Month: July 2018

Home is Where the Blood Pressure Monitor Is

This article regarding the prevalence of Emergency Department visits opens in quite the disarming fashion, noting, casually, the anecdotal impression of increased visits for elevated blood pressure detected by a home machine. That’s a nice way of saying “Every. Damn. Day.”

So, how often are these “worried well” ending up in our Emergency Department? According to these authors – we don’t know. We don’t know because yes, a little over 40% of those visiting the ED with a primary diagnosis of “hypertension” were the result of home blood pressure readings, but 37% of their cohort was “not documented”. It is difficult to interpret the source of the “not documented” – were they in the ED for another symptom? Or was there some other referral source? It’s unfortunately impossible to say. Regardless, this 40% self-referral due to home blood pressure readings dwarfs that of those who detected an elevated blood pressure at a pharmacy (8%) or MD office (13%). So, even if precision is lacking in these data, the proportion is substantial – and probably fits with our anecdotal sense.

Median blood pressure from the referring source, when available, generally exceeded the ED measurement – which was a median of 182/97 in triage. Interestingly, a 41% of patients received some sort of medication for blood pressure control while in the ED. Another 7% of patients necessitated admission – which is where this article sort of starts to get muddy. The overall intent seems to be to describe this influx of aforementioned “worried well” due to home blood pressure monitors, but a 7% admission rate is hardly trivial – and actually 78% of patients complained of some potentially related or important concurrent symptom. The most common somatic complaints were headache (38%), dizziness (30%), and chest pain (16%). This isn’t exactly a cohort of “asymptomatic hypertension”, and shouldn’t be perceived as a proxy for potentially unnecessary ED utilization.

Of course, there is the chicken and egg paradox with these symptoms – are they somatization of anxiety from the elevated blood pressure or true pathology? Considering the relative paucity of admissions from this fairly symptomatic cohort, it does not appear treating clinicians generally considered the elevated blood pressure related to important end-organ dysfunction. Then, there are the obvious limitations to their chart review and the generalization challenges from this regional catchment area in Canada. Many words later, at the least, there is one reasonable takeaway regarding ED patients with home blood pressure monitors – it is true, they’re everywhere!

“The Characteristics and Outcomes of Patients Who Make an Emergency Department Visit for Hypertension After Use of a Home or Pharmacy Blood Pressure Device”
https://www.ncbi.nlm.nih.gov/pubmed/30037583

The Futility of Repeat Imaging in Seizure

In the adult patient with new-onset seizure, it can be reasonable to pursue emergency neuroimaging in many cases. However, the vast majority of presentations to the Emergency Department for seizure are for those with known seizure disorders. In this population, the calculus is different.

This is a retrospective review of 822 presentations for non-index seizures from two hospitals, examining the rate of neuroimaging and incidence of clinically important new findings. Of these, neuroimaging was obtained in about half. Of these 381, only 8 had true positive, clinically important findings on imaging. All of these cases had persistent altered level of consciousness, head trauma, or a focal finding on examination. Absent these factors, there were no cases of true positive imaging findings related to the acute presentation. If imaging were deferred in those cases absent any of those three factors, approximately half of scans could have been obviated.

This is a small sample at two academic institutions and a retrospective evaluation, so it is hardly definitive. However, the authors’ conclusion is reasonable there is certainly an opportunity to further reduce unnecessary imaging in non-index seizures.

“Emergency department neuroimaging for epileptic seizures”

https://www.ncbi.nlm.nih.gov/pubmed/30019464

Bring Back Your Dead

When you take vacation, the relentless march of the medical literature does not. Even though this blog is a week late to this party – an eternity in the world of rapid post-publication peer review – I would be remiss not to here briefly mention PARAMEDIC2.

This is, by far, the largest prospective, randomized, controlled trial of epinephrine in out-of-hospital cardiac arrest. Effectively the mainstay of resuscitation for many decades now, smaller trials and other post-hoc analyses have found inconsistent survival advantages associated with its use. Epinephrine, it has seemed, will flog the heart back into some level of cardiac output compatible with “life”. However, the other deleterious effects of epinephrine – or the context of the peri-arrest physiology – fails to produce an advantage with regard to neurologically-intact survival.

And that’s what we see, again, here.

This trial enrolled 8,014 patients with OHCA with the primary outcome being survival at 30 days. The intervention arm administered 1mg intravenous or intraosseous doses of epinephrine every 3 to 5 minutes during resuscitation or saline placebo. Secondary outcomes were survival to hospital admission, length-of-stay in the intensive care unit, and neurologic outcomes at hospital discharge and at 3 months. A “favorable” neurologic outcome was defined as a score of 3 or less on the modified Rankin scale, which is a little bit different than other trials using Cerebral Performance Category.

Both cohorts were fairly evenly matched with regard to prognostic features, which is to say, they were basically terrible. Nearly 80% of the cohort had a non-shockable rhythm, although over 60% were witnessed arrest and had bystander CPR. Response times by ambulance to the scene were around 7 minutes, and 21 minutes elapsed between call and first use of trial medication.

Just as in the previous evidence, epinephrine functions as advertised – the return of spontaneous circulation in the prehospital setting was 36.3% with epinephrine, compared with 11.7% without. However, with every advancing time point, the gap between the arms narrowed. At hospital admission, epinephrine was favored 23.8% to 8.0%. Survival to hospital discharge favored epinephrine 3.2% to 2.3%, and then 3.0% to 2.0% at three months. Finally, neurologic outcomes were even more narrowly in favor of epinephrine at three months, 2.1% to 1.6%. Further splicing out the outcomes with regard to mRS, the small excess favoring epinephrine were those with mRS 3, whereas the small numbers with mRS 0,1 or 2 were effectively identical. Of note, from these 8,000 starting with cardiac arrest, only 27 survived with an mRS of 0. Bleak.

So, we’re effectively back where we started – but with the best evidence to date regarding the limitations of epinephrine. Giving epinephrine up-front is a rewarding, “life-saving!” experience for the initial treating providers. Unfortunately, the ultimate outcomes are effectively just as dismal – only vastly more costly in terms of real currency and resource utilization when epinephrine is featured. Until substantial advances can be made with regard to improving post-arrest functional outcomes, it is entirely reasonable to consider omitting epinephrine from resuscitation from out-of-hospital arrest.

“A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest”

https://www.nejm.org/doi/full/10.1056/NEJMoa1806842

Urgent Cares (and Emergency Departments and Medical Offices) Are the Worst!

This small research article has been making the rounds in the news over the last couple days. In theory, these findings supposedly surprising and enlightening – although to anyone in medicine, or who follows this blog, they are hardly profound.

This is a simple retrospective, cohort analysis of the Truven Health MarketScan Commercial Claims and Encounters Database, which pools de-identified data from patients with employed-sponsored health insurance. In this study, they simply chopped up claims for office, urgent care, retail clinics, and emergency department visits. They publish rates of antibiotic use for various coded discharge diagnoses, again, chopped into categories of “antibiotic almost always indicated” (e.g., urinary tract infection), to “antibiotic may be indicated”, to “Antibiotic-inappropriate” (e.g., influenza, bronchitis).

The numbers get ugly in this latter category, and reflect least favorably on urgent care clinics. Rates of antibiotic prescribing for viral upper respiratory infection and bronchitis, for example, were 41.6% and 75.8%, respectively. This is obviously pathetic, and urgent care centers are rightfully taking heat for this, but neither the ED nor the medical offices deserve much credit, either. The ED was at 18.7% and 56.6%, and offices were at 29.9% and 73.1%, for viral URI and bronchitis, respectively. Retail clinics were not great, but certainly better, at 10.5% and 31.1%.

Of course, these are coded diagnoses and do not always fairly reflect the underlying clinical presentation or diagnosis. And then there’s this:

“We used facility codes but could not validate whether facilities were actually urgent care centers, retail clinics, EDs, or medical offices.”

When the crux of the study pits these different types of facilities against each other, that’s probably somewhat important.

“Comparison of Antibiotic Prescribing in Retail Clinics, Urgent Care Centers, Emergency Departments, and Traditional Ambulatory Care Settings in the United States”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2687524

tPA in Under 20 Minutes is Recklessness

In my book, “safe” translates to a lack of attributable harm. Therefore, going as fast as possible while still claiming safety – should mean no excess harms resulting from the rush.

There’s no way to precisely tell whether or not this is the case here in Helsinki, where the stroke neurologists have cut their door-to-needle time for thrombolysis to under 20 minutes. The results as described here, however, are not promising, and the authors agree with my impression:

“Our findings support the safety of highly optimized door-to-needle times.”

Ha ha! Of course they don’t.

This is a retrospective review of 1,015 stroke code patients arriving over a two-year period between 2013 and 2015. This institution, incorporating elements of pre-hospital assessment into their initial evaluation, have had door-to-needle times below 20 minutes since 2011. How do they perform?

Of the 1,015, there were 150 (14.8%) patients with misdiagnosis on the initial assessment. Of these, 90 were ultimately diagnosed with a stroke mimic, 59 were eventually diagnosed with a stroke or TIA, and one small basal ganglia hemorrhage was missed. These initial misdiagnoses led, as you might imagine, to both unnecessary treatment and delays to the correct treatment. The most profound effects of these delays were in the context of stroke mimics, whose median delay until a correct diagnosis was 39 hours. Thirteen stroke mimics received thrombolysis, and diagnostic inertia from the initial misdiagnosis led 13 more to have median delays of up to 56 hours for the initiation of condition-specific treatment.

Now, there are limitations here that likely tilt these statistics in favor of the institution. There is no described standard follow-up evaluation to confirm cerebral ischemia, and likely some of those with TIA (146 patients) or who received tPA (331 patients) and improved could further be lumped in with the stroke mimics based on their clinical evaluation and whether they ever underwent MRI. Conversely, even though these authors are speeding headlong in order to give tPA, we can’t actually attribute all these misdiagnoses to their rushed evaluation. It is likely some of these cases would remain clinically challenging, even with a few extra minutes of careful consideration.

However, if they are trying to prove their implementation is safe, this comparison group is exactly what is necessary. They’ve shown their protocol is results in a substantial number of misdiagnosis and documented patient harms; the onus is on this team to prove their pursuit of a handful fewer minutes to tPA is not a contributing factor.  Finally, any possible advantage to shaving a handful of minutes off door-to0-needle times pales in comparison to these obvious misses.

“Diagnosing cerebral ischemia with door-to-thrombolysis times below 20 minutes”
http://n.neurology.org/content/early/2018/07/11/WNL.0000000000005954

Stopping the Alteplase Indication Creep

Ever since the narrow approval and strict inclusion criteria of the first trials for alteplase in stroke, our benevolent corporate overlords have been doing their utmost to expand its indications – all while continuing to unilaterally boost its price. This includes sponsoring “expert” convocations to whittle down contraindications, as well as sponsoring, and then cancelling, trials destined to futility.

This is another example of the latter.

This is the remnants of PRISMS, a trial testing the alteplase versus aspirin in a randomized, placebo-controlled trial of mild stroke. In this trial, “mild stroke” included a NIHSS of ≤5 and the absence of any disabling deficits. That is to say, rather, every patient entered in this trial met, in theory, the primary outcome of an mRS of 0-1 at entry. The trial expected to find an advantage to treatment of 9% and incidence of sICH of 2%, a NNT of 11, NNH of 50, and a requirement of 948 patients for the statistical power to validate such findings.

The trial, however, was stopped after 313 patients due to “slow enrollment”. Of these, 32 were lost to follow-up, leaving 281 available for 90-day assessment without imputation. The bulk of patients ranged in NIHSS 1 to 3, with sensory symptoms, facial palsy, and dysarthria the most frequently represented stroke symptoms. Of those with 90-day follow-up, 83.1% of the aspirin arm achieved mRS 0-1, compared with 77.5% of those randomized to alteplase. Conversely, 3.4% of these mild strokes were ultimately mRS 4-6 – a typical definition of “poor outcome” – in the aspirin arm, compared with 10% of those randomized to alteplase. The 5 patients with sICH following alteplase administration contributed to these poor outcomes, compared with none following administration of aspirin.

So, very clearly, there is no evidence here to support a presumption of benefit from alteplase administration, but quite clearly evidence of harm. The authors – with hardly any conflict-of-interest to speak of – go to great lengths to assure us:

“The findings from the current trial cannot be extrapolated to all patients with lower stroke severity based on an NIHSS score of 0 to 5.”

Please continue, they say, treating this population despite the virtual absence of evidence. Even more comically, they also conclude this ought not be the last word in this patient population:

“… the very early study termination precludes any definitive conclusions, and additional research may be warranted.”

Although these authors go to great lengths to assure us there was no tomfoolery at work in the sponsor’s decision to terminate the trial, it strains credibility to suggest Genentech would be so willing to abandon potential profit relating to an expanded indication. Such decisions to cut their losses would hardly be warranted if an expectation of potential return were in store.

At the very least, this clearly shows not only diminishing returns, but likely harms relating to the use of alteplase in minor stroke. Given the sparse RCT data in this realm – NINDS, for example, included only 58 cases with a NIHSS below 5, and nearly 3,000 patients were actively excluded from other RCTs – these data still ought to move the needle of equipoise with regard to treating a spectrum of low NIHSS, but potentially disabling, deficits.  It would be entirely defensible not to treat this population while awaiting robust trial evidence in support.

Also: 13% stroke mimics!

“Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits”

https://jamanetwork.com/journals/jama/fullarticle/2687354

More Snapshots of Awful Antibiotic Use

Is there ever any good news these days? Geopolitical disasters, unwarranted pharmaceutical price increases – and physicians can’t even manage to get the evaluation for group A strep right.

This is a “successful” quality improvement paper wrapped around depressing and embarrassing data from a typical primary care pediatrics practice. These authors, primarily pediatric infectious disease specialists, were dismayed by the rate of guideline-non-compliant group A streptococcal testing and treatment in their group.

How bad?

The base rate of unnecessary GAS testing was 64% of all rapid strep tests performed. The base rate of inappropriate antibiotic prescribing – driven primarily by treating positive results in those who should never have been tested (e.g., likely non-pathogenic colonization) – was 49%.

After their multifaceted year-long intervention, they were able to achieve the amazing results of: 40% unnecessary testing … and the same, inappropriate 49% for antibiotic prescribing. When restricted to selection of antibiotic, at least, first-line antibiotics used 87% of the time.

Is this really the best we can possibly do, even after intent focus on practice improvement? And for a disease entitiy with such limited benefit for antibiotic in most modern settings?

“Improving Guideline-Based Streptococcal Pharyngitis Testing: A Quality Improvement Initiative”
http://pediatrics.aappublications.org/content/early/2018/06/18/peds.2017-2033

Again With the Failings of CTPA

Most of the unhinged ramblings on this blog involve lamenting the excessive sensitivity of CT pulmonary angiograms for the diagnosis of pulmonary embolism. “Excessively sensitive for PEs of uncertain clinical signifiance!” and “Too many false positives in an inappropriately selected population!” gloomily drones the author (We can’t all, and some of us don’t).

Now, again, come the baffling attacks from the right – the CTPA isn’t sensitive enough:

“The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand-alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.”

Foundational quibbles in the narrative induced by their meta-analysis:

  • Sure, maybe, in the cohort of studies before 2006 – but since then, the number of VTE “missed” by CTPA is less than 1%.
  • A VTE “missed” by CTPA includes lower extremity DVT concurrently diagnosed by duplex ultrasound.  Whether a CTPA should be impugned for failing to include the legs is a separate debate regarding the adequacy of its Natural State of Being.
  • Again, a VTE “missed” by CTPA includes all VTE (including LE DVT) diagnosed in the three-month follow-up period, a timeframe certainly adequate for individuals at high-risk for VTE to develop thrombosis anew.
  • “High” clinical probability in this study refers to those patients with ≥40% pretest likelihood of disease, which is tremendously infrequently encountered in clinical practice.

Clearly, these authors are far from convincing me CTPA is guilty of relevant concerns for inadequate sensitivity in these modern times.  One problem at a time, please; queue up, now.

“Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysis of the management outcome studies”
https://www.ncbi.nlm.nih.gov/pubmed/29645405