Category: Medication Safety

Flumazenil – Seizures, But Not Frequently

It seems as though, when teaching trainees about benzodiazepine overdose, flumazenil is discussed – and in the same breath, the commandment to use it never or with extraordinary caution.  The fundamental issue is whether an underlying pro-convulsant state can be unmasked if the protective effect of benzodiazepines is removed.

The answer from this study, a retrospective review of a decade of flumazenil use in California, is clearly yes.  However, the “yes” is only 13 seizures out of 904 reviewed cases, most of whom had some sort of co-ingestant that contributed to the pro-convulsant state.  The authors also note, for the cases in which data was available, flumazenil was therapeutic (and potentially diagnostic as well) in 53% of administrations, with return of alertness from unresponsiveness or drowsiness.
So, the answer to the clinical question – whether flumazenil use should be as taboo as current dogma – is more complex, and, unfortunately, descends into that dark area where risks must be weighed against benefits.  Is the risk of poor clinical outcome secondary to resuscitative efforts in the field, delayed/missed intubations, etc. greater than the 1-2% risk of seizures?  Or can the patient be safely observed with minimal intervention in a monitored setting?  Or, if flumazenil is effective, how much money was saved by reducing the need for the expansive medical testing performed on unresponsive individuals?  I don’t believe a single blanket answer suffices to cover each individual clinical situation.
“A poison center’s ten-year experience with flumazenil administration to acutely poisoned adults.”

Put Hydroxyethyl Starch Away

The use of colloid solutions as volume expanders is tempting – massive crystalloid resuscitation suffers from third-spacing, limiting the practical intravascular volume provided.  Colloid resuscitation, in theory, uses the oncotic pressure of the solute to favor intravascular expansion.  One of the alternatives that I’d seen use, but was unaware it was widely used, are hydroxyethyl starches.  Earlier studies, at least, the ones I was familiar with, linked the high-molecular weight HES to renal failure.

This trial, from Denmark, evaluated a low-molecular weight HES (Tetraspan) with Ringer’s acetate resuscitation in an intensive care setting, enrolling patients diagnosed with sepsis in need of fluid resuscitation.  The trial was randomized and blinded, with the resuscitation fluids being hung in identical black bags.  Each enrolled patient could receive up to 33 mL per kg ideal body weight of the trial fluid, and additional fluid was unmasked Ringer’s acetate.

With 800 well-matched patients between groups, 51% of the HES group was dead at 90 days, compared with 43% in the Ringer’s acetate group (RR 1.17, CI 1.01 to 1.36).  Renal replacement therapy was needed in 22% of the HES group, compared with 16% of Ringer’s acetate group – and was a predictor of death.

Investigators did not see any particular fluid volume advantage to the HES solution, and the toxic effects of the hydroxyethyl starch molecules, unfortunately, were associated with greater morbidity and mortality.

Seems like another great-sounding idea that needs to be rapidly curtailed until a better safety profile and outcome benefit can be demonstrated.

“Hydroxyethyl Starch 130/0.4 versus Ringer’s Acetate in Severe Sepsis”
http://www.nejm.org/doi/full/10.1056/NEJMoa1204242

Warfarin and tPA Mix – If They’re Subtherapeutic

These authors almost have a conclusion I can’t quibble with – but, rather than “Among patients with ischemic stroke, the use of intravenous tPA among warfarin-treated patients (INR ≥1.7) was not associated with increased sICH risk compared with non-warfarin-treated patients” I would add the caveat to say “after multiple adjustments”.

This is a retrospective registry review published in JAMA, comparing the rate of sICH in warfarin-treated patients with non-warfarin-treated patients who received tPA for ischemic stroke.  And, 5.7% of warfarin patients developed sICH vs. 4.6% in the non-warfarin group.  However, after adjustments for multiple variables – the warfarin group tended to be older, had more previous strokes, and had higher NIHSS – the OR was 1.01.  Not terribly surprising there wasn’t much difference, considering the mean INR in the warfarin cohort was only 1.2.  Their confidence intervals start getting very wide above 1.6, but there’s suggestion of a clear association with increasing sICH as the INR increases.

There are plenty of reasons not to give tPA, but subtherapeutic warfarin use probably should not exclude patients from consideration.

“Risks of Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Receiving Warfarin and Treated With Intravenous Tissue Plasminogen Activator”
http://jama.jamanetwork.com/article.aspx?articleid=1199153

Xigris Isn’t Dead – Just Hibernating

Activated Protein C, also known as Xigris, which has had an infamous and circuitous career of sorts, is back.

After a short life of use in severe sepsis, the continued investigations into its efficacy have finally been unable to establish its benefit.  Although many expensive therapies without conclusive benefit are still in use in medicine, we’ll score this one (belatedly) for the good guys.

This early animal research, published as a letter in Nature Medicine, reports on interventions targeting the aPC pathway to prevent lethal radiation injury to hematopoietic cells.  They say that starting infusions of aPC within 24 hours of lethal radiation exposure mitigated radiation mortality in mice.  Probably quite a long way off for real-world usage, but any potential treatment is better than none.

“Pharmacological targeting of the thrombomodulin–activated protein C pathway mitigates radiation toxicity”

http://www.ncbi.nlm.nih.gov/pubmed/22729286

Failings of Modern Medicine

A brilliant piece that eloquently states many of the ideas espoused on this blog, focusing on pulmonary embolism as the poster child for over-testing, over-diagnosis, and lack of sound evidence underlying treatment.

These authors, in the Archives of Internal Medicine, accurately describe the chimeric nature of pulmonary embolism – historically described as a dreaded disease, diagnosed clinically from the manifestations of pulmonary infarction, to the modern manifestation of filling defects noted on CTA during an episode of pleuritic chest pain.  They discuss the handful of patients who benefited from the first heparinization for treatment, and argue the disease for which anticoagulation is the treatment is not the disease we are diagnosing today.

This article covers so many excellent points, and ties the clinical problems so tightly into the underlying principles, that it’s almost the sort of must-read article to which medical students should be exposed – in order to bring about that frightening moment of maturity in medicine in which you realize the emperor is distinctly lacking in clothes.

Lovely work!

“The Diagnosis and Treatment – of Pulmonary Embolism: A Metaphor for Medicine in the Evidence-Based Medicine Era”
www.ncbi.nlm.nih.gov/pubmed/22473672

Daily Aspirin Harms More Than It Helps

Patients with cardiovascular disease are routinely placed on daily, low-dose aspirin for primary prevention of cardiac events.

Unfortunately, antiplatelet effects promote other types of bleeding, while the cyclooxygenase pathway has a deleterious effect on the gastric mucosal.  This 4.1 million patient propensity matched retrospective database study from Italy demonstrated approximately 2 excess cases of major bleeding events – whether intracranial or gastrointestinal – per 1000 patients treated per year.

Which is approximately the number of major cardiovascular events prevented by the daily aspirin use during the same time period.

Not specifically relevant to Emergency Medicine, but yet another example of how it’s naive to think many treatments in medicine – even those (or particularly those!) that have been part of routine practice for eons – are benefiting patients without a significant risk of harms.

“Association of Aspirin Use With Major Bleeding in Patients With and Without Diabetes”
jama.jamanetwork.com/article.aspx?articleid=1172042

Cephalosporins Can Be Used in Penicillin Allergy

Did you know the literature describing the cross-reactivity between cephalosporins and penicillins is 30-40 years old?  It sort of takes the “modern” out of “modern medicine.”

At any rate, this is a literature review that aims to update the classical teaching that cross-reactivity between cephalosporins and PCN is ~10%.  They identified 406 articles on the topic and distilled it down to 27 respectable articles for inclusion in summary.  They rate the quality of the articles, and, unfortunately, find only a few good or outstanding articles and a preponderance of adequate evidence.
But, essentially, what they find is the cross-reactivity boils down to the presence of a shared R1 side chain present on first-generation and some second-generation cephalosporins.  Specific first-generation cephalosporins, such as cefadroxil (Duracef), were seen to have up to 28% cross-reactivity in some series, though the typical rate was lower, down to 0.11% with cefazolin (Ancef).  The largest meta-analyses estimated the true cross-reactivity at ~1% rather than 10%, with most of these occurring with first-generation cephalosporins.
In summary – 3rd-generation and greater cephalosporins with disimilar R1 side chains can probably be used in appropriate clinical situations despite a PCN allergy without incidence of allergy greater than in those patients who do not have a documented PCN allergy.
“The use of cephalosporins in penicillin-allergic patients: A literature review.”

Dabigatran – In Annals of Internal Medicine

My short review article warning the internists of the dangers associated with rushing into overuse of dabigatran was published today in Annals of Internal Medicine.


It was actually originally entitled “Dabigatran – Sinking Into Uncharted Waters,” but the editor changed it after the Italian cruise ship disaster.


“Dabigatran — Uncharted Waters and Potential Harms”
http://www.annals.org/content/early/2012/05/23/0003-4819-157-1-201207030-00467

The Third International Stroke Trial: IST-3

The Cochrane systematic review of the 11 complete trials of rt-PA for thrombolysis encompasses 3,977 total patients.  IST-3 enrolled 3,035, nearly doubling our cohort of randomized data.  Unfortunately, this influx of new data does very little to resolve any of the outstanding issues regarding stroke care.

Before even looking at the results, it’s particularly important to wade through the dense study design and methods – and realize this is a non-blinded study in which patients were enrolled if the treating clinician was “uncertain of the benefits or harms of TPA”.  Considering this study began back in 2003, prior to ECASS III, a large chunk of their enrolled patients fell into the 3-4.5 hour time frame, with the remaining majority falling into the up to six hour limit.  The other major area of interest this study was intended to evaluate was the efficacy and safety in patients aged >80 years of age, of which they enrolled 1,616.  And, in a shocking twist, this study actually manages to enroll TPA and control cohorts with nearly identical baseline variables.

IST-3 is negative for the primary endpoint, which is the proportion of patients functionally independent at six months (Oxford Handicap Score 0-2, a scoring system similar to the Modified Rankin Score), with a 95% CI of 0.95 to 1.35.  On ordinal secondary analysis, there are non-significant trends towards improvements in OHS favoring rt-PA, which is probably what you’ll hear when people refer to IST-3 as “positive.”

Then, regarding the patients aged >80, there is a trend towards benefit with TPA, CI 0.97-1.88.  Unfortunately, in a neutral study, that means there is actually a trend towards harm in ages <80, CI 0.67-1.26.  Likewise, between 4.5-6 hours, there is a trend towards benefit with TPA, CI 0.89-1.93.  Therefore, between 3 and 4.5 hours, there is a trend towards harm with TPA, CI 0.50-1.07.  TPA is also essentially neutral or trends towards harm up until NIHSS 14, with more pronounced benefit shown in severe strokes.

Interestingly enough, the “blinded” phase of the study trended towards favoring control, CI 0.42-1.98, while the open phase favored TPA, CI 0.89-1.45.

So, what does this all mean?  It means, there’s still plenty of shades of grey open for interpretation and discussion.  Indeed, when added into the systematic review, IST-3 brings several of the previously significant benefits back into the nonsignificant range.  To me, this reinforces what I’ve been arguing for awhile – that the focus shouldn’t be on massive expansion of TPA eligibility, but specifically targeting those who have the best benefit/harm profile.

As with any major stroke trial, many of the investigators have financial associations with Boehringer Ingelheim.

“The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial”
http://www.lancet.com/journals/lancet/article/PIIS0140-6736(12)60738-7/fulltext

Azithromycin – Not Guilty of Murder

The FDA has announced it is reviewing the safety of azithromycin in lieu of a recent NEJM article documenting an association between azithromycin and cardiovascular death.  In theory, azithromycin has been implicated in QT-prolongation and pro-arrhythmic effects, leading to torsades de pointes and polymorphic ventricular tachycardia.  The authors of this study therefore hypothesized an association between azithromycin use and cardiovascular death.

This is a retrospective study of computerized data generated from the Tennessee Medicaid program between 1992 and 2006, linking deaths to any concurrent antibiotic prescriptions.  The authors data-mined for a cohort aged 30 to 74 years of age, had no “life threatening non-cardiovascular illness”, did not abuse drugs, and did not reside in a nursing home.  They compared azithromycin prescriptions to non-prescription controls, as well as amoxicillin, ciprofloxacin, and levofloxacin cohorts.  And, after a little statistical maneuvering, they report a death rate of 85.2 per 1,000,000 courses of antibiotics with azithromycin, which compares to a death rate of 29.8 with no antibiotic and 31.5 with amoxicillin.

So, for every ~20,000 prescriptions of azithromycin written, there is one additional death from cardiovascular causes.  This is another one of those cases where the severity of the absolute difference doesn’t quite match the relative difference – it is likely any efficacy difference between a macrolide and a second-line agent results in greater morbidity than the magnitude of effect found in this study.

Then, azithromycin is frequently prescribed for upper and lower respiratory tract infections – conditions that, in the absence of other specific signs, might be non-infectious cardiovascular disease misdiagnosed as having an infectious etiology.  In their non-propensity matched cohorts, 50% more azithromycin prescriptions were written for respiratory symptoms than amoxicillin.  The propensity matching in their statistical analysis attempts to account for this, but 30% of their azithromycin prescriptions had no documented indication – which I think means there’s likely a hidden statistical difference in underlying pathophysiology secondary to unknown indications.

Finally, this runs contrary to a 2005 article “Azithromycin for the Secondary Prevention of Coronary Events” published in NEJM – at one point, it was theorized that azithromycin would be protective for coronary events.  For 4,000 patients who took azithromycin weekly for a year, there was no difference in cardiovascular outcomes as compared to placebo (CI -13% to +13% relative risk reduction).

There are lots of reasons not to prescribe azithromycin, but this study isn’t the one that should change your practice.

“Azithromycin and the Risk of Cardiovascular Death”
http://www.nejm.org/doi/full/10.1056/NEJMoa1003833