Category: Medication Safety

Ketamine – Cure For Everything

There aren’t many medications I love using more than ketamine.  I use it for adjunctive pain control, to control agitation, and for induction prior to intubation.  Now, chances are, it’s probably useful in seizures.


This is a case report and review of the literature for the use of ketamine in the control of refractory status epilepticus.  The literature is profoundly weak – the “review” is essentially a review of case reports.  And, the patient outcomes describe in the case reports are replete with “All died” or “Survived but severely disabled.”  However, this is primarily due to the serious cause of the underlying disorders – encephalitis, neurosyphilis, meningitis, anoxic brain injury – and less likely the ketamine, although this does not provide the evidence to that effect.  The proposed mechanism is via NMDA receptor antagonism, which the author proposes works better by synergy with GABA antagonism, rather than either as monotherapy.


Seems like a fair physiologic mechanism, and it’s nice to have something additional to consider in refractory disease.  Ketamine also was noted in this case report to counteract the hypotensive effects of midazolam and propofol, consistent with prior literature describing its beneficial effect on cerebral perfusion pressure.  It’s pretty much a “I tried this and I like it” article, but I think it’s probably likable and not the last we’ve heard about ketamine for status.


“Early Ketamine to Treat Refractory Status Epilepticus”

Tramadol: A Myth of Safety

For me, tramadol lands squarely in the gap between oral analgesics I might use for “no pain” – ibuprofen, acetaminophen – and analgesics I might use for “real pain” – hydrocodone derivatives.  The literature describing the analgesic properties of tramadol is bizarre, with multiple comparisons with placebo, nerve blocks, adjunctive epidural anesthesia, etc., and very few head-to-head comparisons to the sorts of medications we routinely use.  When there are comparative efficacy reports, they typically conclude that tramadol is effective…just as effective as the NSAIDs its being compared with.

The theory I’ve heard people use when considering use of tramadol is that it has a better safety profile than hydrocodone and is less dependence-forming.  These claims may be true, but I do not believe they are true to the extent that it is clinically relevant.  Tramadol still generates an opioid withdrawal syndrome and, as this article describes, overdose/abuse still results in apnea with need for ventilatory support.

Additionally, tramadol is a GABA antagonist, lowering seizure threshold.  Of the 525 patients overdosing primarily on tramadol retrospectively identified at this Iranian hospital, 19 experienced apnea and 242 (46.1%) experienced seizures.  This is retrospective and co-ingestants cannot be fully ruled out, but the propensity for seizure is far more surprising than the incidence of apnea.

Tramadol has a role in pain control prescribing, but, in my practice, that role is tiny.

“Tramadol-induced apnea”
http://www.ncbi.nlm.nih.gov/pubmed/22809771

Predicting sICH in Thrombolysis

In contrast to the lunacy of IST-3, this is another piece of work that at least in the right direction – helping us avoid harming patients with thrombolysis.  


These authors use the Get With The Guidelines registry as their derivation and validation group to develop a prediction rule for sICH in the setting of thrombolytic use for acute ischemic stroke with in 3 hours of symptom onset.  Subsequently, they “externally validate” their rule by applying it retrospectively to the NINDS data set.  At the end of it, they come up with a not-so-handy point scale with six clinical features and twenty discrete elements, but basically, these things are bad:
 – Older patients
 – More severe strokes
 – Higher systolic blood pressure
 – Elevated blood glucose
 – Asian ethnicity
 – Male gender


The C-statistic was .71 on their derivation cohort, .70 on their validation cohort, and .68 on the NINDS cohort – which is more or less just OK.  In practical, clinical terms, their tool more or less discriminates between folks who are at 1-3% risk of ICH, and then 6-10% risk of ICH.  And, I think it’s extremely valuable when discussing risks with our patients to not use blanket generalities, and attempt to tailor the discussion to the individual.


“Risk Score for Intracranial Hemorrhage in Patients With Acute Ischemic Stroke Treated

With Intravenous Tissue-Type Plasminogen Activator”
http://www.ncbi.nlm.nih.gov/pubmed/22811458 

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.”