Month: August 2018

The Great Prehospital Airway Debate

… is over! With another 12,000 patients included in two prospective, randomized trials, we’ve finally arrived at unassailable conclusions regarding optimal airway management in the context of out-of-hospital cardiac arrest.

Or, as usual, not.

These two trials, AIRWAYS-2 from the United Kingdom and PART from the United States, randomized paramedics and emergency medical services agencies to routinely providing either endotracheal intubation or a supraglottic airway. The details of both trials are a little bit different, but they are both effectively pragmatic approaches directing the first attempt at airway management in patients deemed eligible in non-traumatic OHCA.

AIRWAYS-2 enrolled over 9,000 patients while PART enrolled over 3,000, and their results were similar, but not precisely the same. The primary outcome for AIRWAYS-2 was “good outcome” (0-3) on the modified Rankin Scale at 30 days, which was achieved by the ETI cohort in 6.8% versus 6.4% with SGA. The primary outcome for PART was 72-hour survival, which was 15.4% in their ETI cohort versus 18.3% with SGA. For rough comparison’s sake, PART also recorded mRS at hospital discharge, which was 5.0% with ETI and 7.1% with SGA.

These are both incredibly messy trials with regard to delivery of the intervention. Substantial fractions of both cohorts in the AIRWAYS-2 trial did not ultimately receive an attempt at an advanced airway, including over a quarter of those randomized to ETI. Then, the success rate for ETI in PART was only 51%, as compared with 90% with SGA. It is an imposing task to parse through their flow diagrams of randomization, patient interventions, and outcomes in both the main body of the articles and in the supplemental material.

Ultimately, while these can be argued back-and-forth due to substantial underlying uncertainty, there is little evidence to suggest ETI should be favored over SGA. This ought not be terribly surprising, as we’ve already seen a trial of ETI versus bag-valve mask ventilation which was unable to conclusively support one method over the other. While these findings probably could be used to substantially affect paramedic training and procedures with respect to ETI, the better, remaining question is whether any advanced airway should be routinely attempted at all.

“Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2698493

“Effect of a Strategy of Initial Laryngeal Tube Insertion vs Endotracheal Intubation on 72-Hour Survival in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2698491

“Autoimmune Encephalitis”? Eh?

Despite its rarity, this is an interesting topic to cover for a couple of reasons. First, in one of my health system administrative roles, I’ve noticed a large uptick in evaluation for this entity. And, then, second, it was picked up by the NEJM Emergency Medicine Journal Watch. So, paradoxically, the purpose here is both to heighten awareness of this disease process while at the same time throwing cold water on it.

The hullabaloo is all about autoimmune encephalitis – and the subset involved in this study concerns the typical onset after herpes simplex encephalitis. A non-trivial number of patients recover from an initial HSV encephalitis only to have recurrence of seizures and/or cognitive decline. Some of these cases can be attributed to reactivation of latent virus, while the others were of uncertain etiology. It now seems clear there is a significant autoimmune link, with increasing reports of antibodies against synaptic receptors detected in CSF.

In part of this very small, prospective study out of Spain, they identified 51 index cases of HSV encephalitis. None of these patients had neuronal antibiodies present at the index presentation.  However, within one year follow-up, a quarter developed new onset encephalitis with neuronal antibodies detectable in the CSF, primarily NMDA-receptor type. The typical presenting features of these patients differed between young children and adults, but most notably included seizures, behavior changes, and psychosis.

Recognition of this disorder is important because patients can have profound improvement with treatment and immunosuppression. That said, this is still an uncommon complication of a fairly rare disease – it took these authors 3 years to prospectively enroll their 51 patients, and even their retrospective case review across 6 years only managed to pick up 48 patients. These antibody responses are extremely rare, and recency bias should not dramatically change your practice. However, in the context of new-onset psychosis, an LP may be reasonable – and, if the remainder of the clinical evaluation supports it, antibody testing could dramatically alter treatment in a small cohort of patients.

“Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis”
https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30244-8/fulltext

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”