Month: January 2012

Congratulations Michelle Lin!

One of the prominent medical education bloggers – who is really much more than just a great blogger – has been awarded an endowed chair by the University of San Francisco School of Medicine to support her medical education efforts.  This is notable to me because, in the press release, they specifically mention part of the mission of the award specifically notes “keep up her active ‘Academic Life in Emergency Medicine‘ blog”.  


It’s fascinating to see how alternative publication sources and online media are influencing the perception of “academic achievement”.  For instance, my JAMA commentary – a journal with Impact Factor of 30 – has been viewed as full text or downloaded as PDF ~2000 times in the last six months.  This blog, on the other hand, exceeds 400 views per day.  There’s no question which has been more rewarding to my brief career so far.


Again, congratulations to Michelle!  Now she has to do, not just great things, but insanely great things!  (also, go Stanford!)


“Inaugural Academy Chair in Emergency Medicine”
http://medschool2.ucsf.edu/sfgh/news/inaugural-academy-chair-emergency-medicine

Dosing Errors With IV Acetaminophen

As a follow-up to the recent posting regarding IV acetaminophen, this recent article in Pediatrics highlights a few case reports regarding overdose.

According to the authors, the most frequent error in administration when the order is written in milligrams, but the medication order is administered in milliliters – a 10-fold overdose.  All of the patients in this series received n-acetylcysteine infusion, and none appeared to suffer significant liver injury specifically attributed to the overdose.

Another lovely demonstration of the potential for iatrogenic injury in healthcare.  Even the most apparently benign orders can have unanticipated harmful consequences, and a demonstration how intravenous administration is at higher risk.

“Intravenous Acetaminophen in the United States: Iatrogenic Dosing Errors”
http://pediatrics.aappublications.org/content/early/2012/01/18/peds.2011-2345.abstract

Scattering Tacks In The Road

I might be the only one who finds the irony in this, but, at long last, we have a rapid assay to estimate the activity of the new oral direct thrombin inhibitor, dabigatran.

Just to recap, with coumadin, we can measure PT/INR; for heparin, PTT; and for enoxaparin and its brood, (less rapidly) Factor Xa levels.

Now, we have the HEMOCLOT test.

Created and marketed by Boehringer Ingelheim, the manufacturers of dabigatran. (Edit: sorry!  This is not manufactured by Boehringer – they only published this study.  Boehringer is, however, working on a FAB antibody to dabigitran to use as an antidote, however.)

It’s a beautiful piece of business to put a dangerous medication on the market, and then sell the only practical means of monitoring levels.

“Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran.”
http://www.ncbi.nlm.nih.gov/pubmed/22227958

Further Harms of IV Contrast

Radiation: cancer.  Iodinated contrast: renal injury.  Now, iodinated contrast: thyroid dysfunction.

This is a retrospective, matched, case-control study performed in Boston to evaluate any association between CT administration of IV contrast and hyper- and hypothyroidism.  They gathered 178 new-onset hyperthyroid and 213 new-onset hypothyroid cases and statistically matched them in their patient database to euthyroid “controls”.  There were no significant differences between the groups at baseline – although, they don’t match between terribly many clinical variables.

In the end, they find the patients who developed thyroid dysfunction had higher rates of iodinated contrast exposure – primarily from cardiac catheterization, but also from CT scans.  For hyperthyroidism, 6.1% of controls had contrast exposure, whereas 10.7% of their hyperthyroid patients had received contrast.  For hypothyroidism, the numbers are 8.5% controls vs. 12.2% hypothyroid.

It’s a bit of a backwards way to approach it – ideally they’d compare a group receiving iodinated contrast against a group that did not, and observe the incidence of thyroid dysfunction – but it seems that’s not the format of data to which they have access.  In any event, the physiologic basis is reasonable for the association – more data needed to confirm these findings.

Just in case you needed another reason to not order a contrasted CT.

“Association Between Iodinated Contrast Media Exposure and Incident Hyperthyroidism and Hypothyroidism”
http://www.ncbi.nlm.nih.gov/pubmed/22271121

The Harmful Rush To Hypothermia

Mild hypothermia seems to be a clinically useful therapeutic modality for improving neurologic outcomes following return of spontaneous circulation in cardiac arrest.

However, like any emerging therapy, the precise details regarding which patients are most likely to benefit and how to best apply it are still in flux.  This is an Italian registry study that gathered prospective data on all individuals at 17 hospitals who underwent therapeutic hypothermia following cardiac arrest.  The specific question asked by these authors is regarding the optimal time for initiation of hypothermia – using 2 hours after ROSC as their cut-off.

Turns out, they found an association between “early” (< 2 hours to initiation) therapeutic hypothermia and worsened mortality – 47% mortality vs. 23% mortality in the ICU.  This ~20% absolute difference in outcomes holds up over the 6 month follow-up period.  No difference in cerebral performance category is observed between the two groups, although there is a nonsignificant trend towards better CPC in the “early” group.

Hard to know what to actually do with data.  Is early hypothermia truly harmful?  Because of the observational design, it’s hard to say whether there aren’t confounding baseline differences in the “late” population that produces selection bias for higher survival rates.  Or, are the mortality rates higher in the early group because patients are incompletely resuscitated before initiating hypothermia?

More questions, no answers.

“Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: Preliminary observations from the experience of 17 Italian intensive care units”

Helping TPA Help Patients Bleed

TPA for stroke, the miracle therapy that has your Emergency Department shoving people out of the way to drag someone to the CT scanner within 10 minutes of ED arrival, isn’t good enough.  After all, TPA, a “clot-busting” drug that saves dying brain cells by restoring flow, only completely opens up the occluded target vessel within 2 hours in 20 to 30% of the cases, with partial recanalization occurring in up to 60%.  So, the “Texas Biotechnology Corporation” and their equity stakeholders at The University of Texas Health Science Center at Houston have undertaken a project to add additional anticoagulation – argatroban – to TPA in the interests of actually delivering on the “clot-busting” part of the promise.


This is an open-label, pilot safety study enrolling 65 patients.  It was stopped after the first 15 patients for safety review after two experienced intracranial hemorrhage.  After review, it was restarted with additional restrictions on only giving it to milder stroke patients with NIHSS score < 15 (right hemisphere) and < 20 (left hemisphere).  All patients subsequently underwent vascular imaging to assess for recanalization, and the authors reported safety outcomes for events within seven days.


The good news: sorry, no good news.  14 had sustained complete recanalization at 2 hours – 30%.  An additional 12 patients had sustained partial recanalization at 2 hours – 25%.  Of course, this isn’t a controlled trial, so comparison to the recanalization rates demonstrated in existing literature is flawed – but it’s certainly not an order of magnitude better.


But, this wasn’t an efficacy trial, this was a safety trial.  And seven patients met the ultimate safety endpoint of death – 10%.  For intracranial hemorrhage, 19 (29%) patients had ICH, 3 of which were symptomatic. Because NIHSS score predicts bleeding, we can compare to the NINDS trial TPA group, whose median NIHSS score of 14 compared with this trial’s median of 13.  The NINDS trial showed a 10.8% rate of ICH and about 4% mortality at 7 days.


Seems like a treatment with triple the ICH and double the mortality, and that isn’t proven superior, shouldn’t support the conclusion of “potentially safe” or that “Further study of this treatment combination appears warranted.”


“The Argatroban and Tissue-Type Plasminogen Activator Stroke Study : Final Results of a Pilot Safety Study”
http://www.ncbi.nlm.nih.gov/pubmed/22223235

Progress In Combating Publication Bias

…if from abysmally terrible to embarrassingly bad represents progress.

A certain subgroup of trials registered with ClinicalTrials.gov are required to report their results within one year of conclusion of study.  These mandatory-reporting requirements include clinical trials of FDA-approved drugs, devices, or biological agents that have at least one study site in the U.S.  In the future, this will expand to include unapproved drugs.  These requirements, ideally, should help reduce publication and sponsorship bias by ensuring result availability regardless of ability to obtain publication or the desire of a pharmaceutical corporation to publish negative results.

And, so far, these authors discover that it is a tremendous success – trials subject to the mandatory reporting complied with the requirement in twice as many of identified trials as compared with registered trials that were not required to report results.

Unfortunately, twice as many was only 22% compared with 10%.  So, there’s still quite a ways to go before we have full transparency in clinical trial reporting – but it’s “progress.”

“Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study”
http://www.bmj.com/content/344/bmj.d7373

Observation For Anticoagulated Head Trauma

Coming in a future issue of Annals, the Editor’s capsule summary: “Delayed intracranial hemorrhage is common after minor head injury when patients are receiving warfarin. A minimum protocol of 24-hour observation followed by repeated scanning is necessary to detect most such occurrences.”

Now, this isn’t a terribly management agnostic statement.  It does not specifically state this is something we need to start doing – but it rather implies that, if you don’t, you’ll be missing this “common” phenomenon.  It isn’t an alien concept – since 2002, the European Federation of Neurological Societies has recommended admission for observation after minor head trauma – but it’s certainly not the standard of care here.  So, for the Annals editors to state that observation and repeat scanning is “necessary”, they must obviously have excellent evidence.

Or they have an observational case series consisting of 87 patients from Italy.

These authors present a prospective case series of all patients at their institution who were admitted for observation specifically for minor head trauma while on oral anticoagulation.  At the time of repeat CT scanning 24 hours later, the authors report five of them had new bleeding detected.  In addition, two patients who were discharged after two negative CT scans returned with symptomatic bleeding, one at two days, and one at eight days.

So, should we be observing and rescanning every anticoagulated minor head trauma patient as these authors suggest (and as they do in Europe)?  If you practice in a zero-miss litigation environment, this article and ACEP’s apparent embrace of the results will hamstring your decision-making.  This data is completely inadequate to change clinical practice, and inconsistent with prior literature documenting delayed hemorrhage in only 2 of 137 patients.

Clearly, some patients will have delayed bleeding – a subset of which will be clinically significant.  However, we simply cannot expose all anticoagulated patients with minor head trauma to the harms and costs of hospitalization.  Better studies are required to prospectively determine the risk profile of patients who require further observation in a hospital setting, rather than a watchful discharge home.

“Management of Minor Head Injury in Patients Receiving Oral Anticoagulant Therapy: A Prospective Study of a 24-Hour Observation Protocol”

Correspondence in Nature Reviews Neurology

After publishing an article that alluded to the “antipathy” of emergency physicians towards TPA in acute ischemic stroke, the editors were nice enough to publish my correspondence defending the reasonableness of a cautious attitude.


“Skepticism about thrombolytics in stroke is not unreasonable.”
http://www.ncbi.nlm.nih.gov/pubmed/22249840