The Secret Ingredient Is: Thiamine

At least, when you’re thiamine deficient.

Of the magic cocktail of profound improvement in sepsis, it is not known the relative importance of the various ingredients, whether it is a synergistic effect, or, technically, whether the treatment is real or artifactual.  Thiamine deficiency, however, is frequently detected in patients with sepsis and septic shock. A small pilot study showed no overall effect of thiamine administration to a general population with sepsis, but a subgroup with documented thiamine deficiency suggested improvements in lactate clearance and mortality.

Following up these findings, these authors performed a retrospective review of outcomes of patients admitted to their single center with sepsis and septic shock, as defined by a lactate greater than 2 mmol/L and a need for vasopressors. They created two matched cohorts using Mahalanobis distance, and, lo: lactate clearance was improved with thiamine, as was overall mortality, with a Hazard ratio of 0.666 (95% CI, 0.490-0.905).

This is, again, retrospective data and statistical tomfoolery to match. But, it is consistent, at least, with other prospective and observational data. It seems quite reasonable to evaluate patients with septic shock for thiamine deficiency, with the expectation supplementation may improve outcomes.

“Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock”

https://www.ncbi.nlm.nih.gov/pubmed/30028362

So Many Strokes, Oddly

There a fairly steady stream of occasional articles describing the evolution of stroke care in the U.S. These are typically pieces praising improvements tied to “Get With The Guidlines-Stroke”, describing decreases in overall stroke mortality, and the like. “Never better!” would probably be how most neurologists describe the current state of stroke care.

These impressions might be a bit of a rose-colored view of the elephant. This is just a simple descriptive analysis in trends for stroke, TIA, and ICH care in U.S. emergency departments and hospitals from 2006 until 2014.  A couple things of curiosity and/or concern stand out:

  • Annual in-hospital mortality from stroke has declined from ~5.8% to ~4.4%. This looks good until it’s noted annual total stroke admissions increased from 353,000 to 415,000. So, in an absolute sense, mortality hasn’t changed much – we’ve probably just been adding additional cases that wouldn’t otherwise have been diagnosed as stroke.
  • Costs of hospitalization for all diagnoses have almost doubled. For stroke, hospitalization charges have risen from a mean of $27,000 to $48,000. I’d love to chalk up the cost increase solely to the accompany increased frequency of use of our favorite clot-buster, but the relative cost increases are similar for TIA, as well.

The overall gist I get from these data is the value, overall, of our care for acute neurologic emergencies is diminishing. I’m certain we’re doing a much better job of post-stroke care these days for those who would truly benefit, but clearly we’re also sinking a lot more money into an expanding population where the average benefit is probably lower.  It’s shaping up to be an interesting race to see which aspect of healthcare can bankrupt our economy first.

“National trends in stroke and TIA care in U.S. emergency departments and inpatient hospitalizations”

https://www.ajemjournal.com/article/S0735-6757(18)30648-X/fulltext

Minor Head Injury and Anticoagulants

Guidelines advise performing imaging in those patients on anticoagulants who have suffered minor head injury. We virtually all dutifully obey, because, even though the incidence of intracranial hemorrhage is low – it’s still much higher than zero. But, how high, really? Particularly when they’re sitting there, looking normal, with a GCS of 15?

This systematic review and meta-analysis gathered together 5 studies comprising 4,080 anticoagulated patients with GCS 15 following a head injury. Three of the studies mandated imaging, while the others allowed physician discretion with observation, telephone, and chart-review follow-up to ascertain outcomes. The vast majority of patients were on Vitamin K antagonists, and most mechanisms of injury – where documented – were falls.

Overall, there were 209 (5%) patients with ICH after their fall, nearly all of which were diagnosed at the index visit. There was a wide range of findings, ranging from 4% in the largest studies to 22% in the smaller. However, the larger studies were the ones with the least-complete follow-up after the index event. Therefore, these authors’ random effects analysis and sensitivity analysis generated higher estimates of the incidence, up to 10.9%.

So, while yield is low, we’re still far from having a strategy to support selective scanning to improve value. While it is unlikely many of these would have neurosurgical intervention indicated, a substantial portion likely underwent anticoagulation reversal to prevent further morbidity or mortality. While resource stewardship is always an important consideration, it is unlikely we will anytime soon be altering our approach to minor head injury in the context of anticoagulation.

“Incidence of intracranial bleeding in anticoagulated patients with minor head injury: a systematic review and meta-analysis of prospective studies”

https://www.ncbi.nlm.nih.gov/pubmed/30028001

Magical Biomarkers in TBI

Decision instruments be damned. Clinical judgment be damned. We need a test! We need a biomarker test to tell us whether we should perform a CT in traumatic brain injury!

Thus enter ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), mated together in loving embrace by Banyan Biomarkers in a prospective, observational trial – ALERT-TBI. The aim of this study was to validate these biomarkers, each with their pre-set cut-off thresholds, as accurate predictors of intracranial injuries on CT. Specifically, as accurate predictors in a convenience sample of patients presenting to one of 22 investigational sites with a GCS between 9 and 15.

These trialists collected samples on 1,977 patients, 125 of whom were “CT-positive” – meaning intracranial blood, as typical, but also “bland sheer injury … brain oedema, brain herniation, non-haemorrhagic contusion, ventricular compression, ventricular trapping, cranial fractures, depressed skull fractures, facial fractures, scalp injury, or skull base fractures.”  Only 8 of these patients ultimately underwent neurosurgical intervention.

The good news: these assays were 100% sensitive for neurosurgical lesions. The bad news: the lower bound of the 95% confidence interval is 63%. The other bad news: the specificity of the test is only ~35%, meaning it recommends CTs in two-thirds of your TBI patients. And, also: median time from injury to blood draw was 3.2 hours, meaning we can’t actually generalize these findings to potential phlebotomy in the the acute peri-injury trauma evaluation. And, we could keep going on with the bad news, to be certain, but I think we’ll stop there.

The final point to make is to note this study concluded in 2014. It is now, of course, past the midpoint of 2018. It probably goes without saying study findings with obvious advantages to their funding sponsor are not neglected for several years, nor shuffled into Lancet Neurology absent any fanfare.

Chalk this study up as yet another failed dalliance into potential biomarker use for TBI.

“Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study”

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30231-X/fulltext

Anything But Crystalloid

The balanced transfusion ratio has been in vogue for many years in military settings (read: whole blood), but, until recently, less popular with civilians. There are probably still kinks to be worked out with respect to improving the value of resource consumption in massive transfusion, but, at the least, it appears roughly equivalent ratios of plasma to blood cells are beneficial.

So, given the opportunity, why not initiate this sort of balanced resuscitation in the prehospital setting?

This somewhat messy and heterogenous trial does precisely that – randomizing 523 unstable trauma patients to either standard resuscitation or transfusion of 2 units of FFP, followed by standard resuscitation. The randomization took place in clusters at the aeromedical transport base level, and included bases whose initial protocol included PRBC transfusions for eligible patients. In these instances, the FFP was transfused first, and then the PRBCs. Additionally, 111 of the enrolled aeromedical transports were transfers from an outlying hospital. This meant the pre-enrollment resuscitation could be virtually any permutation of potential volume replacement. While the two groups were roughly balanced as far as etiologies of trauma, injury severity, and other baseline features, the initiation of FFP prior to standard resuscitation did skew the numbers with respect towards prehospital PRBCs, as they had to wait until the intervention transfusion was complete.

Overall, 24-hour mortality was 22% in the “standard care” group and 14% in the plasma group. Only a handful of potentially transfusion-related adverse events occurred, and this early survival advantage proved durable through the length of follow-up. There is enough in the pre-specified subgroup analysis to fuel any number of editorials, other retrospective analyses, and homegrown inclusion or exclusion criteria for prehospital FFP – but, overall, this grossly consistent with our priors for a survival advantage associated with balanced transfusions.

Now, what we really need, is a plasma product with a better shelf-life ….

“Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock”

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