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

- Rogue Medic

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.

 

.

Drug Shortages Affecting EMS


 

The most recent FDA (Food and Drug Administration) listing of drug shortages, editing out the many cancer drugs, and other non-EMS drugs, includes the following:
 

Generic Name or Active Ingredient                                                 Status
 

Albuterol Sulfate Inhalation Solution (0.5%)         Resolved

This is important, but one way of dealing with a nebulized albuterol shortage is to alternate albuterol with nebulized saline. this prevents giving too much albuterol to the patient who is maintaining a reasonable oxygen saturation and keeping the airway humidified.
 

Atropine Sulfate Injection         Currently in Shortage

We should be accumulating atropine, since we no longer use atropine for asystole. Atropine maintains its strength, even when stored for extended periods, so we should only discard atropine when there is contamination.
 

Calcium Chloride Injection, USP         Currently in Shortage

Calcium (chloride or gluconate) appears to be the best drug for hyperkalemia. We are fortunate in EMS to not have to deal with sodium polystyrene (Kayexalate), which is just a means of creating the appearance of clostridium difficlie. Senna glycoside (ex-lax) can be just as effective at causing diarrhea and anything that causes diarrhea will cause some removal of potassium.
 

Calcium Gluconate Injection         Currently in Shortage

See above.
 

Cromolyn Sodium Inhalation Solution, USP         Currently in Shortage
 

Dexamethasone Sodium Phosphate Injection         Resolved
 

Dextrose 50% Injection         Currently in Shortage

We should be using 10% dextrose, rather than 50%, but we are slow to learn from our mistakes.

Comment on 10% Dextrose vs 50% Dextrose.
 

Epinephrine Injection, 0.1 mg/mL         Currently in Shortage

Maybe we will be using less epinephrine after the results of the Paramedic2 trial are published. I expect that some patients will be shown to benefit from epinephrine in cardiac arrest. I hope that the results will help us to identify which patients benefit from epinephrine in cardiac arrest and which patients have worse outcomes because of receiving epinephrine in cardiac arrest. I don’t really expect these answers, because we seem to be trying to avoid asking appropriate questions about drug treatment.
 

Epinephrine Injection, 1 mg/mL         Resolved
 

Fentanyl Citrate (Sublimaze) Injection         Currently in Shortage

There are other drugs that are effective for pain management. Hydromorphone (Dilaudid) can be used safely by EMS.
 

Labetalol Hydrochloride Injection         Currently in Shortage
 

Lidocaine Hydrochloride (Xylocaine) Injection         Currently in Shortage

EMS should have disposed of our supplies of lidocaine and amiodarone following the ALPS and PROCAMIO.

Dr. Kudenchuk is Misrepresenting ALPS as ‘Significant’

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

Lidocaine Hydrochloride (Xylocaine) Injection with Epinephrine         Currently in Shortage

This is more for wilderness EMS, than urban.
 

Methylprednisolone Sodium Succinate for Injection, USP         Currently in Shortage

This is an important drug for reactive airway conditions.
 

Nitrous Oxide, Gas         Currently in Shortage

A lot of people are uncomfortable with the idea of using nitrous oxide, but it is safe – as long as there is good circulation of fresh air.
 

Pantoprazole (Protonix) Powder for Injection         Currently in Shortage

This is usually not the part of allergic reaction that EMS treats, but it can be helpful.
 

Potassium Chloride Injection         Currently in Shortage

Not generally prehospital EMS, but interfacility.
 

Procainamide Hydrochloride Injection, USP         Currently in Shortage

This is an antiarrhythmic drug that actually works, but we tend to avoid it out of a lack of understanding and a lack of familiarity with the evidence.
 

Promethazine (Phenergan) Injection         Currently in Shortage
 

Ranitidine Injection, USP         Currently in Shortage
 

Rocuronium Bromide Injection         Currently in Shortage

Succinylcholine may end up as a shortage because of the rocuronium shortage.
 

Sodium Bicarbonate Injection, USP         Currently in Shortage

After calcium, sodium bicarbonate can be effective for hyperkalemia. Flush the line. Even better, use a different line for these incompatible medications.

We should not be wasting sodium bicarbonate in cardiac arrest patients, since it is not going to do anything to make things better, but it will make it more difficult to get sodium bicarbonate for the patients who can actually benefit.
 

Sodium Chloride 0.9% Injection Bags         Currently in Shortage

Do we really need to start as many IV (IntraVenous) lines with a drip?
 

Sodium Chloride 23.4% Injection         Currently in Shortage

Also effective for hyperkalemia, since it is the sodium that moves the potassium, not any myth of alkalinizing the patient.

.

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

.

‘Narcan by Everyone’ Does Not Seem to be Such a Good Idea

 
Now that we have almost everyone giving naloxone (Narcan) to suspected heroin overdose patients, the fatality rate must have dropped. The panacea must have worked. My criticism of the Narcan by Everyone programs must have made me a laughing stock.[1],[2],[3],[4]

No.

Does that mean that I am a prophet and that you should worship me?

No.

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.

I have been pointing out that the plans assumed that there would not be any unintended consequences. I explained what some of the unintended consequences would be. Many people used logical fallacies to justify ignoring the likelihood of unintended consequences. The reasonable thing to do would have been to study the implementation, so that problems would be noticed quickly.

Misdiagnosis – giving naloxone to people who have a change in level of consciousness that is not due to an opioid (heroin, fentanyl, carfentanyl, . . . ) overdose.
 

Six of the 25 complete responders to naloxone (24%) ultimately were proven to have had false-positive responses, as they were not ultimately given a diagnosis of opiate overdose. In four of these patients, the acute episode of AMS was related to a seizure, whereas in two, it was due to head trauma; in none of these cases did the ultimate diagnosis include opiates or any other class of drug overdose (which might have responded directly to naloxone). Thus, what was apparently misinterpreted as a response to naloxone in these cases appears in retrospect to have been due to the natural lightening that occurs with time during the postictal period or after head trauma.[5]

Bold highlighting is mine.

 

Failure to ventilate – not providing ventilations to a patient who is not breathing. These patients are often hypoxic (don’t have enough oxygen to maintain life) and hypercarbic (have too much carbon dioxide to maintain life). If the patient is alive, ventilation should keep the patient alive, even if naloxone is not given or if the naloxone is not effective. If the patient is dead, giving naloxone will not improve the outcome.[6]

But . . . But . . . But . . . Narcan is the miracle drug!
 


Image credit.
 

In Akron, a small Ohio city, medical examiner Dr. Lisa Kohler has seen over 50 people die of carfentanil since July. Police Lieutenant Rick Edwards says his officers are “giving four to eight doses of [naloxone] just to get a response.”[7]

 

“Every day our paramedics start CPR on someone surrounded by empty naloxone vials… people give the naloxone and walk away,” she (Ambulance Paramedics of BC president Bronwyn Barter) said in an interview.[7]

 

Where should we start?
 

All patients considered to have opioid intoxication should have a stable airway and adequate ventilation established before the administration of naloxone.[8]

 

We keep making excuses for solutions that are neat, plausible, and wrong. Why don’t we start acting like responsible medical professionals and do what is best for our patients?
 

Thank you to Gary Thompson of Agnotology for linking to this for me.

Go read Response: ‘What happens when drugs become too powerful for overdose kits’

Footnotes:

[1] The Myth that Narcan Reverses Cardiac Arrest
Wed, 12 Dec 2012 20:45:29
Rogue Medic
Article

[2] Should Basic EMTs Give Naloxone (Narcan)?
Fri, 27 Dec 2013 14:00:22
Rogue Medic
Article

[3] Is ‘Narcan by Everyone’ a Good Idea?
Tue, 03 Jun 2014 23:00:38
Rogue Medic
Article

[4] Is First Responder Narcan the Same as First Responder AED?
Wed, 18 Jun 2014 17:15:43
Rogue Medic
Article

[5] Acute heroin overdose.
Sporer KA.
Ann Intern Med. 1999 Apr 6;130(7):584-90. Review.
PMID: 10189329 [PubMed – indexed for MEDLINE]

[6] The Kitchen Sink Approach to Cardiac Arrest
Mon, 16 Feb 2015 16:00:53
Rogue Medic
Article

[7] What Happens When Drugs Become Too Powerful for Overdose Kits?
Dr. Blair Bigham
Oct 4 2016, 12:11pm
Article

[8] Naloxone for the Reversal of Opioid Adverse Effects
Marcia L. Buck, PharmD, FCCP
Pediatr Pharm. 2002;8(8)
Medscape (free registration required?)
Clinical Uses

.

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

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Dr. Kudenchuk is Misrepresenting ALPS as ‘Significant’

ResearchBlogging.org
 

The results of ALPS (Amiodarone, Lidocaine, Placebo Study) are clear. There is no statistically significant difference in cardiac arrest outcomes with amiodarone or lidocaine, when compared with placebo.
 

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.[1]

 

This study was very well done, but it was not designed to provide valid information about the effects of amiodarone or lidocaine on witnessed arrests or on EMS Witnessed arrests. Maybe the authors were overconfident.

In resuscitation research, we have abundant evidence that overconfidence is much more common than improvements in outcomes. There is no study that has shown an improvement in neurologically intact survival to discharge with any drug. Leaving the hospital with a working brain is the result that matters most to patients. We give drugs because we have too much confidence in the drugs and we are treating our confidence, not because we are doing anything to benefit the patients.
 

I WANT TO BE DECEIVED version of Domenichino, Virgin and Unicorn 1 copy
 

In ALPS there was a subgroup that might have reached statistical significance, but the researchers never determined what would be statistically significant when setting up the study, so these results are merely post hoc data mining (fitting the numbers to allow for a positive spin).

This is the Texas sharpshooter fallacy. The Texas sharpshooter shoots at the side of a barn, then draws targets around the bullet holes so that the the bullet holes are in the bull’s eyes.
 


 

The Texas sharpshooter didn’t shoot at any target, but he went back later and made it look like he hit the center of the target, because he drew the target around the bullet holes. Science requires that we state our hypotheses ahead of time, so that scientists are kept honest. Science requires that we calculate statistical significance ahead of time, especially for secondary outcomes/subgroup analysis, which may mean decreasing the p value to less than 0.03, or to less than 0.01, or even lower to reach statistical significance, so that scientists are kept honest. You are not permitted to bet on the outcome of a horse race that is already in progress for the same reason.

Why do we need to keep scientists honest? Because, as Dr. Peter Kudenchuk unintentionally demonstrates, scientists are just as biased as everyone else. Scientists need to follow the rules of science to minimize the influence of prejudices, such as overconfidence. When scientists do not follow these rules, they are just as easily fooled as everyone else and they may use that self-delusion, and their reputation, to fool others. Dr. Oz makes a fortune telling people what they want to hear about treatments that do not work.

I don’t claim that Dr. Kudenchuk, or even Dr. Oz, is deliberately fooling others, only that they have fooled themselves and are trying to convince others that their prejudices are accurate representations of reality. Here is what Dr. Kudenchuk has been telling people –
 

Researchers have confirmed that certain heart rhythm medications, when given by paramedics to patients with out-of-hospital cardiac arrest who had failed electrical shock treatment, improved likelihood of patients surviving transport to the hospital.[2]

 

The researchers have not confirmed any such thing.

If Dr. Kudenchuk wants to study whether amiodarone or lidocaine or both improve outcomes for witnessed cardiac arrest patients, or for EMS witnessed cardiac arrest patients, he needs to set up a study with all of the criteria for a positive result specified before the start of the study, because this study did not. The study explicitly states this, so Dr. Kudenchuk should be able to just read the study and see that he is wrong. Here is another statement that contradicts the information that was published.
 

Two groups of patients were pre-specified by the study as likely to respond differently to treatment: those with a witnessed cardiac arrest and those with an unwitnessed arrest. When it was originally designed, the study predicted that because patients with witnessed cardiac arrest are recognized and treated sooner, they would more likely be responsive to effective treatments than unwitnessed arrests. When first discovered, patients with an unwitnessed arrest are more likely to have already sustained irreversible organ damage resulting from a longer “down time” and less likely to respond to any treatment. This is precisely what was seen in the study – a statistically significant 5% improvement in survival to hospital discharge in witnessed arrests, and no effect from the drugs in unwitnessed arrests.[3]

 

Why does the published version of the paper contradict Dr. Kudenchuk? One of our biases is to remember things differently from the way things really happened. This is why eyewitness testimony is so often wrong. Here is what the published paper states about the witnessed arrest results.
 

We observed an interaction of treatment with the witnessed status of out-of-hospital cardiac arrest, which is often taken as a surrogate for early recognition of cardiac arrest, a short interval between the patient’s collapse from cardiac arrest and the initiation of treatment, and a greater likelihood of therapeutic responsiveness. Though prespecified, this subgroup analysis was performed in the context of an insignificant difference for the overall analysis, and the P value for heterogeneity in this subgroup analysis was not adjusted for the number of subgroup comparisons. Nonetheless, the suggestion that survival was improved by drug treatment in patients with witnessed out-of-hospital cardiac arrest, without evidence of harm in those with unwitnessed arrest, merits thoughtful consideration.[1]

 

The authors did not adjust the p value, so the authors do not claim that the witnessed cardiac arrest results are statistically significant. They only state that these results merit thoughtful consideration. In other words, if we want to claim this hypothesis is true, we need to set up a study to actually examine this hypothesis.

One earlier study (also by ROC – the Resuscitation Outcomes Consortium) even has similar results.[4],[5] These results are also not statistically significant, but suggest that with larger numbers the results might be significant. So why did the authors set up such a small study? Overconfidence and an apparent lack of familiarity with their own research.
 


 

The Seattle phenomenon (they claim that their resuscitation rate is the highest in America) seems to be due to excellent bystander CPR rates (apparently the highest in America), but that is only good enough for them to be experts on improving bystander CPR rates. The rest is probably due to defibrillation and chest compressions, which are the only prehospital interventions demonstrated to improve neurologically intact survival.

Why does a bystander CPR specialist focus on drugs? Overconfidence and an apparent lack of understanding of the resuscitation research. Dr. Kudenchuk preaches like Timothy Leary about the benefits of drugs and with just as little evidence. We should give appropriate credit for Dr. Kudenchuk’s work on CPR, but we should not mistake that for a thorough understanding of the resuscitation research, even the research with his name attached.
 

A new podcast reviews ALPS. Dominick Walenczak does not notice the mistakes of Dr. Kudenchuk, but he is not one of the researchers, so that is easy to overlook. The rest of the podcast is excellent. Listen to it here.
 

Episode 8: Conquering the ALPS (Study)
CritMedic – Critical Care Paramedicine Podcast
Dominick Walenczak
April 7, 2016
Podcast page
 

Footnotes:

[1] 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 Apr 4. [Epub ahead of print]
PMID: 27043165

Free Full Text from NEJM

[2] Antiarrhythmic drugs found beneficial when used by EMS treating cardiac arrest
Press release
For Immediate Release:April 4, 2016
NHLBI (National Heart Lung and Blood Institute)
Press release

[3] Dr. Kudenchuk: Study reveals exciting news about cardiac arrest treatment
Lindsay Bosslet
18 hours ago
Public Health Insider
Article

[4] Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium.
Glover BM, Brown SP, Morrison L, Davis D, Kudenchuk PJ, Van Ottingham L, Vaillancourt C, Cheskes S, Atkins DL, Dorian P; Resuscitation Outcomes Consortium Investigators.
Resuscitation. 2012 Nov;83(11):1324-30. doi: 10.1016/j.resuscitation.2012.07.008. Epub 2012 Jul 31.
PMID: 22858552 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

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

 
Kudenchuk, P., Brown, S., Daya, M., Rea, T., Nichol, G., Morrison, L., Leroux, B., Vaillancourt, C., Wittwer, L., Callaway, C., Christenson, J., Egan, D., Ornato, J., Weisfeldt, M., Stiell, I., Idris, A., Aufderheide, T., Dunford, J., Colella, M., Vilke, G., Brienza, A., Desvigne-Nickens, P., Gray, P., Gray, R., Seals, N., Straight, R., & Dorian, P. (2016). Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest New England Journal of Medicine DOI: 10.1056/NEJMoa1514204

 

Glover BM, Brown SP, Morrison L, Davis D, Kudenchuk PJ, Van Ottingham L, Vaillancourt C, Cheskes S, Atkins DL, Dorian P, & the Resuscitation Outcomes Consortium Investigators (2012). Wide variability in drug use in out-of-hospital cardiac arrest: A report from the resuscitation outcomes consortium. Resuscitation PMID: 22858552

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Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest

ResearchBlogging.org
 

I wrote about the start of the ALPS (Amiodarone, Lidocaine, Placebo Study) in 2012[1] and the results are now in.
 

In this randomized, double-blind, placebo-controlled, prehospital trial, we found that treatment with amiodarone or lidocaine did not result in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome at discharge than the rate with placebo after out-of-hospital cardiac arrest caused by shock-refractory initial ventricular fibrillation or pulseless ventricular tachycardia. There were also no significant differences in these outcomes between amiodarone and lidocaine.[2]

 

The primary endpoint is that amiodarone does not improve survival to discharge and neither does lidocaine. However, the results are a bit more complicated than just throw out the drugs.

Two subgroups did have better outcomes, but as the authors appropriately point out, subgroup analysis requires a higher level of significance, because you are essentially getting extra shots at the goal for every subgroup. The more subgroups we have, the more likely that one of them will reach the p value of <0.05.  

We observed an interaction of treatment with the witnessed status of out-of-hospital cardiac arrest, which is often taken as a surrogate for early recognition of cardiac arrest, a short interval between the patient’s collapse from cardiac arrest and the initiation of treatment, and a greater likelihood of therapeutic responsiveness. Though prespecified, this subgroup analysis was performed in the context of an insignificant difference for the overall analysis, and the P value for heterogeneity in this subgroup analysis was not adjusted for the number of subgroup comparisons. Nonetheless, the suggestion that survival was improved by drug treatment in patients with witnessed out-of-hospital cardiac arrest, without evidence of harm in those with unwitnessed arrest, merits thoughtful consideration.[2]

 

Another important point is that the possibility of an effect was probably overestimated by the researchers. A much larger study would be needed to show this smaller effect.
 

Finally, the point estimates of the survival rates in the placebo group and the amiodarone group differed less than anticipated when the trial was designed, which suggests that the trial may have been underpowered. If amiodarone has a true treatment effect of 3 percentage points, approximately 9000 patients across the three trial groups would be needed to establish this difference in outcome with 90% power. Though seemingly small, a confirmed overall difference of 3 percentage points in survival with drug therapy would mean that 1800 additional lives could be saved each year in North America alone after out-of-hospital cardiac arrest.[2]

 

How could the top doctors in the field be so far off in their estimate?

We dramatically overestimate the good we do and we dramatically underestimate the harm we do. We are unreasonably optimistic.
 

Monty Hall problem vs medicine 1
Image credit.
 

We still do not have any evidence that anything other than compressions and defibrillation improve outcomes for adult patients with cardiac arrest, but we insist on using these treatments, because we believe in magic pills.

Should we consider giving amiodarone or lidocaine to only witnessed cardiac arrest patients or only EMS-witnessed cardiac arrest? Yes, but that is really just limiting the use of these drugs to those who have some weak evidence of benefit.

We are already giving too many treatments to too many patients, based on too little evidence.

That is assuming that we have any valid evidence at all. Medical ethics appears to be only for other people, because we don’t care enough to find out if our treatments work. We just make excuses for the harm we cause to our patients.

Footnotes:

[1] What Will Be the Next Standard Of Care We Eliminate
Wed, 28 Mar 2012
Rogue Medic
Article

[2] Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest
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 Apr 4. [Epub ahead of print]
PMID: 27043165

Free Full Text from NEJM

 
Kudenchuk, P., Brown, S., Daya, M., Rea, T., Nichol, G., Morrison, L., Leroux, B., Vaillancourt, C., Wittwer, L., Callaway, C., Christenson, J., Egan, D., Ornato, J., Weisfeldt, M., Stiell, I., Idris, A., Aufderheide, T., Dunford, J., Colella, M., Vilke, G., Brienza, A., Desvigne-Nickens, P., Gray, P., Gray, R., Seals, N., Straight, R., & Dorian, P. (2016). Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest New England Journal of Medicine DOI: 10.1056/NEJMoa1514204

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