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

- Rogue Medic

Droperidol, QT prolongation, and sudden death – what is the evidence – Part I


ResearchBlogging.org
Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

I am continuing to look for evidence that droperidol deserves to be given a scarlet letter black box warning. The authors of this literature review take a look at several articles and some case studies.

Because the outcome of interest, sudden death caused by torsades de pointes, is uncommon and difficult to assess, QT prolongation has become a surrogate marker for potential arrhythmogenicity and is therefore commonly used in research and by regulatory agencies.18[1]

Surrogate endpoints are great for making it seem that we know more than we actually do know. When there is not enough information, surrogate end points are a way of saying, If this belief is true, and this other belief is also true, then Treatment Z is safe (or dangerous), or saves X number of lives per year (or kills X number of patients who otherwise would have been expected to live).

The example that I repeatedly use is the Cardiac Arrhythmia Suppression Trial,[2] which ended up demonstrating that treatment based on the surrogate endpoint of eliminating PVCs (Premature Ventricular Contractions) because they are associated with a higher rate of death actually resulted in tens of thousands of extra deaths.[3] That is the difference between looking at surrogate endpoints (making assumptions about death rates) and looking at actual death rates.

a consistent relationship between the length of the QT interval and the risk of torsades de pointes or sudden death is not clearly established and might vary from drug to drug and from individual to individual. Hundreds of drugs are known to prolong the QT interval, with widely variable degrees of evidence for clinical dysrhythmias.16,17 [1]

What did the authors find?

Because of the small number of studies and articles identified, we were unable to perform a true systematic review (ie, meta-analysis)22 [1]

First, what does the FDA (Food and Drug Administration) label recommend as the dosage of droperidol?

Adult Dosage: The maximum recommended initial dose of droperidol is 2.5 mg I.M. or slow I.V. Additional 1.25 mg doses of droperidol may be administered to achieve the desired effect. However, additional doses should be administered with caution, and only if the potential benefit outweighs the potential risk.[4]

As if that caution does not apply to the use of every medication.

In one surgical study of 40 patients receiving three weight-based doses of droperidaol, which if given to a 70 kg adult, would be doses of 7 mg, 12.25 mg, and 17.5 mg. Much higher than 2.5 mg. Yes, this is surgery, so what does the FDA recommend about surgical dosing?

Dosage should be individualized. Some of the factors to be considered in determining dose are age, body weight, physical status, underlying pathological condition, use of other drugs, the type of anesthesia to be used, and the surgical procedure involved.[4]

They certainly were not excluding surgery from their dosing recommendation.

QTc interval prolongation occurred within 1 minute of injection and did not increase with time. Prolongation of the median QTc interval occurred by 37, 44, and 59 ms, respectively, in a dose-dependent fashion; this was also statistically significant (P<.003). [1]

Of these patients receiving very high doses, how many died?

No dysrhythmias developed. [1]

There was a lower dose surgical study and a long-term psychiatric study. Again, there was QT prolongation, but no arrhythmia (dysrhythmia and arrhythmia are synonyms).

And there is one ED (Emergency Department) retrospective study –

Over a 4-year period, 15,374 patients received 18,020 doses of droperidol. Of the 682 patients who had an ECG performed after droperidol administration, 14 (3.1%) had prolonged QT intervals (defined as >480 ms) without evidence of any bundle branch block. Four of the 14 patients had previously documented prolonged QT intervals not associated with droperidol use. A control group (n=100) who had ECGs performed without the administration of droperidol had a similar incidence of prolonged QT intervals (4.0%). [1]

The patients who received droperidol appear to have been less likely to develop QT segment prolongation. With droperidol – 3.1% had QT prolongation. Without droperidol – 4.0% had QT prolongation.

The control group only had 100 patients, so each patient represents 1.0%, but if droperidol is so dangerous there should be more QT prolongation in the droperidol group. Maybe there is something about the way that droperidol is used in the ED that decreases the supposed danger.

These studies do not mean that droperidol is safe, but they do raise questions about the rush to add a black box warning to the droperidol label.

With the black box warning, the FDA essentially says, Lawyers, look here. You don’t have to demonstrate that droperidol is dangerous – we did that for you. Go sue some doctors.

These studies do not support the claim by the FDA that droperidol is dangerous. In Part II, I will continue with the case studies reviewed by the authors.

Footnotes:

[1] Droperidol, QT prolongation, and sudden death: what is the evidence?
Kao LW, Kirk MA, Evers SJ, Rosenfeld SH.
Ann Emerg Med. 2003 Apr;41(4):546-58. Review.
PMID: 12658255 [PubMed – indexed for MEDLINE]

[2] Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.
N Engl J Med. 1991 Mar 21;324(12):781-8.
PMID: 1900101 [PubMed – indexed for MEDLINE]

Free Full Text Article from N Engl J Med with links to Free Full Text PDF download

CONCLUSIONS. There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

[3] C A S T and Narrative Fallacy
Rogue Medic
Article

[4] DROPERIDOL injection, solution
[Hospira, Inc.]

FDA label
DailyMed
Dosage and administration

Kao LW, Kirk MA, Evers SJ, & Rosenfeld SH (2003). Droperidol, QT prolongation, and sudden death: what is the evidence? Annals of emergency medicine, 41 (4), 546-58 PMID: 12658255

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Comments

  1. In addition to droperidol, I fear for the future of ondansetron after the FDA issued a safety alert for it a couple of months ago based on (very few) case reports and some safety information they don’t feel like releasing. They’re also requiring the manufacturer to study its QT-effects. Of note, which I’m sure you’ll pick up immediately, is that they’re not instructing them to study the actual outcomes of patients taking ondansetron, nor even the incidence of Torsades. The FDA just want to know if it prolongs the QT interval and I’m sure that’ll be enough for them to slap a black box warning on it. It’s not the holy grail of anti-emetics, but it seems to work well enough and creating an aura of fear over giving ondansetron would probably be an even bigger step backwards than the current reluctance to use droperidol.

    I can see the commercials already: “Have you or a loved one been given Zofran? You may be entitled to a CASH SETTLEMENT…”

  2. In September10, 2001 I went to Holycross Hospital in Mission Hills, CA and had been with Nausea for 2 weeks after I got the Droperidol injection I passed out unconscious for hours my body would twitch eyes really bad trauma and ever since then have so much health problems like Ulceratice Colitis and immune system problems, nerve problems. It ruined my life. I was only 20 yrs old when all this happen. So yes bad experience careful not to use it. It was a new shot back then they never told me so I was pretty much a guinea pig

    • Aurora A,

      Droperidol has been used in the US since 1964, so your statement that it was new in 2001 is inaccurate. Droperidol is quite a bit older than you.

      It is unlikely that your ulcerative colitis, or immune system problems, are due to droperidol. Droperidol is used to treat ulcerative colitis and other immune system problems.

      I hope that you are able to control your symptoms, but I do not think that they are due to droperidol.

      .

  3. In my case not safe. Every case is different. They told me it was new. I started by feeling out of it, shaking, eyes twitching, hot cold flashes till I fainted. After that couldn’t walk for some time on a wheel chair lost tremendous weight loss and fear, depression, anxiety and just through out years developed so much health problems. I never had illnesses before that. My records will show you that very healthy before injection. So ho we can DROPERIDOL be safe? If it would of then im pretty sure I would have not gone through all that trauma. Specially when I hace never in my life been allergic to anything. So explain that! So why when I have gone to others Dr.’s no one seems to know that injection?

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