Month: March 2019

Lacunar Infarcts & Thrombolysis

For some period of time, folks have debated the utility of thrombolysis in lacunar infarcts. The underlying concern is with regard to their underlying suspected pathology relating to non-thrombotic occlusion of small perforating arteries, in contrast to the process seen in small- or large-vessel stroke. This little subgroup analysis of WAKE-UP – the MRI-driven tissue-based trial of alteplase for ischemic stroke – tries to shed further light on this specific concern.

Of the 503 patients included in WAKE-UP (out of 1,362 patients screened), 108 had imaging-defined lacunar infarcts. The median NIHSS of these patients was 4 to 5, and about half were randomized to alteplase and half to placebo. Overall, this subgroup – underpowered for any definitive conclusion – demonstrated similar outcomes as those whose stroke subtype was not lacunar.

The issue is not so much the finding observed here, but the effort in the Discussion and accompanying editorial to generalize WAKE-UP to all strokes. There is only a loose association between DWI and FLAIR findings and predicting time of stroke onset in their cited reference. A little fewer than 2/3rds of strokes of ≤4.5h age seem to have positive DWI and negative FLAIR, and this study enrolled only a tiny fraction of patients with potential lacunar infarcts.

Long story short, a treatment effect observed in this tissue-based enrollment cohort cannot reliably predict treatment response for lacunar strokes screened and treated based on routine non-contrast imaging. Most patients screened for WAKE-UP were excluded based on not meeting imaging criteria, potentially around half of whom were otherwise within 4.5 hour stroke onset (based on their citation above). Thrombolysis does benefit the patients in WAKE-UP, overall, but this almost certainly represents the ceiling for a positive effect size – and in routine practice, effectiveness is likely much lower.

Related aside: when we start routinely screening strokes with MRI in that happy future time, do we exclude DWI+/FLAIR+ from thrombolysis, even if within the “treatment window”? I would think so.

“Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial”
https://jamanetwork.com/journals/jamaneurology/fullarticle/2729091

The “True” 99th Percentile for Troponin

Not. All. Troponin. Elevations. Are. Acute Coronary Syndrome.

This is just a simple, prospective, observtional study of 20,000 high-sensitivity troponin I results from a single hospital in the United Kingdom. All blood samples submitted to the lab were evaluated with a troponin assay, regardless of clinical indications or reasons for order. About half of included samples were outpatients, a quarter were Emergency Department patients, and the remainder were inpatients.

The manufacturer-stated upper limit of normal for the assay – Beckman Coulter Access AccuTnI+3, specifically – is 40 ng/L, with a coefficient of variation of less than 10% at that cut-off. Outpatients were the least likely to exceed this limit, at 2%, with an observed 99th percentile of 65 ng/L. In the Emergency Department, 6.1% exceeded the manufacturer-defined cut-off, with an observed 99th percentile of 215 ng/L. Finally, 7.3% of inpatients exceeded the manufacturer cut-off, with an observed 99th percentile of 563 ng/L.

The authors also tracked whether the patients had a troponin ordered by the clinical team, or had a final diagnosis of acute myocardial infarction, and perform some multivariate analyses with these patients excluded. Those only comprised 1,829 patients from this cohort, and excluding these patients made only small impacts upon their new “normal” 99th percentiles. Effectively, the point of this article is a reminder of the effect of concomitant illness on circulating troponin levels – and to take into account the likelihood of an ACS when interpreting troponin elevations above the manufacturer’s 99th percentile cut-off.

“True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study”
https://www.bmj.com/content/364/bmj.l729

Emergencies in Medicine

Just a quick note to follow-up this splendid little conference in Park City, UT, where I featured in a debate regarding the utility of tPA for stroke. We had a generally respectful discussion about the state of stroke care and our vision for the future.

Unfortunately, it – as you might expect – looks a lot like a future where tPA flows like water.

The overall gist of the presentation by Chris Lewandowski, one of the original NINDS investigators: pool the trial data, and the benefit is clear. My gripes, well-chronicled on this site: benefit is not uniformly distributed, we should tailor its use, rather than expand it.

Interesting tidbits from the follow-up discussion:

  • No one is going to re-do NINDS in this country. They couldn’t even complete PRISMS because too many mild, non-disabling strokes were already being treated.
  • Treating vast numbers of stroke mimics is not troublesome to them – Lewandowski claims to have never heard of one ever having a bleed.
  • The expected benefit to mobile stroke units relates to “fresh” clot being more likely to lyse, as much as the brief time savings.
  • Studies like TIMELESS and other tissue-based thrombolytic studies will likely extend the treatment window, just like WAKE-UP.
  • No qualms about treating NIHSS scores of 1 causing only mild disability (say, unilateral leg weakness). They’ve seen that some NIHSS 1 deteriorate, and believe tPA will prevent it.
  • They are utterly comfortable with forever using NINDS as their default NNT/NNH consent – and no problem using the same numbers now matter what the NIHSS. Except, they just reduce their risk number for harm, as ICH is generally related to infarct size/NIHSS. This drives me mad.
  • They feel strongly tPA has been proven “cost-effective”, while I would note those analyses are based on assumptions and models not matching current practice and treatment population.
  • Treating cervical artery dissection with tPA is favored to them because they expect the clot that showers distally will benefit from lysis, though they agree there is no evidence to support their claims.
  • They agreed that, overall, the recommendations issued by the AHA overstate the strength of the evidence.

Would be fun to do again – even if it is effectively just shouting into the wind!

PE in Pregnancy & YEARS Protocol

So, I generally like the YEARS protocol. It’s an incremental step forwards towards incorporating a pretest likelihood of disease into the interpretation of the D-dimer result. At the least, considering our reckless overdiagnosis of pulmonary embolism, it doesn’t make the situation worse.

Now, pregnancy. There is a mild increase in risk for PE while pregnant, and subsequent puerperal risk is even higher. Unfortunately this leads to a paradox: the index of suspicion for PE during pregnancy is so high, the yield of testing is frighteningly low – on the order of 5% or less for those undergoing evaluation for PE. Little prospective data regarding safe exclusion of PE during pregnancy are available.

These investigators – the Artemis Study – applied the YEARS algorithm, to the diagnosis of PE during pregnancy, attempting generally to demonstrate its safety while describing its yield and test characteristics. The primary modification to the baseline YEARS algorithm was patients having clinical signs of deep-vein thrombosis underwent compression ultrasonography prior to being evaluated with D-dimer and potential CTPA.

They enrolled 498 patients in whom PE was considered a relevant clinical diagnosis, about half of whom met no “high-risk” YEARS criteria. About a fifth of the patients were first trimester, and the remainder were split between second and third. The news is good and bad, unfortunately. Overall, the incidence of PE in their cohort was only 4.0% – typical of our deranged gestalt for PE in pregnancy. In the first trimester, their algorithm excluded PE without CTPA in 65% of those enrolled – meaning only 26 CTPA were indicated to diagnose the 5 PEs in this cohort. This is a reasonable yield.

However, second and third trimester excluded only 46% and 32% of patients from CTPA – meaning 261 CTPAs would be allowed to diagnosis 15 PEs – a yield of only 5.7%. This is better than performing a CT on everyone, but it’s still abysmal. This results, effectively, from the gradual physiologic increase in D-dimer throughout pregnancy – from a median of 505 ng/mL in their first trimester cohort, to 730 and 1,120 in subsequent trimesters.

So, while their algorithm is clearly safe – only one DVT occurred within their 3-month follow-up period, basically the expected rate of occurrence in their enrolled cohort – it’s not the final answer with regard to pregnancy. The next likely step required is to use our observational data to test specific trimester-related normals and pretest-related multipliers to find the optimal cut-offs, such that second and third trimester performance may approach that of the first.

“Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism”
https://www.nejm.org/doi/full/10.1056/NEJMoa1813865

Shocked: To the Cath Lab?

Just a couple weeks ago, I pointed out a recent evidence summary regarding the utility of cardiac catheterization following out-of-hospital cardiac arrest. The general between-the-lines theme of the article: sure seems useful, but the observational evidence is potentially really biased.

This, the Coronary Angiography after Cardiac Arrest (COACT) trial, is one of the randomized trials noted in that aforementioned evidence review. These authors conducted a randomized, multi-center trial enrolling patients with out-of-hospital cardiac arrest, shockable initial rhythms, unconscious on ED arrival, but no ST-segment elevation. Based on their survey of the literature, they gave themselves an 85% power to detect a 13% absolute difference in survival to 90 days, and enrolled 552 patients over three years. Patients undergoing early coronary angiography did so generally within 2 hours, while those in the delayed strategy – if they underwent angiography at all – did so several days later.

Overall – no difference. Survival to 90 days did not differ between groups at 64.5% for immediate angiography and 67.2% for delayed, nor did any secondary outcomes regarding post-resuscitation morbidity or neurologic survival. Of course, the key element being: unless an intervention occurs, there likely won’t be any effect. Only about a third of patients in each group underwent revascularization during their hospital stay, meaning any difference in overall survival would ultimately need be affected by outcomes in this specific population. Absent a massive effect size, the results observed are basically as expected.

So, I think the basic takeaway here is – within the limitations of this small sample – immediate angiography is not supported as a universal strategy for patients with OHCA, shockable rhythms, and lack of ST-segment elevation. It appears either a delayed strategy, or one guided by yet-to-be-determined clinical features, is preferred.

“Coronary Angiography after Cardiac Arrest without ST-Segment Elevation”

https://www.nejm.org/doi/full/10.1056/NEJMoa1816897

Wisdom of the Crowds

This is a fun little article presenting data relating to the Human Diagnosis Project, an online medical platform in which medical students and physicians create and solve teaching cases. Cases can be created by anyone, and are “solved” by submitting a ranked differential diagnosis to the system. Approximately 14,000 users have created or solved 230,000 cases in the few years it has been operational.

The article here, generally, highlights the diagnostic accuracy of respondents for 1,572 cases with 10 or more solve attempts. In their analysis, diagnostic performance, as measured by the likelihood for including the correct diagnosis in their top three, increased as additional physicians were added to the mix – effectively from 60-70% diagnostic accuracy up to a ceiling of about 90% when the collective diagnoses from 9 physicians were pooled.

While there are obvious limitations to using this platform to fully evaluate diagnostic performance and pooled diagnostic performance, my other takeaway: regardless of the actual number, even with the combined intelligence of multiple clinicians, accuracy is never 100%. While the expectation of our patients (and medicolegal systems) is perfect performance, it is not reasonable to expect perfection.

“Comparative Accuracy of Diagnosis by Collective Intelligence
of Multiple Physicians vs Individual Physicians”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2726709

Please Click Here to Reset Your Password

Please enter your social security number and the last four digits of your credit card to complete the process.

Your credentials could not be confirmed. Please enter your mother’s maiden name, the first car you drove, and the number of dollars remaining on the mortgage to your house.

… when this happens to you, it’s a big problem. When it provides malicious attackers a backdoor into your healthcare delivery system, it’s a much, much bigger problem. Our institution, like many others, implemented a “phishing” training program, complete with online modules and test e-mails sent periodically to our institutional accounts.

But does it work?

Considering we’re starting from the bottom, the answer is a qualified “yes”.

In these authors’ report, they detail their experience with 5,416 unique employees at a single institution undergoing a campaign aimed at education about phishing. Their intervention and program consisted of 20 fake malicious e-mails sent periodically at 2- to 3-month intervals. Only 975 (17.9%) clicked on zero malicious links in e-mails during their educational campaign. An almost equal number, 772, clicked on five or more malicious links. Generally, over the course of the intervention, rates of click-through gradually decreased from highs in the 70% range to well below 10%.

Additionally, after 15 e-mails, those who had clicked on enough e-mails to be labelled “offenders” underwent a mandatory training program. Unfortunately, this training program had no subsequent effect on click-through rates. Those who had been offenders before, remained offenders – with click rates on malicious links of 10-25%, depending on the fake example.

Grim news for security consultants trying to prevent massive data breaches.

“Evaluation of a mandatory phishing training program for high-risk employees at a US healthcare system”
https://academic.oup.com/jamia/advance-article/doi/10.1093/jamia/ocz005/5376646

OK, Google: Discharge My Patient

Within my electronic health record, I have standardized discharge instructions in many languages. Many of these, I can read or edit with some fluency – such as Spanish – and those of which I have no facility whatsoever – such at Vietnamese. These function adequately for general reading material regarding any specific diagnosis made in the Emergency Department.

However, frequently, additional free text clarification is necessary regarding a treatment plan – whether it be time until suture removal, specifics about follow-up, or clarifications relevant to an individual patient. This level of language art is beyond my capacity in Spanish, let alone any sort of logographic or morphographic writing.

These authors performed a simple study in which they processed 100 free-text Emergency Department discharge instructions through the Google Translate blender to produce Spanish- and Chinese-language editions. The accuracy of the Spanish translation was 92%, as measured by the number of sentences preserving meaning and readability. Chinese fared less well, at 81%. Finally, authors assessed the errors for clinically relevant and potential harm – and found 2% of Spanish instructions and 8% of Chinese met their criteria.

Of course, there are a couple potential strategies to mitigate these potential issues – including back-translating the text from the foreign language back into English, as they did as part of these methods, or spending time verbally confirming the clarity of the written instructions with the patient. Instructions can also be improved prior to instruction by avoiding abbreviations and utilizing simple sentence structures.

Imperfect as they may be, using a translation tool is still likely better than giving no written instruction at all.

“Assessing the Use of Google Translate for Spanish and Chinese Translations of Emergency Department Discharge Instructions”
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2725080

The “OHCA to the Cath Lab?” Update

STEMI: cardiac catheterization.

Out of hospital arrest: now what?

This scientific statement provides a lovely – and detailed – overview of the state of the science regarding which survivors of cardiac arrest should be considered for cardiac catheterization. They start with the easiest of answers: arrest with return of circulation and ST-segment elevation on a 12-lead ECGs are likely to benefit from catheterization. Then, patients with persistent ventricular fibrillation or ventricular tachycardia are, similarly, highly likely to have coronary artery disease and a suspected culprit lesion precipitating their arrest.

Now, the trickier issue remains what to do with those who do not have ST-segment elevation on their ECG. Pooled data from registry and observational studies indicates the prevalence of coronary artery disease is between 25-50%, while a potential culprit lesion is identified about 25-35% of the time. The data from these same studies indicates a substantial survival advantage for those – and this is the key word – selected for cardiac catheterization, and in whom percutaneous coronary intervention is performed. The authors go on to note at least nine randomized trials are underway or planned to address the utility of catheterization in the subgroup without STE.

Lastly, the authors note the emerging role of VA-ECMO in cardiac arrest. With only a handful of patients from observational registries, survival with cerebral performance category 1 or 2 has been observed in 15-40% of patients. This is, again, likely subject to selection bias, but remains a potentially promising approach. The ARREST trial, evaluating such a strategy, is ongoing with completion expected in 2023.

At the minimum, it is a worthwhile review article for anyone looking to catch up to speed – even if there isn’t much within to change current thinking or practice, at the moment.

“The Evolving Role of the Cardiac Catheterization Laboratory in the Management of Patients With Out-of-Hospital Cardiac Arrest A Scientific Statement From the American Heart Association”
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000630