Category: Neurology

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”

Empiric Measurement of Bias in Unblinded Trials

This lovely article was passed along to me by David Newman during a discussion of IST-3 – the recently infamous, massive randomized trial of thrombolysis for acute stroke.  There are two ways of thinking about IST-3, and how the results are viewed in the literature seems to depend how much funding you receive from Boehringer or Genentech.  The first way of thinking seems to be accept the results as published, pick apart the subgroups, do statistical contortions, and then either come out in the “pro” camp (Boehringer) or the “con” camp.


The second way of thinking, supported by this article, is “garbage-in, garbage-out”.  The key issue for this approach is that IST-3 is an unblinded, open trial, which introduces bias – treating clinicians and patients who believe TPA is a “promising, yet unproven” treatment (from the uncertainty principle of the study) are perceived as more likely to contribute to favorable reported outcomes when receiving the experimental intervention.  This effect is probably even more pronounced given that much of the follow-up scoring for the Oxford Handicap Scale was performed by mail-in questionnaire, rather than standardized expert evaluation – which has rather poor kappa to begin with.


Page three of this article delves into the empiric analysis of the impact of blinding, and the relative likelihood of unblinded trials to report favorable outcomes.  Essentially, the relative chance of reporting both favorable and unfavorable outcomes are significantly affected.  In clinical terms, this leads to presentation of results in which the benefits are exaggerated and the harms are minimized.  In the context of IST-3, this essentially means the likelihood of any hidden positive effects vanishes, while the poor outcomes are underreported – and it’s more “negative” than “neutral”.


The authors also note they are preparing a systematic review of trials with blind and non-blind outcome assessors, which would be particularly apt to IST-3, as well.


“Blinding in Randomized Clinical Trials: Imposed Impartiality”
http://www.ncbi.nlm.nih.gov/pubmed/21993424

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

ABCD2 For Cerebrovascular Dizziness

This is a bit of an interesting idea – a repurposing of the ABCD2 prediction instrument for TIAs as a risk-stratification instrument for cerebrovascular causes of “dizziness.”

Every ED physician loves the complaint of “dizziness.”  It’s either giddiness, unsteadiness, lightheadedness, vertigo, and it’s frequently difficult to elicit any pertinent neurologic symptoms to clarify one of the benign causes of vertigo or a cerebrovascular cause.

This is a retrospective chart review in which they evaluated the charts of 907 “dizzy patients”, 37 of which had a cerebrovascular cause – 4.1%.  It’s a small sample size – so the confidence intervals for their odds ratios are very wide – but for multivariable adjusted odds, age > 60 had an increased OR of 5.1, BP >140/90 had an increased OR of 2.9, speech disturbance had an OR of 6.2, and unilateral weakness had an OR of 10.9.  Essentially, it’s interesting to see – and it makes sense – that the same features that generally portend stroke after TIA also might help predict which of your dizzy patients will be higher yield for a more intensive evaluation.

“Application of the ABCD2 Score to Identify Cerebrovascular Causes of Dizziness in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/22442167

TPA is Dead, Long Live TPA

I’m sure this saturating the medical airwaves this morning, but yesterday’s NEJM published a study which they succinctly summarize on Twitter as “In trial of 75 pts w/ acute ischemic #stroke, tenecteplase assoc w/ better reperfusion, clin outcomes than alteplase.”


Well, that’s very exciting!  It’s still smashing a teacup with a sledgehammer, but it does appear to be a more functional sledgehammer.  Particularly encouraging were the rates of sustained complete recanalization – which were 36% at 24 hours for alteplase and 58% for tenecteplase – and the rates of intracranial hemorrhage – which were 20% for alteplase and 6% for tenecteplase.


However, the enthusiasm promoted by NEJM, and likely the rest of the internet, should be tempered by the fact that there were only 25 patients in each arm, and there is enough clinical variability between groups that it is not yet practice changing.  This was a phase 2B trial, and it is certainly reasonable evidence to proceed with a phase III trial.


Unfortunately, in a replay of prior literature, the authors are all affiliated with Boehringer Ingelheim, the manufacturer of tenecteplase.


“A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1109842

Addendum:  As Andy Neil appropriately points out, tenecteplase has been studied before – 112 patients over several years, terminated early due to slow enrollment – without seeing a significant advantage.

Mechanical Thrombectomy – Promising, But Still Unsafe

This article is just a retrospective, consecutive case series from Spain reporting outcomes and adverse events from mechanical thrombectomy in acute stroke.  Most of their patients are significantly disabled from their strokes, with NIHSS ranging from 12 to 20 – unlikely to have great outcomes – but 14% developed intraparenchymal hemorrhage and 25% were deceased at 90 days.  Six patients had vessel wall perforation from the thrombectomy device.

The key sentence is the last sentence:
“Clinical efficacy of this approach compared with standard medical therapy remains to be demonstrated in prospective, randomized controlled trials.”

When mortality is 25% here, and 33% at 90 days in MERCI, multi-MERCI, and Penumbra trials, I’m still not sure this strategy is quite ready for prime time.  They do report that 54% had a “good outcome”, but it’s interesting to see that “good outcome” in stroke trials has progressed from Rankin Scores of 0 or 1 in NINDS etc. to ≤2 in these new trials.  They  also don’t offer a lot of granularity in their outcomes data.

But, as usual, as long as there are authors out there who “receive consulting and speaker fees from Co-Axia, ev3, Concentric Medical, and Micrus,” we’ll keep seeing reports like this.

“Manual Aspiration Thrombectomy : Adjunctive Endovascular Recanalization Technique in Acute Stroke Interventions”
http://www.ncbi.nlm.nih.gov/pubmed/22382156

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

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

100,000 Incorrect TIA Diagnoses Every Year

…if we extrapolate the results from this single-center study to the entire United States.

In Annals this month, a chart review of the “discordance” between the final neurologist “gold standard” diagnosis and the provisional Emergency Department diagnosis.  Apparently, in Cleveland, 36% of the patients receiving an initial diagnosis of transient ischemic attack in the Emergency Department are subsequently evaluated by a neurologist and given an alternative diagnosis.  As the authors note in their introduction, the diagnosis of TIA is made 300,000 yearly – and if 36% of those cases are made incorrectly, then we’re theoretically admitting 100,000 patients for extensive and expensive evaluation.

So, are they right?  Well, if the three neurologists responsible for 93% of their 427 evaluations are representative of the entire country, perhaps.  Or, if their chart review methods are adequate – as the authors note, one of their chart audits changed an abstracted diagnosis of TIA to “right hip pain” – then, perhaps.  If you ignore that ED physicians have a few minutes of history, examination, and limited imaging available at their disposal – compared with the neurologists that can subsequently perform any manner of inpatient studies that might uncover an alternative diagnosis mimicking a TIA – then, perhaps.

If neurologists are walking into the ED and evaluating patients under the same constraints as we are and producing this level of discordance, then we have a problem.  But, I don’t think this study tells us anything we can use to evaluate ED physicians’ ability to appropriately include or exclude TIA in the differential for neurologic complaints of a transient nature.

Somewhat disappointing that a small, retrospective chart review with results that might not be internally or externally valid are in the premier, #1 Impact Factor journal of our profession.

“Variables Associated With Discordance Between Emergency Physician and Neurologist Diagnoses of Transient Ischemic Attacks in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/21624703