Category: Medication Safety

Zolpidem and Benzodiazepines Will Kill You

Apparently!

Especially if you’re elderly.

It’s an interesting observational, statistically matched-control study using Electronic Health Records to monitor prescriptions of zolpidem (Ambien) and other benzodiazepines (Temazepam), commonly used as sleep aids, particularly in the shift-work population.

I think this graph pretty well sums up their results:

Blue lines are hypnotic-free, orange lines are patients taking hypnotics.  Downward slopes – exaggerated by the vertical scale – are bad.  An increased hazard for cancer was also found in patients prescribed hypnotics.

There are, of course, flaws with this study – but it is consistent with other published literature suggesting harms associated with hypnotic use.  The huge limitation of a study like this is controlling retrospectively for all the comorbid cofounders.  They attempt to do this statistically with a small set of comorbid disease, but it remains a limitation.

“Hypnotics’ association with mortality or cancer: a matched cohort study”
http://bmjopen.bmj.com/content/2/1/e000850

Is Midazolam Really Superior to Lorazepam?

Or, more accurately, is it reasonable to perform an intramuscular injection of midazolam rather than an intravenous injection of lorazepam for seizure-like activity in the prehospital setting?

Almost certainly.

In fact, some folks are taking this article and claiming that intramuscular midazolam is superior to intravenous lorazepam, that it’s a “game changer.”

Well, let’s not go crazy here.

As with any piece of literature, the more vocal the giddiness I see perpetuated about the internet, the more cautious I am with rushing to judgement.  It is, of course, a very well-designed, prospective, double-dummy, randomized, non-inferiority comparison between midazolam and lorazepam.  The aim of the study is, essentially, to show that, even though midazolam is not typically as rapidly effective at terminating seizures, the time difference is made up by intramuscular route versus the time required for an IV start.

What’s kind of odd that I see in this article is that nearly a third of the lorazepam group did not receive the benzodiazepine portion of the intervention – and they compare it to the midazolam group in which all but 5 patients received the intervention.  When their primary outcome is the number of folks who arrived seizure-free in the Emergency Department – it seems as though the 7% absolute difference between the two groups could be easily explained by the fact that a third of the lorazepam group didn’t receive an intervention.  Most of the lorazepam group had the intervention withheld because they stopped seizing of their own accord at the time of enrollment, with a minority having the intervention withheld because IV access could not be obtained.

And, the differences favoring midazolam are hard to pin down whether it’s actually medication superiority, or something different about the seizures.  42 patients in the lorazepam group failed to stop seizing after additional therapy, compared with only 22 in the midazolam group – is this a difference in efficacy, or a difference in the underlying disease process – which appears to be more resistant to any therapy, including rescue, in the lorazepam group?

But, in any event, this just nitpicking against the superiority argument, and not the non-inferiority argument.  From a clinical standpoint, it is clearly safe and effective to use intramuscular midazolam for seizures in the prehospital setting.  However, what I’d prefer to see is a similarly powered trial of intranasal midazolam, which takes all the injection risks for patient and provider out of the equation during the seizure.  This is a good first step, but I think we can make effective treatment even safer if intranasal can be shown non-inferior as well.

“Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus”
http://www.nejm.org/doi/full/10.1056/NEJMoa1107494

Ketamine For Acute Pain Control

So, there’s effective.  And then there’s effective, but insane.  I am aware that low-dose continuous infusions of ketamine are excellent adjunctive therapies to decrease narcotic use in trauma and orthopedic patients, but I have never seen ketamine used in bolus form to treat acute pain in the out-of-hospital setting.

But, that’s what we have.  After an initial 5mg IV bolus of morphine, patients were randomized to receive either additional morphine or ketamine boluses – 1 to 5mg of morphine every five minutes, or 10 to 20mg of ketamine every three minutes.  Pain medication was given per protocol until relief or adverse events.  And, the ketamine group was superior – pain scores dropped 5.6 points on the numerical verbal scale with ketamine and 3.2 with morphine.

However, the ketamine group also had a 39% incidence of adverse effects, compared with 14% of the morphine group.  The morphine group had mostly nausea, with one patient exhibiting a change in level of consciousness.  However, the ketamine group had multiple patients with decreased consciousness, disorientation, and emergence phenomena.  So, while the editor capsule summary states “Supplementing out-of-hospital opiods with low-dose ketamine is an effective strategy to mitigate trauma pain” he is technically correct, but the insanity of this strategy is trying to make an evidence-based decision about intracranial imaging after iatrogenically altering your patients prehospital.

What I appreciate best about this paper is how aggressive the paramedics were with treating pain – the patients receiving morphine averaged 14.4mg, with a standard deviation of 9.4mg!  I see my residents ordering 2mg at a time and it drives me nuts.

“Morphine and Ketamine Is Superior to Morphine Alone for Out-of-Hospital Trauma Analgesia: A Randomized Controlled Trial”
www.ncbi.nlm.nih.gov/pubmed/22243959

Finally, A Useful TPA Concept

Frequent readers of this site will be familiar with my distaste for TPA in stroke – not because I think it’s a therapeutically invalid option, but mostly because its use is being promoted beyond its original scope, too many stroke mimics are receiving TPA, and the published literature supporting new “innovations” in TPA have a skewed interpretation of “safe”.

This paper from Stroke is the first I’ve seen that finally tries to determine whether a patient will actually benefit from TPA in acute ischemic stroke, rather than chaining together studies in a logical fallacy to extend treatment to a larger population.  These authors have developed the “iScore” (no affiliation with Apple Computer), which was developed by logistic regression to predict outcomes in patients with ischemic stroke not treated with TPA.  The components include age, stroke severity, stroke subtype, and medical comorbidities in a scoring system that defines low (>50% good outcome), moderate (10-50%), and high-risk (<10%) groups.

These authors then apply the iScore in a retrospective fashion to their stroke database, looking both at their TPA recipients as well as propensity-matched patients in their non-TPA group.  Now, it’s not exactly prospective, randomized, controlled, but it’s an interesting trick that provides a limited comparison.  The stroke patients in the low-risk group had ~12% absolute outcomes benefit from TPA, the, the moderate group ~10% benefit, and the high-risk group ~2.6%.  There were no statistically significant benefits (or harms) from TPA in the high-risk group, but those patients were >90% disabled or dead at 30 days, regardless of therapy.

One weakness the authors point out in their study – it is sometimes clinically difficult to determine stroke subtype in the acute setting based solely off clinical presentation, particularly when baseline functional status is not perfect.  Regardless, it’s nice to see a paper that looks at better individualizing the risk/benefit equation for TPA – seems as though the 400 patients in the high-risk group did not benefit from spending $2000 on alteplase or the associated increased DRG billing associated with it.  Money isn’t free, after all….

“The iScore Predicts Effectiveness of Thrombolytic Therapy for Acute Ischemic Stroke”
http://stroke.ahajournals.org/content/early/2012/02/02/STROKEAHA.111.646265.short

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

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”