Author: Ryan Radecki

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

Defensive Medicine is Defensive

Sometimes, people order a CTA chest to evaluate for pulmonary embolism because they’ve used the available evidence to risk-stratify the patient for a pulmonary embolism, and it’s an important diagnosis to make.  Sometimes, people order CTAs of the chest to evaluate for pulmonary embolism out of defensive practice, in order to avoid missing a pulmonary embolism.

There are some holes in this paper, considering how few patients in their cohort received the study intervention.  However, the general statistical gist was is that physicians who indicated that defensive medicine played a role in their ordering decisions had a much lower yield on their CTA for PE.  Conversely, elevated Wells/Geneva scores were associated with higher yield CTA.  Positive d-Dimers and patient request were non-significantly positively associated with increased CTA yield.

Not precisely an earthshaking paper, but it does weakly reinforce what we probably already suspected – defensive medicine harms the patient and the healthcare system.

“Ordering CT pulmonary angiography to exclude pulmonary embolism: defense versus evidence in the emergency room”
www.ncbi.nlm.nih.gov/pubmed/22584801

Plain C-Spine Radiography in Children

In adults, the use of plain radiography has largely been replaced in the U.S. by computed tomography over concerns regarding missed injuries – and some literature even argues that, given the right clinical circumstances, even a normal CT scan is inadequate.  But, in children, the harms of radiation exposure are greater, so pediatrics has been more hesitant to move to CT as the first imaging study of the cervical spine in blunt trauma.

Unfortunately, this retrospective PECARN study of children with cervical spine injuries isn’t as helpful as one would hope.  The authors identified 204 children, 58 of whom were aged less than 7 years, who sustained a CSI and had plain radiographs of the cervical spine performed.  Of these patients, 127 patients had a definite injury on plain radiography.  41 additional patients had “possible” abnormalities.  Then, 20 films were judged to be inadequate by technique.  And, finally, there were 18 adequate radiographs with normal findings who subsequently had a CSI identified.  The overall sensitivity, then, was 90% (CI 85-94%) – which compares very similarly to the sensitivity in adults from the 34,000 patients in the NEXUS study.
The authors note that most missed injuries fell into two general categories: they were either subtle and non-morbid, or the patients were altered/intubated/focal neurologic findings.  It is probably still reasonable to start with screening plain-film radiography and use clinical judgment to determine when CT may be necessary, but if you’re looking for airtight evidence to guide your decision-making, CSI in children is too rare to generate that sort of data.
“Utility of Plain Radiographs in Detecting Traumatic Injuries of the Cervical Spine in Children”

Azithromycin – Not Guilty of Murder

The FDA has announced it is reviewing the safety of azithromycin in lieu of a recent NEJM article documenting an association between azithromycin and cardiovascular death.  In theory, azithromycin has been implicated in QT-prolongation and pro-arrhythmic effects, leading to torsades de pointes and polymorphic ventricular tachycardia.  The authors of this study therefore hypothesized an association between azithromycin use and cardiovascular death.

This is a retrospective study of computerized data generated from the Tennessee Medicaid program between 1992 and 2006, linking deaths to any concurrent antibiotic prescriptions.  The authors data-mined for a cohort aged 30 to 74 years of age, had no “life threatening non-cardiovascular illness”, did not abuse drugs, and did not reside in a nursing home.  They compared azithromycin prescriptions to non-prescription controls, as well as amoxicillin, ciprofloxacin, and levofloxacin cohorts.  And, after a little statistical maneuvering, they report a death rate of 85.2 per 1,000,000 courses of antibiotics with azithromycin, which compares to a death rate of 29.8 with no antibiotic and 31.5 with amoxicillin.

So, for every ~20,000 prescriptions of azithromycin written, there is one additional death from cardiovascular causes.  This is another one of those cases where the severity of the absolute difference doesn’t quite match the relative difference – it is likely any efficacy difference between a macrolide and a second-line agent results in greater morbidity than the magnitude of effect found in this study.

Then, azithromycin is frequently prescribed for upper and lower respiratory tract infections – conditions that, in the absence of other specific signs, might be non-infectious cardiovascular disease misdiagnosed as having an infectious etiology.  In their non-propensity matched cohorts, 50% more azithromycin prescriptions were written for respiratory symptoms than amoxicillin.  The propensity matching in their statistical analysis attempts to account for this, but 30% of their azithromycin prescriptions had no documented indication – which I think means there’s likely a hidden statistical difference in underlying pathophysiology secondary to unknown indications.

Finally, this runs contrary to a 2005 article “Azithromycin for the Secondary Prevention of Coronary Events” published in NEJM – at one point, it was theorized that azithromycin would be protective for coronary events.  For 4,000 patients who took azithromycin weekly for a year, there was no difference in cardiovascular outcomes as compared to placebo (CI -13% to +13% relative risk reduction).

There are lots of reasons not to prescribe azithromycin, but this study isn’t the one that should change your practice.

“Azithromycin and the Risk of Cardiovascular Death”
http://www.nejm.org/doi/full/10.1056/NEJMoa1003833

The Papermate Flexgrip Cricothyroidotomy

Emergency Medicine has more than a little MacGyver instinct to it – and one of the semi-urban legend aspects of EM is the ability to perform a cricothyroidotomy as a life-saving measure in any situation.  The most commonly described version is performed using simple, commonly available tools – any sort of cutting blade and a hollow tube, such as a hollow pen.

Several studies have approached feasibility by describing the flow dynamics of various pens, but this is the first study to evaluate the procedural feasibility of bystander cric.  This is an observational, cadaveric study using non-EM junior physicians and medical students in which they used a 26-blade scalpel and a Papermate ballpoint pen of 8.9mm external diameter to attempt an “off-the-cuff” cric.  The 9 participants attempting 14 procedures were successful 8 times, although complications were frequent, including vascular and muscular/cartilaginous injuries.

Whether this is externally valid to the living, or to patient-oriented outcomes of effective ventilation, I’m not so certain – but, then again, if the alternative is 100% mortality via no possible ventilation, it’s a fun study to see.

“Observational cadaveric study of emergency bystander cricothyroidotomy with a ballpoint pen by untrained junior doctors and medical students”
http://emj.bmj.com/content/early/2012/05/04/emermed-2012-201317.short

Reducing ED Overcrowding Reduces Mortality


In Western Australia, in 2008, a mandate was undertaken in which Emergency Departments were to implement processes requiring patients to be discharged or admitted within four hours of presentation.  These rules phased in through 2009 in the tertiary hospitals, and then in 2010 in the secondary hospitals.

Of course, with an arbitrary mandate to simply “work faster,” the concerns were that this would have adverse effects on mortality.  Rather, the overall mortality of patients admitted through the Emergency Department tended to decrease during this time period.  Each of the hospitals spent less time of ED diversion (“access block”) as well.

The article doesn’t mention specifically what process changes were implemented, but it does allude to and likely understates the resistance met while making ED overcrowding a problem for the entire hospital.  Authors report that shifting patients out of the Emergency Department led to a greater proportion of the initial investigations being performed on the inpatient wards, leading to some professional stress.

Regardless, this article seems to suggest that it is feasible, in a culture accepting of change in practice pattern, to decrease the amount of time patients spend in the Emergency Department.  It also seems to demonstrate it is, at least, potentially safe.  That being said, it would be quite a feat to accomplish something similar here in the U.S., given the various warring incentives at work in our highly dysfunctional system.

Emergency department overcrowding, mortality and the 4-hour rule in Western Australia”
www.ncbi.nlm.nih.gov/pubmed/22304606

Codeine, Potentially Unpredictably Lethal

Frequently used in the pediatric population, codeine is a narcotic analgesic in prodrug form.  In the body, codeine is metabolized to morphine through the CYP2D6 pathway.  In the general population, it is estimated that approximate 10% of codeine undergoes conversion to morphine.

We’re generally familiar with the concept that a certain percentage of the population is ineffective at metabolizing codeine, and therefore receives no additional analgesic effect.  However, the flip side, as these authors report, is a CYP2D6 genotype of over-metabolizers.  In this case series, the over-metabolism of codeine in three post-surgical children likely resulted in supra-therapeutic conversion to morphine, leading to respiratory arrest.

The short summary – when possible, avoid medications that are unpredictably metabolized – such as codeine.

“More Codeine Fatalities After Tonsillectomy in North American Children”
www.ncbi.nlm.nih.gov/pubmed/22492761

Suprapubic Tap Should Be Used for Urinalysis in Children?

“Ideally, SPA should be used for microbiological assessment of urine in young children,” states the abstract conclusion for this article from Australia.


Looking retrospectively at urine samples from 599 children with an average age of 7 months, these authors conclude that suprapubic aspiration is superior to all other methods of obtaining urine samples for contamination rates.  Contamination rates were 46% with bag urine, 26% for clean catch, 12% for catheterization, and 1% for suprapubic aspiration.


We generally rely on catheterized urine samples in our Emergency Departments – and we even have difficulty convincing some parents that this is required, let alone a suprapubic aspiration.  In fact, I’m rather surprised they had 84 patients (14%) in their cohort receiving suprapubic aspiration, considering I have never seen it performed.


While I have no issue with their conclusion from a microbiologic accuracy standpoint, I’m not so sure such an invasive and painful procedure has a place in routine practice.


“Contamination rates of different urine collection methods for the diagnosis of urinary tract infections in young children: An observational cohort study.“
www.ncbi.nlm.nih.gov/pubmed/22537082

A Chest Pain Disposition Decision Instrument

This article has three things I like – information graphics, informed patients, and an attempt to reduce low-yield chest pain admissions.  Unfortunately, in the end, I’m not sure about the strategy.

This is a prospective study in which the authors developed an information graphic attempting to illustrate the outcome risks for low-risk chest pain presentations.  They use this information graphic as the intervention in their study population to help educate patients regarding the decision whether to be observed in the hospital with potential provocative stress testing, or whether they would like to be discharged from the Emergency Department to follow-up for an outpatient provocative test.  They were attempting to show that use of this decision aid would lead to increased patient knowledge and satisfaction, as well as reduce observation admissions for low-risk chest pain.

The good news: it definitely works.  Patients reported increased knowledge, most were happy with the decision instrument, and a significantly increased proportion elected to be discharged from the Emergency Department – 58% of the decision aid group wanted to stay vs. 77% of the “usual care” arm wanted to stay.

My only problem: this study truly exposes the invalidity of our current management of chest pain.  If these patients are low-risk and they’re judged safe enough for the outpatient strategy in this study – why are any of them being offered admission?  Of course, it’s probably because they don’t have timely follow-up, and AHA guidelines dictate stress testing urgently following the index visit.  But, truly, in an ideal world, few (if any) of these low-risk patients – such as the one who ruled in by enzymes – should be offered admission.

But, other than that, I’m all for information graphics and patient education techniques to include them in a shared decision-making process!

“The Chest Pain Choice Decision Aid : A Randomized Trial”
www.ncbi.nlm.nih.gov/pubmed/22496116

Outpatient Management of PE – With ERCast

Hosted by the mellifluous Rob Orman, we discuss a couple recent articles regarding the outpatient management of low-morbidity pulmonary emboli.  Short summary:  overdiagnosis of pulmonary emboli of uncertain clinical significance notwithstanding, the key to managing physiologically intact patients with pulmonary emboli is close follow-up to minimize the length of time patients are subject to dual anticoagulation.

Listen at:  ERCast – Pulmonary Embolus Outpatient Treatment