Ryan Radecki

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

The “Fragility Index” in Emergency Medicine

This little paper is an interesting look at trials in Emergency Medicine and their robustness – or lack thereof.

The “fragility index“, as described by its proprietors, is effectively a “number needed to treat” for confidence intervals and p-values. In simplest form, the fragility index is the number of patients needed to change their primary outcome in order to nullify an otherwise statistically significant result. Effectively, if a trial result would change if only two patients had different outcomes, the fragility would be 2 – and this would reflect a trial whose results are not terribly robust.

The authors then go on to use their tool to evaluate 180 trials across emergency medicine and emergency medicine journals. The medial fragility index across all trials: 4. Of course, this is not terribly unexpected, as the median sample size across all trials was only 140 – not usually enough to illuminate a reliable result except in only the most impressive of effect sizes.

The tool itself is not a novel reinvention of statistical significance or analysis, but just another mechanism for knowledge translation to reflect the relative stability or robustness of a result from a trial. Interpretation of frequentist statistics, p-values, and confidence intervals can frequently be rather opaque or misleading, and reporting a fragility index can be considered one approach to conceptualizing the strength of a result. The real solution, also noted by these authors, is simply to interpret individual trial results in a Bayesian context – adding one trial to a Bayesian prior, when available, to see how a trial shifts the current evidence.

“The Results of Randomized Controlled Trials in Emergency Medicine Are Frequently Fragile”

https://www.ncbi.nlm.nih.gov/pubmed/30551894

More Bad News for Influenza Antivirals

Deep in the throes of influenza season, I’m sure the oseltamivir is flying off the shelves around the country. In Japan, however, it’s baloxavir that’s flying off the shelves. Unfortunately, as was presaged by the data from their definitive clinical trial, resistance to baloxavir is rapidly increasing.

And, now, tucked into this retrospective look at “early” versus “late” oseltamivir treatment in the critically ill – additional data regarding its general futility. In this 1,330 patient ICU cohort of patients who received osteltamivir within 48 hours of symptom onset (“early”) or later (“late”), overall mortality was 46.8% – and no different between the two groups. There are obvious issues here with regards to confounding and baseline differences, but it should be apparent a beneficial treatment … provides some benefit.

The authors did observe an absolute 10% survival advantage associated with “early” treatment in those infected with A/H3N2 – but as this accounted for a minority of their cases, overall, the entire cohort was a wash. This is consistent with another review specific to data from the 2009A/H1N1 pandemic. Mortality in included studies was only 8%, but no survival advantage was seen in those treated with oseltamivir. While universal and indiscriminate treatment with neuraminidase inhibitors is engrained in the conflict-of-interest-infested IDSA guidelines, one can only hope these data points encourage additional prospective evaluation into the true narrow value of our tools for the treatment of influenza.

“Effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study”

https://www.ncbi.nlm.nih.gov/pubmed/30753349

Lactate is Dead! Long Live Lactate?

Our use of serum lactates as targets for resuscitation in sepsis is more than a little flawed. Once upon a time, we resuscitated using central venous oxygenation as part of the Rivers’ trial. Whether those targets were actually a valid part of the multi-pronged bundle remains an excellent and open question. Of course, CVO2 requires invasive monitoring – and serum lactate became our less-invasive surrogate. And, yes, patients with high lactates do poorly – but that doesn’t specifically address the assumption lactate-guided resuscitation is tied to outcomes, or the optimal resuscitation strategy.

This multi-center trial out of Latin America looks at another marker of perfusion status, capillary refill time, that is likewise observationally associated with mortality in sepsis. In a randomized, open-label trial, the first eight hours of resuscitation was guided either by lactate levels or capillary refill time. Resuscitation in both arms used a specific protocol of fluids, fluid-responsiveness assessments, vasopressors, and inodilators.

Without unpacking these specifics in too great of detail, as will be done by many other critical care physicians, the results are quite interesting: of 424 patients randomized, they observed 34.9% mortality in the CRT-guided cohort compared with 43.4% in the lactate-guided cohort. Other secondary outcomes, including lactates at 48 and 72 hours, SOFA scores at 72 hours, generally favored the CRT cohort.

Is this the end of lacate? Certainly, in a resource austere setting, it would generally indicate there’s no rush to adopt lactate use in the context of a just-as-good, zero-cost means of assessment. The accompanying editorial wonders aloud: why not use both? While this seems like a reasonable idea, it probably doesn’t go far enough – why not use all the data for an individual patient to determine their optimal treatment, rather than our current one-size-fits-all nuclear option? Reliance on any single approach to resuscitation – perhaps mandated by “quality” measures – is almost certain to be short-sighted. While I do not advocate a return to the wild west of late recognition and neglect, these data should add further fuel to a reassessment of our golden idols and targets in the treatment of sepsis.

“Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2724361