28988962

Free Full text Article from Resuscitation.

[2] Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation.
Arrich J, Holzer M, Havel C, Müllner M, Herkner H.
Cochrane Database Syst Rev. 2016 Feb 15;2:CD004128. doi: 10.1002/14651858.CD004128.pub4. Review.
PMID: 26878327

[3] Targeted temperature management (TTM) after cardiac arrest
Life In The Fast Lane
Chris Nickson
Reviewed and revised Aug 1, 2017 @ 7:07 pm
Article

Scales DC, Cheskes S, Verbeek PR, Pinto R, Austin D, Brooks SC, Dainty KN, Goncharenko K, Mamdani M, Thorpe KE, Morrison LJ, & Strategies for Post-Arrest Care SPARC Network (2017). Prehospital cooling to improve successful targeted temperature management after cardiac arrest: A randomized controlled trial Resuscitation, 121 (December), 187-194 : PMID: 28988962

Arrich J, Holzer M, Havel C, Müllner M, & Herkner H (2016). Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation Cochrane Database Syst Rev : PMID: 26878327

.

2016 – Amiodarone is Useless, but Ketamine Gets Another Use

amiodarone-edit-1
 

I didn’t write a lot in 2016, but 2016 may have been the year we put the final nail in the coffin of amiodarone. Two major studies were published and both were very negative for amiodarone.

If we give enough amiodarone to have an effect on ventricular tachycardia, it will usually be a negative effect.[1]

Only 38% of ventricular tachycardia patients improved after amiodarone, but 48% had major adverse cardiac events after amiodarone.

There are better drugs, including adenosine, sotalol, procainamide, and ketamine for ventricular tachycardia. Sedation and cardioversion is a much better choice. Cardioversion is actually expected after giving amiodarone.

For cardiac arrest, amiodarone is not any better than placebo or lidocaine. What ever happened to the study of amiodarone that was showing such wonderful results over a decade ago? It still hasn’t been published, so it is reasonable to conclude that the results were negative for amiodarone. It is time to make room in the drug bag for something that works.[2],[3]

On the other hand, now that we have improved the quality of CPR by focusing on compressions, rather than drugs, more patients are waking up while chest compressions are being performed, but without spontaneous circulation, so ketamine has another promising use. And ketamine is still good for sedation for intubation, for getting a patient to tolerate high flow oxygen, for agitated delirium, for pain management, . . . .[4],[5]

Masimo’s RAD 57 still doesn’t have any evidence that it works well on real patients.[6]

When intubating, breathe. Breathing is good. Isn’t inability to breathe the reason for intubation?[7]

Footnotes:

[1] The PROCAMIO Trial – IV Procainamide vs IV Amiodarone for the Acute Treatment of Stable Wide Complex Tachycardia
Wed, 17 Aug 2016
Rogue Medic
Article

[2] Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest
Mon, 04 Apr 2016
Rogue Medic
Article

[3] Dr. Kudenchuk is Misrepresenting ALPS as ‘Significant’
Tue, 12 Apr 2016
Rogue Medic
Article

[4] What do you do when a patient wakes up during CPR?
Tue, 08 Mar 2016
Rogue Medic
Article

[5] Ketamine For Anger Management
Sun, 06 Mar 2016
Rogue Medic
Article

[6] The RAD-57 – Still Unsafe?
Wed, 03 Feb 2016
Rogue Medic
Article

[7] Should you hold your breath while intubating?
Tue, 19 Jan 2016
Rogue Medic
Article

.

The PROCAMIO Trial – IV Procainamide vs IV Amiodarone for the Acute Treatment of Stable Wide Complex Tachycardia

ResearchBlogging.org
 

This is a very interesting trial that may surprise the many outspoken amiodarone advocates, but it should not surprise anyone who pays attention to research.

ALPS showed that we should stop giving amiodarone for unwitnessed shockable cardiac arrest. The lead researcher is still trying to spin amiodarone for witnessed shockable cardiac arrest, even though the results do not show improvement in the one outcome that matters – leaving the hospital with a brain that still works.[1],[2],[3]

There is an excellent discussion of the study on the podcast by Dr. Salim Rezaie and Dr. Anand Swaminathan REBELCast: The PROCAMIO Trial – IV Procainamide vs IV Amiodarone for the Acute Treatment of Stable Wide Complex Tachycardia.

One problem with the study that they do not address on the podcast is that the patients in the study appear to have had time to watch Casablanca before treatment started. Here’s looking at you, while we’re waiting, kid. This is apparently unintentional one way of doing a placebo washout. If we wait long enough . . . .
 

Time from arrival to start of infusion was 87 ± 21 min for procainamide and 115 ± 36 min for amiodarone patients (P = 0.58).[4]

 

If nothing else, this demonstrates how little we need to worry about immediately pushing drugs for stable monomorphic VT (V Tach or Ventricular Tachycardia). Should we expect much from antiarrhythmic treatment?

Research shows that for stable monomorphic VT (V Tach or Ventricular Tachycardia) amiodarone is not very likely to be followed by an improvement. Only 29%[5] or only 25%[6] or only 15% within 20 minutes, but if we don’t mind waiting an hour it can be as much as 29%.[7] For those of you who are not good at math, that means amiodarone is about the same as doing nothing, only it comes in a syringe. Even though these poor outcomes ignore the side effects, they are the best evidence in favor of amiodarone, so what Kool-Aid are the advocates drinking?

Adenosine, yes adenosine the SVT (SupraVentricular Tachycardia) drug, appears to be more effective at treating ventricular tachycardia than amiodarone – and adenosine is faster and safer than amiodarone.[8]

What if the patient becomes unstable? First start an IV (IntraVenous) line. Then sedate the patient. Then apply defibrillator pads. After the patient is adequately sedated, then cardiovert. We do not need the pads on the patient first. If it takes a while to put the pads on, that is a problem with the ability of the doctors and nurses, not a medical problem.

It does not appear as if any patient received amiodarone or procainamide until after waiting in the ED (Emergency Department) for over an hour. Were some patients cardioverted in well under an hour? Probably. The important consideration is that the doctors and nurses be able to apply the defibrillator pads properly and quickly and deliver a synchronized cardioversion in less than a minute. If the patient has not yet been sedated, the cardioversion should be delayed until after the patient is adequately sedated, so the intervention that depends most on time is the sedation of the patient.
 

VT + Amiodarone Cardioversion
 

Is there a better treatment than amiodarone? Sedate the patient before the patient becomes unstable, then cardiovert. How do the MACEs (Major Adverse Cardiac Events) compare with sedation and cardioversion vs. antiarrhythmic treatment.
 

5.4 Proarrhythmia
Amiodarone may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with amiodarone. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.
[9]

 

All antiarrhythmic drugs can cause arrhythmias. In the absence of information about a specific problem that is best addressed by a specific drug (amiodarone is the opposite of specific), we should avoid treatments that have such a high potential for harm.

Amiodarone doesn’t even do a good job of preventing arrhythmias.
 

Intravenous amiodarone did not prevent induction of sustained ventricular tachycardia in any of five patients inducible at baseline. Of six patients with non-sustained ventricular tachycardia, five had sustained ventricular tachycardia or fibrillation induced after amiodarone infusion.[10]

 

Is anything worse than amiodarone? Even epinephrine, yes epinephrine the inadequately tested cardiac arrest drug, has been followed by improved outcomes from V Tach after amiodarone failed.[11]
 

What is best for the patient?

Sedation, search for reversible causes, apply defibrillator pads, and be prepared to cardiovert.

Maybe sedation isn’t that important? This is by Dr. Peter Kowey, one of the top cardiologists in the world.
 

The man’s very first utterance was, “If it happens again, just let me die.”

As I discovered, the reason for this patient’s terror was that he had been cardioverted in an awake state. Ventricular tachycardia had been relatively slow, he had not lost consciousness, and the physicians, in the heat of the moment, had not administered adequate anesthesia. Although the 5 mg of intravenous diazepam had made him a bit drowsy, he felt the electric current on his chest and remembered the event clearly.

The patient’s mental state complicated the case considerably.[12]

 

How unimportant is sedation? How unimportant is consent?

For sedation, I would recommend ketamine, but etomidate was recommended in the podcast. Both work quickly and the most important obstacle to immediate treatment of a patient who suddenly deteriorates is the time to effect of sedation. Neither drug is expected to interfere with perfusion, which is the main excuse given for avoiding sedation for cardioversion.

This study is very small (not the fault of the authors), but it adds to the evidence that amiodarone is not a good first treatment for the patient.
 

Go listen to the podcast by Dr. Salim Rezaie and Dr. Anand Swaminathan REBELCast: The PROCAMIO Trial – IV Procainamide vs IV Amiodarone for the Acute Treatment of Stable Wide Complex Tachycardia

 

Over the years, I have written a bit about cardioversion and the importance of sedation –

Cardioversion – I’m not doing that, you do it! – Mon, 24 Mar 2008

Cardioversion – 2010 ACLS – Part I – Mon, 25 Oct 2010

Cardioversion – 2010 ACLS – Part II – Sun, 31 Oct 2010

Cardioversion – 2010 ACLS – Part III – Thu, 11 Nov 2010

On the relative wisdom of synchronized cardioversion without sedation – Part I – Thu, 11 Nov 2010

On the relative wisdom of synchronized cardioversion without sedation – Part II – Fri, 12 Nov 2010

Synchronized Cardioversion Without Sedation – Part II Scallywag’s Response – Sun, 14 Nov 2010

On the relative wisdom of synchronized cardioversion without sedation – Part III – Tue, 16 Nov 2010

On the relative wisdom of synchronized cardioversion without sedation – Part IV – Wed, 24 Nov 2010

Comments on Cardioversion – 2010 ACLS – Part II – Mon, 16 Apr 2012
 

I have also written a bit about amiodarone –

Merit Badge Courses, Amiodarone, and tPA – Fri, 17 Sep 2010

Amiodarone for Cardiac Arrest in the 2010 ACLS – Part I – Wed, 01 Dec 2010

Amiodarone for Cardiac Arrest in the 2010 ACLS – Part II – Fri, 03 Dec 2010

Is Nexterone the Next Amiodarone? – Sat, 04 Dec 2010

Amiodarone for Cardiac Arrest in the 2010 ACLS – Part III – Mon, 06 Dec 2010

Where are the Black Box Warnings on These Drugs – I – Mon, 05 Dec 2011

Where are the Black Box Warnings on These Drugs – II – Sun, 11 Dec 2011

Is Amiodarone the Best Drug for Stable Ventricular Tachycardia – Wed, 14 Dec 2011

V Tach Storm – Part I – Wed, 28 Dec 2011

V Tach Storm – Part II – Thu, 29 Dec 2011

Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia – Wed, 04 Jan 2012

NIH launches trials to evaluate CPR and drugs after sudden cardiac arrest – Sun, 29 Jan 2012

What Will Be the Next Standard Of Care We Eliminate – Wed, 28 Mar 2012

Happy Adenosine Day – Tue, 12 Jun 2012

Too Much Medicine and Evidence-Based Guidelines – Part I – Tue, 26 Jun 2012

Too Much Medicine and Evidence-Based Guidelines – Part II – Tue, 03 Jul 2012

Ondansetron (Zofran) Warning for QT Prolongation – is Amiodarone next? – Part I – Mon, 02 Jul 2012

Ondansetron (Zofran) Warning for QT Prolongation – is Amiodarone next? – Part II – Thu, 05 Jul 2012

Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium – Part I – Mon, 17 Sep 2012

Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium – Part II – Tue, 18 Sep 2012

How do we measure the QT segment when there are prominent U waves? – Thu, 13 Dec 2012

Woman with Risks for Torsades de Pointes Dying within Hours of Leaving the Emergency Department – Wed, 02 Jan 2013

Examples of Ventricular Tachycardia Caused by Amiodarone – Part I – Tue, 28 May 2013

Publication Bias – The Lit Whisperers – Tue, 11 Jun 2013

Standards Of Care – Ventricular Tachycardia – Wed, 31 Jul 2013

Footnotes:

[1] Dr. Kudenchuk is Misrepresenting ALPS as ‘Significant’
Tue, 12 Apr 2016
Rogue Medic
Article

[2] Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest
Mon, 04 Apr 2016
Rogue Medic
Article

[3] Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
Kudenchuk PJ, Brown SP, Daya M, Rea T, Nichol G, Morrison LJ, Leroux B, Vaillancourt C, Wittwer L, Callaway CW, Christenson J, Egan D, Ornato JP, Weisfeldt ML, Stiell IG, Idris AH, Aufderheide TP, Dunford JV, Colella MR, Vilke GM, Brienza AM, Desvigne-Nickens P, Gray PC, Gray R, Seals N, Straight R, Dorian P; Resuscitation Outcomes Consortium Investigators.
N Engl J Med. 2016 May 5;374(18):1711-22. doi: 10.1056/NEJMoa1514204. Epub 2016 Apr 4.
PMID: 27043165

CONCLUSIONS
Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

[4] Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study.
Ortiz M, Martín A, Arribas F, Coll-Vinent B, Del Arco C, Peinado R, Almendral J; PROCAMIO Study Investigators.
Eur Heart J. 2016 Jun 28. pii: ehw230. [Epub ahead of print]
PMID: 27354046

Free Full Text from European Heart Journal.

[5] Amiodarone or procainamide for the termination of sustained stable ventricular tachycardia: an historical multicenter comparison.
Marill KA, deSouza IS, Nishijima DK, Senecal EL, Setnik GS, Stair TO, Ruskin JN, Ellinor PT.
Acad Emerg Med. 2010 Mar;17(3):297-306.
PMID: 20370763 [PubMed – indexed for MEDLINE]

Free Full Text from Academic Emergency Medicine.

[6] Amiodarone is poorly effective for the acute termination of ventricular tachycardia.
Marill KA, deSouza IS, Nishijima DK, Stair TO, Setnik GS, Ruskin JN.
Ann Emerg Med. 2006 Mar;47(3):217-24. Epub 2005 Nov 21.
PMID: 16492484 [PubMed – indexed for MEDLINE]

[7] Intravenous amiodarone for the pharmacological termination of haemodynamically-tolerated sustained ventricular tachycardia: is bolus dose amiodarone an appropriate first-line treatment?
Tomlinson DR, Cherian P, Betts TR, Bashir Y.
Emerg Med J. 2008 Jan;25(1):15-8.
PMID: 18156531 [PubMed – indexed for MEDLINE]

[8] Adenosine for wide-complex tachycardia – diagnostic?
Thu, 23 Aug 2012
Rogue Medic
Article

[9] AMIODARONE HYDROCHLORIDE- amiodarone hydrochloride injection, solution
DailyMed
5 WARNINGS AND PRECAUTIONS
FDA Label

[10] Effects of intravenous amiodarone on ventricular refractoriness, intraventricular conduction, and ventricular tachycardia induction.
Kułakowski P, Karczmarewicz S, Karpiński G, Soszyńska M, Ceremuzyński L.
Europace. 2000 Jul;2(3):207-15.
PMID: 11227590 [PubMed – indexed for MEDLINE]

Free Full Text PDF + HTML from Europace

[11] Low doses of intravenous epinephrine for refractory sustained monomorphic ventricular tachycardia.
Bonny A, De Sisti A, Márquez MF, Megbemado R, Hidden-Lucet F, Fontaine G.
World J Cardiol. 2012 Oct 26;4(10):296-301. doi: 10.4330/wjc.v4.i10.296.
PMID: 23110246 [PubMed]

Free Full Text from PubMed Central.

[12] The calamity of cardioversion of conscious patients.
Kowey PR.
Am J Cardiol. 1988 May 1;61(13):1106-7. No abstract available.
PMID: 3364364

Kudenchuk PJ, Brown SP, Daya M, Rea T, Nichol G, Morrison LJ, Leroux B, Vaillancourt C, Wittwer L, Callaway CW, Christenson J, Egan D, Ornato JP, Weisfeldt ML, Stiell IG, Idris AH, Aufderheide TP, Dunford JV, Colella MR, Vilke GM, Brienza AM, Desvigne-Nickens P, Gray PC, Gray R, Seals N, Straight R, Dorian P, & Resuscitation Outcomes Consortium Investigators (2016). Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. The New England journal of medicine, 374 (18), 1711-22 PMID: 27043165

Ortiz M, Martín A, Arribas F, Coll-Vinent B, Del Arco C, Peinado R, Almendral J, & PROCAMIO Study Investigators (2016). Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. European heart journal PMID: 27354046

Marill KA, deSouza IS, Nishijima DK, Senecal EL, Setnik GS, Stair TO, Ruskin JN, & Ellinor PT (2010). Amiodarone or procainamide for the termination of sustained stable ventricular tachycardia: an historical multicenter comparison. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 17 (3), 297-306 PMID: 20370763

Marill KA, deSouza IS, Nishijima DK, Stair TO, Setnik GS, & Ruskin JN (2006). Amiodarone is poorly effective for the acute termination of ventricular tachycardia. Annals of emergency medicine, 47 (3), 217-24 PMID: 16492484

Tomlinson DR, Cherian P, Betts TR, & Bashir Y (2008). Intravenous amiodarone for the pharmacological termination of haemodynamically-tolerated sustained ventricular tachycardia: is bolus dose amiodarone an appropriate first-line treatment? Emergency medicine journal : EMJ, 25 (1), 15-8 PMID: 18156531

Kułakowski P, Karczmarewicz S, Karpiński G, Soszyńska M, & Ceremuzyński L (2000). Effects of intravenous amiodarone on ventricular refractoriness, intraventricular conduction, and ventricular tachycardia induction. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 2 (3), 207-15 PMID: 11227590

Bonny A, De Sisti A, Márquez MF, Megbemado R, Hidden-Lucet F, & Fontaine G (2012). Low doses of intravenous epinephrine for refractory sustained monomorphic ventricular tachycardia. World journal of cardiology, 4 (10), 296-301 PMID: 23110246

Kowey PR (1988). The calamity of cardioversion of conscious patients. The American journal of cardiology, 61 (13), 1106-7 PMID: 3364364

.

Ketamine For Anger Management

 

I have been meaning to write about this ketamine study, but Greg Friese wrote about one of the comments on a review of the paper –
 

Most intriguing is this reader comment “talk to your damn patients calm them down and you can avoid this knee jerk, sedate first ask questions later whilst risking side effects, response ,that seems to be coming the norm” which seems disconnected to the actual syndrome of ExDS and the danger to medics, cops, and the patient when a patient’s behavior is out of control.[1]

 

Intriguing?
 

Tasmanian Devil - from outbackcooking dot blogspot dot com 1
 

The review was by Dr. Ryan Radecki of Emergency Medicine Literature of Note (the best quick and to the point reviews of research I know of on line). Did Dr. Radecki even suggest that we should avoid attempts at talking the patient down?
 

From the land of “we still have droperidol”, this case series details the use of ketamine as “rescue” treatment for “agitated delirium”. In lay terms, the situation they’re describing is the utterly bonkers patient being physically restrained by law enforcement for whom nothing else has worked.[2]

 

No.

Did the authors of the original paper suggest that we should avoid attempts at talking the patient down (verbal de-escalation)?
 

The sedation of agitated and aggressive patients in the emergency department (ED) and other acute care areas is a major problem for health care workers. Patients with acute behavioral disturbance may respond to verbal de-escalation or oral sedation, but a substantial proportion of this group requires parenteral sedation and mechanical restraint.1, 2, 3, 4, 5 [3]

 

No.

What about the studies cited above?

This is from one –
 

Combined pharmacological sedation and physical restraint were required on 66 (46%) occasions, pharmacological sedation alone on 20 (14%), physical restraint alone on 14 (10%) and neither on 43 (30%) occasions.[4]

 

30% of patients did not require physical and/or chemical restraint.

What does require mean?

How many patients can be managed by just talking them down? Should we avoid preparation for chemical and physical restraints, just because we are trying to talk the patient down?
 

There is indirect evidence from pharmacologic studies of agitation that verbal techniques can be successful in a substantial percentage of patients. In a recent study, patients were excluded from a clinical trial of droperidol if they were successfully managed with verbal de-escalation; however, the specific verbal de-escalation techniques were not identified or studied.12 [5]

 

Research on chemical management of excited delirium should not be interpreted as discouraging us from talking patients down.
 

Clinicians who work in acute care settings must be good multitaskers and tolerate rapidly changing patient priorities. In this environment, tolerating and even enjoying dealing with agitated patients takes a certain temperament, and all clinicians are encouraged to assess their temperament for this work.[5]

 

There is a lot of good information in the article, but approaching every patient with the expectation that verbal de-escalation will work is unrealistic. A lack of preparation sets everyone up for a worse outcome in the cases where verbal de-escalation does not work. Injuries and death become more likely, when we are not prepared to switch to sedation and have only physical restraint to respond to rapidly changing patient priorities.

We need to be able to adapt to the agitated patient. Verbal de-escalation and excited delirium do not get enough attention. This paper does not address the use of verbal de-escalation, because the enrolled patients had to fail to respond to other chemical sedation first. The patients who failed chemical sedation are also the ones who failed to respond to whatever attempts at verbal de-escalation were used.
 

Read the full paper on verbal de-escalation.

Footnotes:

[1] Sunday morning reader – coffee, ketamine, and EMS news
Everyday EMS Tips
by Greg Friese
March 6, 2016
Article

[2] Ketamine For Anger Management
Emergency Medicine Literature of Note
Friday, March 4, 2016
Posted by Ryan Radecki
Article

[3] Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department.
Isbister GK, Calver LA, Downes MA, Page CB.
Ann Emerg Med. 2016 Feb 10. pii: S0196-0644(15)01562-0. doi: 10.1016/j.annemergmed.2015.11.028. [Epub ahead of print]
PMID: 26899459

[4] Structured team approach to the agitated patient in the emergency department.
Downes MA, Healy P, Page CB, Bryant JL, Isbister GK.
Emerg Med Australas. 2009 Jun;21(3):196-202. doi: 10.1111/j.1742-6723.2009.01182.x.
PMID: 19527279

[5] Verbal De-escalation of the Agitated Patient: Consensus Statement of the American Association for Emergency Psychiatry Project BETA De-escalation Workgroup.
Richmond JS, Berlin JS, Fishkind AB, Holloman GH Jr, Zeller SL, Wilson MP, Rifai MA, Ng AT.
West J Emerg Med. 2012 Feb;13(1):17-25. doi: 10.5811/westjem.2011.9.6864.
PMID: 22461917

Free Full Text from PubMed Central.

.

How Bad is the Evidence for the New 2015 ACLS Guidelines?

ResearchBlogging.org
 
    The new ACLS guidelines are out. How bad is the evidence?

    The short answer – The Advanced Cardiac Life Support guidelines could be worse.

How does the American Heart Association determine that a recommendation is not beneficial?
 

Class III: No Benefit, is a moderate recommendation, generally reserved for therapies or tests that have been shown in high-level studies (generally LOE A or B) to provide no benefit when tested against a placebo or control.[1]

 

The tobacco enema has been used successfully as a treatment for cardiac arrest, so the evidence of lack of benefit is poor.[2] Clearly, the Advanced Cardiac Life Support guidelines cannot claim that the tobacco enema is Class III. Successfully? The treatment was used and a dead person was no longer dead. In other words, just as successfully as most of the ACLS treatments.
 

From Eisenberg, MS. Life in the balance: emergency medicine and the quest to reverse sudden death. 1997; Oxford University Press. [betterworldbooks][3]

 

This is one way to make excuses for justify doing something just because of ideology. In the absence of good evidence of benefit, we should not harm our patients to protect our ideology. We used to do this with blood-letting, which was defended even after there was clear evidence of harm. That is just the best known example, but this dishonesty continues and continues to be defended.

Why don’t we hold anyone accountable, when we have the evidence that our treatments are harmful? Because we all seem to go along to get along.

The 2015 ACLS guidelines are not all bad, but they clearly do not encourage withholding harmful treatments until we have obvious evidence of harm. Should we assume that a treatment works just because the explanation appeals to some experts as much as the explanation for blood-letting appealed to the experts when that was in vogue?

This is not medicine. This is a fashion show. Our patients are the ones harmed.
 

Footnotes:

[1] 2015 AHA Classes of Recommendation
2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 2: Evidence Evaluation and Management of Conflicts of Interest
Development of the 2015 Guidelines Update
Circulation.
2015; 132: S368-S382
Free Full Text from Circulation.

[2] Tobacco smoke enemas
Ghislaine Lawrence
Volume 359, No. 9315, p1442,
20 April 2002
Lancet
Abstract with link to Full Text PDF download.

[3] Ever tried smoking?
by Chris Nickson
Life in the Fast Lane
Article

Morrison LJ, Gent LM, Lang E, Nunnally ME, Parker MJ, Callaway CW, Nadkarni VM, Fernandez AR, Billi JE, Egan JR, Griffin RE, Shuster M, & Hazinski MF (2015). Part 2: Evidence Evaluation and Management of Conflicts of Interest: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 132 (18 Suppl 2) PMID: 26472990
 

Lawrence, G. (2002). Tobacco smoke enemas The Lancet, 359 (9315) DOI: 10.1016/S0140-6736(02)08339-3

.