Prime Time for Dexamethasone in Asthma?

We adore dexamethasone here at EMLoN headquarters.  A pharmacy stocked solely with ketamine, droperidol, and dexamethasone could carry you far in life.  Unfortunately, because of our established bias, the challenge then arises to reconcile the actual results of a trial with what is so desperately wished to be true.

This is a randomized, double-blinded, non-inferiority trial comparing single-dose dexamethasone with five days of prednisone in the treatment of asthma with acute exacerbation.  Single-dose and double-dose dexamethasone protocols have been evaluated in pediatric trials of reasonable size, but data in adults has been lacking.  However, many clinicians – including myself – have assumed generalizability of the pediatric findings to adults, and have been using single-dose dexamethasone protocols for years.

If only one takeaway can be had from this trial, it is: never, ever, skimp on sample size. Far easier said than done, of course, but due to the complex structure and assumptions required for non-inferiority trials, this is a negative trial.  There were 465 subjects randomized – but 89 excluded from analysis as either subsequent admissions or as lost to follow-up.  Of the remaining 376 patients, 9.8% of the prednisone group demonstrated Emergency Department recidivism compared with 12.1% of dexamethasone.  This 2.3% difference between groups, however, suffers a 95% of -4.1 to 8.6%, and exceeds the pre-determined clinically-relevant non-inferiority margin of 8%.

So, unfortunately, we still do not have a precise estimate for the effectiveness difference between a prednisone-based strategy and dexamethasone.  Considering the healthcare burden of asthma in our Emergency Departments, it is somewhat surprising we still have such a paucity of data – as even a small difference in effectiveness may have profound effects on Emergency Department utilization.  In the end, it comes down to where you lay on the spectrum of pre-study odds for non-inferiority or equivalence.  For me, the guarantee of compliance with treatment derived from a single-dose of dexamethasone outweighs the continued uncertainty over its true effectiveness, and this study gives me no cause to change my practice.

“A Randomized Controlled Noninferiority Trial of Single Dose of Oral Dexamethasone Versus 5 Days of Oral Prednisone in Acute Adult Asthma”

Endovascular for Stroke – Even Better than the Evidence

What happens when you let Medtronic, et al, author an article on endovascular therapy in The Lancet:  exactly what you’d expect.

We are, in principle, fans of endovascular therapy for acute stroke as presented in the major trials: ESCAPE, EXTEND-IA, and SWIFT-PRIME.  These trials carefully selected eligible patients by use of advanced perfusion imaging and demonstrated high rates of revascularization.  Viable brain plus restored flow has face validity for improved outcomes.

However, these sponsored authors use the meta-analysis for its most nefarious purpose: to obfuscate the important subtleties and eligibility criteria of its included trials.  These authors pool the aforementioned trials, along with MR CLEAN and REVASCAT to provide the following conclusion:

“Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location.”(emphasis mine)

The authors also provide a staggering number-needed-to-treat for endovascular therapy of 2.6.

But, of course, this was written to shock and awe the lay press and general medicine community, rather than edify the astute clinician.  Their NNT is not based on the typical dichotomous cut-off used in stroke trials of mRS 0-1 or 0-2 – but rather the hopelessly flawed ordinal shift analysis.  As the decades turn, apparently, we have forgotten why this approach was frowned upon from the start: it is not appropriate to equate the outcome value difference between mRS 5 and 4 with the difference between mRS 3 and 2, and the limitations in inter-rater reliability in the mRS introduce a vast additional amount of measurement error.  Then, by burying any mention of the strict imaging criteria responsible for the bulk of benefit seen in these trials, they mislead the reader into considering this therapy appropriate for all-comers.

Is there any value to these data as presented?  A little.  There is hypothesis generating evidence that tPA prior to endovascular therapy provides no additive benefit.  There is also evidence that increasingly distal sites of occlusion may not benefit from intervention.

Unfortunately, the flaws in this article outweigh the few potentially usable insights.  This is just yet another piece of direct-to-physician marketing masquerading as scientific evidence.

“Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials”

How Many ED Visits are Truly Inappropriate?

I’ve seen quite a bit of feedback on social media regarding this research letter in JAMA Internal Medicine.

This study evaluated, using National Hospital Ambulatory Medical Care Survey data, the incidence of hospital admission stratified by triage Emergency Severity Index.  They analyzed 59,293 representative visits from the sample and found 7.5% of them, on a weighted basis, were categorized as “non-urgent” – an ESI level 5 or presumed equivalent.  The typical assumption regarding these non-urgent visits is they represent inappropriate Emergency Department utilization.  This study found, however:

“… a nontrivial proportion of ED visits that were deemed nonurgent arrived by ambulance, received diagnostic services, had procedures performed, and were admitted to the hospital, including to critical care units.”

There are always limitations regarding the NHAMCS data, particularly with missing and imputed data.  Based on this, I tend to feel these data lack face validity.  The weighted incidence of admission for non-urgent patients was 4.4% compared with 12.8% of urgent visits, while 0.7% of non-urgent visits were to critical care units compared with 1.3% of urgent visits.  I certainly do not see similar relative proportions of admission, and then to critical care, for level 5 patients in my multiple practice environments.

Regardless, the general implication made by these authors is probably reasonable, refuting usage of ESI triage level 5 to accurately represent inappropriate Emergency Department visits.  However, left equally unstated, is an acknowledgement that ESI also fails to accurately categorize urgent visits – which ties to the rhetoric of trying to conflate “non-urgent” as “inappropriate and “urgent” as “appropriate”.

ESI, as currently implemented, will not be a reliable tool for directing patients to other sources of care – but, with some fuzziness, probably still gives a reasonable estimate of the overall burden of inappropriate ED visits for some policy applications.

“Urgent Care Needs Among Nonurgent Visits to the Emergency Department”

Try to Avoid tPA When Already Bleeding

Coming to us from the Department of Common Sense: don’t give tPA to stroke patients who already have intracranial hemorrhage.  There’s a little more subtlety here, of course, because in this instance, we’re dealing with cerebral microbleeds – tiny foci of angiographic damage visualized only on MRI.

These authors performed a pooled and individual-patient meta-analysis of those undergoing MRI prior to treatment with intravenous thrombolysis.  When stratified by CMB burden, arbitrarily divided into “none”, “1-10”, and “>10”, the obvious is … obvious: patients who are already bleeding are more likely to continue bleeding.  In the unadjusted raw numbers, patients with no CMB had a symptomatic intracranial hemorrhage rate of 4.3%, those with 1-10 CMB had 6.1%, and those with >10 had 40.0%.

There are many technical limitations inherent to the retrospective nature of their study, as well as likely other confounding variables – but, the basic gist: our current practice relying only on non-contrast CT likely misses an important safety indicator in the setting of tPA use.

“Risk of Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke and High Cerebral Microbleed Burden”

Trauma is Still Trauma the Next Day

Acute closed head trauma is easy enough – and challenging enough.  There are validated decision instruments and guidelines, yet still plenty of CTs performed absent sound indications.  However, the question this study addresses is slightly different: what to do with those who present in a delayed fashion following minor head trauma?

The authors probably sum it up best in a reasonably concise fashion:

“Patients presenting after 24h of injury are a potentially distinct subpopulation. They could be at lower risk, as there is evidence that patients with mild/minor head injury who have injuries requiring neurosurgery will deteriorate within 24h. Alternatively, they could be a self-selecting higher-risk group attending due to the worsening or persistence of symptoms.”

These authors reviewed 2,240 patient encounters resulting in a CT scan of the head, with a goal of winnowing it down to just those performed for a traumatic indication.  Of those, 549 were performed within 24 hours of injury and 101 were delayed presentations.  There were 46 (8.4%) CTs positive for traumatic injury in the acute presentations and 10 (9.9%) in delayed, while 5 and 3 patients each underwent neurosurgical intervention, respectively.  So, the answer to their research question, at least in pragmatic terms, may be that the two forces balance each other out.

These authors also present “sensitivity” statistics regarding the utility of guidelines at predicting the presence of an important TBI, and quote a sensitivity of 70% based on chart review.  The denominator for sensitivity would more appropriately the entire population of presentations for trauma, not simply those who underwent CT scanning.  It is also probably more likely, given these patients had important TBI on CT, there may have been undocumented, guideline-compliant, indications not abstracted by chart review.

While our decision instruments for closed head injury were derived in typically an acute population, I would not yet draw any conclusions refuting their generalizability to delayed presentations.

“CT head imaging in patients with head injury who present after 24 h of injury: a retrospective cohort study”

The Unmagical Checklist

The checklist has reached ascendant status in medicine.  As introduced into the mainstream by Atul Gawande, they have begun to permeate every nook of healthcare delivery.  However, evidence of benefit when applied to one particular problem in one particular setting is no guarantee of universal utility.

These authors performed a study in Brazilian intensive care units, using a cluster-randomized pre/post design to evaluate the effect of a quality improvement effort built around a checklist.  Each element on the checklist represented a consensus or evidence-based practice associated with improvement in surrogate markers for patient outcomes.  The combined intervention was hoped to improve overall in-hospital mortality for ICU patients at the intervention hospitals.

It didn’t – mortality increased similarly for both intervention and control ICUs.

In fact, for all secondary clinical outcomes – catheter-related infections, ventilator-associated pneumonia, urinary tract infections, ICU days, etc. – there were no significant improvements over the baseline period, and no difference compared with controls.  There were small improvements in processes of care, such as VTE prophylaxis, catheter use, and appropriate tidal volumes during ventilation – but without corresponding clinical outcome improvement.

Interestingly, clinicians working in the intervention ICUs typically felt as though their ICUs were safer.  They were more likely, sometimes significantly so, to provide answers reflecting positive associations regarding their working conditions and safety climate.  Indeed, the intervention was perceived as so likely to be beneficial even prior to the start of the study that a short duration was mandated for the trial so all ICUs could eventually start using the checklist.

These authors have several justifications for why their checklist did not function appropriately, focusing on various details regarding the trial.  I think the simplest expression regarding the effectiveness of a checklist relates to the magnitude of effect and the baseline frequency of adherence.  Unless a significant magnitude of effect is seen by improving compliance with an intervention, and the intervention itself is infrequently performed, returns will diminish dramatically.  A checklist such as this, with multiple low-yield elements, is unlikely to return substantial patient-oriented outcome improvements.  Indeed, the resources devoted to checklist rounding and adherence may even dilute the focus on important clinical considerations.

“Effect of a Quality Improvement Intervention With Daily Round Checklists, Goal Setting, and Clinician Prompting on Mortality of Critically Ill Patients”

Putting Children to the Flame

Many readers here are students, trainees, or otherwise academic-affiliated, and have limited exposure to the world of community practice.  In these settings, frequently, our pediatric exposure is supervised by clinician-educator sub-specialists in Pediatric Emergency Medicine.  We see the very best evidence translated into acute care of children in the Emergency Department.

The real world is a little different.

These two articles describe the shortcomings of advanced imaging practice in community pediatric settings – in the diagnosis of appendicitis, and in the evaluation of closed head injury.

In the appendicitis article, the authors compare two settings both staffed by PEM physicians – an academic medical center with in-house pediatric surgical coverage, and a community center with consultation available only by phone.  Each site had similar rates of appendicitis diagnoses – 4.7% vs. 4.0% at the academic and community site, respectively.  The academic site, however, evaluated fewer patients with abdominal pain with blood work, and then fewer still of those went on to advanced imaging.  Then, of those receiving advanced imaging, the rates were 10.8% CT at the academic center vs. 28.1% CT at the community center.  Ultrasound however, was employed in 16.6% of cases at the academic center versus 6.5% at the community practice.  Nearly all this difference, however, seemed to be made up of patients admitted to the hospital without any operative intervention.  The obvious reality, then:  radiation in lieu of observation.

The second article here describes the neuroimaging (CT or MRI) of patients evaluated following trauma, along with their ultimate disposition.  Of 2,679 patients reviewed, there were 94 patients with important non-surgical, trauma-related diagnoses, and an additional 16 patients who required neurosurgical intervention.  These authors, however, based on GCS estimates recorded and the distribution of outcomes in the PECARN study, estimate the prevalence of entry criteria into appropriate scanning would have obviated >2000 of these scans.  While I believe they are probably mis-applying the evidence and overstating the inappropriateness of CT, the rarity of serious diagnoses suggests at least a majority of these CTs probably could have been avoided.

In short, we’re still doing too many CTs on children.  Some of the contributing issues are systems based, and some are related to practice re-education.  More ultrasound and more observation, please – and less nuking of children.

“Imaging for Suspected Appendicitis: Variation Between Academic and Private Practice Models”

“Neuroimaging Rates for Closed Head Trauma in a Community Hospital”

Hello, Have You Heard of NEXUS/CCR?

In the same vein as my previous post inappropriate imaging despite the presence of PERC, this next article takes our evaluation of minor trauma to task.

This brief retrospective series looked only at presentations to the Emergency Department following “ground level fall” leading to a CT of the cervical spine.  These authors defined a “ground level fall” as fall of fewer than 3 feet or 5 stairs.  These authors then reviewed the documentation associated with each case for criteria specifically excluding the case from NEXUS or CCR and appropriate for CT imaging.

Of the 760 patients with ground-level falls included in this study, there were 7 cervical spine fractures – 6 stable, and 1 unstable.  All patients with a cervical spine fracture had documented criteria supporting appropriate CT imaging.  However, based on their retrospective review, 22.0% and 20.7% of encounters specifically documented criteria meeting NEXUS and CCR, and should not have led to CT imaging.  An additional 9.3% and 29.9% of patients had insufficient documentation of NEXUS or CCR criteria needed to determine appropriateness.

These authors posit there may be substantial cost savings to the healthcare system if these decision instruments are appropriately applied.  I tend to agree – although, there are obvious limitations to this sort of retrospective review.  It does, at least, back up my own anecdotal experience witnessing clinically questionable use of advanced imaging in minor trauma.

“Utility of computed tomography imaging of the cervical spine in trauma evaluation of ground level fall”

Amiodarone, Lidocaine, or … Nothing

The prehospital game has always been muddy, particularly when it comes to the various pharmacologic interventions fixed in the constellation of Advanced Life Support.  You could – and some have – go as far as to say virtually nothing in the armamentarium of prehospital care has been proven to improve meaningful survival following cardiac arrest.

This latest evidence drop is the ALPS trial from the Resuscitation Outcomes Consortium – amiodarone, lidocaine, or placebo in patients with shock-refractory ventricular fibrillation/ventricular tachycardia.  The underlying physiologic theory would be that there’s a period of time between onset of VF/VT and death where drugs are the answer.  Early on, an appropriately delivered shock solves the disorganized electrical problem.  Later on, after the intracellular rigor sets in, nothing will be reliably beneficial.  In some intervening period, there is hope that amiodarone or lidocaine provides a little extra stabilization to help a shock take hold.

These authors performed a prospective, double-blinded, placebo-controlled, randomized trial with three arms to compare each antiarrhythmic therapy to placebo.  With a 90% power to detect a 6% survival to hospital discharge between arms, these authors enrolled 3,026 patients.  Groups were generally well-balanced for important prognostic features, adjunctive treatments, and post-admission care.  But, unfortunately, the survival advantage seen was 3.2% for amiodarone and 2.6% for lidocaine – meaning the confidence intervals each cross unity and the p-values are 0.08 and 0.16, respectively.

So, we have, yet again, a study that provides more to argue about than to inform practice.  Delving into the secondary outcomes and the supplementary appendix, it is clear that both antiarrhythmic drugs are doing something.  Patients receiving the active arms in the trial required fewer shocks, received fewer doses of alternative antiarrhythmic drugs (e.g., magnesium, procainamide), and had significantly higher rates of hospital admission – 45.7% vs. 47.0% as. 39.7% for amiodarone, lidocaine, and placebo, respectively.  However, all these advantages on the front-end decayed into smaller and smaller absolute differences on the back end – where mRS 3 or better discharge status was only 18.8% vs. 17.5% vs. 16.6%.

The glass half-full look at this is: even though it’s not statistically significant, even a couple percentage points of life vs. death represents a couple thousand additional neurologically intact survivors each year.  The glass half-empty look at this is: 26.9% of the amiodarone group required immense resource outlay and ICU care and was still ultimately dead or disabled, along with 29.5% of the lidocaine group, but only 23.1% of the placebo group.

These data suggest many reasonable choices may be made.  The signal may not be strong enough, and the downstream costs high enough, that a case could be made to dramatically curtail use of both active drugs.  Or, specific instances of use or delivery improvements could be proposed, based on other survival signals hidden in the secondary data.  Finally, costs, ease of use, and other secondary signals could make dueling cases to discontinue use of one of the two active drugs.

I think these drugs probably have value – but, their value won’t be maximized until in-hospital care produces either a better yield of neurologically intact survivors or better prognosticates resuscitation to reduce ultimate resource utilization.

“Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest”

Where Acute Otitis Media is Born

Is it 3 AM in your Emergency Department?  Is there a febrile infant with their still-awake parents straggling in the door?  Do you hear the first few bars of the “it’s just a virus” song start playing over Spotify?

This little study prospectively enrolled healthy infants at birth and followed them to their first episode of acute otitis media or 12 months of age.  They were followed specifically to determine predictive clinical and epidemiological factors influencing the first diagnosis of AOM.  Additionally, as they aged and during illness, nasopharyngeal swabs were taken to evaluate viral and bacterial flora.

Based on a sample of 367 infants followed for a total of 286 child-years, there were 887 presentations for viral URIs and 180 presentations for AOM –and all but two of AOMs were preceded by a URI.  The median time from URI presentation to AOM diagnosis was 3 days.  These authors also present a fair bit of microbiologic data regarding specific risks for URI and AOM, although these are not specifically modifiable and of lesser clinical relevance.  From a modifiable environmental outlook, however, there are a few interesting tidbits tying into what we already suspected to be true:  breastfeeding is good, the new PC13 vaccine is good, and daycare is a cesspool.

Overall, this would tend to support our typical advice to parents to have their children present for a recheck 48-72 hours following Emergency Department visit, particularly if there has not been clinical improvement or in the context of apparent clinical re-worsening.

“Acute Otitis Media and Other Complications of Viral Respiratory Infection”