Get on the Haloperidol Wagon

For many years, droperidol has been a valuable tool for nausea, vomiting, headache, and termination of psychosomatic contributors to patient distress.  Alas, droperidol availability has been markedly diminished in the U.S. in recent years, depriving us of one of our most efficacious management tools.

But, we still have plenty of haloperidol.  So, let’s use it for the same purposes.

What’s the difference between droperidol and haloperidol?  From a pharmacologic standpoint, the metabolism of haloperidol to active and toxic metabolites is far more complex than droperidol.  But, from a clinical standpoint, there is very little difference – they are both butyrophenones with similar receptor antagonism.

This paper is not terribly robust, but compares the use of haloperidol against metoclopramide for acute headache in the Emergency Department.  After pre-treatment with 25mg of IV diphenhydramine, either 10mg of IV metoclopromide or 5mg IV haloperidol was administered in double-blinded fashion.  Owing to the small sample size of 64 patients, all measures of pain reduction, nausea, restlessness, and sedation were statistically equivalent between groups, although 8 of 33 of the metoclopromide cohort required rescue medications, compared with just 1 of 31 in the haloperidol cohort.  However, telephone follow-up of patients following discharge also found the sedation and restlessness symptoms were more persistent in the haloperidol group compared with metoclopramide.

But, regardless, most of these differences – or lack thereof – is all small sample-size theatre.  However, in addition to anachronistic anesthesia research into post-operative nausea and vomiting, this reasonably reinforces what we already know: if you’ve been suffering the loss of droperidol, you ought now be using haloperidol.

“A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department.”

What Does EAST Say About ED Thoracotomy?

The resuscitative emergency thoracotomy in trauma – rarely used and rarely successful.  However, for appropriately selected patients in extremis, such timely intervention may be literally life-saving.

The downside: resource utilization associated with saving the neurologically unsalvageable and the risks to providers associated with the procedure.

This is an evidence synthesis performed by a group of authors affiliated with the Eastern Association for the Surgery of Trauma, addressing the topic of patient selection for Emergency Department thoracotomy.  Screening 2,152 studies to review, ultimately, 72, these authors review a total of 10,238 patient encounters in which patients underwent ED thoracotomy.  This results in six recommendations for patients presenting pulseless to the Emergency Department after trauma:
  • In patients with signs of life after penetrating thoracic injury: strongly recommend EDT.
  • In patients without signs of life after penetrating thoracic injury: conditionally recommend EDT.
  • In patients with signs of life after penetrating extra-thoracic injury: conditionally recommend EDT.
  • In patients without signs of life after penetrating extra-thoracic injury: conditionally recommend EDT.
  • In patients with signs of life after blunt injury: conditionally recommend EDT.
  • In patients without signs of life after blunt injury: conditionally recommend against EDT.
However, before you start rummaging around in your toolbox for the rib spreaders, it should be recognized the conditional recommendations – except in penetrating thoracic injury – result in absolute intact survival increases only in the range of 20-40 patients per 1000.  Therefore, unless you’re working in a setting of maximal effectiveness and experience, it is unlikely you’ll see even this small absolute benefit.  And, even in the setting with the strong recommendations and excess intact survival benefits of 100 patients per 1000 – your individual hospital system, based on institutional support and experience level of the providers involved, will need to develop specific policies for these situations.  Even though many ED physicians are capable of performing these heroic procedures based on their training, the remaining ED staff and systems in place may not be adequate to support the intervention.

“An evidence-based approach to patient selection for emergency department thoracotomy: A practice management guideline from the Eastern Association for the Surgery of Trauma”

New AHA/ASA Endovascular Guidelines

How did I find out about the final publication of the new AHA/ASA Guidelines regarding endovascular intervention in acute ischemic stroke?  I received unsolicited e-mail spam from their representative at a public relations firm, gushing about the technology and offering to put me in touch with their generously available expert.

Before getting into the content, the standard housekeeping exercise regarding declared financial conflicts of interest:
  • Dr. Powers: None
  • Dr. Derdeyn: Microvention, Penumbra, SILK Road, Pulse Therapeutics
  • Dr. Biller: None
  • Dr. Coffey: None
  • Dr. Hoh: None
  • Dr. Jauch: Covidien, Genentech, Penumbra, Stryker
  • Dr. K. Johnston: Roche/Genentech
  • Dr. S. Johnston: None
  • Dr. Khalessi: Covidien, Microvention, Penumbra, Sequent, Codman, Stryker
  • Dr. Kidwell: None
  • Dr. Meschia: None
  • Dr. Ovbiagele: None
  • Dr. Yavagal: Covidien/Medtronic, Penumbra
Yes, Virginia, despite the worldwide availability of methodologists and clinicians to review evidence for guidelines, the AHA/ASA were unable to compose such content absent individuals with professional and financial relationships to the manufacturers of the products involved.  Another sad failure regarding the Institute of Medicine’s Guidelines We Can Trust.

So, what’s wrong with these guidelines?  I’ve written and published multiple times regarding endovascular intervention, and it’s a therapy I’m excited about.  For once, the theory and the practice seem to demonstrably align.  The new stent retrievers seem to substantially benefit patients with viable tissue behind a clot – whether because of collateral circulation, retrograde flow, or semi-permeable occlusion – and have the clot safely removed in a timely fashion.

But, that isn’t everyone.  The most successful trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – were all designed to intervene on a narrow population with salvageable tissue.  The less successful, but still positive, trials – REVASCAT and MR-CLEAN – generally intervened based only on broadly eligible angiographic occlusions.  Such a strategy will definitely catch the few patients with salvageable tissue, but also involves significant resource utilization and procedural risk conferred upon those without the possibility of benefit.

However, that’s what these guidelines suggest – to treat all-comers presenting within six hours, discarding the use of tissue-based criteria for intervention.  The benefit to the corporations involved is obvious, as routine angiography – let alone rapid perfusion calculation – is not widespread.  Without the broadest possible criteria, many centers might not refer patients for intervention.  Given the choice between maximizing yield of this intervention and generating profits for their financial and professional affiliates, the authors of this guideline have chosen the latter.

Not only that, these authors give this recommendation the strongest possible Class I and Level A qualifiers.  The body of the text states this is a result of the findings of the five aforementioned trials published at the time this was drafted.  Unfortunately, from just a simple methodologic standpoint, the authors have developed complete amnesia regarding the entire prior body of negative evidence regarding endovascular intervention – nor acknowledged the open-label nature of these trials stopped early, nor other threats to bias.

So, yet again – from the folks who gave us flawed tPA guidelines and “quality measures” – a guideline we can’t trust.  The Society for Academic Emergency Medicine was solicited to endorse this guideline several months ago, and I was involved in the review process at that time.  Unfortunately, none of the concerns expressed at that time appear to have been addressed – and as such, SAEM is not included among the professional societies endorsing this guideline.

Endovascular therapy is coming.  And, unfortunately, it is certainly going to be coming to many more than for whom appropriate.

“2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment”

The New, Improved, ACEP Clinical Policy for tPA in Stroke

Released with minimal fanfare, approved by the ACEP Board of Directors on June 24th, the revised ACEP Clinical Policy regarding the use of TPA for acute ischemic stroke has gone final.

It is, of course, a vast improvement over the 2012 version – but has, unfortunately, changed for the worse since the draft was posted.

The highlights:

  • The Level A suggestion to consider the risk of ICH with tPA administration has been eliminated.  It has been moved, nonsensically into the Level B recommendations for offering tPA – when, frankly, it’s the only consistent finding across all the evidence.
  • The Level B recommendation in which tPA “may be given” within 3 hours has been strengthened to “should be offered and may be given”.  Obviously, a profound difference.
  • The Level B recommendation for 3-4.5 hours remains unchanged, based on only one flawed piece of Class II evidence (ECASS III), and conflicting Class III evidence (ATLANTIS, IST-3, meta-analyses).
  • The Level C recommendation to engage in shared decision-making now states “when feasible”, which is obviously open to interpretation.
  • No further clarification of “carefully selected patients” or “systems … in place to safely administer the medication” is provided.

Some wins, some losses.  Obviously, the shared decision-making supporting any “offer” of tPA can be very different, depending on an individual clinicians’ interpretation of the evidence – and it is nice to see the prior COI-infested husk of rotten guidelines finally, officially, tossed on the compost heap.  Let us hope (irrationally, of course) the efforts underway in the United Kingdom spur further, independent, investigation with which to better understand and individualize the risks and benefits of treatment with tPA.

“Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department”

It’s the Flu! It’s Not the Flu!

Every year, influenza season travels the globe, led by the four horsemen of the apocalypse, bringing toys and good cheer to obedient little girls and boys.  Unfortunately, this very same influenza contributes to hundreds of thousands of hospitalizations and tens of thousands of deaths in the U.S. alone.  And, despite such ubiquity, clinicians are utterly inept at rapid, accurate diagnosis.

This small study reviews the diagnostic performance of clinicians at a single hospital during the influenza season of 2012-13.  A convenience sample of 270 patients presenting with any history of respiratory or febrile illness were screened and swabbed for influenza, and the results of eventual PCR testing were compared with the sensitivity of the CDC definition of “influenza-like illness” and accuracy of subsequent clinical diagnosis.

The highlights:
  • 42 of 228 patients were positive for influenza.
  • Only 40 out of the entire cohort of 270 met the CDC definition of ILI, a cough or sore throat coupled with fever.
  • 15 of influenza positive patients were thought to have influenza by the treating clinician, as well as 50 of the influenza-negative.
  • A third of actual influenza patients received an antiviral, while half were treated with antibiotics.
Certainly not a paragon of medical prowess.

The authors, unfortunately, use their data as a platform for wickedness.  In the context of inadequate diagnostic skill, the authors call for improved rapid diagnostic tools – such as those manufactured by the study sponsor.  Furthermore, the entire need for such rapid tools is predicated on the assumption of benefit from antiviral therapy – which is also espoused by the authors, who have undeclared ROI with Roche.

“Clinical diagnosis of influenza in the ED”

Let’s Reverse: Dabigatran

‘Round EMLoN headquarters, we’re big fans of a few medications.  Oseltamivir.  Ticagrelor.  Alteplase.  And, finally, dabigatran.  After all, a blog needs content – and controversy begets content.  Dabigatran, if you need any reminder, is an irreversible direct thrombin inhibitor, whose sponsored trial results continue to receive “updates” for additional "newly discovered" adverse events.  It was also subject to a $650M legal settlement related to its under-emphasized risks to patients.

This pair of articles, presumably, addresses one critical issue with dabigatran – lack of effective reversal options.  The first, published in the Lancet, relates to controlled pharmacokinetics of the monoclonal antibody fragment binding dabigatran, idarucizumab.  Healthy volunteers, all men, were loaded with four days of dabigatran, and the four cohorts of 12 participants each were assigned to receive various doses of idarucizumab.  By every measure of coagulation function, the two highest-dose cohorts effectively reversed dabigatran.  However, given the small number of participants, it is impossible to claim idarucizumab is safe, even in the setting of only a handful of adverse events.  Entertainingly, almost half the research participants complained of at least two subjective adverse symptoms during the dabigatran load.

The second article, in the NEJM, is bizarrely an interim analysis of the first 90 patients enrolled of a planned 300 patient phase III study of idarucizumab.  The appropriateness of reporting a fraction of enrollment from a sponsored phase III study, let alone in the NEJM, is unfathomable.  Regardless, the study enrolled patients requiring urgent reversal for life-threatening bleeding or urgent surgery.  As in the Lancet publication, administration of idarucizumab reversed coagulation parameters almost instantly.  There was, however, a small rebound in anticoagulation and dabigatran activity approximately 12 hours after the initial dose, suggesting a limit to the durability of the reversal in some patients.

Clinically, outcomes are a little difficult to evaluate without a specific control or comparison group.  The patients generally did poorly – 18 of 90 died – but, probably as expected in an elderly, anticoagulated cohort confronted by acute medical issues.  In the patients with life-threatening bleeding, time to resolution was 11.4 hours following administration of idarucizumab – not dissimilar to the use of prothrombin-concentrate complexes for warfarin or Factor Xa inhibitors.  Of course, nearly a quarter of patients were enrolled despite what turned out to be normal initial coagulation profiles – inflating any measure of apparent reversal or bleeding time cessation.  And, again, in such a small sample, without a control population, no obvious statement on safety may be made, even in the setting of just a handful of thromboembolic events.

In short, Boehringer Ingelheim, having scattered the nails in the street, is almost ready to sell you new tires.  Certainly, whatever the adverse effects of idarucizumab, it is better than uncontrolled bleeding – and will doubtless be a welcome addition to many formularies.  The costs, however, will be quite unwelcome – and without a method to readily detect dabigatran activity in the clinical setting, this expensive antidote will likely be uselessly given to many patients without the possibility of benefit, as seen in a quarter of patients here.

Finally, as a bit of an aside, the accompanying editorial is penned by a physician who receives consulting fees from both Boehringer Ingelheim and Portola specifically for his work on the antidotes for dabigatran and the Factor Xa inhibitors.  Is it really so difficult to identify qualified editorialists without the most egregious possible COI?

“Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy  male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial”

“Idarucizumab for Dabigatran Reversal”