January 2018 – Emergency Medicine Literature of Note

DEFUSE-3 is DAWN All Over Again

A couple months ago the stroke community was presented with the results of DAWN – an acute stroke trial leaving us longing wistfully of the simple days where we just bickered over tPA in the 3-hour window. With DAWN, the authors evaluated patients with symptoms of 6 to 24 hour duration and found, with specific perfusion mismatch criteria, revascularization was likely beneficial. DEFUSE-3 is the second member of this club.

This is an open-label, blinded-assessor, randomized trial of patients presenting 6 to 16 hours following “last known well”. Dynamic randomization stratified based on age, core infarct, time from symptom onset, and NIHSS. Proximal middle cerebral artery and internal carotid occlusions were required, as was perfusion imaging demonstrating an ischemic core of less than 70 mL and a clinically important penumbra of at least 15 mL. The primary outcome was the clinically and statistically flawed ordinal shift in the modified Rankin scale.

As is become virtually routine in these endovascular trials, this one was stopped early – after 182 of 476 originally planned. These authors halted enrollment after the DAWN publication, and applied their protocol for interim analysis for early stoppage – which was met. Ignoring their ordinal shift measure and going straight for the typical mRS 0-2, we find 45% meeting that outcome with endovascular intervention, and 17% with medical therapy. Adverse events, including intracranial hemorrhage, were modestly increased in the endovascular arm, although mortality in the endovascular cohort are halved. Revascularization rates at 24 hours, interestingly, were only 79% in the endovascular cohort, and they still had a fair bit of infarct growth – but, sample size limitations notwithstanding, clinical outcomes obviously vastly favor the endovascular cohort. The American Stroke Association has wasted no time updating their guidelines to incorporate new time windows, up to 24 hours, using the DAWN and DEFUSE criteria.

Obviously, in an open-label trial, the scales can be tilted by the intensity of follow-up care – for instance, in IST-3, more stroke patients receiving tPA ended up in intensive care units. ICUs, with their more favorable nursing ratios, are virtually guaranteed to be more likely to be on top of all the other components of high-quality post-stroke care. In open-label trials, as well, it is reasonable to suggest different conversations may be had about comfort care measures, depending on whether an intervention were performed with the hopes of potential downstream improvement. These are just a couple examples of the many ways these sorts of trials may exaggerate the magnitude of potential benefit.

All that said, the Bayesian position – colored by sponsored trials as it is – still suggests these data are on the right track. The key to stroke care is tissue viability, not arbitrary time metrics. Either the collateral flow is there, or it isn’t – with the caveat that, yes, eventually those collaterals can collapse and complete the infarction. How these new tissue-based considerations fit into systems of stroke care – and who needs to be transferred for specialized imaging – is an open question/headache we’ll all be struggling to figure out over the next months/years.

“Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging”
http://www.nejm.org/doi/full/10.1056/NEJMoa1713973

Is the Urinalysis Reliable in Young Infants?

The evaluation of the very young infant with a fever is complex, with multiple competing factors including the rarity of serious illness, the severity of serious illness, and the cost of the intensive evaluation frequently required. The most commonly identified bacterial source for fever is a urinary tract infection, and our bedside test in the Emergency Department is the urinalysis.

So, how reliable and accurate is that test?

This is an analysis of prospectively collected data from the PECARN network, looking at the evaluation of febrile infants fewer than 60 days of age. Of 4,147 patients enrolled, 289 patients had UTIs by a 50,000 CFUs/mL definition on the subsequent urine culture. Only 27 patients had bacteremia and a UTI. The news is generally mixed: using the 50,000 CFUs/mL cut-off, any abnormality on the UA was 94% sensitive for UTI and 91% specific, but was 100% sensitive for a UTI associated with bacteremia.

The authors also do analyses including different cut-offs for UTI based down to 10,000 CFUs/mL and, as you might expect, the sensitivity for any UTI diminishes. While the interpretation of the urine culture result is less applicable to the initial Emergency Department evaluation, the subsequent threshold for diagnosis is relevant to the ongoing follow-up care for the febrile infant, particularly if an initial decision involved observation without antibiotics and the infant remains symptomatic without another source.

Overall, it is reasonable to suggest – if the UA is negative, a serious bacterial illness is unlikely to be present. Some consideration should be made to the duration of illness, and natural course of delayed onset of development of cystitis or pyuria in the urine. A positive UA, however, despite the apparent high specificity, does not reliably indicate a true positive for UTI, owing to the low prevalence. This should also be taken into consideration regarding whether additional invasive evaluation is indicated.

“Accuracy of the Urinalysis for Urinary Tract Infections in Febrile Infants 60 Days and Younger”
http://pediatrics.aappublications.org/content/early/2018/01/12/peds.2017-3068

The Definitive Word on Steroids in Septic Shock

As the authors say in their introduction, glucocorticoids have been in and out of favor as adjunctive treatment of patients in septic shock for over 40 years. Various trials have found results both favoring and discounting their utility – leading, finally, to this trial to end all trials: ADRENAL.

Of course, there’s hardly ever any such definitive thing in medicine – but this is as close as it comes. This multi-center, multi-country, blinded, placebo-controlled, randomized trial evaluated the use of hydrocortisone in critically ill patients on vasopressors in septic shock. Patients were randomized to receive either 200mg of hydrocortisone daily as continuous infusion, or placebo. The primary outcome was 90-day mortality, with multiple secondary outcomes regarding length of ICU stay, hemodynamics, and others.

With 3,800 patients enrolled, this trial – if any could ever say to do so – should be essentially the final word with regard to detecting any significant difference in outcomes. And the final answer is: choose your own adventure!

For the primary outcome, there was no statistically significance difference in mortality at 90 days – 27.9% in the hydrocortisone cohort, and 28.8% with placebo. Looking at secondary outcomes, the results here tended to favor hydrocortisone – a slightly faster resolution of shock, shorter ICU stays, and, oddly, decreased transfusion requirements. The purist would say: negative trial. The Bayesian would say: this doesn’t change my prior opinion. The answer is, probably, somewhere in between.

Effectively, when a massive trial fails to find a difference, there is still the possibility of there actually being a difference – but any magnitude of effect is likely to be quite small. “Small” in this case, looks to be on the order of numbers-needed-to-treat ranging from 20 to 200, depending on the outcome. To take this into context, the much lauded WOMAN trial celebrating tranexamic acid found only a 0.4% absolute reduction in death due to bleeding. Hydrocortisone, similarly, is inexpensive, displayed few serious adverse effects, and even a small advantage with regard to an outcome such as mortality ought to be considered valuable.

Thus, the choose your own adventure. I tend to feel this is a reasonable treatment adjunct, but, as far as moving the needle on outcomes, there are many other higher-yield clinical interventions to prioritize above hydrocortisone. The critically ill are complex, and there are many aspects to high-quality intensive clinical and nursing care that have a greater impact on ultimate outcomes. To spend much time engaged in debate regarding hydrocortisone should be done only to the extent it does not distract and detract from other, more important aspects of their care.

“Adjunctive Glucocorticoid Therapy in Patients with Septic Shock”

http://www.nejm.org/doi/full/10.1056/NEJMoa1705835

TACO Time!

One of the best acronyms in medicine: TACO. Of no solace to those afflicted by it, transfusion-related circulatory overload is one of the least-explicitly recognized complications of blood product transfusion. The consent for blood products typically focuses on the rare transmissibility of viruses and occurrence of autoimmune reactions, yet TACO is far more frequent.

This report from an ongoing transfusion surveillance study catalogued 20,845 patients receiving transfusions of 128,263 blood components. The incidence of TACO was one case per 100 transfused patients. Then, these authors identified 200 patients suffering TACO, and compared their baseline characteristics to 405 patients receiving similar transfusion intensity, but who did not develop TACO. Clinically relevant risk factors for developing TACO identified in their analysis were, essentially:

Congestive heart failure
End-stage or acute renal disease
End-stage liver disease
Need for emergency surgery

… or, basically, the population for whom a propensity for circulatory overload would be expected. It appears, generally speaking, clinicians were aware of the increased risks in these specific patients, as a greater percentage received diuretic treatment prior to transfusion as well. 30-day mortality in those suffering TACO was approximately 20%, roughly double that of those matched controls.

More good reasons to adhere to as many restrictive transfusion guidelines as feasible.

“Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload”

https://www.ncbi.nlm.nih.gov/pubmed/29300236

The Gabapentinoid Cure-All

Gabapentinoids – gabapentin and pregabalin – were traditionally prescribed for their approved indications: the treatment of seizures and various manifestations of neuropathic pain. Of course, there are many newer agents for epilepsy, and the the market for neuropathic pain ought to remain fairly stable. Therefore, why has gabapentinoid use effectively tripled over the past decade, as generally described by this research letter?

Most notably, in this letter, gapapentin use increased most in those with multiple comorbidities, as well as those with concurrent opioid and benzodiazepine prescriptions. Considering the lack of proven efficacy and the potential for misuse or adverse effects, there’s frankly no excuse for such rampant overuse. Nearly all this expansion represents waste and harm in our health system, with mixed and scattershot evaluation of its various applications almost certain to mislead rather than inform true treatment effects.

It seems it really ought to be time to reduce prescribing of gabapentinoids – particularly off-label – but the reverse seems true!

“Gabapentinoid Use in the United States 2002 Through 2015”
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2666788

Would You Use A Syncope SDM Instrument?

Much has been made, off and on, about the chest pain shared decision-making tool rolled out over the past couple years. It turns out, when properly informed of their low risk for subsequent cardiac events, most patients look at you sideways and wonder why anyone was offering them admission in the first place. Whether that was its intended purpose, or a happy little accident, is a subject of controversy.

Their next target: syncope.

The content of this article is not very profound, other than to show the first step in the process of developing such an SDM instrument. These authors detail their involvement of emergency physicians, cardiologists, and patient stakeholders to inform their iterative design process. In the end, their tool looks a lot like the their chest pain instrument:

Generally speaking, because the approach to low-risk syncope has some of the same issues as low-risk chest pain, I have essentially the same fundamental problems. Much like for chest pain, inpatient evaluations for syncope are generally unrevealing. We probably ought not be admitting most of these patients. Therefore, this SDM instrument is again addressing the problem of low-value resource utilization by shifting the burden of the decision onto the patient, and trying to convince them to make what we already know to be the correct one (go home). That’s not how the Force works.

Then, just like the chest pain tool, this fails to convey the benefit of hospitalization for comparison. In their pictogram, two out of 100 patients suffer an adverse event after fainting. Is admission to the hospital protective against those adverse events – even if a diagnosis is made? The patient needs to receive some simplified visualization of their expected benefit from staying in the hospital, not just simply the base rate for deterioration.

I love shared decision-making. I use it constantly in my practice in situations where the next step in evaluation or treatment has no clearly superior path. Again, I don’t think this reflects the same uncertainty.

“Development of a Patient Decision Aid for Syncope in the Emergency Department: the SynDA tool”

https://www.ncbi.nlm.nih.gov/pubmed/29288554

The HSV Meningitis Question

This is one of those questions that always crops up when evaluating an infant for sepsis and meningitis – should we test and/or empirically cover for herpes simplex virus infection? Just how frequently is this diagnosis made?

The answers, as described in this retrospective, multi-center study, are complex. First, the basics: 26,533 total encounters analyzed, with 112 children ultimately diagnosed with HSV meningitis. Then, it’s basically chaos. The percent of patients whose CSF was tested for HSV ranged from 12.5% to 70.9% across hospitals included, along with empiric coverage with acyclovir ranging from 4.2% to 53.0%. Rates of positive HSV results were unrelated to overall institutional testing or empiric acyclovir coverage rates, excepting in the sense that HSV infection was more frequent in younger infants – and younger infants were more likely to be tested and empirically treated, in general. A handful of patients with ultimate diagnoses of HSV meningitis were not treated or tested initially, and were found on a subsequent visit.

The authors go into some detail regarding the questionable value of empiric treatment, citing a number needed to treat of 152 for infants 0-28 days and an NNT of 583 for infants from 29-60 days. Generally speaking, these authors agree with a prior cost-effectiveness analysis recommending waiting for the initial CSF cell count, and empirically treating those with a CSF pleocytosis. Consequently, these authors would therefore recommend testing only those ultimately treated empirically – but this is naturally a pragmatic consideration, rather than a statistically modeled balance between sensitivity and specificity.

There are a few more nuances within the paper with regard to their gold standard for diagnosis of HSV meningitis, limitations with regard to selection of patients undergoing testing, and generalizability from these tertiary referral settings, but it is still generally an interesting snapshot of data. Unfortunately, their ultimate conclusion is still back at square one – reiterating a call for specific clinical and laboratory data to help guide clinicians in selecting patients for HSV testing and empiric treatment. In the meantime, we’ll just keep doing our best to differentiate the ill child at the bedside based on gestalt and the culture of our practice setting.

“Herpes Simplex Virus Infection in Infants Undergoing Meningitis Evaluation”
http://pediatrics.aappublications.org/content/early/2017/12/29/peds.2017-1688

Influenza, Sideways

Hello, everyone! Influenza, influenza, influenza. Influenza? Influenza. Influenza influenza, influenza – influenza – influenza, influenza!

It’s that time of year in the Northern Hemisphere, following up last year’s busy season, and a terrible one in the Southern Hemisphere in the interim. At this point, for your general ambulatory patient, I hope you’ve stopped sending swabs. If you think they have it, they probably do – although, there is some respiratory syncytial virus out there, too.

But, I’ve also been surprised by a couple of people who didn’t look like typical influenza, and this little expert commentary is a nice reminder of the less-common manifestations of influenza infection. The respiratory compromise is well-documented, but patients can not uncommonly become seriously ill with myocarditis, myositis, and viral encephalitis, as well as causing less serious serious hepatic injury and acute tubular necrosis. There have also been case reports implicating influenza less frequently in a scattershot of clinically interesting entities.

Just in case you weren’t getting enough influenza in your life.

“The hidden burden of influenza: A review of the extra- pulmonary complications of influenza infection”
http://onlinelibrary.wiley.com/doi/10.1111/irv.12470/abstract [open access]

Month: January 2018

More Data Questioning PESIT