The tPA Pushback Begins

It isn’t news to anyone in the Emergency Medicine community that tPA isn’t as effective as its efficacy trials suggested, and its overuse is driven by “quality” measures and medicolegal concerns more than any true belief in its usefulness.  However, it remains rare in the Neurology literature to challenge the primacy of tPA – it is much more frequent to see articles promoting and/or defending its expanded use.

This small retrospective series looks at a registry of stroke patients eligible for alteplase who received a CT perfusion study as part of their initial evaluation.  As criteria for review, the CT perfusion lesion needed to be <15mL in calculated volume.  Their final cohort included 366 patients with mostly mild-to-moderate strokes (NIHSS median 8 in each), and a little over half were treated with alteplase, while the remainder were not.  As a retrospective and confounded study, the level of evidence is weak, but the untreated population had significantly better outcomes (mRS 0-1 in 57% vs. 69%), and avoided such complications as parenchymal hemorrhage.

The authors conclude:

“we suggest that neither CTA nor standard clinical/NCCT assessment can appropriately define a relatively large sub-group of patients who are clinically eligible for alteplase, yet appear to have no benefit from treatment.”

Yes, if the volume of acutely injured tissue is quite small, the potential benefit of any therapy has an obvious ceiling – even before considering the viability of the affected tissue or the potential effectiveness of reperfusion.  But the key point here is one I’ve made, most recently at #smaccDUB: we can better individualize care, and avoid costs and risks, with more information.

Thanks to Robert Goulden for sending this in!

“Too good to treat? Ischemic stroke patients with small CT perfusion lesions may not benefit from thrombolysis”

The Sweetest Emergency Department Discharge

When the writers of television drama imagine the Emergency Department, they imagine – you know – emergencies.  Life, death, gray areas in between, and the drama of the critically ill.  People with – you know – symptoms.

Now, our Emergency Departments fill up with the asymptomatic – hypertension and hyperglycemia.  Silent killers, to be sure, but on geologic time scales compared to the attention span of the average Emergency Physician.  As we covered last week, asymptomatic hypertension is nearly always an inappropriate Emergency Department referral.  Now, just the same, we see the same strains of futile pedaling in hyperglycemia.

This is a retrospective, single-center evaluation of all patients arriving with a glucose level ≥400 mg/dL and subsequently discharged.  Patient admission and discharge glucose level were measured, any testing and treatment recorded, and each was followed-up specifically for healthcare encounters and hospitalizations within seven days.  All told, they identified 422 patients and 566 ED encounters for chart review.

In their cohort, the median arrival and discharge glucose levels were 491 mg/dL and 334 mg/dL.  Treatment and testing varied wildly, with most receiving some sort of chemistry or urine testing, most receiving some intravenous fluid, and the majority receiving some subcutaneous insulin.  Fabulously, 11 patients were even discharged (most AMA) with glucose beyond the range of the point-of-care machine (600 mg/dL).  Nearly everyone in their cohort for whom they were able to follow-up did well: only 25 (4%) were hospitalized on a re-visit within 7 days, and only two did so for a glucose-metabolism complications, both diabetic ketoacidosis.  The reasonable conclusion of these authors: “attaining a specific glucose-level goal before discharge in patients with moderate to severe hyperglycemia may be less important than traditionally thought.”

This study does not review the downstream resource utilization and outcomes for those admitted on their initial visit.  A comparison with an admitted versus discharged cohort might have given some representation of benefit derived from intensive treatment and re-education, although, the surrogate and patient-oriented complications relating to poor glucose control are infrequent and generally long-term complications.  Furthermore, patients with poor glucose control are not always those for whom an inpatient hospitalization resolves the issues relating to their future poor glucose control.

These patients are still a challenge to manage appropriately.  The role of the Emergency Department is in ruling out treatable pathology or complications of sustained hyperglycemic or insulin-deficient states.  Unlike hypertension, a little more work is usually indicated for these patients.  The ED evaluation is the easy part; finding ways to keep these patients healthy long term is the larger question.

“Discharge Glucose Is Not Associated With Short-Term Adverse Outcomes in Emergency Department Patients With Moderate to Severe Hyperglycemia”

Still Meandering Towards Apneic Oxygenation

The use of apneic oxygenation – so-called NODESAT – has been gaining rapidly in popularity.  Curiously enough, however, its continued promotion occurs in the absence of high-quality evidence for benefit.

This most recent study is a prospective, observational evaluation of two years’ worth of intubation procedural outcomes.  Patients receiving passive oxygenation during intubation were compared with those who did not, with the primary outcome being hypoxia (O2 saturation <90%) on the first-pass of intubation.  During this time period, the use of apneic oxygenation was explicitly encouraged as a quality improvement initiative.  Of the 1,140 intubations during this time period, 635 patients were included for analysis; 380 utilized apneic oxygenation and 255 did not.  The apneic oxygenation cohort had a 17.9% incidence of hypoxia on the first intubation attempt, compared with 31.0% without.  The authors conclude their observational data favors apnea oxygenation, and may improve safety.

This is a reasonable conclusion, to be certain.  There were, of course, massive confounders regarding the two cohorts – and the largest predictor of hypoxia was not apneic oxygenation or technical factors, but simply whether the baseline oxygen saturation was >93%.  An observational study, particularly one excluding 20% of potentially eligible patients due to incomplete data, simply continues to serve as hypothesis-generating for definitive evaluation.

I am not opposed to the use of apneic oxygenation, but it is reasonable to be realistic about the underlying evidence and not to behave dogmatically regarding its use.  There are probably a few acute procedural delays associated with its use, but any patient-oriented harms or benefits would seem to be rather difficult to detect.

Other notes:

  • LITFL publishes a lovely synopsis on the topic here.
  • Yes, I’m about four months late to the party on this article – having missed the electronic publication back in February!

“First Pass Success Without Hypoxemia Is Increased With the Use of Apneic Oxygenation During Rapid Sequence Intubation in the Emergency Department”

You Can’t Spell “Insanity” Without tPA

When you think you’ve seen it all – a call to administer tPA to acute stroke patients without a prior non-contrast CT.

Indeed, in this “Views & Reviews” article, the authors ask explicitly the question: “Is the administration of alteplase to patients with primary ICH that harmful?”  After much stimulating confabulation, the authors bafflingly conclude: “we cannot argue with confidence that alteplase administration to patients with ICH is harmful”.

Perhaps they’ve never treated patients with alteplase personally, and they further mis-cite or misinterpret the evidence regarding the influence of cerebral microbleeds on symptomatic intracranial hemorrhage.  Despite the clear evidence from multiple meta-analyses that cerebral microbleed burden prior to alteplase administration leads to substantially increased risk of ICH and neurologic worsening, these authors sum up this evidence as “either no increased risk of symptomatic ICH or an increased risk that does not necessarily preclude an overall benefit from alteplase.”


Even better, the entire purpose of their intellectual exercise boils down to discarding the inconvenience of pre-lytic CT so that alteplase can be delivered pre-hospital.  Yes, rather than clinically correlating the presentation with maximal vascular and perfusion information to consider the safest, most potentially effective (if any) reperfusion therapy – these authors are promoting administration of a $6000 medication in a pre-hospital setting with a paucity of diagnostic expertise or technology available.

Good plan.

“And why not thrombolysis in the ambulance (at least for some)?”

Excitement and Ennui in the ED

It goes without saying some patient encounters are more energizing and rewarding than others.  As a corollary, some chief complaints similarly suck the joy out of the shift even before beginning the patient encounter.

This entertaining study simply looks for any particular time differential relating to physician self-assignment on the electronic trackboard between presenting chief complaints.  The general gist of this study would be that time-to-assignment reflects a surrogate of a composite of prioritization and/or desirability.

These authors looked at 30,382 presentations unrelated to trauma activations, and there were clear winners and losers.  This figure of the shortest and longest 10 complaints is a fairly concise summary of findings:

door to eval times

Despite consistently longer self-assignment times for certain complaints, the absolute difference in minutes is still quite small.  Furthermore, there are always issues with relying on these time stamps, particularly for higher-acuity patients; the priority of “being at the patient’s bedside” always trumps such housekeeping measures.  I highly doubt ankle sprains and finger injuries are truly seen more quickly than overdoses and stroke symptoms.

Vaginal bleeding, on the other hand … is deservedly pulling up the rear.

“Cherry Picking Patients: Examining the Interval Between Patient Rooming and Resident Self-assignment”

High Blood Pressure is Not a Crime

And you don’t need to be sent to “time out” – i.e., referred to the Emergency Department – solely because of it.

This is a retrospective, single-center report regarding the incidence of adverse events in patients found to have “hypertensive urgency” in the outpatient setting.  This was defined formally as any systolic blood pressure measurement ≥180 mmHg or diastolic measurement ≥110 mmHg.  Their question of interest was, specifically, whether patients referred to the ED received clinically-important diagnosis (“major adverse cardiovascular events”), with a secondary interest in whether their blood pressure was under better control at future outpatient visits.

Over their five-year study period, there were 59,535 patient encounters meeting their criteria for “hypertensive urgency”.  Astoundingly, only 426 were referred to the Emergency Department.  Of those referred to the ED, 2 (0.5%) received a MACE diagnosis within 7 days, compared with 61 (0.1%) of the remaining 58,109.  By 6 months, MACE had equalized between the two populations – now 4 (0.9%) in the ED referral cohort compared with 492 (0.8%) in those sent home.  Hospital admission, obviously, was higher in those referred to the ED, but apparently conferred a small difference in blood pressure control in follow-up.

The authors go on to perform a propensity-matched comparison of the ED referrals to the sent home cohort, but this is largely uninsightful.  The more interesting observation is simply that these patients largely do quite well – and any adverse events probably happen at actuarial levels rather than having any specific relationship to the index event.

I appreciate how few patients were ultimately referred to the Emergency Department in this study; fewer than 1% is an inoffensive number.  That said, zero percent would be better.

“Characteristics and Outcomes of Patients Presenting With Hypertensive Urgency in the Office Setting”

Futility, Thy Name is ATTACH-2

Intracranial hemorrhage tends to have a poor prognosis – the cascade of inflammation, vasospasm, and necrosis leaves the vast majority with some residual disability.  INTERACT-2 offered some glimpse of hope, at least, from a surrogate standpoint – finding that patients with “intensive” blood pressure control showed reduced hematoma growth.  It seems logical that reduced hematoma growth would directly correlate with improved clinical outcomes, and there was a reasonable suggestion this was present, as well.

And, so, ATTACH-2.

This trial randomized patients with ICH to “standard” 140-179 mmHg blood pressure control versus “intensive” 110-139 mmHg blood pressure control, with a primary outcome of modified Rankin scale of 4 to 6.  All patients were treated using nicardipine by continuous infusion, and generally achieved their blood pressure targets within 2 hours of randomization.  They included 500 in each arm of the trial before stopping prematurely when a pre-specified threshold for futility was crossed.

Since I’ve used the word “futility” twice so far, you’ve probably already discerned the result.  At 90 day follow-up, there were 38.7% with mRS 4-6 in the intensive group versus 37.7% in the standard group.  No other long-term clinical outcomes seemed to reflect an advantage to one arm or the other.  In both adjusted and unadjusted analyses, there were a few interesting tidbits.  Hematoma expansion was, indeed, attenuated by intensive control.  However, as a counterweight, the intensive treatment group was more likely to suffer neurologic deterioration within 24 hours (11.0% vs. 8.0%) and more likely to suffer a serious adverse event within 3 months (25.6% vs. 20.0%).

It certainly seemed plausible such intensive lowering might be of value – but, instead, we have an excellent example where patient-oriented outcomes trump surrogates, and the adverse effects from treatment seem to counterbalanced any benefit picked up along the way.

“Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage”

ENCHANTED – Positive or Negative?

I am probably the last person to comment on ENCHANTED, the trial testing low-dose vs. standard-dose tPA in “Asians”.  When it was released, to some fanfare in the New England Journal of Medicine, I had little to say – it is, frankly, a rather bland contribution to the science.  What has been fascinating, however, is the unusually divergent interpretation of the results.  To wit, the accompanying editorial in the NEJM states:

“ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes.”

This is a relatively reasonable interpretation of the results – hinging on the word “compelling”.  No one’s hearts are to be set a-flutter over these results, but that does a disservice to the ultimate clinical question of which dose is appropriate.  The lay press, however, is here to clear things up – or is it?

“ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke?” 
“ENCHANTED results challenge reduced alteplase dose in Asian stroke patients”
“Low-Dose tPA Not as Effective, Even for Asians”
“Lower Dose of Clot-Busting Drug Reduces Brain Bleeding”
“Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke”
“Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke”

The question, simply, comes down to how easily one interprets “non-inferiority” – a point made nicely by Rory Spiegel in his post – and, further, how one interprets these findings in a Bayesian sense.  The prevailing opinion going into this trial was that low-dose tPA was safer and similarly efficacious in certain ethnic subpopulations on the Asian continent.  The nonsignificant difference (OR 1.09; 95% CI 0.95 to 1.25) in patients having excellent outcomes (mRS 0-1) and the even smaller difference (OR 1.03; 95% CI 0.89 to 1.19) in those having good outcomes (mRS 0-2) does nothing to move the needle on the prevailing clinical hypothesis.  If there is unlikely to be a profound difference in clinical outcomes, what of the safety outcomes?  Here, low-dose alteplase is obviously a winner – significant reductions in hemorrhage and a corresponding decrease in 90-day mortality (p=0.07).

If ECASS failed gloriously due to adverse effects at 1.1 mg/kg, subsequent trials found some favorable risk/benefit at 0.9 mg/kg, and the (supposed) clinical efficacy seems preserved with even greater safety at 0.6 mg/kg, it seems logical to expand interest in lower doses of tPA.  I disagree with those who would dismiss this trial as an unimportant “failure”.

“Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke”

Stroke – Reversed!

Breathless miracle treatment coverage!  Walk, talk, have a baby, win the Olympic decathalon – all despite having severe stroke!  All it takes is a “simple procedure”!

The lay coverage reads like clickbait.  In contrast – at least – the published abstract Results section leads off with “All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event.”

So, not quite such exaggerated hyperbole.

This is the PISCES II trial, implantation of modified bone marrow–derived mesenchymal stem cells directly into the brain.  Cells were implanted via craniostomy, and five 20 μL cell deposits were made at 5 to 6 mm intervals along each of three cannula tracks into the peri-infarct area.  18 patients were enrolled after 379 were screened, and three differing dose concentrations of stem cells were used.  The baseline NIHSS of the population had a mean of 9.44, and patients were all mRS 3 or 4.

With regards to that aforementioned “treatment-emergent adverse event”, thankfully, the vast majority were headache related to the procedure, along with nausea and vomiting.  A few patients developed muscle spasticity, and among relevant serious adverse events, one patient had a seizure and one an asymptomatic subdural/hygroma.  NIHSS improved by 2.00 points among the 16 patients available for 12 month follow-up, and there were other motor improvements and global functional improvements measured on the Fugl-Meyer score.  MRI changes seemed to correlate with improvements in functional status, as well.

Literally every aspect of this trial was controlled by SanBio Inc., the purveyors of this recovery technology.  The manuscript was ghostwritten by professionals funded by SanBio, and SanBio funded almost everything.  Several authors are full-time employees of SanBio, and other authors are former employees and/or stockholders.  It is nice to think this might offer promise and hope for stroke survivors, but this small trial is far from the breathless coverage provided.

“Clinical Outcomes of Transplanted Modifed Bone Marrow–Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study”

Zeno’s Zero-Hour Rule-Outs

This is TRAPID-AMI, a prospective Roche hs-TnT (99th percentile 14ng/L) study for patients presenting within 6 hours of peak chest pain symptoms.  Samples were drawn on arrival, then serially over the next two hours, and a final sample drawn 4-14h after presentation.  The primary outcome was acute MI, as adjudicated by a panel of cardiologists blinded to the hs-TnT result but aware of a Siemens conventional troponin I (99th percentile 40ng/L) result.  Interestingly, they powered their study specifically for a negative predictive value, rather than a specific sensitivity result – certainly an easier enrollment target, but also potentially more difficult to generalize.

All told, they included 1,282 patients in the study and there were 213 patients ultimately diagnosed with AMI on their initial presentation.  In 30-day follow-up, 11 patients could not be contacted, and an additional 18 patients not originally diagnosed with AMI met their combined MACE endpoint, 15 of which were revascularlization.  Of these 213 patients with initial diagnosis of AMI, there were four false-negatives with respect to the troponin assays being below the limit of detection.  For their primary outcome, then, sensitivity was 98.1% (95.3-99.5) with specificity 52.0% (49.0-55.0).  The authors go on to present several different strategies based on various cut-offs and various EKG findings, the effect of which are various trade-offs between number of patients eligible for a zero-hour rule-out, the sensitivity, and the specificity.  Negative predictive values, of course, generally ran >99%, owing the the relative infrequency of AMI diagnoses.

This study, like most before it, provides little additional insight.  Sensitive troponin assays are, indeed, more sensitive.  The sensitivity comes at a cost of specificity.  We are also encountering a sort of Zeno’s Paradox with regard to our evaluation of these strategies.  We employ more sensitive assays both to detect AMI up-front, but also as our gold-standard for adjudicated final outcome.  The increased sensitivity, then, cuts both ways – as we detect tinier and tinier nSTEMI as a sort of ceiling for our sensitivity of any rapid rule-out strategy.  Is it reasonable to suggest the occasional 1-in-200 tiny myocardial injury missed is unlikely to have serious clinical consequences?  If so, the best question to address is how to continue the care of these patients after they leave the Emergency Department such that those who would benefit from additional medical and endovascular intervention are not lost.

“The use of very low concentrations of high sensitivity troponin T to rule out acute myocardial infarction using a single blood test”