Category: Medication Safety

Dabigatran Worsens/Does Not Worsen Bleeding

Stroke and Circulation are both Journals under the umbrella of the American Heart Association.  So, when they publish articles that come to contrasting conclusions, I find that entertaining.

Both of these articles are mouse models of bleeding on dagibatran, C57BL/6 or CD-1 mice.  Sadly, they are frighteningly complex in their adjustments and statistical analyses – which means it defeats my ability to concisely summarize the findings and methods.

In short, one of these articles looks at intracranial hemorrhage after collagenase injection for mice receiving several different doses of oral dabigatran, and compare it to controls, warfarin, lepirudin, fondaparinux, and heparin.  It appears, and the author’s final conclusion is, that dabigatran is the least harmful of all anticoagulants – about halfway between controls and the other anticoagulants.  They also shoot the mice with lasers in another portion of the study, and dabigatran “wins” that as well.

The other article looks at trying to reverse dabigatran – which, if you recall the human study I posted a few weeks back, was not successful in humans.  However, human trials were all surrogate markers of bleeding as measured by laboratory measurements of clotting.  What entertains me is, in contrast to the other study, these authors have no trouble inducing bleeding and significant ICH formation with dabigatran.  In any event, once the mice were adequately bleeding, the authors compared prothrombin concentrate complexes (specifically, Beriplex), FFP, and FVIIa for treatment of ICH 30 minutes after induced injury with collagenase.  Happily, PCCs, in a dose-dependent manner, attenuated the induced ICH, while the others failed.

So, perhaps this “novel, reversible” anticoagulant has a treatment option for life-threatening bleeding.  Human confirmation, at least case reports, needed.

“Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage”
http://circ.ahajournals.org/content/early/2011/09/11/CIRCULATIONAHA.111.035972.abstract

“Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran”


A Third of TPA Patients Do Not Have Stroke

…but they almost all do well!  Only 5.1% of patients without stroke who receive TPA end up with intracerebral hemorrhage – so it’s OK that we give TPA to a ton of patients without a confirmed diagnosis of stroke, right?

This is a retrospective Finnish registry study of 1,104 consecutive TPA patients enrolled in a prospective cohort.  Of these, 119 had basilar artery occlusion, which is angiographically proven prior to treatment, and are excluded from their analysis, and a couple others were excluded for other reasons.  This left 985 patients who were initially diagnosed with ischemic stroke, and, eventually, 14 of those patients were diagnosed as a stroke mimic such as migrane, epilepsy, or a demyelinating disorder.  The authors then go on to say that stroke mimics such as these accounted for a mere 1.4% of all TPA patients, and none of them had ICH.

But, this isn’t exactly a true reading of their data.  The authors also state that 275 of their patients had “neuroimaging negative ischemic stroke”, which is to say, their follow-up MRI detected no sign of infarct.  Now, there is a false-negative rate on DWI MRI for stroke, but it’s in the range of 5% for acute infarcts, and generally involves small lacunar, small cortical, and some posterior circulation strokes.  Not only that, it’s reasonable to suggest that around 40% of TIAs actually have DWI or FLAIR sequence abnormalities as well.

So, some of their “neuroimaging negative ischemic stroke” group probably does have ischemic stroke with false negative MRI – but not 30% of the study population.  And, some of their neuroimaging positive group is likely false positive from TIA as well.  These numbers for stroke mimics are also far below other reported case series, which have estimated 10-30% incidence, depending on whether TIAs are included.

I absolutely cannot fathom this line of reasoning and distortion Neurology is developing in justify recklessly pushing TPA onto a larger population.

“Stroke Mimics and Intravenous Thrombolysis”
http://www.ncbi.nlm.nih.gov/pubmed/22000770

N-acetylcysteine Overdose With Anaphylactoid Reaction and Myocardial Infarction

This is another toxicology case that illustrates a point I make (probably too often) to my residents – that every action we take has a risk of harm, whether known or unanticipated.  I’m probably the only attending who cancels their IM ketorolac orders and changes them to PO ibuprofen.  Why?  Because of cases like this.

This is an entirely appropriate therapy – N-acetylcysteine given for hydrocodone-acetaminophen overdose – gone wrong because of a mixing error resulting in 10-fold overdose (126,000mg loading dose!).  Anaphylactoid reactions are known side effects in N-acetylcysteine, and, unfortunately, this patient’s reaction was more severe than most, suffering an inferior MI with a peak troponin of 658ng/mL.  He expired 17 hour after the N-acetylcysteine overdose.

I’ve seen epinephrine given IV instead of SQ more than once (one time resulting in an MI), many medications are tissue toxic if they extravasate, you can get sterile abscess formation from intramuscular injections, etc.  The fewer interventions and the less invasive the interventions, the less risk at which we place our patients.

“Fatal myocardial infarction associated with intravenous N-acetylcysteine error”

No Reversing The Harm of Etomidate

A small, but growing body of evidence is starting to correlate the physiologic adrenal suppression of etomidate with worsening clinical outcomes.  This study is a French prospective cohort that really likes etomidate for RSI, so, they decided to ask the question whether a continuous hydrocortisone infusion has any substantial effect on cardiovascular parameters in the setting of etomidate use.

Short answer, no.

Their randomized groups are awfully small – 45 patients in each group – so their power to detect a difference is not great.  But, at the minimum, there’s no profoundly obvious difference or any seemingly clinically significant trend between the two groups.

I trained using etomidate for everyone, but I’ve almost completely moved to alternative agents, ketamine being the most prominent of those agents.  Most significantly, ketamine differs from the other agents in terms of having analgesic properties as well, and I think it is reasonable to provide some treatment for the pain associated with laryngoscopy.  There is evidence that ketamine is a myocardial depressant and may be deleterious in patients with limited cardiac reserve, but so far in limited literature it holds up clinically well against etomidate and midazolam.

“Corticosteroid after etomidate in critically ill patients: A randomized controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/21926601

“Intubating ICU patients with ketamine: adverse effects that can occur.”
http://www.ncbi.nlm.nih.gov/pubmed/18079246

Ondansetron, Just Like Droperidol

Droperidol used to be one of the most widely used anti-nausea medications, particularly in the peri-operative period.  Now, none of my residents are familiar with it because it’s rarely used since the FDA gave it a black box warning for its QT-prolonging effects.  We have largely and copiously replaced it with ondansetron, the supposedly safe alternative.


Now, the FDA is asking GlaxoSmithKline to go back and look at the safety profile for ondansetron…due to QT-prolonging effects: http://reut.rs/pDq6Yw  They are already changing the labels to reflect cardiovascular risk in the meantime.


It should be interesting to see the results.  It is fairly clear that ondansetron prolongs the QT interval probably nearly, but not quite, as much as droperidol.  The droperidol black box was based on cardiovascular events including only a mere 10 patients receiving doses in the therapeutic range of 0.625mg to 1.25mg, and those events had multiple confounding factors or drug co-administrations.  It would not surprise me if ample, if equally flimsy, evidence exists implicating ondansetron as well.

“Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases.”

“Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study.”

“The effects of droperidol and ondansetron on dispersion of myocardial repolarization in children.”

Rivaroxaban Can Be Reversed, But Not Dabigatran

We all hate coumadin – difficult to control levels and causes life-threatening bleeding, but at least we can measure its activity and reverse it in a straightforward manner.  However, coumadin’s days are at an end with the approval of the new oral anticoagulants – and the two most extensively evaluated are dabigatran (direct thrombin inhibitor) and rivaroxaban (factor Xa inhibitor).

This is a randomized, placebo-controlled trial of the reversal of dabigatran and rivaroxaban using prothrombin complexe concentrates – which, most importantly, have been theorized to be the only used agent for dabigatran.  Their results – in groups of 12 healthy volunteers – is that PCCs have no effect on any of the laboratory clotting parameters for dabigatran, but fully reverse rivaroxaban.
So, while there are no studies as of yet describing the acute reversal of either of these agents in a clinical situation, this is definitely concerning that we still have no theoretical way to treat life-threatening bleeding with dabigatran.
“Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate.”

More Mistakes In An Unfamiliar System

Probably tells us what we already know – and likely underestimates the problem.

These authors take a retrospective look at all the reported medication errors between 2000 and 2005, and then try to associate increased errors with the involvement of a temporary staff member.  The problem is, they don’t actually have staffing documents that report which employees are temporary – they rely on the population of a QA field listing “contributing factors”, under which temporary staff is an option.  So, you can dismiss this as a bit of garbage-in/garbage-out depending on how accurate the reporting is – but, I figure, if anything, people will forget to implicate temporary staffing more frequently than not.
More interesting – and potentially confounding re: temporary vs. permanent – are the perceived reported reasons behind the medication error.  Temporary staff were more likely to be reported to have knowledge deficits, performance deficits, and fail to follow appropriate procedures.  I might read into that data that it’s easier for an unfamiliar temp to appear knowledge-deficient, although that’s just my own imagination.
From a risk management standpoint, the solution seems to be: whatever the retention costs of your permanent staff members, they are almost assuredly lower than the costs associated with the errors inflicted upon patients by temps.
“Are Temporary Staff Associated with More Severe Emergency Department Medication Errors?”

Does EHR Decision Support Make You More Liable?

That’s the question these JAMA article authors asked themselves, and they say – probably.  The way they present it, it’s probably true – using the specific example of drug-drug interactions.  If you put an anticoagulated elderly person on TMP-SMX and they come back a few days later bleeding with an INR of 7, you might be in trouble for clicking away the one important drug alert out of the one hundred you’re inundated on your shift.  The authors note how poorly designed the alerts are, how few are relevant, and “alert fatigue” – but really, if you’re getting any kind of alerts or have any EHR tools available to you during your practice, each time you dismiss one, someone could turn it around against you.

The authors potential solutions are an “expert” drug-drug interaction list or legislative legal safe harbors.

“Clinical Decision Support and Malpractice Risk.”
www.ncbi.nlm.nih.gov/pubmed/21730245

“Narcotic Bowel Syndrome”

I had never heard this specific diagnosis bandied about in an Emergency Medicine context – but, essentially, it’s a gastroenterology entity (and diagnosis of exclusion) that entails, essentially, chronic, intractable, crampy abdominal pain of unknown etiology and concurrent narcotic use.  I can’t even describe how many of these patients I saw each shift during residency – and how many of those people had multiple CT scans in the past year.  The key feature in this particular diagnosis, as described in their case, is they had extensive follow-up evaluation, were weaned from their narcotics, and had resolution of symptoms.

I think this is a diagnosis spectrum we see a lot in the ED – whether it be constipation, IBS, cyclic vomiting syndrome, “feeling sick”, or the multitudinous abdominal pain of unknown etiology.  With more and more patients being prescribed (or secretly taking) narcotics, what we see in our EDs is not just the overdose emergencies, but the various side effect spectrums of dependence and withdrawal.

You’d think that with all our medical technological prowess we’d have better mechanisms to treat pain than they did thousands of years ago.

“Narcotic Bowel Syndrome”
http://www.ncbi.nlm.nih.gov/pubmed/21719232

“Time-Out” In The ED Is Nearly Universally Useless

…but still probably a good idea.

Out of 225 ACEP councillors responding to a survey, 5 knew of an instance in the past year where a time-out may have prevented an error.  So, a year’s worth of personal patient encounters, plus whatever they heard about in their department, multiplied by 225 – which means we’re looking at hundreds of thousands of patient encounters – and there were only a handful of events where a time-out would have helped.

That being said, time-outs have been a Universal Protocol with the National Patient Safety Goals since 2004 because performing the wrong procedure, at the wrong site, on the wrong patient really falls into a category of a “never event”.  It does seem like a no-brainer in the ED, where the procedures we’re performing on patients are specifically related to the unique presenting event, but errors still occur – and the magnitude of the harm to the patients who are being harmed is probably greater than the consequences of the additive delay in care to other patients from the cumulative time performing the time-out.

“A Survey of the Use of Time-Out Protocols in Emergency Medicine”