Monday, December 17, 2012

Pouring Money Into Prehospital Stroke Thrombolysis

Staying consistent with the "brain attack!" slogan folks developed for stroke, the innovations in treatment continue to progress in their attempts to mimic myocardial infarction.  In myocardial infarction, a great deal of focus has been placed on rapid diagnosis and either thrombolysis or interventional catheterization.  This extends to the prehospital arena, with experimentation with ECG transmission, pre-hospital lytics, and pre-hospital cath lab activations.

For stroke, they're still trying to replicate this pre-hospital diagnosis and treatment – made slightly more complex because the diagnostics involved requires CT scanning.  However, with enough funding from telehealth and imaging industry, "mobile stroke units" have been created for feasibility evaluations. 

And, these authors have certainly demonstrated that it is feasible, diagnosing 48 acute strokes in the prehospital setting and giving half of them thrombolysis.  One patient given rt-PA had sepsis rather than an acute stroke, which is of uncertain significance in an underpowered feasibility case series such as this.

However, there's a difference between can and should.  I'm uncertain whether we should even be exploring the can portion in this pilot, considering should means a grossly excessive allocation of resources for a therapy of uncertain benefit.  Given the small absolute benefits seen in the handful of trials that even showed a benefit, I can't possibly see how trials of pre-hospital lytics could favor anything but surrogate endpoints, rather than patient-oriented endpoints.  30 minutes faster to TPA?  At what cost, and did outcomes change?

I won't fault the authors for their interesting experiment – as long as they don't seriously propose it as The Future based on our current evidence.

"Prehospital thrombolysis in acute stroke : Results of the PHANTOM-S pilot study"

Friday, December 14, 2012

More C-Spine "Doom and Gloom"

If you haven't been paying attention to the literature, then you're practicing completely unawares of an epidemic of missed spinal cord injuries.  From the literature that suggests CT isn't adequately sensitive and the final common pathway for c-spine clearance should be MRI, to this new article that says all of those studies in summary aren't enough – and patients might also need "erect cervical spine radiographs".

This is a case series – the authors bill it as a retrospective review, but the methods are laughably absent, at best – of four patients the authors identified as having cervical spine instability missed through traditional diagnostic methods.  These patients, aged 61 through 87, received Emergency Department evaluation for cervical spine injury, were treated conservatively initially, and eventually needed operative intervention.  The ED work-up of these patients can probably best be described as "interesting" – e.g., a 61 year-old female thrown from horse whose initial work-up involved only three-view radiographs of the cervical spine.  Or, a seventy-five year old man with a cervical fracture on CT who was managed initially in a semi-rigid collar without other assessment for ligamentous injury.

Regardless, each of these patients had some combination of eventual CT or MRI that failed to adequately describe the extent of cervical spine instability, but a simple erect radiograph demonstrated subluxation.  Interestingly, this is a little bit of full circle back to the days of flexion/extension films.  While other studies have demonstrated MRI picks up signal abnormalities not detected on CT imaging, the clinical significance of this is debatable.  Conversely, these dynamic/load-bearing plain radiographs offer a true functional test without precisely describing the injury – akin to the difference between cardiac stress testing and coronary angiograms.

These injuries are quite rare, and not every patient needs an MRI or dynamic testing for cervical stability.  However, in the end, these tests have a role and should be utilized as necessary in the appropriate clinical situation.

"Erect Radiographs to Assess Clinical Instability in Patients with Blunt Cervical Spine Trauma"

Wednesday, December 12, 2012

Next Up – Apixaban!

The latest installment of propaganda in the NEJM comes from Pfizer and Bristol-Meyers Squibb, the joint venture behind apixaban.  Along with rivaroxaban, apixaban is an oral Factor Xa inhibitor, another option in the procession of potential warfarin replacements.  The Xa inhibitors, while they've had their problems, improve upon their main competitor – dabigatran – because they can be reversed in the emergency setting using prothrombin concentrate complexes (PCCs).  Dabigatran, as we all know, has no practical reversal strategy.

This is AMPLIFY-EXT, the extended treatment option from AMPLIFY – where apixaban is continued for an additional 12 months for prophylaxis against recurrent venous thromboembolism.  In isolation, looks great!  The placebo group had an 8.8% VTE recurrence in the study period vs. 1.7% in either of the two apixaban doses.  And, major bleeding in the placebo group exceeded the apixaban groups – 0.5% vs. 0.2% and 0.1%.  More effective and safer than a sugar pill!

So, what's the problem?  Well, this is the third apixaban trial to be published in the NEJM in the last two years.  The first one, apixaban for acute coronary syndrome, showed no benefit and increased bleeding.  The next, apixaban for stroke prevention in non-valvular atrial fibrillation (ARISTOTLE), showed non-inferiority to warfarin – but the rate of major bleeding in that study was 2.1% per year.  Then, the NEJM also has a recent article regarding aspirin for the prevention of recurrent VTE – where the placebo group only had a VTE recurrence risk of 6.5% rather than the 8.8% observed in AMPLIFY-EXT.

You can't directly compare trial populations, of course, but it doesn't make any sense that bleeding would be reduced compared to placebo.  And, it's a straw man comparison with placebo – the correct comparison is rather head-to-head against a potentially efficacious agent, such as low-dose aspirin.  After all, low-dose ASA is pennies a day, rather than the ~$10 per day for apixaban.

Can't blame the pharmaceutical companies for selling, can only blame the suckers for buying.

"Apixaban for Extended Treatment of Venous Thromboembolism"

Monday, December 10, 2012

End-Tidal to Predict Operative Intervention in Trauma

In penetrating trauma, sometimes it's very simple to predict operative intervention.  However, sometimes, the perfusion states of our patients are less easy predict – vital signs frequently obfuscate the underlying clinical picture as the body compensates.

This is a prospective study that indirectly aims to validate end-tidal CO2 as a predictor of operative intervention in penetrating trauma by correlating it to serum lactate levels.  And, as their primary outcome, these investigators observed a strong correlation between ETCO2 and lactate levels (R^2 = 0.74).  For secondary endpoints – unsurprisingly, considering it was correlated with lactate – ETCO2 was also predictive of operative intervention.  In fact, the authors report ETCO2 was more predictive of intervention than lactate, although it seems a little odd to significantly outperform lactate, given the strength of their linear correlation.

Compared with systolic blood pressure, the test performance characteristics essentially tell us what we already know: normal blood pressure isn't helpful, low blood pressure is obviously helpful (98% specificity).  Lactate and ETCO2 are more sensitive to hypoperfusion states not reflected in vital signs, although, in this small study, even elevated ETCO2 would miss 1 in 5 operative interventions (sensitivity 82%) and would incorrectly predict 1 operative intervention for every 4 correct predictions (specificity 82%).

If prospective study confirms that ETCO2 outperforms lactate levels as an indicator of hypoperfusion, perhaps it adds something to the trauma bay evaluation.  Otherwise, it seems the most useful function might be to add to prehospital triage protocols – an environment where lactate wouldn't be available.

"Nasal cannula end-tidal CO2 correlates with serum lactate levels and odds of operative intervention in penetrating trauma patients: A prospective cohort study"

Friday, December 7, 2012

More About ABIs Than You Ever Needed

These American Heart Association scientific statements are really quite lovely.  Although much of the scientific discussion in this article pertains to the diagnosis of chronic vascular disease in the outpatient setting, measuring the ankle-brachial index has a place the the Emergency Department as well.

While most of the studies included in their mini-systematic review report AUCs for chronic peripheral vascular disease, the same principles apply for determination of acute peripheral vascular disease – relevant after lower-extremity penetrating trauma or fracture.  And, if you're going to use a test, sometimes it's fun to know all the gritty details underpinning the evidence, how the cut-offs were determined, the difference between doppler and oscillometric devices, how discrepancies between legs should be handled, etc.

In any event, an interesting piece of literature to skim and save as a reference.

"Measurement and Interpretation of the Ankle-Brachial Index : A Scientific Statement From the American Heart Association"

Wednesday, December 5, 2012

Send Your PE Patient to MRI!

Well, not exactly...but this is at least a "proof of concept" for cardiovascular magnetic resonance and the diagnosis of pulmonary embolism.

Obviously, helical CT has become the standard diagnostic modality for pulmonary embolism due to its rapid acquisition time and high sensitivity.  Unfortunately, contrast-enhanced scans through the thorax carry with them short- and long-term health risks.  So, what about MRI?

This small case series of twelve PE+ patients and twelve healthy controls undergoing CMR showed fair discriminatory power for pulmonary embolism.  On a per-patient basis, sensitivity was 100% – but to best evaluate a diagnostic test, it's probably important to consider a higher-resolution measure.  On a per-lobe basis, sensitivity was only 71% – with a kappa of only 0.69 for the reading radiologists.

And, then there's the minor issue that CMR is a 20-minute scan with 10 minutes of post-processing, so even when this is ready for prime-time, it's still going to have some practical limitations.

"Pulmonary Perfusion Imaging: New Insights Into Functional Consequences of Pulmonary Embolism Using a Multicomponent Cardiovascular Magnetic Resonance Imaging Protocol"

Monday, December 3, 2012

Don't Put Away the LP Needles Yet

There's been a bit of a healthy debate regarding the sensitivity of a negative non-contrast head CT for the diagnosis of subarachnoid hemorrhage.  At least one prominent Emergency Physician educator used some time at ACEP this year to describe why it wasn't time to rely solely on imaging, while a second prominent EP used his lecture time to say essentially the opposite.

This publication, in Annals of Emergency Medicine, tries to address this question and determine just how frequently a negative CT misses a subarachnoid hemorrhage from occult aneurysmal leakage.  Over 11 years, in 21 Emergency Departments, they were able to identify 55 cases in which CT missed a subarachnoid hemorrhage – some of whom had negative CTs within six hours of headache onset.

This study suffers as studies tend to suffer from the retrospective nature of chart review, from missing and imputed data, and from a small sample size despite the extensive time frame reviewed.  Overall, though, I would score it as a point for the "still needs LP" crowd – clearly, you will miss some SAH by foregoing LP.  But, modern CT scanners may have better sensitivity than the ones included from the early part of this decade-long review – and the false-positives and harms from false-positive LPs grow ever-closer to the the false-negatives from CT.

Still not a perfect argument in either direction.

"Nontraumatic Subarachnoid Hemorrhage in the Setting of Negative Cranial Computed Tomography Results: External Validation of a Clinical and Imaging Prediction Rule"

Friday, November 30, 2012

Dabigatran: Hidden Danger in the Home

The flaws with dabigatran have been well-described on this blog – mostly focusing on its lack of realistic reversal options.  However, less obvious are the unanticipated ways patients end up in situations requiring such reversal.

This case report from the Rocky Mountain Poison Center describes an elderly male on dabigatran who does something commonly seen in the elderly: he suffers acute renal failure from a minor medical illness.  Unlike warfarin, dabigatran is renally excreted, and should not be used by patients with reduced glomerular filtration rates – these patients were excluded from the Phase III trials.  In the presence of renal failure, the half-life increases from 12-17 hours to 18-27 hours, depending on the severity of the renal dysfunction.  This leads to supratherapeutic levels.

This patient was noted to have a dabigatran plasma concentration nearly triple the therapeutic mean and developed spontaneous, unremitting gastrointestinal hemorrhage.  Despite resuscitation, blood products, and emergency dialysis – which halved the dabigatran concentration within four hours – the patient expired. 

Clinicians using dabigatran, therefore, need be acutely aware of any clinical changes in their patients that may reduce renal function.

"Fatal dabigatran toxicity secondary to acute renal failure"

Wednesday, November 28, 2012

Make Ketamine Work For You

Along with droperidol and dexamethasone, ketamine is on my short list of favorite medications for use in the Emergency Department.  As this correspondence from authors at Highland Hospital summarizes, it's a floor wax and a dessert topping:
 - Use as peri-procedural pain control/anxiolytic to assist with subcutaneous infiltrative local anesthesia.
 - Use as adjunctive pain control in patients who are failing high-dose narcotics.
 - Use as pain control/anxiolytic in patients with significant supratentorial comorbidities.

These authors state "In clinical practice, chronic pain, psychologic distress, and behavioral disorders frequently overlap", and I couldn't agree more.  Sub-disassociative doses of ketamine (0.1 to 0.3 mg/kg) have an excellent safety profile and represent an ideal option for multiple common clinical situations in the ED.

If your ED restricts the use of ketamine, you need to make that stop.

"Emerging applications of low-dose ketamine for pain management in the ED"

Monday, November 26, 2012

Ultrasound – For Long Bone Fracture

I have to say, I'm a little confused by all the new SonoSite television ads – direct-to-consumer marketing for sports medicine ultrasonography?  Or for zero-complication central line placement?  Weird.

But, I digress.  A little.  This is a pediatric study of lightly trained ultrasonographers with varying levels of expertise using ultrasound to diagnose long-bone fractures.  They performed 98 ultrasound examinations that were followed up by plain radiography, and they picked up 41 of the 43 fractures present, with 8 false positives:  95% sensitivity and 85% specificity.  Six required reduction, all of which were identified as meeting criteria for reduction on ultrasound – as well as one additional false positive from a distal radius fracture.

As a feasibility study, it's a nice little pilot.  As a practice-changing strategy, it needs larger sample sizes and external validity.  However, it does seem as though it will soon become reasonable to use bedside ultrasound to quickly rule-out fracture in patients with a low pre-test probability, while plain radiography will continue to play a role in advanced orthopedics management.

"Emergency Ultrasound in the Detection of Pediatric Long-Bone Fractures"

Wednesday, November 21, 2012

All Elevated Troponins Are Not MI

Have you ever received sign-out on a patient, heparinized, awaiting cardiology consultation – and later, at your leisure, realized the troponin level just barely tips into positive territory and probably has nothing to do with acute coronary syndrome?

I know you have.

This is the cardiology "expert consensus" on interpretation of troponin elevations – 25 pages of clinical summary and 360 references worth of dissecting what an elevated troponin really means.  There's an hour-long lecture worth giving based on this publication.

The key portions include:
 - Figure 1, which is a nice conceptual overview in which elevated troponins are separated into their "ACS" and "non-ACS" categories.
 - Section 6, which discusses the possible role (if any) for troponins in non-ischemic conditions.
 - Appendix 4, the clinical conditions in which positive troponins are non-cardiac and confounding in origin.

Positive troponins need to be evaluated properly in their clinical context, and this is a lovely (if very, very long) reference document for describing it.

"ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations"

Monday, November 19, 2012


This is my favorite sort of article to feature on this site – a probably-overlooked letter about a certainly-overlooked feature of a landmark trial.

This author, from Mt. Sinai, notes last year, the authors of ECASS III updated their online manuscript to change a p-value in their baseline characteristics from 0.03 to 0.003.  Since these are p-values for baseline characteristics, they're only for illustrative purposes – considering, in randomized controlled trials, all the differences do occur by "chance".  However, the conceptual interpretation of this change in ECASS III is the placebo group was inadvertently randomized to have a history of prior stroke by a 7% absolute difference – and the chance of that occurring randomly has now admitted to be 1 in 300 rather than 1 in 30.  When tremendously unlikely differences in baseline characteristics occur "by chance", it raises troubling questions regarding whether they truly occurred randomly.

Additionally, the author of this letter also makes the astute point that, because this difference in baseline characteristics did not reach statistical significance by the ECASS III authors' definition (0.004), it was not adjusted for in their data analysis.  
In his adjusted reanalysis (data not shown), the significance of outcomes favoring thrombolysis disappears (OR 1.19, CI 0.89-1.59).  Not necessarily surprising, considering the updated meta-analysis including IST-3 data published in The Lancet also makes the statistical significance of the benefit of thrombolysis disappear past 3 hours.

Thrombolysis for acute stroke remains some of the most distorted treatment data in emergency medicine, where this heterogenous patient population is being overtreated based on "eligibility", rather than "likelihood of benefit".

"Implication of ECASS III error on emergency department treatment of ischemic stroke."